Is RAG1 p.Arg699Trp (c.2095C>T) pathogenic?

RAG1 p.Arg699Trp (c.2095C>T) is classified Likely pathogenic in RAG1 (ClinVar, Expert panel, 11 submitters; last evaluated 2026-05-06). AlphaMissense: likely pathogenic (0.803); Ultra-rare (popmax 0.0164%, mid); Associated with recombinase activating gene 1 deficiency.

How common is RAG1 p.Arg699Trp (c.2095C>T) in the general population?

RAG1 p.Arg699Trp (c.2095C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about RAG1 p.Arg699Trp (c.2095C>T)?

AlphaMissense predicts likely pathogenic (score 0.803) — an in-silico prediction, not a clinical call.

RAG1 p.Arg699Trp

Q: What condition is associated with RAG1 p.Arg699Trp (c.2095C>T)?

RAG1 p.Arg699Trp (c.2095C>T) is associated with recombinase activating gene 1 deficiency, combined immunodeficiency with skin granulomas, severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive (ClinVar).

c.2095C>T · rs199474676 · VCV68689

Likely pathogenic Expert panel

Classification

Likely pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 11 submitters

AlphaMissense

likely pathogenic

0.803 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

recombinase activating gene 1 deficiency

ClinGen expert panel — Severe Combined Immunodeficiency Disease VCEP

Likely Pathogenic for recombinase activating gene 1 deficiency. Applied ACMG criteria (verbatim):

PM2_Supporting PS3_Moderate PM1_Supporting PP4 PM3

Curation rationale (ClinGen, verbatim)

NM_000448.3(RAG1):c.2095C>T is a missense variant predicted to cause substitution of Arginine by Tryptophan at amino acid 699 (p.Arg699Trp).The filtering allele frequency (the upper threshold of the 95% CI of 5/1179830) of the c.2095C>T variant in RAG1 is 0.000001320 for European Non-Finnish chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.000102) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting).This missense variant is located in the core domain (amino acids 387-1011) (PM1_supporting).Patient with SCID (0.5 pt.), genome sequencing conducted (0.5 pt.),T-B-NK+ lymphocyte subset profile (0.5 pt.) Total :1.5 pts. (PMID: 29107076) (PP4). The VDJ recombination activity was found to be 19.3 +/- 1.8 % of WT (mean +/- SE) in a flow cytometry based assay. PMID : 24290284 (PS3_Moderate).The patient (PMID: 21771083) was found heterozygous for R699W & Y1001X (not yet curated by SCID VCEP); p.R699W & p.393fsX402 (not yet curated by SCID VCEP)(PMID: 21184155); homozygous in 3 individuals (PMIDs: 24122031,31503426, 32447396) (Pt.: 1)(PM3). In summary, this variant meets the criteria to be classified as Likely Pathogenic variant for autosomal recessive severe combined immunodeficiency due to RAG1 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM1_supporting,PM2_Supporting, PP4,PS3_Moderate,PM3(VCEP specifications version 2.1.0).

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.803	likely pathogenic ✓ concordant with ClinVar
REVEL	0.817	moderately pathogenic-leaning
SaProt	LLR -12.78	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP -1.3, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 2,313 bp · p 3.1e-06 · regional, not allelic
Overall
CADD	26.4	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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.00062% 10/1,613,786 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
East Asian	0.00668%	14,963
African / African-American	0.00134%	74,890
European (non-Finnish)	0.000424%	235,966

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.Arg699Trp
Coding: c.2095C>T
MANE Select: NM_000448
dbSNP: rs199474676
Type: single nucleotide variant
Location: chr11:36575399 (GRCh38)
Gene constraint: LOEUF 0.703 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.68
Residue 699: a UniProt-annotated variant site (in os; also in a patient with multiple autoimmune disorders)

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

Disease context

recombinase activating gene 1 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 combined immunodeficiency due to partial RAG1 deficiency

Similar variants

RAG1 p.Arg699Gln Likely 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
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-arg699trp (accessed [today's date]).

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