Is RAG2 p.Arg464Cys (c.1390C>T) pathogenic?

RAG2 p.Arg464Cys (c.1390C>T) is classified Uncertain significance in RAG2 (ClinVar, Single submitter, 2 submitters; last evaluated 2022-08-09). AlphaMissense: likely benign (0.0993); Ultra-rare (popmax 0.0317%, amr); Associated with severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive.

How common is RAG2 p.Arg464Cys (c.1390C>T) in the general population?

RAG2 p.Arg464Cys (c.1390C>T) is ultra-rare (popmax 0.0317%, amr) (gnomAD).

What do computational predictors say about RAG2 p.Arg464Cys (c.1390C>T)?

AlphaMissense predicts likely benign (score 0.0993) — an in-silico prediction, not a clinical call.

RAG2 p.Arg464Cys

Q: What condition is associated with RAG2 p.Arg464Cys (c.1390C>T)?

RAG2 p.Arg464Cys (c.1390C>T) is associated with severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive, combined immunodeficiency with skin granulomas, Omenn syndrome (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.1390C>T · rs189020262 · VCV972658

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0993 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0317%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.0993	likely benign
REVEL	0.186	benign-leaning
SaProt	LLR -7.53	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 0.29	GERP -5.3, phastCons 0.002
Regional constraint	o/e 0.99	unconstrained · MANE · 1,580 bp · p 0.79 · regional, not allelic
Overall
CADD	16.38	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0317% Admixed American · 19/60,022 alleles

Filtering AF 0.0207% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0172%

Overall 0.00266% 43/1,614,082 alleles · ultra-rare exomes 38/1,461,892 · genomes 5/152,190 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0317%	3,159
Middle Eastern	0.0165%	6,062
African / African-American	0.00667%	14,996
Remaining individualsnot grpmax-eligible	0.0032%	31,255
Finnishnot grpmax-eligible	0.00312%	32,014
East Asian	0.00223%	44,862
South Asian	0.0022%	45,534
European (non-Finnish)	0.000932%	107,275

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.Arg464Cys
Coding: c.1390C>T
MANE Select: NM_000536
dbSNP: rs189020262
Type: single nucleotide variant
Location: chr11:36592779 (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

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 Omenn syndrome

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.Arg464His Conflicting classifications of pathogenicity ★ ⚠ 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-arg464cys (accessed [today's date]).

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