Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_000536.4(RAG2):c.1442A>C (p.His481Pro)

CA380140350

496634 (ClinVar)

Gene: RAG2 (HGNC:5897)

Condition: recombinase activating gene 2 deficiency (MONDO:0000573)

Inheritance Mode: Autosomal recessive inheritance

UUID: fb072d65-3bb3-4c1e-b63e-d1852a6cbada

Approved on: 2025-09-26

Published on: 2025-09-26

HGVS expressions

NM_000536.4(RAG2):c.1442A>C (p.His481Pro)

NM_000536.4:c.1442A>C

NC_000011.10:g.36592727T>G

CM000673.2:g.36592727T>G

NC_000011.9:g.36614277T>G

CM000673.1:g.36614277T>G

NC_000011.8:g.36570853T>G

NG_007573.1:g.10510A>C

NG_033154.1:g.3235T>G

ENST00000527033.6:c.1442A>C

ENST00000529083.2:c.1442A>C

ENST00000532616.2:c.1442A>C

ENST00000311485.8:c.1442A>C

ENST00000311485.7:c.1442A>C

ENST00000524423.1:n.131+5375A>C

ENST00000534663.1:c.*86-240T>G

ENST00000618712.4:c.1442A>C

NM_000536.3:c.1442A>C

NM_001243785.1:c.1442A>C

NM_001243786.1:c.1442A>C

NM_001243785.2:c.1442A>C

NM_001243786.2:c.1442A>C

Likely Pathogenic

PS3_Moderate PP4 PM1 PM2_Supporting

PM3

Evidence Links 1

Expert Panel

Severe Combined Immunodeficiency Disease VCEP

Criteria Specification Information

Criteria Specification: ClinGen Severe Combined Immunodeficiency Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RAG2 Version 2.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Severe Combined Immunodeficiency Disease VCEP

The NM_000536.4(RAG2):c.1442A>C variant in RAG2 is a missense variant predicted to cause substitution of histidine by proline at amino acid 481 (p.His481Pro). The variant has been reported in one individual from a consanguineous family with T-B-SCID, zygosity unspecified (PP4, PM3_not met, PMID:12200379). The variant is absent from gnomAD (PM2_Supporting). This variant resides within the PHD domain (amino acids 414-487) of RAG2, defined as a critical functional domain by the ClinGen SCID VCEP (PM1). An in vitro recombination activity assay shows that the relevant activity of the p.H481P variant compared to wildtype RAG2 is 23.8%, which is below the threshold (<25%) established by the SCID VCEP for PS3_Moderate (PMID 29772310). In summary, this variant meets the criteria to be classified as likely pathogenic for SCID based upon the ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PP4, PM2_Supporting, PM1, PS3_Moderate (SCID VCEP specifications version 2)

PS3_Moderate

The variant has a mean recombination activity of 23.8% compared to WT, which is less than 25% of wild type activity in Tirosh et al., 2019 (PMID: 29772310, PS3_moderate).

The variant has a mean recombination activity of 23.8% compared to WT. PubMed:29772310

PP4

One patient, SCID-3 with the His481Pro variant, displayed diagnostic criteria for SCID met (0.5) and a T-B-NK+ lymphocyte subset profile (0.5), meeting PP4 (1 point, PMID:12200379).

PM1

The variant is a missense variant located in the PHD domain (amino acids 414-487), which is an important functional domain. PM1_Moderate is met.

PM2_Supporting

This variant is absent in gnomAD v4.1.0. PM2_Supporting is met.

PM3

Phasing unspecified for individual SCID-3 from PMID:12200379, though family consanguinity is reported.

Curation History

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.