Is RAG2 p.Met1Val (c.1A>G) pathogenic?

RAG2 p.Met1Val (c.1A>G) is classified Uncertain significance in RAG2 (ClinVar, Expert panel, 2 submitters; last evaluated 2024-06-14). Very rare (popmax 0.000345%, nfe); Associated with recombinase activating gene 2 deficiency.

How common is RAG2 p.Met1Val (c.1A>G) in the general population?

RAG2 p.Met1Val (c.1A>G) is very rare (popmax 0.000345%, nfe) (gnomAD).

RAG2 p.Met1Val

Q: What condition is associated with RAG2 p.Met1Val (c.1A>G)?

RAG2 p.Met1Val (c.1A>G) 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.1A>G · rs1564997814 · VCV624606

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 2 submitters

Consequence

start-loss

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000345%, nfe)

Conditions

recombinase activating gene 2 deficiency

ClinGen expert panel — Severe Combined Immunodeficiency Disease VCEP

Uncertain Significance for recombinase activating gene 2 deficiency. Applied ACMG criteria (verbatim):

PVS1_Supporting PM2_Supporting PM1_Supporting PP4

Curation rationale (ClinGen, verbatim)

NM_000536.4(RAG2):c.1A>G is a missense variant predicted to cause substitution of Methionine by Valine at amino acid 1 (p.Met1Val). This sequence change affects the initiator methionine of the RAG2 mRNA. The next possible initiation codon is at codon 5. This region does not contain known pathogenic/likely pathogenic variants (PVS1_Supporting). This missense variant is located in the core domain (amino acids 1-383) (PM1_supporting). The variant is absent in gnomAD v4 (PM2_supporting). Female with SCID (0.5 pt.), genome sequencing conducted (0.5 pt.)& T-B-NK+ lymphocyte subset profile (0.5 pt.) (Total :1.5 pts) (PP4 met) (PMID: 31031743). The patient was found compound heterozygous for c.1A>G; p.M1V and c.1403_1406delATCT (not evaluated by SCID VCEP yet) (PMID: 31031743) (PM3 not evaluated). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to RAG2 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PVS1_Supporting,PM1_supporting, PM2_supporting,PP4 met(VCEP specifications version 1).

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

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	start-loss	predicted loss-of-function
REVEL	0.731	pathogenic-leaning
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6.5	GERP 2.6, phastCons 1
Overall
CADD	19.2	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000345% European (non-Finnish) · 4/1,160,240 alleles

Filtering AF 8.1e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000377% 6/1,592,216 alleles · very rare exomes 6/1,439,874 · genomes 0/152,342 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00323%	30,916
European (non-Finnish)grpmax	0.000345%	290,060

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.Met1Val
Coding: c.1A>G
MANE Select: NM_000536
dbSNP: rs1564997814
Type: single nucleotide variant
Location: chr11:36594168 (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

Similar variants

RAG2 p.Met1Ile Likely pathogenic ★★★ same residue
RAG2 p.Met1Thr Uncertain significance ★★★ 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

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-met1val (accessed [today's date]).

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