RAG2 p.Ser365=
c.1095T>C · rs140519815 · VCV304552
ClinGen expert panel — Severe Combined Immunodeficiency Disease VCEP
Likely Benign for recombinase activating gene 2 deficiency. Applied ACMG criteria (verbatim):
BS1 BP7
Curation rationale (ClinGen, verbatim)
The NM_000536.4:c.1095T>C variant is a synonymous (silent) variant (p.Ser365=) with no predicted splice impact (BP7). This variant has not been reported in the literature in individuals with RAG2-related conditions. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00314 (79/25120) in the Finnish population, which is higher than the ClinGen SCID VCEP's threshold for BS1 (>0.00195). In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive SCID based on the ACMG criteria applied BS1 and BP7, as specified by the ClinGen SCID VCEP (VCEP specifications 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. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP 4.2 | GERP 2.7, phastCons 1 |
| Overall | ||
| CADD | 7.175 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Finnishnot grpmax-eligible | 0.326% | 306 |
| European (non-Finnish)grpmax | 0.204% | 491 |
| Remaining individualsnot grpmax-eligible | 0.157% | 638 |
| South Asian | 0.0648% | 1,544 |
| Admixed American | 0.0633% | 1,579 |
| Ashkenazi Jewishnot grpmax-eligible | 0.0405% | 2,467 |
| African / African-American | 0.0333% | 3,002 |
| Middle Eastern | 0.0165% | 6,062 |
Finnish 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
- RAG2
- Protein
- p.Ser365=
- Coding
- c.1095T>C
- MANE Select
- NM_000536
- dbSNP
- rs140519815
- Type
- single nucleotide variant
- Location
- chr11:36593074 (GRCh38)
- Gene constraint
- LOEUF 0.733 · pLI 0.02 (gnomAD)
- Structure
- AlphaFold pLDDT 75.98 · 1 PDB
- Residue 365
- the 'disordered' region
Disease context
recombinase activating gene 2 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
- 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
- RAG2 p.Asp65Tyr Likely pathogenic ★★★ ⚠ same condition
- RAG2 p.Cys446Trp Likely pathogenic ★★★ same condition
- RAG2 p.Glu437Lys Likely pathogenic ★★★ ⚠ same condition
- RAG2 p.Gly319Ter 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-ser365 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown