Is RAG2 p.His481= (c.1443T>C) pathogenic?

RAG2 p.His481= (c.1443T>C) is classified Likely benign in RAG2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-20). Ultra-rare (popmax 0.0584%, eas); Associated with combined immunodeficiency with skin granulomas.

What condition is associated with RAG2 p.His481= (c.1443T>C)?

RAG2 p.His481= (c.1443T>C) 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 RAG2 p.His481= (c.1443T>C) in the general population?

RAG2 p.His481= (c.1443T>C) is ultra-rare (popmax 0.0584%, eas) (gnomAD).

How is Combined immunodeficiency with granulomatosis inherited?

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

RAG2 p.His481=

c.1443T>C · rs560115611 · VCV728292

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0584%, eas)

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	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.55	GERP -1.9, phastCons 0.78
Overall
CADD	4.167	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0584% East Asian · 26/44,532 alleles

Filtering AF 0.0408% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.035%

Overall 0.00243% 39/1,605,764 alleles · ultra-rare exomes 31/1,460,246 · genomes 8/145,518 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0584%	1,713
Remaining individualsnot grpmax-eligible	0.0112%	8,903
South Asian	0.00664%	15,064

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.His481=
Coding: c.1443T>C
MANE Select: NM_000536
dbSNP: rs560115611
Type: single nucleotide variant
Location: chr11:36592726 (GRCh38)
Gene constraint: LOEUF 0.733 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 75.98 · 1 PDB
Residue 481: a binding site; a turn

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.His481Arg Pathogenic ★ same residue
RAG2 p.His481Asp Pathogenic ★ same residue
RAG2 p.His481Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
RAG2 p.His481Pro Conflicting classifications of pathogenicity ★ ⚠ 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

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-his481 (accessed [today's date]).

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