Is RAG2 p.Val50Ile (c.148G>A) pathogenic?

RAG2 p.Val50Ile (c.148G>A) is classified Uncertain significance in RAG2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-11). AlphaMissense: likely benign (0.0638); Very rare (popmax 8.47e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with RAG2 p.Val50Ile (c.148G>A)?

RAG2 p.Val50Ile (c.148G>A) is associated with Inborn genetic diseases (ClinVar).

How common is RAG2 p.Val50Ile (c.148G>A) in the general population?

RAG2 p.Val50Ile (c.148G>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about RAG2 p.Val50Ile (c.148G>A)?

AlphaMissense predicts likely benign (score 0.0638) — an in-silico prediction, not a clinical call.

RAG2 p.Val50Ile

c.148G>A · VCV4150081

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0638 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0638	likely benign
REVEL	0.189	benign-leaning
SaProt	LLR -5.63	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -3	GERP -5.3
Regional constraint	o/e 0.99	unconstrained · MANE · 1,580 bp · p 0.79 · regional, not allelic
Overall
CADD	0.093	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 8.47e-05% European (non-Finnish) · 1/1,180,028 alleles

Overall 6.2e-05% 1/1,614,200 alleles · very rare exomes 1/1,461,882 · genomes 0/152,318 · 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.Val50Ile
Coding: c.148G>A
MANE Select: NM_000536
Type: single nucleotide variant
Location: chr11:36594021 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

RAG2 p.Arg300Cys Uncertain significance ★★ ⚠ same condition
RAG2 p.Asn268Ser Uncertain significance ★★ ⚠ same condition
RAG2 p.Asn53His Uncertain significance ★★ ⚠ same condition
RAG2 p.Gln90Glu Uncertain significance ★★ ⚠ same condition
RAG2 p.Glu303Gly Uncertain significance ★★ ⚠ same condition
RAG2 p.Gly373Arg Uncertain significance ★★ ⚠ same condition
RAG2 p.His468Arg Uncertain significance ★★ ⚠ same condition
RAG2 p.Thr515Asn Uncertain significance ★★ ⚠ 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-val50ile (accessed [today's date]).

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