Is RAG1 p.Pro132Ser (c.394C>T) pathogenic?

RAG1 p.Pro132Ser (c.394C>T) is classified Uncertain significance in RAG1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-05-11). AlphaMissense: ambiguous (0.4158); Ultra-rare (popmax 0.0233%, amr); Associated with combined immunodeficiency with skin granulomas.

What condition is associated with RAG1 p.Pro132Ser (c.394C>T)?

RAG1 p.Pro132Ser (c.394C>T) is associated with combined immunodeficiency with skin granulomas, severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive, Omenn syndrome (ClinVar).

How common is RAG1 p.Pro132Ser (c.394C>T) in the general population?

RAG1 p.Pro132Ser (c.394C>T) is ultra-rare (popmax 0.0233%, amr) (gnomAD).

How is Combined immunodeficiency with granulomatosis inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about RAG1 p.Pro132Ser (c.394C>T)?

AlphaMissense predicts ambiguous (score 0.4158) — an in-silico prediction, not a clinical call.

RAG1 p.Pro132Ser

c.394C>T · rs773742414 · VCV656345

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4158 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0233%, amr)

Conditions

combined immunodeficiency with skin granulomas

Computational evidence

Protein change
AlphaMissense	0.4158	ambiguous
REVEL	0.373	indeterminate
SaProt	LLR -8.19	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.4, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 814 bp · p 0.066 · regional, not allelic
Overall
CADD	25.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0233% Admixed American · 14/59,998 alleles

Filtering AF 0.0141% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0112%

Overall 0.00328% 53/1,613,950 alleles · ultra-rare exomes 49/1,461,814 · genomes 4/152,136 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0233%	4,286
Remaining individualsnot grpmax-eligible	0.0032%	31,241
European (non-Finnish)	0.00305%	32,779
African / African-American	0.00134%	74,898

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.Pro132Ser
Coding: c.394C>T
MANE Select: NM_000448
dbSNP: rs773742414
Type: single nucleotide variant
Location: chr11:36573698 (GRCh38)
Gene constraint: LOEUF 0.703 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.68
Residue 132: the 'interaction with importin alpha-1' region

Full RAG1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

combined immunodeficiency with skin granulomas — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive Omenn syndrome

For Combined immunodeficiency with granulomatosis (Orphanet):

Inheritance: Autosomal recessive

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-pro132ser (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown