Is RAG1 p.Gln911His (c.2733G>C) pathogenic?

RAG1 p.Gln911His (c.2733G>C) is classified Uncertain significance in RAG1 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-02-17). AlphaMissense: ambiguous (0.527); Very rare (popmax 0.000169%, nfe); Associated with severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive.

How common is RAG1 p.Gln911His (c.2733G>C) in the general population?

RAG1 p.Gln911His (c.2733G>C) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about RAG1 p.Gln911His (c.2733G>C)?

AlphaMissense predicts ambiguous (score 0.527) — an in-silico prediction, not a clinical call.

RAG1 p.Gln911His

Q: What condition is associated with RAG1 p.Gln911His (c.2733G>C)?

RAG1 p.Gln911His (c.2733G>C) is associated with severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive, combined immunodeficiency with skin granulomas (ClinVar).

Q: How is Severe combined immunodeficiency due to complete RAG1/2 deficiency inherited?

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

c.2733G>C · rs2133298067 · VCV1051999

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.527 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive

Computational evidence

Protein change
AlphaMissense	0.527	ambiguous
REVEL	0.695	pathogenic-leaning
SaProt	LLR -7.05	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.8	GERP 0.61, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 2,313 bp · p 3.1e-06 · regional, not allelic
Overall
CADD	24.1	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 0.000169% European (non-Finnish) · 2/1,180,042 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,614,136 alleles · very rare exomes 2/1,461,806 · genomes 0/152,330 · joint denominator

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.Gln911His
Coding: c.2733G>C
MANE Select: NM_000448
dbSNP: rs2133298067
Type: single nucleotide variant
Location: chr11:36576037 (GRCh38)
Gene constraint: LOEUF 0.703 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.68
Residue 911: 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

severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: combined immunodeficiency with skin granulomas

For Severe combined immunodeficiency due to complete RAG1/2 deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

RAG1 p.Gln911Arg Uncertain significance ★★ ⚠ 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
RAG1 p.Arg396His Pathogenic ★★★ same condition
RAG1 p.Arg404Gln 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-gln911his (accessed [today's date]).

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