RAG2 p.His481Pro
c.1442A>C · rs1564995465 · VCV496634
ClinGen expert panel — Severe Combined Immunodeficiency Disease VCEP
Likely Pathogenic for recombinase activating gene 2 deficiency. Applied ACMG criteria (verbatim):
PM2_Supporting PS3_Moderate PM1 PP4
Curation rationale (ClinGen, verbatim)
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)
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.8526 | likely pathogenic |
|---|---|---|
| REVEL | 0.897 | moderately pathogenic-leaning |
| SaProt | LLR -12.91 | damaging |
| ⇒ AlphaMissense, REVEL and SaProt all call this damaging. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 7.9 | GERP 2.6, phastCons 1 |
| Regional constraint | o/e 0.99 | unconstrained · MANE · 1,580 bp · p 0.79 · regional, not allelic |
| Overall | ||
| CADD | 26.2 | PHRED · no single calibrated threshold — expert panels disagree |
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.
Variant & gene context
- Gene
- RAG2
- Protein
- p.His481Pro
- Coding
- c.1442A>C
- MANE Select
- NM_000536
- dbSNP
- rs1564995465
- Type
- single nucleotide variant
- Location
- chr11:36592727 (GRCh38)
- Gene constraint
- LOEUF 0.733 · pLI 0.02 (gnomAD)
- Structure
- AlphaFold pLDDT 75.98 · 1 PDB
- Residue 481
- a binding site; a turn
Similar variants
- RAG2 p.His481= Likely benign ★★ same residue
- RAG2 p.His481Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
- RAG2 p.His481Arg Pathogenic ★ same residue
- RAG2 p.His481Asp Pathogenic ★ same residue
- RAG2 p.Arg229Gln Pathogenic ★★★ ⚠ same condition
- RAG2 p.Arg229Trp Pathogenic ★★★ ⚠ same condition
- RAG2 p.Arg39Gly Pathogenic ★★★ ⚠ same condition
- RAG2 p.Arg73Cys Likely pathogenic ★★★ ⚠ same condition
Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →
Cite Sugi Variant
Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/rag2-p-his481pro (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown