Is RAG1 p.Arg34Gln (c.101G>A) pathogenic?

RAG1 p.Arg34Gln (c.101G>A) is classified Uncertain significance in RAG1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-05-03). AlphaMissense: likely benign (0.2666); Ultra-rare (popmax 0.0267%, amr); Associated with combined immunodeficiency due to partial RAG1 deficiency.

How common is RAG1 p.Arg34Gln (c.101G>A) in the general population?

RAG1 p.Arg34Gln (c.101G>A) is ultra-rare (popmax 0.0267%, amr) (gnomAD).

What do computational predictors say about RAG1 p.Arg34Gln (c.101G>A)?

AlphaMissense predicts likely benign (score 0.2666) — an in-silico prediction, not a clinical call.

RAG1 p.Arg34Gln

Q: What condition is associated with RAG1 p.Arg34Gln (c.101G>A)?

RAG1 p.Arg34Gln (c.101G>A) is associated with combined immunodeficiency due to partial RAG1 deficiency, combined immunodeficiency with skin granulomas, severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive (ClinVar).

Q: How is Combined immunodeficiency due to partial RAG1 deficiency inherited?

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

c.101G>A · rs377307948 · VCV536958

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2666 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0267%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

combined immunodeficiency due to partial RAG1 deficiency

Computational evidence

Protein change
AlphaMissense	0.2666	likely benign
REVEL	0.437	indeterminate
SaProt	LLR -6.27	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 2.4, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 814 bp · p 0.066 · regional, not allelic
Overall
CADD	28.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0267% Admixed American · 16/59,984 alleles

Filtering AF 0.0166% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0136%

Overall 0.0052% 84/1,613,906 alleles · ultra-rare exomes 72/1,461,892 · genomes 12/152,014 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0267%	3,749
Middle Eastern	0.0164%	6,084
African / African-American	0.00935%	10,694
European (non-Finnish)	0.00458%	21,852
South Asian	0.00329%	30,355
Remaining individualsnot grpmax-eligible	0.0032%	31,241
Finnishnot grpmax-eligible	0.00156%	64,002

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.Arg34Gln
Coding: c.101G>A
MANE Select: NM_000448
dbSNP: rs377307948
Type: single nucleotide variant
Location: chr11:36573405 (GRCh38)
Gene constraint: LOEUF 0.703 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.68
Residue 34: 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 due to partial RAG1 deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

For Combined immunodeficiency due to partial RAG1 deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

RAG1 p.Arg34= Likely benign ★ same residue
RAG1 p.Arg34Trp 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

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-arg34gln (accessed [today's date]).

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