ClinGen expert panel — Severe Combined Immunodeficiency Disease VCEP
Benign for recombinase activating gene 1 deficiency. Applied ACMG criteria (verbatim):
BS2_Supporting BP7 BA1
Curation rationale (ClinGen, verbatim)
The c.303G>A (p.Ala101=) variant (NM_000022.4) is a synonymous (silent) variant that is not predicted by SpliceAI and varSEAK to impact splicing (BP7). The filtering allele frequency (the lower threshold of the 95% CI of 799/30614) of the c.303G>A variant in RAG1 is 0.02460 for South Asian chromosomes by gnomAD v2.1.1 which is higher than the ClinGen SCID VCEP threshold (>0.00872) for BA1 and therefore meets this criterion (BA1). Additionally, 76 homozygous individuals were reported (BS2_Supporting is met). In summary, this variant is classified as a Benign for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): BA1, BS2_Supporting, and BP7.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP -1.5 | GERP -4.8 |
| Overall | ||
| CADD | 0.666 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| South Asiangrpmax | 2.66% | 38 |
| European (non-Finnish) | 2.47% | 40 |
| Remaining individualsnot grpmax-eligible | 1.99% | 50 |
| Middle Eastern | 1.91% | 52 |
| Amishnot grpmax-eligible | 1.54% | 65 |
| Finnishnot grpmax-eligible | 1.09% | 92 |
| Ashkenazi Jewishnot grpmax-eligible | 1.06% | 94 |
| Admixed American | 1.01% | 99 |
| African / African-American | 0.365% | 274 |
| East Asian | 0.029% | 3,453 |
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.Ala101=
- Coding
- c.303G>A
- MANE Select
- NM_000448
- dbSNP
- rs4151025
- Type
- single nucleotide variant
- Location
- chr11:36573607 (GRCh38)
- Gene constraint
- LOEUF 0.703 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 81.68
- Residue 101
- the 'interaction with importin alpha-1' region
Disease context
recombinase activating gene 1 deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatmentsAlso linked: combined immunodeficiency with skin granulomassevere combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positiveOmenn syndrome
Similar variants
- 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
- RAG1 p.Arg561Cys 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-ala101 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown