Is RAG1 p.Cys730Phe (c.2189G>T) pathogenic?

RAG1 p.Cys730Phe (c.2189G>T) is classified Pathogenic/Likely pathogenic in RAG1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-06-08). AlphaMissense: likely pathogenic (0.9943); Very rare (popmax 0.00534%, afr); Associated with combined immunodeficiency with skin granulomas.

What condition is associated with RAG1 p.Cys730Phe (c.2189G>T)?

RAG1 p.Cys730Phe (c.2189G>T) is associated with combined immunodeficiency with skin granulomas, severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive, Omenn syndrome (ClinVar).

How common is RAG1 p.Cys730Phe (c.2189G>T) in the general population?

RAG1 p.Cys730Phe (c.2189G>T) is very rare (popmax 0.00534%, afr) (gnomAD).

How is Combined immunodeficiency with granulomatosis inherited?

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

What do computational predictors say about RAG1 p.Cys730Phe (c.2189G>T)?

AlphaMissense predicts likely pathogenic (score 0.9943) — an in-silico prediction, not a clinical call.

RAG1 p.Cys730Phe

c.2189G>T · rs770771227 · VCV3251834

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9943 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

combined immunodeficiency with skin granulomas

Computational evidence

Protein change
AlphaMissense	0.9943	likely pathogenic ✓ concordant with ClinVar · top 4% in RAG1
REVEL	0.875	moderately pathogenic-leaning
SaProt	LLR -14.50	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 12	GERP 2.9, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 2,313 bp · p 3.1e-06 · regional, not allelic
Overall
CADD	29.5	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 0.00534% African / African-American · 4/74,922 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000248% 4/1,614,092 alleles · very rare exomes 0/1,461,894 · genomes 4/152,198 · 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.Cys730Phe
Coding: c.2189G>T
MANE Select: NM_000448
dbSNP: rs770771227
Type: single nucleotide variant
Location: chr11:36575493 (GRCh38)
Gene constraint: LOEUF 0.703 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.68

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 Omenn syndrome combined immunodeficiency due to partial RAG1 deficiency severe combined immunodeficiency

For Combined immunodeficiency with granulomatosis (Orphanet):

Inheritance: Autosomal recessive

Similar variants

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
RAG1 p.Arg561Cys 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-cys730phe (accessed [today's date]).

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