Is RAG1 p.Val433fs (c.1297del) pathogenic?

RAG1 p.Val433fs (c.1297del) is classified Pathogenic in RAG1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-27). Absent from gnomAD; Associated with combined immunodeficiency with skin granulomas.

What condition is associated with RAG1 p.Val433fs (c.1297del)?

RAG1 p.Val433fs (c.1297del) 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.Val433fs (c.1297del) in the general population?

RAG1 p.Val433fs (c.1297del) is absent from gnomAD (gnomAD).

How is Combined immunodeficiency with granulomatosis inherited?

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

RAG1 p.Val433fs

c.1297del · rs2494755383 · VCV2118233

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

combined immunodeficiency with skin granulomas

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 -7.1	GERP -5.4

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

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: RAG1
Protein: p.Val433fs
Coding: c.1297del
MANE Select: NM_000448
dbSNP: rs2494755383
Type: Deletion
Location: chr11:36574601 (GRCh38)
Gene constraint: LOEUF 0.703 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.68
Residue 433: a DNA-binding region; a UniProt-annotated variant site (in os and t(-)b(-)nk(+) scid; found in a patient with an atypical form of severe combined immunodeficiency/omenn syndrome)

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.Val433Met Pathogenic/Likely pathogenic ★★ 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
RAG1 p.Glu174fs Pathogenic ★★ same condition
RAG1 p.Glu817fs 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-val433fs (accessed [today's date]).

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