The hemizygous p.Arg464Ter variant in ABCD1 was identified by our study in one individual with adrenoleukodystrophy. The p.Arg464Ter variant in ABCD1 has been reported in 1 individual with adrenoleukodystrophy (PMID: 8040304), and was absent from large population studies. This variant has also been reported pathogenic by OMIM in ClinVar (Variation ID: 11302). This nonsense variant leads to a premature termination codon at position 464, which is predicted to lead to a truncated or absent protein. Loss of function of the ABCD1 gene is an established disease mechanism in autosomal recessive adrenoleukodystrophy. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PVS1 (Richards 2015).
NM_000033.4(ABCD1):c.1390C>T (p.Arg464Ter)
Germline
Classification
Help
criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.
Pathogenic/Likely pathogenic
10 out of 12 submissions contributed to this classification
Help
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.
12
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000033.4(ABCD1):c.1390C>T (p.Arg464Ter)
Variation ID: 11302 Accession: VCV000011302.31
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: Xq28 X: 153736510 (GRCh38) [ NCBI UCSC ] X: 153001964 (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 Apr 4, 2013 Feb 15, 2026 Apr 11, 2025 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000033.4:c.1390C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000024.2:p.Arg464Ter nonsense NC_000023.11:g.153736510C>T NC_000023.10:g.153001964C>T NG_009022.2:g.16643C>T LRG_1017:g.16643C>T LRG_1017t1:c.1390C>T LRG_1017p1:p.Arg464Ter - Protein change
- R464*
- Other names
- -
- Canonical SPDI
- NC_000023.11:153736509:C:T
-
Global minor allele
frequency (GMAF) HelpThe 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.
- -
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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 |
839 | 2047 | |
| PLXNB3-AS1 | - | - | - | GRCh38 | 1 | 1083 |
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. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (9) |
criteria provided, multiple submitters, no conflicts
|
Apr 11, 2025 | RCV000012054.25 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Oct 28, 2024 | RCV001781250.7 | |
|
ABCD1-related disorder
|
Pathogenic (1) |
criteria provided, single submitter
|
Apr 13, 2023 | RCV003415686.4 |
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. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(Dec 03, 2018)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Adrenoleukodystrophy
(X-linked inheritance)
|
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001164369.1
First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020 |
Comment:
show
The hemizygous p.Arg464Ter variant in ABCD1 was identified by our study in one individual with adrenoleukodystrophy. The p.Arg464Ter variant in ABCD1 has been reported in 1 individual with adrenoleukodystrophy (PMID: 8040304), and was absent from large population studies. This variant has also been reported pathogenic by OMIM in ClinVar (Variation ID: 11302). This nonsense variant leads to a premature termination codon at position 464, which is predicted to lead to a truncated or absent protein. Loss of function of the ABCD1 gene is an established disease mechanism in autosomal recessive adrenoleukodystrophy. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PVS1 (Richards 2015). (less)
Observation 1
Collection method: research
Allele origin: germline
Affected status: yes
Platform type: WES
|
|
|
Pathogenic
(May 28, 2020)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Adrenoleukodystrophy |
Illumina Laboratory Services, Illumina
Accession: SCV001451528.1
First in ClinVar: Dec 23, 2020 Last updated: Dec 23, 2020 |
Comment:
show
The ABCD1 c.1390C>T (p.Arg464Ter) variant is a stop-gained variant that is predicted to result in premature termination of the protein. Across a selection of the available literature, this variant has been identified in at least six unrelated individuals with X-linked adrenoleukodystrophy, including five hemizygous males and one heterozygous female (Kemp et al. 2001; Pan et al. 2005; Asheuer et al. 2005; Wang et al. 2011; Horn et al. 2013). The phenotypes of the males included childhood cerebral adrenoleukodystrophy and adult-onset adrenomyeloneuropathy and the female had a phenotype of adrenomyeloneuropathy, and both maternal and de novo inheritance was observed (Pan et al. 2005; Asheuer et al. 2005; Wang et al. 2011; Horn et al. 2013). Control data are unavailable for the p.Arg464Ter variant, and it is absent from the Genome Aggregation Database in a region of good sequence coverage, so the variant is presumed to be rare. Based on the collective evidence and application of the ACMG criteria, the p.Arg464Ter variant is classified as pathogenic for X-linked adrenoleukodystrophy. (less)
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
(Oct 01, 2021)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Adrenoleukodystrophy |
Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV001976944.1
First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: yes
|
|
|
Pathogenic
(Jun 28, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Adrenoleukodystrophy |
Johns Hopkins Genomics, Johns Hopkins University
Accession: SCV004024513.2
First in ClinVar: Aug 19, 2023 Last updated: Nov 11, 2023 |
Comment:
show
This ABCD1 variant has been reported in multiple unrelated individuals with ABCD1 - related disorders, including as a de novo occurrence. It has also been reported in ClinVar (Variation ID 11302), but is absent from a large population dataset6. This nonsense variant results in a premature stop codon in exon 4 of 10, likely leading to nonsense-mediated decay and lack of protein production. We consider c.1390C>T in ABCD1 to be 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
(Apr 13, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
ABCD1-related condition
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004118413.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
show
The ABCD1 c.1390C>T variant is predicted to result in premature protein termination (p.Arg464*). This variant has been reported to be causative for X-Linked adrenoleukodystrophy (reported as C1776T in Fanen et al. 1994. PMID: 8040304). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare and has been interpreted as pathogenic/likely pathogenic by multiple submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/11302/). Nonsense variants in ABCD1 are expected to be pathogenic. 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
|
|
|
Pathogenic
(Dec 13, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Adrenoleukodystrophy
(X-linked dominant inheritance)
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV004242462.2
First in ClinVar: Feb 14, 2024 Last updated: Apr 13, 2025 |
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: yes
Clinical Features:
Dysphagia (present) , Gait ataxia (present) , Cognitive impairment (present) , Functional abnormality of the bladder (present) , Peripheral neuropathy (present) , Myelopathy (present) , Adrenal insufficiency (present) , Dysarthria (present)
Sex: male
|
|
|
Pathogenic
(Apr 05, 2022)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
GeneDx
Accession: SCV006081328.1
First in ClinVar: May 31, 2025 Last updated: May 31, 2025 |
Comment:
show
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 36046390, 36380532, 25525159, 14767898, 24480483, Priestley2022, 15800013, 16087056, 11336405, 8040304, 11748843, 34008892, 23419472, 34162029, 19089597, 21700483, 16415970, 34946879, 29766460) (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 28, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Revvity Omics, Revvity
Accession: SCV002018728.4
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 07, 2021)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Adrenoleukodystrophy |
Genome-Nilou Lab
Accession: SCV002045826.1
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
(Apr 11, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Adrenoleukodystrophy |
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001578275.6
First in ClinVar: May 10, 2021 Last updated: Feb 15, 2026 |
Comment:
show
This sequence change creates a premature translational stop signal (p.Arg464*) in the ABCD1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ABCD1 are known to be pathogenic (PMID: 11748843). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with X-linked adrenoleukodystrophy (PMID: 8040304, 16087056, 21700483, 23419472, 24480483). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 11302). 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 16, 2020)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
X-linked adrenoleukodystrophy |
Natera, Inc.
Accession: SCV002084638.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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
(Aug 01, 1994)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
ADRENOMYELONEUROPATHY |
OMIM
Accession: SCV000032288.2
First in ClinVar: Apr 04, 2013 Last updated: Sep 08, 2024 |
Observation: 1
Collection method: literature only
Allele origin: germline
Affected status: not provided
Observation 1
Collection method: literature only
Allele origin: germline
Affected status: not provided
Comment on evidence:
In 1 patient with Addison disease at age 10 years and adrenomyeloneuropathy (AMN; see 300100) at age 15 years, Fanen et al. (1994) identified a … (more)
In 1 patient with Addison disease at age 10 years and adrenomyeloneuropathy (AMN; see 300100) at age 15 years, Fanen et al. (1994) identified a C-to-T transition at nucleotide 1776 in exon 4 of the ALD gene, converting arginine to a premature termination codon at residue 464. The mutation creates a new BglII restriction site. (less)
|
|
Comment:
Comment:
The ABCD1 c.1390C>T (p.Arg464Ter) variant is a stop-gained variant that is predicted to result in premature termination of the protein. Across a selection of the available literature, this variant has been identified in at least six unrelated individuals with X-linked adrenoleukodystrophy, including five hemizygous males and one heterozygous female (Kemp et al. 2001; Pan et al. 2005; Asheuer et al. 2005; Wang et al. 2011; Horn et al. 2013). The phenotypes of the males included childhood cerebral adrenoleukodystrophy and adult-onset adrenomyeloneuropathy and the female had a phenotype of adrenomyeloneuropathy, and both maternal and de novo inheritance was observed (Pan et al. 2005; Asheuer et al. 2005; Wang et al. 2011; Horn et al. 2013). Control data are unavailable for the p.Arg464Ter variant, and it is absent from the Genome Aggregation Database in a region of good sequence coverage, so the variant is presumed to be rare. Based on the collective evidence and application of the ACMG criteria, the p.Arg464Ter variant is classified as pathogenic for X-linked adrenoleukodystrophy.
Comment:
PVS1, PM2, PP3
Comment:
This ABCD1 variant has been reported in multiple unrelated individuals with ABCD1 - related disorders, including as a de novo occurrence. It has also been reported in ClinVar (Variation ID 11302), but is absent from a large population dataset6. This nonsense variant results in a premature stop codon in exon 4 of 10, likely leading to nonsense-mediated decay and lack of protein production. We consider c.1390C>T in ABCD1 to be pathogenic.
Comment:
The ABCD1 c.1390C>T variant is predicted to result in premature protein termination (p.Arg464*). This variant has been reported to be causative for X-Linked adrenoleukodystrophy (reported as C1776T in Fanen et al. 1994. PMID: 8040304). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare and has been interpreted as pathogenic/likely pathogenic by multiple submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/11302/). Nonsense variants in ABCD1 are expected to be pathogenic. This variant is interpreted as pathogenic.
Comment:
Criteria applied: PVS1,PS4,PS2_MOD,PM2_SUP
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 36046390, 36380532, 25525159, 14767898, 24480483, Priestley2022, 15800013, 16087056, 11336405, 8040304, 11748843, 34008892, 23419472, 34162029, 19089597, 21700483, 16415970, 34946879, 29766460)
Comment:
This sequence change creates a premature translational stop signal (p.Arg464*) in the ABCD1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ABCD1 are known to be pathogenic (PMID: 11748843). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with X-linked adrenoleukodystrophy (PMID: 8040304, 16087056, 21700483, 23419472, 24480483). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 11302). For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Phenotype-driven variant filtration strategy in exome sequencing toward a high diagnostic yield and identification of 85 novel variants in 400 patients with rare Mendelian disorders. | Marinakis NM | American journal of medical genetics. Part A | 2021 | PMID: 34008892 |
| X-linked adrenoleukodystrophy in women: a cross-sectional cohort study. | Engelen M | Brain : a journal of neurology | 2014 | PMID: 24480483 |
| Adrenoleukodystrophy in Norway: high rate of de novo mutations and age-dependent penetrance. | Horn MA | Pediatric neurology | 2013 | PMID: 23419472 |
| X-linked adrenoleukodystrophy: ABCD1 de novo mutations and mosaicism. | Wang Y | Molecular genetics and metabolism | 2011 | PMID: 21700483 |
| ABCD1 gene mutations in Chinese patients with X-linked adrenoleukodystrophy. | Pan H | Pediatric neurology | 2005 | PMID: 16087056 |
| Decreased expression of ABCD4 and BG1 genes early in the pathogenesis of X-linked adrenoleukodystrophy. | Asheuer M | Human molecular genetics | 2005 | PMID: 15800013 |
| ABCD1 mutations and the X-linked adrenoleukodystrophy mutation database: role in diagnosis and clinical correlations. | Kemp S | Human mutation | 2001 | PMID: 11748843 |
| Identification of mutations in the putative ATP-binding domain of the adrenoleukodystrophy gene. | Fanen P | The Journal of clinical investigation | 1994 | PMID: 8040304 |
Text-mined citations for rs128624221 ...
HelpThese 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 Feb 15, 2026
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.