Is RAG1 p.Val65Phe (c.193G>T) pathogenic?

RAG1 p.Val65Phe (c.193G>T) is classified Uncertain significance in RAG1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-03). AlphaMissense: likely benign (0.0739); Very rare (popmax 0.00167%, amr); Associated with severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive.

How common is RAG1 p.Val65Phe (c.193G>T) in the general population?

RAG1 p.Val65Phe (c.193G>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about RAG1 p.Val65Phe (c.193G>T)?

AlphaMissense predicts likely benign (score 0.0739) — an in-silico prediction, not a clinical call.

RAG1 p.Val65Phe

Q: What condition is associated with RAG1 p.Val65Phe (c.193G>T)?

RAG1 p.Val65Phe (c.193G>T) 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.193G>T · rs750032999 · VCV1038262

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0739 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.0739	likely benign
REVEL	0.114	moderately benign-leaning
SaProt	LLR -7.50	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.3	GERP -0.41, phastCons 0.034
Regional constraint	o/e 1.10	unconstrained · MANE · 814 bp · p 0.066 · regional, not allelic
Overall
CADD	14.79	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 0.00167% Admixed American · 1/60,004 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.00062% 10/1,614,092 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,004
European (non-Finnish)	0.000763%	131,116

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.Val65Phe
Coding: c.193G>T
MANE Select: NM_000448
dbSNP: rs750032999
Type: single nucleotide variant
Location: chr11:36573497 (GRCh38)
Gene constraint: LOEUF 0.703 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.68
Residue 65: the 'interaction with importin alpha-1' region; the 'disordered' region

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.Val65Ala Uncertain significance ★ ⚠ same residue
RAG1 p.Val65Ile 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-val65phe (accessed [today's date]).

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