Is RAG1 p.Arg396fs (c.1182del) pathogenic?

RAG1 p.Arg396fs (c.1182del) is classified Likely pathogenic in RAG1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-01). Associated with combined immunodeficiency due to partial RAG1 deficiency.

RAG1 p.Arg396fs

Q: What condition is associated with RAG1 p.Arg396fs (c.1182del)?

RAG1 p.Arg396fs (c.1182del) is associated with combined immunodeficiency due to partial RAG1 deficiency, combined immunodeficiency with skin granulomas, severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive (ClinVar).

Q: How is Combined immunodeficiency due to partial RAG1 deficiency inherited?

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

c.1182del · VCV3599577

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Conditions

combined immunodeficiency due to partial RAG1 deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (2 of 2) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 3.4	GERP 1.8, phastCons 1

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

Variant & gene context

Gene: RAG1
Protein: p.Arg396fs
Coding: c.1182del
MANE Select: NM_000448
Type: Deletion
Location: chr11:36574485 (GRCh38)
Gene constraint: LOEUF 0.703 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.68
Residue 396: a DNA-binding region; a UniProt-annotated variant site (in os)

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

Disease context

combined immunodeficiency due to partial RAG1 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

For Combined immunodeficiency due to partial RAG1 deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

RAG1 p.Arg396His Pathogenic ★★★ same residue
RAG1 p.Arg396Cys Pathogenic ★★ same residue
RAG1 p.Arg396= Likely benign ★ same residue
RAG1 p.Lys86fs Pathogenic ★★★ same condition
RAG1 p.Ser259fs Pathogenic ★★★ same condition
RAG1 p.Ala456fs Pathogenic/Likely pathogenic ★★ same condition
RAG1 p.Ala69fs Pathogenic/Likely pathogenic ★★ same condition
RAG1 p.Asn743fs Pathogenic/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/rag1-p-arg396fs (accessed [today's date]).

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