VCV000092317.52 - ClinVar

NM_000033.4(ABCD1):c.1553G>A (p.Arg518Gln)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Pathogenic

12 out of 13 submissions contributed to this classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000033.4(ABCD1):c.1553G>A (p.Arg518Gln)

Variation ID: 92317 Accession: VCV000092317.52

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xq28 X: 153740156 (GRCh38) [ NCBI UCSC ] X: 153005610 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jun 28, 2015	Feb 15, 2026	Oct 21, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_000033.4:c.1553G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000024.2:p.Arg518Gln	missense
NC_000023.11:g.153740156G>A
NC_000023.10:g.153005610G>A
NG_009022.2:g.20289G>A
LRG_1017:g.20289G>A
LRG_1017t1:c.1553G>A	LRG_1017p1:p.Arg518Gln
	P33897:p.Arg518Gln

... more HGVS ... less HGVS

Protein change

R518Q

Other names

Canonical SPDI

NC_000023.11:153740155:G:A

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00000

The Genome Aggregation Database (gnomAD), exomes 0.00001

Exome Aggregation Consortium (ExAC) 0.00001

Links

ClinGen: CA278403 UniProtKB: P33897#VAR_000070 dbSNP: rs398123102 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
ABCD1		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	833	2035
PLXNB3-AS1	-	-	-	GRCh38	-	1076

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Adrenoleukodystrophy	Pathogenic (7)	criteria provided, multiple submitters, no conflicts	Oct 21, 2025	RCV000077955.31
not provided	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Mar 17, 2025	RCV000723540.46
ABCD1-related disorder	Pathogenic (1)	no assertion criteria provided	May 29, 2024	RCV004752737.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	Expand all rows Collapse all rows Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Apr 26, 2017) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Adrenoleukodystrophy	Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota Accession: SCV000840437.1 First in ClinVar: Jun 28, 2015 Last updated: Jun 28, 2015	Publications: PubMed (1) PubMed: 15811009 Other databases http://www.x-ald.nl http://www.x-ald.nl Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Number of individuals with the variant: 1

Pathogenic (Apr 16, 2020) C Contributing to aggregate classification	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Adrenoleukodystrophy	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV001338473.1 First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020	Publications: PubMed (10) PubMed: 10190819‚ 11330045‚ 11438993‚ 11748843‚ 12175782‚ 15811009‚ 16087056‚ 16996397‚ 31074578‚ 9212180 Comment: show Variant summary: ABCD1 c.1553G>A (p.Arg518Gln) results in a conservative amino acid change located in the AAA+ ATPase domain (IPR003593) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.5e-06 in 182500 control chromosomes (gnomAD). The variant c.1553G>A (also known as 1939G>A) has been reported in the literature in numerous individuals affected with Adrenoleukodystrophy (e.g. Imamura_1997, Takano_1999, Dvorakova_2001, Guimaraes_2002, Pan_2005, Coll_2005, Wiens_2019), and in several cases the lack of ALD protein in patient derived fibroblasts was demonstrated (e.g. Imamura_1997, Guimaraes_2002, Coll_2005). These data indicate that the variant is very likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and both of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (May 24, 2022) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Adrenoleukodystrophy	Baylor Genetics Accession: SCV004206299.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Pathogenic (May 12, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Adrenoleukodystrophy	Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre Accession: SCV004231793.2 First in ClinVar: Jan 26, 2024 Last updated: May 12, 2024	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (May 22, 2024) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	not provided	GeneDx Accession: SCV001812929.2 First in ClinVar: Sep 08, 2021 Last updated: Sep 16, 2024	Comment: show Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16996397, 25920484, 12175782, 23566833, 33920672, 30968598, 34826210, 21068741, 16415970, 20661612, 16087056, 27766264, 26260157, 11438993, 15811009, 23346902, 10190819, 27991992, 31074578, 32798492, 23419472, 24719486, 22479560, 15642351) (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (Oct 08, 2012) C Contributing to aggregate classification	criteria provided, single submitter (EGL Classification Definitions 2015)	not provided	Eurofins Ntd Llc (ga) Accession: SCV000109784.9 First in ClinVar: Jan 17, 2014 Last updated: Apr 13, 2025	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ABCD1 Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Number of individuals with the variant: 5 Zygosity: Hemizygote, Single Heterozygote Sex: mixed

Pathogenic (Mar 17, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not provided	Revvity Omics, Revvity Accession: SCV002022800.4 First in ClinVar: Nov 29, 2021 Last updated: Sep 06, 2025	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Nov 01, 2022) C Contributing to aggregate classification	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	not provided	CeGaT Center for Human Genetics Tuebingen Accession: SCV002822049.24 First in ClinVar: Jan 21, 2023 Last updated: Jan 11, 2026	Comment: show ABCD1: PM1, PM2, PS4:Moderate, PM5:Supporting, PP3, PP4, PS3:Supporting (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Number of individuals with the variant: 1

Pathogenic (Oct 21, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Adrenoleukodystrophy	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001207477.7 First in ClinVar: Apr 15, 2020 Last updated: Feb 15, 2026	Publications: PubMed (12) PubMed: 10190819‚ 12175782‚ 14767898‚ 15811009‚ 16087056‚ 16415970‚ 21068741‚ 21700483‚ 22479560‚ 23419472‚ 23566833‚ 26260157 Comment: show This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 518 of the ABCD1 protein (p.Arg518Gln). This variant is present in population databases (rs398123102, gnomAD 0.001%). This missense change has been observed in individual(s) with ABCD1-related conditions (PMID: 10190819, 12175782, 15811009, 16087056, 21068741, 21700483, 22479560, 23419472, 23566833, 26260157). In at least one individual the variant was observed to be de novo. This variant is also known as c.1939G>A. ClinVar contains an entry for this variant (Variation ID: 92317). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ABCD1 protein function with a positive predictive value of 95%. This variant disrupts the p.Arg518 amino acid residue in ABCD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14767898, 16415970). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Nov 07, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Adrenoleukodystrophy	Genome-Nilou Lab Accession: SCV002045832.1 First in ClinVar: Jan 03, 2022 Last updated: Jan 03, 2022	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: no Observation 1 Collection method: clinical testing Allele origin: germline Affected status: no

Pathogenic (Oct 23, 2020) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not provided (Unknown mechanism)	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001447138.2 First in ClinVar: Nov 28, 2020 Last updated: Apr 13, 2025	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Clinical Features: Spastic paraplegia (present) , Unsteady gait (present) Sex: male

Pathogenic (-) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Adrenoleukodystrophy	Juno Genomics, Hangzhou Juno Genomics, Inc Accession: SCV005418721.2 First in ClinVar: Nov 30, 2024 Last updated: Oct 05, 2025	Comment: show Absent from controls (or at extremely low frequency if recessive) in Genome Aggregation Database, Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.;The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.;Assumed de novo, but without confirmation of paternity and maternity.;Patient's phenotype or family history is highly specific for a disease with a single genetic etiology.;Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (May 29, 2024) N Not contributing to aggregate classification	no assertion criteria provided	ABCD1-related condition	PreventionGenetics, part of Exact Sciences Accession: SCV005362137.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: show The ABCD1 c.1553G>A variant is predicted to result in the amino acid substitution p.Arg518Gln. This variant has been reported in multiple individuals with X-linked adrenoleukodystrophy (see for example, Table 3, Ping et al. 2006. PubMed ID: 16415970; Table 1, Coll et al. 2005. PubMed ID: 15811009; Table 2, Matsukawa et al. 2011. PubMed ID: 20661612). This variant is reported in 0.0012% of alleles in individuals of European (non-Finnish) descent in gnomAD. Alternate missense variants affecting the same amino acid (p.Arg518Trp and p.Arg518Gly) have been reported to be causative for X-linked adrenoleukodystrophy (Table 3, Ping et al. 2006. PubMed ID: 16415970; Table 2, Matsukawa et al. 2011. PubMed ID: 20661612). This variant is interpreted as pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Comment:

Variant summary: ABCD1 c.1553G>A (p.Arg518Gln) results in a conservative amino acid change located in the AAA+ ATPase domain (IPR003593) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.5e-06 in 182500 control chromosomes (gnomAD). The variant c.1553G>A (also known as 1939G>A) has been reported in the literature in numerous individuals affected with Adrenoleukodystrophy (e.g. Imamura_1997, Takano_1999, Dvorakova_2001, Guimaraes_2002, Pan_2005, Coll_2005, Wiens_2019), and in several cases the lack of ALD protein in patient derived fibroblasts was demonstrated (e.g. Imamura_1997, Guimaraes_2002, Coll_2005). These data indicate that the variant is very likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and both of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16996397, 25920484, 12175782, 23566833, 33920672, 30968598, 34826210, 21068741, 16415970, 20661612, 16087056, 27766264, 26260157, 11438993, 15811009, 23346902, 10190819, 27991992, 31074578, 32798492, 23419472, 24719486, 22479560, 15642351)

Comment:

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 518 of the ABCD1 protein (p.Arg518Gln). This variant is present in population databases (rs398123102, gnomAD 0.001%). This missense change has been observed in individual(s) with ABCD1-related conditions (PMID: 10190819, 12175782, 15811009, 16087056, 21068741, 21700483, 22479560, 23419472, 23566833, 26260157). In at least one individual the variant was observed to be de novo. This variant is also known as c.1939G>A. ClinVar contains an entry for this variant (Variation ID: 92317). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ABCD1 protein function with a positive predictive value of 95%. This variant disrupts the p.Arg518 amino acid residue in ABCD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14767898, 16415970). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

Comment:

Absent from controls (or at extremely low frequency if recessive) in Genome Aggregation Database, Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.;The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.;Assumed de novo, but without confirmation of paternity and maternity.;Patient's phenotype or family history is highly specific for a disease with a single genetic etiology.;Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.

Comment:

The ABCD1 c.1553G>A variant is predicted to result in the amino acid substitution p.Arg518Gln. This variant has been reported in multiple individuals with X-linked adrenoleukodystrophy (see for example, Table 3, Ping et al. 2006. PubMed ID: 16415970; Table 1, Coll et al. 2005. PubMed ID: 15811009; Table 2, Matsukawa et al. 2011. PubMed ID: 20661612). This variant is reported in 0.0012% of alleles in individuals of European (non-Finnish) descent in gnomAD. Alternate missense variants affecting the same amino acid (p.Arg518Trp and p.Arg518Gly) have been reported to be causative for X-linked adrenoleukodystrophy (Table 3, Ping et al. 2006. PubMed ID: 16415970; Table 2, Matsukawa et al. 2011. PubMed ID: 20661612). This variant is interpreted as pathogenic.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
A report on state-wide implementation of newborn screening for X-linked Adrenoleukodystrophy.	Wiens K	American journal of medical genetics. Part A	2019	PMID: 31074578
Clinical, biochemical, neuroimaging and molecular findings of X-linked Adrenoleukodystrophy patients in South China.	Jiang MY	Metabolic brain disease	2015	PMID: 26260157
ABCD1 mutations and phenotype distribution in Chinese patients with X-linked adrenoleukodystrophy.	Niu YF	Gene	2013	PMID: 23566833
Adrenoleukodystrophy in Norway: high rate of de novo mutations and age-dependent penetrance.	Horn MA	Pediatric neurology	2013	PMID: 23419472
Mutations, clinical findings and survival estimates in South American patients with X-linked adrenoleukodystrophy.	Pereira Fdos S	PloS one	2012	PMID: 22479560
X-linked adrenoleukodystrophy: ABCD1 de novo mutations and mosaicism.	Wang Y	Molecular genetics and metabolism	2011	PMID: 21700483
X-linked adrenoleukodystrophy: diagnostic and follow-up system in Japan.	Shimozawa N	Journal of human genetics	2011	PMID: 21068741
Mutational analyses of Taiwanese kindred with X-linked adrenoleukodystrophy.	Chiu HC	Pediatric neurology	2006	PMID: 16996397
The genotype and phenotype studies of 40 Chinese patients with X-linked adrenoleukodystrophy (X-ALD).	Ping LL	Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences	2006	PMID: 16415970
ABCD1 gene mutations in Chinese patients with X-linked adrenoleukodystrophy.	Pan H	Pediatric neurology	2005	PMID: 16087056
X-linked adrenoleukodystrophy in Spain. Identification of 26 novel mutations in the ABCD1 gene in 80 patients. Improvement of genetic counseling in 162 relative females.	Coll MJ	Clinical genetics	2005	PMID: 15811009
[X-linked adrenoleukodystrophy ABCD1 gene mutation analysis in China].	Pan H	Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics	2004	PMID: 14767898
Molecular characterization of 21 X-ALD Portuguese families: identification of eight novel mutations in the ABCD1 gene.	Guimarães CP	Molecular genetics and metabolism	2002	PMID: 12175782
ABCD1 mutations and the X-linked adrenoleukodystrophy mutation database: role in diagnosis and clinical correlations.	Kemp S	Human mutation	2001	PMID: 11748843
Eight novel ABCD1 gene mutations and three polymorphisms in patients with X-linked adrenoleukodystrophy: The first polymorphism causing an amino acid exchange.	Dvoráková L	Human mutation	2001	PMID: 11438993
Mutational analysis of X-linked adrenoleukodystrophy gene.	Takano H	Cell biochemistry and biophysics	2000	PMID: 11330045
Mutational analysis and genotype-phenotype correlation of 29 unrelated Japanese patients with X-linked adrenoleukodystrophy.	Takano H	Archives of neurology	1999	PMID: 10190819
Two novel missense mutations in the ATP-binding domain of the adrenoleukodystrophy gene: immunoblotting and immunocytological study of two patients.	Imamura A	Clinical genetics	1997	PMID: 9212180
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ABCD1	-	-	-	-
http://www.x-ald.nl	-	-	-	-
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Text-mined citations for rs398123102 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Mar 01, 2026