Is RAG2 p.Cys41= (c.123C>T) pathogenic?

RAG2 p.Cys41= (c.123C>T) is classified Likely benign in RAG2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-04). Ultra-rare (popmax 0.0176%, sas); Associated with combined immunodeficiency with skin granulomas.

What condition is associated with RAG2 p.Cys41= (c.123C>T)?

RAG2 p.Cys41= (c.123C>T) is associated with combined immunodeficiency with skin granulomas, severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive (ClinVar).

How common is RAG2 p.Cys41= (c.123C>T) in the general population?

RAG2 p.Cys41= (c.123C>T) is ultra-rare (popmax 0.0176%, sas) (gnomAD).

How is Combined immunodeficiency with granulomatosis inherited?

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

RAG2 p.Cys41=

c.123C>T · rs121917895 · VCV2930385

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0176%, sas)

Conditions

combined immunodeficiency with skin granulomas

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.49	GERP -2.1, phastCons 0.99
Overall
CADD	7.126	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0176% South Asian · 16/91,082 alleles

Filtering AF 0.011% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00898%

Overall 0.00112% 18/1,613,976 alleles · ultra-rare exomes 16/1,461,818 · genomes 2/152,158 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0176%	5,693
Remaining individualsnot grpmax-eligible	0.0032%	31,241

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: RAG2
Protein: p.Cys41=
Coding: c.123C>T
MANE Select: NM_000536
dbSNP: rs121917895
Type: single nucleotide variant
Location: chr11:36594046 (GRCh38)
Gene constraint: LOEUF 0.733 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 75.98 · 1 PDB
Residue 41: a UniProt-annotated variant site (in os)

Full RAG2 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

For Combined immunodeficiency with granulomatosis (Orphanet):

Inheritance: Autosomal recessive

Similar variants

RAG2 p.Cys41Trp Pathogenic/Likely pathogenic ★★ ⚠ same residue
RAG2 p.Cys41Tyr Likely pathogenic ★ ⚠ same residue
RAG2 p.Cys41fs Likely pathogenic ★ same residue
RAG2 p.Arg229Gln Pathogenic ★★★ ⚠ same condition
RAG2 p.Arg229Trp Pathogenic ★★★ ⚠ same condition
RAG2 p.Arg39Gly Pathogenic ★★★ ⚠ same condition
RAG2 p.Arg73Cys Likely pathogenic ★★★ ⚠ same condition
RAG2 p.Asp65Tyr Likely 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/rag2-p-cys41 (accessed [today's date]).

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