Is RAG2 p.His481Arg (c.1442A>G) pathogenic?

RAG2 p.His481Arg (c.1442A>G) is classified Pathogenic in RAG2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-31). AlphaMissense: likely pathogenic (0.8361); Very rare (popmax 0.0011%, sas); Associated with severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive.

How common is RAG2 p.His481Arg (c.1442A>G) in the general population?

RAG2 p.His481Arg (c.1442A>G) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about RAG2 p.His481Arg (c.1442A>G)?

AlphaMissense predicts likely pathogenic (score 0.8361) — an in-silico prediction, not a clinical call.

RAG2 p.His481Arg

Q: What condition is associated with RAG2 p.His481Arg (c.1442A>G)?

RAG2 p.His481Arg (c.1442A>G) 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.1442A>G · rs1564995465 · VCV2938106

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8361 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.8361	likely pathogenic ✓ concordant with ClinVar
REVEL	0.886	moderately pathogenic-leaning
SaProt	LLR -12.86	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 7.9	GERP 2.6, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 1,580 bp · p 0.79 · regional, not allelic
Overall
CADD	25.3	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 0.0011% South Asian · 1/90,828 alleles

Overall 6.21e-05% 1/1,610,044 alleles · very rare exomes 1/1,461,264 · genomes 0/148,780 · 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: RAG2
Protein: p.His481Arg
Coding: c.1442A>G
MANE Select: NM_000536
dbSNP: rs1564995465
Type: single nucleotide variant
Location: chr11:36592727 (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

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

RAG2 p.His481= Likely benign ★★ 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-his481arg (accessed [today's date]).

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