Is RAG2 p.Val8Ile (c.22G>A) pathogenic?

RAG2 p.Val8Ile (c.22G>A) is classified Likely benign in RAG2 (ClinVar, Expert panel, 12 submitters; last evaluated 2023-11-14). AlphaMissense: likely benign (0.0854); Rare (popmax 0.66%, mid); Associated with recombinase activating gene 2 deficiency.

How common is RAG2 p.Val8Ile (c.22G>A) in the general population?

RAG2 p.Val8Ile (c.22G>A) is rare (popmax 0.66%, mid) (gnomAD).

What do computational predictors say about RAG2 p.Val8Ile (c.22G>A)?

AlphaMissense predicts likely benign (score 0.0854) — an in-silico prediction, not a clinical call.

RAG2 p.Val8Ile

Q: What condition is associated with RAG2 p.Val8Ile (c.22G>A)?

RAG2 p.Val8Ile (c.22G>A) is associated with recombinase activating gene 2 deficiency, combined immunodeficiency with skin granulomas, severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive (ClinVar).

c.22G>A · rs150762709 · VCV138885

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 12 submitters

AlphaMissense

likely benign

0.0854 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.66%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

recombinase activating gene 2 deficiency

ClinGen expert panel — Severe Combined Immunodeficiency Disease VCEP

Likely Benign for recombinase activating gene 2 deficiency. Applied ACMG criteria (verbatim):

BS1 BS2_Supporting

Curation rationale (ClinGen, verbatim)

The NM_000536.4:c.22G>A variant in RAG2 is a missense variant predicted to cause substitution of valine by isoleucine at amino acid 8 (p.Val8Ile). This variant has a population max filtering allele frequency of 0.004397 in gnomAD, which is above the threshold for BS1 set by the ClinGen SCID VCEP for RAG2 (>0.00195). This variant has not been identified in individuals with SCID, though it has been identified in one individual with CID (PMID: 28769923) who carried a co-occurring variant p.D200H (phase unknown, p.D200H not curated by ClinGen SCID VCEP). In addition, this variant is present in 5 homozygotes in gnomAD (BS2_Supporting). In summary, this variant is classified as a Likely Benign for autosomal recessive SCID based on the ACMG criteria applied: BS1 and BS2_Supporting as specified by the ClinGen SCID VCEP (VCEP specifications version 1).

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.0854	likely benign
REVEL	0.166	moderately benign-leaning
SaProt	LLR -7.17	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 3.4	GERP 1.8, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 1,580 bp · p 0.79 · regional, not allelic
Overall
CADD	20.5	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 0.66% Middle Eastern · 40/6,058 alleles

Filtering AF 0.498% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.483%

Overall 0.444% 7,155/1,611,954 alleles · rare exomes 6,689/1,459,636 · genomes 466/152,318 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	1.63%	62
Middle Easterngrpmax	0.66%	151
Remaining individualsnot grpmax-eligible	0.503%	199
European (non-Finnish)	0.498%	201
Finnishnot grpmax-eligible	0.266%	376
South Asian	0.161%	619
Admixed American	0.148%	674
African / African-American	0.0627%	1,595

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.Val8Ile
Coding: c.22G>A
MANE Select: NM_000536
dbSNP: rs150762709
Type: single nucleotide variant
Location: chr11:36594147 (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

recombinase activating gene 2 deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: combined immunodeficiency with skin granulomas severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive Omenn syndrome

Similar variants

RAG2 p.Val8= 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
RAG2 p.Cys446Trp Likely pathogenic ★★★ same condition
RAG2 p.Glu437Lys 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-val8ile (accessed [today's date]).

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