RAG1 p.Ser26Pro
c.76T>C · rs2494749976 · VCV2269371
ClinGen expert panel — Severe Combined Immunodeficiency Disease VCEP
Uncertain Significance for recombinase activating gene 1 deficiency. Applied ACMG criteria (verbatim):
PM2_Supporting
Curation rationale (ClinGen, verbatim)
The NM_000448.3:c.76T>C variant in RAG1 is a missense variant predicted to cause a substitution of serine by proline at amino acid 26 (p.Ser26Pro). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has not been reported in the literature in individuals with SCID. In ClinVar, the variant was reported in one entry without the information of the second allele, and the variant was classified as Uncertain Significance (Ambry Genetics, SCV003601680.1). There is no functional evidence for this variant. Due to insufficient evidence, this variant is classified as a variant of uncertain significance for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PM2_supporting (SCID VCEP specifications version 1.0).
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.1539 | likely benign |
|---|---|---|
| REVEL | 0.387 | indeterminate |
| SaProt | LLR -6.00 | tolerated |
| ⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 4.2 | GERP 1.2, phastCons 1 |
| Regional constraint | o/e 1.10 | unconstrained · MANE · 814 bp · p 0.066 · regional, not allelic |
| Overall | ||
| CADD | 24.2 | PHRED · no single calibrated threshold — expert panels disagree |
ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.
Variant & gene context
- Gene
- RAG1
- Protein
- p.Ser26Pro
- Coding
- c.76T>C
- MANE Select
- NM_000448
- dbSNP
- rs2494749976
- Type
- single nucleotide variant
- Location
- chr11:36573380 (GRCh38)
- Gene constraint
- LOEUF 0.703 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 81.68
- Residue 26
- the 'interaction with importin alpha-1' region
Similar variants
- RAG1 p.Ser26= Likely benign ★ same residue
- RAG1 p.Ala444Val Pathogenic ★★★ same condition
- RAG1 p.Arg108Ter Pathogenic ★★★ same condition
- RAG1 p.Arg142Ter Pathogenic ★★★ same condition
- RAG1 p.Arg394Gln Likely pathogenic ★★★ same condition
- RAG1 p.Arg394Trp Pathogenic ★★★ same condition
- RAG1 p.Arg396His Pathogenic ★★★ same condition
- RAG1 p.Arg404Gln 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/rag1-p-ser26pro (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown