Is RAG1 p.Lys40= (c.120G>A) pathogenic?

RAG1 p.Lys40= (c.120G>A) is classified Likely benign in RAG1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-22). Very rare (popmax 0.000339%, nfe); Associated with combined immunodeficiency with skin granulomas.

What condition is associated with RAG1 p.Lys40= (c.120G>A)?

RAG1 p.Lys40= (c.120G>A) 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 RAG1 p.Lys40= (c.120G>A) in the general population?

RAG1 p.Lys40= (c.120G>A) is very rare (popmax 0.000339%, nfe) (gnomAD).

How is Combined immunodeficiency with granulomatosis inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

RAG1 p.Lys40=

c.120G>A · rs779958394 · VCV2933670

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Conditions

combined immunodeficiency with skin granulomas

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.6	GERP -0.44, phastCons 1
Overall
CADD	8.404	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,180,028 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.00031% 5/1,613,960 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,486
European (non-Finnish)grpmax	0.000339%	295,007

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: RAG1
Protein: p.Lys40=
Coding: c.120G>A
MANE Select: NM_000448
dbSNP: rs779958394
Type: single nucleotide variant
Location: chr11:36573424 (GRCh38)
Gene constraint: LOEUF 0.703 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.68
Residue 40: the 'interaction with importin alpha-1' region; the 'disordered' region

Full RAG1 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

RAG1 p.Ala444Val Pathogenic ★★★ same condition
RAG1 p.Arg108Ter Pathogenic ★★★ same condition
RAG1 p.Arg142Ter Pathogenic ★★★ same condition
RAG1 p.Arg394Gln Likely pathogenic ★★★ same condition
RAG1 p.Arg394Trp Pathogenic ★★★ same condition
RAG1 p.Arg396His Pathogenic ★★★ same condition
RAG1 p.Arg404Gln Pathogenic ★★★ ⚠ same condition
RAG1 p.Arg561Cys 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/rag1-p-lys40 (accessed [today's date]).

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