Is RAG2 p.Val247= (c.741G>A) pathogenic?

RAG2 p.Val247= (c.741G>A) is classified Benign in RAG2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-02). Common (popmax 6.35%, afr) — too common for a highly-penetrant pathogenic allele; Associated with combined immunodeficiency with skin granulomas.

What condition is associated with RAG2 p.Val247= (c.741G>A)?

RAG2 p.Val247= (c.741G>A) 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 is Combined immunodeficiency with granulomatosis inherited?

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

RAG2 p.Val247=

Q: How common is RAG2 p.Val247= (c.741G>A) in the general population?

RAG2 p.Val247= (c.741G>A) is common (popmax 6.35%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.741G>A · rs34092949 · VCV138886

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Common

common (popmax 6.35%, afr) — too common for a highly-penetrant pathogenic allele

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 0.28	GERP -4.1, phastCons 0.96
Overall
CADD	3.426	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.35% African / African-American · 4,762/75,048 alleles

Filtering AF 6.19% ClinGen BA1/BS1 input FAF95, joint · FAF99 6.13%

Overall 0.333% 5,367/1,614,008 alleles · common exomes 2,683/1,461,710 · genomes 2,684/152,298 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	6.35%	16
Remaining individualsnot grpmax-eligible	0.453%	221
Admixed American	0.396%	252
Middle Eastern	0.214%	466
South Asian	0.0242%	4,140
European (non-Finnish)	0.00407%	24,584
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606

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.Val247=
Coding: c.741G>A
MANE Select: NM_000536
dbSNP: rs34092949
Type: single nucleotide variant
Location: chr11:36593428 (GRCh38)
Gene constraint: LOEUF 0.733 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 75.98 · 1 PDB

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 Omenn syndrome

For Combined immunodeficiency with granulomatosis (Orphanet):

Inheritance: Autosomal recessive

Similar variants

RAG2 p.Val247Glu Uncertain significance ★ ⚠ 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
RAG2 p.Cys446Trp Likely pathogenic ★★★ same condition
RAG2 p.Glu437Lys 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-val247 (accessed [today's date]).

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