Is RAG2 p.Arg464His (c.1391G>A) pathogenic?

RAG2 p.Arg464His (c.1391G>A) is classified Conflicting classifications of pathogenicity in RAG2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.0751); Ultra-rare (popmax 0.0334%, nfe); Associated with combined immunodeficiency with skin granulomas.

What condition is associated with RAG2 p.Arg464His (c.1391G>A)?

RAG2 p.Arg464His (c.1391G>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 common is RAG2 p.Arg464His (c.1391G>A) in the general population?

RAG2 p.Arg464His (c.1391G>A) is ultra-rare (popmax 0.0334%, nfe) (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 RAG2 p.Arg464His (c.1391G>A)?

AlphaMissense predicts likely benign (score 0.0751) — an in-silico prediction, not a clinical call.

RAG2 p.Arg464His

c.1391G>A · rs147748696 · VCV432772

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0751 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0334%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

combined immunodeficiency with skin granulomas

Computational evidence

Protein change
AlphaMissense	0.0751	likely benign
REVEL	0.246	benign-leaning
SaProt	LLR -6.82	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.1	GERP -4.7
Regional constraint	o/e 0.99	unconstrained · MANE · 1,580 bp · p 0.79 · regional, not allelic
Overall
CADD	12.39	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 0.0334% European (non-Finnish) · 394/1,180,014 alleles

Filtering AF 0.0306% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0295%

Overall 0.0368% 594/1,613,910 alleles · ultra-rare exomes 529/1,461,890 · genomes 65/152,020 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.321%	312
Finnishnot grpmax-eligible	0.125%	800
European (non-Finnish)grpmax	0.0334%	2,995
Remaining individualsnot grpmax-eligible	0.0304%	3,289
African / African-American	0.00401%	24,957
Admixed American	0.00333%	29,991
South Asian	0.0011%	91,078

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg464His
Coding: c.1391G>A
MANE Select: NM_000536
dbSNP: rs147748696
Type: single nucleotide variant
Location: chr11:36592778 (GRCh38)
Gene constraint: LOEUF 0.733 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 75.98 · 1 PDB
Residue 464: an α-helix

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.Arg464Cys Uncertain significance ★ ⚠ same residue
RAG2 p.Arg464Pro Uncertain significance ★ ⚠ same residue
RAG2 p.Arg464= Likely benign ★ 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-arg464his (accessed [today's date]).

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