Is RAG1 p.Thr925= (c.2775G>A) pathogenic?

RAG1 p.Thr925= (c.2775G>A) is classified Likely benign in RAG1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-26). Very rare (popmax 0.00223%, eas); Associated with combined immunodeficiency with skin granulomas.

What condition is associated with RAG1 p.Thr925= (c.2775G>A)?

RAG1 p.Thr925= (c.2775G>A) is associated with combined immunodeficiency with skin granulomas, severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive (ClinVar).

How common is RAG1 p.Thr925= (c.2775G>A) in the general population?

RAG1 p.Thr925= (c.2775G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

How is Combined immunodeficiency with granulomatosis inherited?

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

RAG1 p.Thr925=

c.2775G>A · rs777246735 · VCV2936284

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

combined immunodeficiency with skin granulomas

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.40 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.42	GERP 0.05, phastCons 0.99
Overall
CADD	7.695	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,886 alleles

Filtering AF 0.00111% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0009%

Overall 0.00155% 25/1,613,886 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,886
European (non-Finnish)	0.00169%	59,003
Admixed American	0.00167%	60,000
Remaining individualsnot grpmax-eligible	0.0016%	62,480
Finnishnot grpmax-eligible	0.00157%	63,882
South Asian	0.0011%	91,078

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.Thr925=
Coding: c.2775G>A
MANE Select: NM_000448
dbSNP: rs777246735
Type: single nucleotide variant
Location: chr11:36576079 (GRCh38)
Gene constraint: LOEUF 0.703 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.68
Residue 925: a UniProt-annotated variant site (in t(-)b(-)nk(+) scid; uncertain significance); a UniProt-annotated variant site (in t(-)b(-)nk(+) scid; uncertain significance; also found in patients with an atypical form of severe combined immunodeficiency/omenn syndrome; uncertain significance; loss of recombination activity)

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

For Combined immunodeficiency with granulomatosis (Orphanet):

Inheritance: Autosomal recessive

Similar variants

RAG1 p.Thr925Met Uncertain significance ★ ⚠ same residue
RAG1 p.Thr925delinsPhePhePhePhePhePhePhePhePhePhePhePhePhePheLeuArgArgSerLeuAlaLeuSerProArgProAspCysGlyLeuGlnTrpArgAsnLeuGlySerLeuGlnAlaProLeuProGlyPheThrProPheSerCysLeuSerLeuProSerSerTrpAspTyrArgArgProProProArgProAlaAsnPheLeuTyrPheTer Likely pathogenic ★ same residue
RAG1 p.Thr925delinsPhePhePhePhePhePheXaaXaaXaaXaaSerIleSerTer Pathogenic ★ 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

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-thr925 (accessed [today's date]).

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