Is RAG1 p.Arg449Lys (c.1346G>A) pathogenic?

RAG1 p.Arg449Lys (c.1346G>A) is classified Benign in RAG1 (ClinVar, Expert panel, 10 submitters; last evaluated 2024-01-23). AlphaMissense: likely benign (0.1122); Low-frequency (popmax 1.85%, nfe); Associated with recombinase activating gene 1 deficiency.

How common is RAG1 p.Arg449Lys (c.1346G>A) in the general population?

RAG1 p.Arg449Lys (c.1346G>A) is low-frequency (popmax 1.85%, nfe) (gnomAD).

What do computational predictors say about RAG1 p.Arg449Lys (c.1346G>A)?

AlphaMissense predicts likely benign (score 0.1122) — an in-silico prediction, not a clinical call.

RAG1 p.Arg449Lys

Q: What condition is associated with RAG1 p.Arg449Lys (c.1346G>A)?

RAG1 p.Arg449Lys (c.1346G>A) is associated with recombinase activating gene 1 deficiency, combined immunodeficiency with skin granulomas, severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive (ClinVar).

c.1346G>A · rs4151031 · VCV256188

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 10 submitters

AlphaMissense

likely benign

0.1122 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.85%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

recombinase activating gene 1 deficiency

ClinGen expert panel — Severe Combined Immunodeficiency Disease VCEP

Benign for recombinase activating gene 1 deficiency. Applied ACMG criteria (verbatim):

BS2_Supporting BA1

Curation rationale (ClinGen, verbatim)

The NM_000448.3:c.1346G>A variant in RAG1 is a missense variant predicted to cause the substitution of Arginine by Lysine at amino acid 449 (p.Arg449Lys). The filtering allele frequency (the lower threshold of the 95% CI of 21803/1180030) of the c.1346G>A variant in RAG1 is 0.01837 for European (non-Finnish) chromosomes by gnomAD v.4, which is higher than the ClinGen SCID VCEP threshold (>0.00872) for BA1 and, therefore, meets this criterion (BA1). Additionally, 207 homozygous adults are reported on gnomAD v.4 (BS2_Supporting). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: BA1 and BS2_Supporting. (VCEP specifications version 1).

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

Computational evidence

Protein change
AlphaMissense	0.1122	likely benign
REVEL	0.309	indeterminate
SaProt	LLR -7.15	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP -0.06, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 2,313 bp · p 3.1e-06 · regional, not allelic
Overall
CADD	22.6	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 1.85% European (non-Finnish) · 21,803/1,180,030 alleles

Filtering AF 1.83% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.82%

Overall 1.49% 24,033/1,614,222 alleles · low-frequency

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	5.27%	19
European (non-Finnish)grpmax	1.85%	54
Finnishnot grpmax-eligible	1.38%	73
Remaining individualsnot grpmax-eligible	1.1%	91
Admixed American	0.393%	254
African / African-American	0.266%	375
Ashkenazi Jewishnot grpmax-eligible	0.189%	529
South Asian	0.122%	821
Middle Eastern	0.0825%	1,212
East Asian	0.00446%	22,439

Amish 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: RAG1
Protein: p.Arg449Lys
Coding: c.1346G>A
MANE Select: NM_000448
dbSNP: rs4151031
Type: single nucleotide variant
Location: chr11:36574650 (GRCh38)
Gene constraint: LOEUF 0.703 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.68
Residue 449: a DNA-binding region; a UniProt-annotated variant site (in)

Full RAG1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

recombinase activating gene 1 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

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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/rag1-p-arg449lys (accessed [today's date]).

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