Is RAG2 p.Val154Ala (c.461T>C) pathogenic?

RAG2 p.Val154Ala (c.461T>C) is classified Uncertain significance in RAG2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-26). AlphaMissense: ambiguous (0.5056); Very rare (popmax 0.000678%, nfe); Associated with combined immunodeficiency with skin granulomas.

What condition is associated with RAG2 p.Val154Ala (c.461T>C)?

RAG2 p.Val154Ala (c.461T>C) is associated with combined immunodeficiency with skin granulomas, severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive (ClinVar).

How common is RAG2 p.Val154Ala (c.461T>C) in the general population?

RAG2 p.Val154Ala (c.461T>C) is very rare (popmax 0.000678%, 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.Val154Ala (c.461T>C)?

AlphaMissense predicts ambiguous (score 0.5056) — an in-silico prediction, not a clinical call.

RAG2 p.Val154Ala

c.461T>C · rs17852002 · VCV2085699

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5056 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000678%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

combined immunodeficiency with skin granulomas

Computational evidence

Protein change
AlphaMissense	0.5056	ambiguous
REVEL	0.794	moderately pathogenic-leaning
SaProt	LLR -12.42	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 2.6, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 1,580 bp · p 0.79 · regional, not allelic
Overall
CADD	26.2	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 0.000678% European (non-Finnish) · 8/1,180,016 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000558% 9/1,614,182 alleles · very rare exomes 9/1,461,856 · genomes 0/152,326 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,506
European (non-Finnish)grpmax	0.000678%	147,502

Remaining individuals 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.Val154Ala
Coding: c.461T>C
MANE Select: NM_000536
dbSNP: rs17852002
Type: single nucleotide variant
Location: chr11:36593708 (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

For Combined immunodeficiency with granulomatosis (Orphanet):

Inheritance: Autosomal recessive

Similar variants

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
RAG2 p.Gly319Ter 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-val154ala (accessed [today's date]).

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