Is RAG1 p.Ala69fs (c.206del) pathogenic?

RAG1 p.Ala69fs (c.206del) is classified Pathogenic/Likely pathogenic in RAG1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-01-31). No gnomAD frequency available for this variant; Associated with severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive.

What condition is associated with RAG1 p.Ala69fs (c.206del)?

RAG1 p.Ala69fs (c.206del) is associated with severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive, combined immunodeficiency with skin granulomas, combined immunodeficiency due to partial RAG1 deficiency (ClinVar).

How common is RAG1 p.Ala69fs (c.206del) in the general population?

RAG1 p.Ala69fs (c.206del) is no gnomAD frequency available for this variant (gnomAD).

RAG1 p.Ala69fs

Q: How is Severe combined immunodeficiency due to complete RAG1/2 deficiency inherited?

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

c.206del · rs2494750488 · VCV2921388

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive

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 -0.65	GERP -4.8

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.Ala69fs
Coding: c.206del
MANE Select: NM_000448
dbSNP: rs2494750488
Type: Deletion
Location: chr11:36573510 (GRCh38)
Gene constraint: LOEUF 0.703 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.68
Residue 69: 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

severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: combined immunodeficiency with skin granulomas combined immunodeficiency due to partial RAG1 deficiency

For Severe combined immunodeficiency due to complete RAG1/2 deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

RAG1 p.Ala69Gly Uncertain significance ★★ ⚠ same residue
RAG1 p.Lys86fs Pathogenic ★★★ same condition
RAG1 p.Ser259fs Pathogenic ★★★ same condition
RAG1 p.Ala456fs 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
RAG1 p.His379fs 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-ala69fs (accessed [today's date]).

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