VCV000133472.43 - ClinVar

NM_004304.5(ALK):c.4381A>G (p.Ile1461Val)

Germline

Classification

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

Benign
Benign (15)

15 out of 20 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_004304.5(ALK):c.4381A>G (p.Ile1461Val)

Variation ID: 133472 Accession: VCV000133472.43

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2p23.2 2: 29193706 (GRCh38) [ NCBI UCSC ] 2: 29416572 (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 9, 2014	Mar 7, 2026	Feb 4, 2026

HGVS

Nucleotide	Protein	Molecular consequence
NM_004304.5:c.4381A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004295.2:p.Ile1461Val	missense
NM_001353765.2:c.1177A>G	NP_001340694.1:p.Ile393Val	missense
NC_000002.12:g.29193706T>C
NC_000002.11:g.29416572T>C
NG_009445.1:g.732861A>G
LRG_488:g.732861A>G
LRG_488t1:c.4381A>G
	Q9UM73:p.Ile1461Val

... more HGVS ... less HGVS

Protein change

I1461V, I393V

Other names

Canonical SPDI

NC_000002.12:29193705:T:C

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.

0.00779 (T)

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

Trans-Omics for Precision Medicine (TOPMed) 0.99011

The Genome Aggregation Database (gnomAD) 0.99030

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.99031

The Genome Aggregation Database (gnomAD) 0.99121

1000 Genomes Project 30x 0.99219

1000 Genomes Project 0.99221

The Genome Aggregation Database (gnomAD), exomes 0.99903

Exome Aggregation Consortium (ExAC) 0.99716

The Genome Aggregation Database (gnomAD), exomes 0.99755

Links

ClinGen: CA156632 UniProtKB: Q9UM73#VAR_031042 dbSNP: rs1670283 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.
ALK		No evidence available	No evidence available	GRCh38 GRCh37	6431	6473

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.
not specified	Benign (7)	criteria provided, multiple submitters, no conflicts	Mar 3, 2022	RCV000119976.17
not provided	Benign (2)	criteria provided, multiple submitters, no conflicts	Apr 27, 2016	RCV000590065.2
Hereditary cancer-predisposing syndrome	Benign (1)	criteria provided, single submitter	Dec 8, 2016	RCV000573143.3
Neuroblastoma, susceptibility to, 3	Benign (9)	criteria provided, multiple submitters, no conflicts	Feb 4, 2026	RCV000608829.30
Squamous cell lung carcinoma	Likely pathogenic (1)	no assertion criteria provided	May 5, 2020	RCV001250949.3

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.
Benign (Dec 08, 2016) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Hereditary cancer-predisposing syndrome	Ambry Genetics Accession: SCV000664939.5 First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024	Comment: show This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (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

Benign (Feb 04, 2026) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Neuroblastoma, susceptibility to, 3	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001733357.6 First in ClinVar: Jun 15, 2021 Last updated: Mar 07, 2026	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Benign (Sep 21, 2015) C Contributing to aggregate classification	criteria provided, single submitter (ACGS Guidelines, 2013)	Neuroblastoma, susceptibility to, 3	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Study: VKGL Data-share Consensus Accession: SCV000744251.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Benign (Jan 15, 2016) C Contributing to aggregate classification	criteria provided, single submitter (ACGS Guidelines, 2013)	Neuroblastoma, susceptibility to, 3	Genome Diagnostics Laboratory, Amsterdam University Medical Center Study: VKGL Data-share Consensus Accession: SCV000745623.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Benign (Jul 07, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Neuroblastoma, susceptibility to, 3	KCCC/NGS Laboratory, Kuwait Cancer Control Center Accession: SCV004016408.1 First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Benign (Jul 30, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Neuroblastoma, susceptibility to, 3	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV001472433.9 First in ClinVar: Jan 26, 2021 Last updated: Jan 24, 2026	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Benign (-) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	NOT SPECIFIED	PreventionGenetics, part of Exact Sciences Accession: SCV000310077.1 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Benign (Apr 27, 2016) C Contributing to aggregate classification	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	not provided	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000698296.1 First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018	Comment: show Variant summary: The c.4381A>G variant affects a non-conserved nucleotide, resulting in amino acid change from Ile to Val. 4/4 in-silico tools predict benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is found in 120930/121274 control chromosomes (60296 homozygotes) at a frequency of 0.9971634, which is about 2393192 times of the maximal expected frequency of a pathogenic allele (0.0000004), suggesting the variant to be the ancestral allele; therefore it is classified as Benign. (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

Benign (Mar 02, 2016) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification (06012015))	not specified	GeneDx Accession: SCV000518936.4 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Comment: show This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (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

Benign (Jan 12, 2018) C Contributing to aggregate classification	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Neuroblastoma, susceptibility to, 3	Illumina Laboratory Services, Illumina Accession: SCV000429918.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: show This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (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

Benign (-) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not provided (Unknown mechanism)	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005238702.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024	Observation: 1 Collection method: not provided Allele origin: germline Affected status: yes Observation 1 Collection method: not provided Allele origin: germline Affected status: yes

Benign (Apr 17, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	neuroblastoma, susceptibility to, 3	Department of Pathology and Laboratory Medicine, Sinai Health System Accession: SCV005915173.1 First in ClinVar: Apr 28, 2025 Last updated: Apr 28, 2025	Observation: 1 Collection method: research Allele origin: germline Affected status: unknown Observation 1 Collection method: research Allele origin: germline Affected status: unknown

Benign (Mar 03, 2022) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Not specified	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV007320401.1 First in ClinVar: Jan 17, 2026 Last updated: Jan 17, 2026	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: 270

Benign (Dec 19, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Neuroblastoma, susceptibility to, 3	Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre Accession: SCV005442073.1 First in ClinVar: Jan 04, 2025 Last updated: Jan 04, 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

Benign (Sep 10, 2015) C Contributing to aggregate classification	criteria provided, single submitter (EGL Classification Definitions 2015)	not specified	Eurofins Ntd Llc (ga) Accession: SCV000331391.5 First in ClinVar: Dec 06, 2016 Last updated: Apr 13, 2025	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ALK 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: 3 Zygosity: 2 Homozygotes, 1 Single Heterozygote Sex: mixed

Benign (-) N Not contributing to aggregate classification	no assertion criteria provided	not specified	Genome Diagnostics Laboratory, University Medical Center Utrecht Study: VKGL Data-share Consensus Accession: SCV001927068.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Benign (-) N Not contributing to aggregate classification	no assertion criteria provided	Neuroblastoma, susceptibility to, 3	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV000734186.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Likely pathogenic (May 05, 2020) N Not contributing to aggregate classification	no assertion criteria provided	Squamous Cell Lung Carcinoma	Faculté Pluridciplinaire Nador, Université Mohamed Premier Accession: SCV001250932.2 First in ClinVar: Aug 08, 2020 Last updated: Apr 13, 2025	Publications: DOI: 10.3389/fonc.2020.01215 DOI: 10.3389/fonc.2020.01215 Observation: 2 Observation 1 Collection method: clinical testing Allele origin: somatic Affected status: yes Number of individuals with the variant: 1 Test name: cancer related genes Platform type: Illumina Miseq Observation 2 Collection method: in vivo Allele origin: somatic Affected status: yes Sex: male Tissue: Liver metastasis Tumor Result: Percentage of variant in tissue sample = 99.83%

Benign (-) N Not contributing to aggregate classification	no assertion criteria provided	not specified	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Study: VKGL Data-share Consensus Accession: SCV001953657.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

not provided (Sep 19, 2013) N Not contributing to aggregate classification	no classification provided	AllHighlyPenetrant	ITMI Accession: SCV000084106.1 First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014 Comment: Please see associated publication for description of ethnicities	Publications: PubMed (1) PubMed: 24728327 Observation: 7 Observation 1 Collection method: reference population Allele origin: germline Affected status: unknown Ethnicity/Population group: Whole_cohort Platform type: next-gen sequencing Platform name: Complete Genomics Observation 2 Collection method: reference population Allele origin: germline Affected status: unknown Ethnicity/Population group: African Platform type: next-gen sequencing Platform name: Complete Genomics Observation 3 Collection method: reference population Allele origin: germline Affected status: unknown Ethnicity/Population group: African_European Platform type: next-gen sequencing Platform name: Complete Genomics Observation 4 Collection method: reference population Allele origin: germline Affected status: unknown Ethnicity/Population group: Central_Asian Platform type: next-gen sequencing Platform name: Complete Genomics Observation 5 Collection method: reference population Allele origin: germline Affected status: unknown Ethnicity/Population group: East_Asian Platform type: next-gen sequencing Platform name: Complete Genomics Observation 6 Collection method: reference population Allele origin: germline Affected status: unknown Ethnicity/Population group: European Platform type: next-gen sequencing Platform name: Complete Genomics Observation 7 Collection method: reference population Allele origin: germline Affected status: unknown Ethnicity/Population group: Hispanic Platform Type: next-gen sequencing Platform Name: Complete Genomics

Comment:

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Comment:

Variant summary: The c.4381A>G variant affects a non-conserved nucleotide, resulting in amino acid change from Ile to Val. 4/4 in-silico tools predict benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is found in 120930/121274 control chromosomes (60296 homozygotes) at a frequency of 0.9971634, which is about 2393192 times of the maximal expected frequency of a pathogenic allele (0.0000004), suggesting the variant to be the ancestral allele; therefore it is classified as Benign.

Comment:

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
-	-	-	-	DOI: 10.3389/fonc.2020.01215
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ALK	-	-	-	-

Text-mined citations for rs1670283 ...

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 Apr 13, 2026