VCV000496632.12 - ClinVar

NM_000536.4(RAG2):c.1375A>C (p.Met459Leu)

Germline

Classification

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

Likely pathogenic
Likely pathogenic (3)

3 out of 3 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_000536.4(RAG2):c.1375A>C (p.Met459Leu)

Variation ID: 496632 Accession: VCV000496632.12

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p12 11: 36592794 (GRCh38) [ NCBI UCSC ] 11: 36614344 (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	Sep 29, 2018	Apr 4, 2026	Jun 1, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_000536.4:c.1375A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000527.2:p.Met459Leu	missense
NM_001243785.2:c.1375A>C	NP_001230714.1:p.Met459Leu	missense
NM_001243786.2:c.1375A>C	NP_001230715.1:p.Met459Leu	missense
NC_000011.10:g.36592794T>G
NC_000011.9:g.36614344T>G
NG_007573.1:g.10443A>C
NG_033154.1:g.3302T>G
LRG_99:g.10443A>C

... more HGVS ... less HGVS

Protein change

M459L

Other names

Canonical SPDI

NC_000011.10:36592793:T:G

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.

Links

ClinGen: CA380140499 dbSNP: rs1204766339 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.
RAG2		Gene associated with autosomal recessive phenotype	Not yet evaluated	GRCh38 GRCh37	622	657

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.
Atypical severe combined immunodeficiency due to complete RAG1/2 deficiency Combined immunodeficiency with skin granulomas Histiocytic medullary reticulosis Inborn error of immunity Recombinase activating gene 2 deficiency	Likely pathogenic (1)	criteria provided, single submitter	Mar 6, 2018	RCV000681600.2
Combined immunodeficiency with skin granulomas Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	Likely pathogenic (1)	criteria provided, single submitter	May 27, 2020	RCV001378887.9
Histiocytic medullary reticulosis	Likely pathogenic (1)	criteria provided, single submitter	Jun 1, 2025	RCV001834862.2

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 (Mar 06, 2018) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	RAG2 deficiency Primary immunodeficiency Combined immunodeficiency with skin granulomas Atypical severe combined immunodeficiency due to complete RAG1/2 deficiency Omenn syndrome	Pediatric Immunology Service, The Chaim Sheba Medical Center at Tel HaShomer Accession: SCV000693948.2 First in ClinVar: Sep 29, 2018 Last updated: Aug 03, 2025	Publications: PubMed (2) PubMed: 22841008‚ 26457731 Observation: 1 Collection method: research Allele origin: germline Affected status: yes more Observation 1 Collection method: research Allele origin: germline Affected status: yes Comment on evidence: "effect on catalytic protein function" was previously submitted as the functional consequence for NM_000536.3:c.1375A>C, but without providing the result of a functional assay.

Likely pathogenic (May 27, 2020) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Combined immunodeficiency with skin granulomas Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001576576.6 First in ClinVar: May 10, 2021 Last updated: Feb 23, 2026	Publications: PubMed (4) PubMed: 22841008‚ 26457731‚ 26692406‚ 29772310 Comment: show In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant has been reported to affect RAG2 protein function (PMID: 22841008, 29772310, 26692406). This variant has been observed to be homozygous or in combination with another RAG2 variant in individuals affected with Omenn syndrome, combined immunodeficiency with granulomatous disease and/or autoimmunity (CID-G/AI) and hyper-IgM syndrome (PMID: 22841008, 26457731). ClinVar contains an entry for this variant (Variation ID: 496632). This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with leucine at codon 459 of the RAG2 protein (p.Met459Leu). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and leucine. (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

Likely pathogenic (Jun 01, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Natera Variant Classification Schema (03/2026))	Omenn syndrome	Natera, Inc. Accession: SCV002090400.2 First in ClinVar: Feb 13, 2022 Last updated: Apr 04, 2026	Publications: PubMed (3) PubMed: 22841008‚ 26457731‚ 29410113 Comment: show The c.1375A>C variant in RAG2 is a missense variant predicted to cause substitution of methionine to leucine at amino acid 459. This variant is rare in the general population with a frequency below the threshold expected for the associated phenotype(s). This variant has been observed in one or more individuals affected with the associated recessive disease, as either homozygous or compound heterozygous with a second variant (PMID: 29410113, 26457731, 22841008). Additionally, this variant has been observed to segregate in affected family members (PMID: 22841008). Functional studies show that this variant may disrupt protein function (PMID: 22841008). Computational prediction algorithms indicate this variant is likely to affect gene or protein function. Given the available evidence, this variant is classified as Likely 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:

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant has been reported to affect RAG2 protein function (PMID: 22841008, 29772310, 26692406). This variant has been observed to be homozygous or in combination with another RAG2 variant in individuals affected with Omenn syndrome, combined immunodeficiency with granulomatous disease and/or autoimmunity (CID-G/AI) and hyper-IgM syndrome (PMID: 22841008, 26457731). ClinVar contains an entry for this variant (Variation ID: 496632). This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with leucine at codon 459 of the RAG2 protein (p.Met459Leu). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and leucine.

Comment:

The c.1375A>C variant in RAG2 is a missense variant predicted to cause substitution of methionine to leucine at amino acid 459. This variant is rare in the general population with a frequency below the threshold expected for the associated phenotype(s). This variant has been observed in one or more individuals affected with the associated recessive disease, as either homozygous or compound heterozygous with a second variant (PMID: 29410113, 26457731, 22841008). Additionally, this variant has been observed to segregate in affected family members (PMID: 22841008). Functional studies show that this variant may disrupt protein function (PMID: 22841008). Computational prediction algorithms indicate this variant is likely to affect gene or protein function. Given the available evidence, this variant is classified as Likely Pathogenic.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Recombination activity of human recombination-activating gene 2 (RAG2) mutations and correlation with clinical phenotype.	Tirosh I	The Journal of allergy and clinical immunology	2019	PMID: 29772310
Partial RAG deficiency in a patient with varicella infection, autoimmune cytopenia, and anticytokine antibodies.	Goda V	The journal of allergy and clinical immunology. In practice	2018	PMID: 29410113
Disruption of the RAG2 zinc finger motif impairs protein stability and causes immunodeficiency.	Xu K	European journal of immunology	2016	PMID: 26692406
Broad-spectrum antibodies against self-antigens and cytokines in RAG deficiency.	Walter JE	The Journal of clinical investigation	2015	PMID: 26457731
A novel homozygous mutation in recombination activating gene 2 in 2 relatives with different clinical phenotypes: Omenn syndrome and hyper-IgM syndrome.	Chou J	The Journal of allergy and clinical immunology	2012	PMID: 22841008

Text-mined citations for rs1204766339 ...

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