RAG1 p.Ser259fs
c.775del · rs878853031 · VCV235411
ClinGen expert panel — Severe Combined Immunodeficiency Disease VCEP
Pathogenic for recombinase activating gene 1 deficiency. Applied ACMG criteria (verbatim):
PVS1 PM3_Supporting PM2_Supporting
Curation rationale (ClinGen, verbatim)
The nonsense variant NM_000448.3(RAG1):c.775del (p.Ser259AlafsTer5) occurs in exon 2 of 2 (the only coding exon of RAG1) and is not predicted to result in nonsense mediated decay but does truncate 75% of the protein, including the entirety of the core domain (amino acids 387-1011) which is critical to protein function (PMID: 26996199; PVS1). This variant is absent from gnomADv2.1.1 (PM2_Supporting). It has been reported homozygous in one patient with Omenn syndrome (PM3_supporting) with insufficient information to determine that the patient's phenotype is highly specific to recombinase activating gene 1 deficiency (PP4_NotMet). In summary, this variant meets the criteria to be classified as pathogenic for recombinase activating gene 1 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PVS1, PM3_Supporting, and PM2_Supporting. (VCEP specifications version 1).
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. | ||
| Consequence | frameshift | predicted loss-of-function |
|---|---|---|
| NMD | escapes | premature termination codon in the last exon (2 of 2) — the truncated protein is likely expressed. PVS1 input, not an applied code |
| Splicing | ||
| SpliceAI | — | not assessed · substitutions only |
| Constraint at this position | ||
| Conservation | phyloP -3.2 | GERP -1.8 |
Predicted loss-of-function is descriptive, not an applied PVS1 code.
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Remaining individualsnot grpmax-eligible | 0.0016% | 62,504 |
| European (non-Finnish)grpmax | 0.000593% | 168,575 |
Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.
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.Ser259fs
- Coding
- c.775del
- MANE Select
- NM_000448
- dbSNP
- rs878853031
- Type
- Deletion
- Location
- chr11:36574079 (GRCh38)
- Gene constraint
- LOEUF 0.703 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 81.68
- Residue 259
- 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 syndromecombined immunodeficiency due to partial RAG1 deficiency
Similar variants
- RAG1 p.Ser259Ile Uncertain significance ★ ⚠ same residue
- RAG1 p.Ser259= Likely benign ★ same residue
- RAG1 p.Lys86fs Pathogenic ★★★ same condition
- RAG1 p.Met977fs Pathogenic ★★★ same condition
- RAG1 p.Ala456fs Pathogenic/Likely pathogenic ★★ same condition
- RAG1 p.Ala69fs Pathogenic/Likely pathogenic ★★ same condition
- RAG1 p.Asn743fs Pathogenic/Likely pathogenic ★★ same condition
- RAG1 p.Glu174fs 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-ser259fs (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown