Is RAG1 p.Val643fs (c.1908_1926dup) pathogenic?

RAG1 p.Val643fs (c.19081926dup) is classified Pathogenic in RAG1 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-03-24). Very rare (popmax 0.000169%, nfe); Associated with severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive.

How common is RAG1 p.Val643fs (c.1908_1926dup) in the general population?

RAG1 p.Val643fs (c.1908_1926dup) is very rare (popmax 0.000169%, nfe) (gnomAD).

RAG1 p.Val643fs

Q: What condition is associated with RAG1 p.Val643fs (c.1908_1926dup)?

RAG1 p.Val643fs (c.1908_1926dup) is associated with severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive (ClinVar).

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.1908_1926dup · VCV4819696

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

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 1.4	GERP 1.9, phastCons 0.001
Overall
CADD	23.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,180,024 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,614,020 alleles · very rare exomes 1/1,461,880 · genomes 1/152,140 · joint denominator

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.Val643fs
Coding: c.1908_1926dup
MANE Select: NM_000448
Type: Duplication
Location: chr11:36575210 (GRCh38)
Gene constraint: LOEUF 0.703 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.68

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

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.Ile113fs Pathogenic/Likely pathogenic ★★ same condition
RAG1 p.Leu236fs Pathogenic/Likely pathogenic ★★ same condition
RAG1 p.Gly135_Lys136insTer Pathogenic ★ same condition
RAG1 p.Gly854fs Pathogenic ★ same condition
RAG1 p.Met263fs Likely pathogenic ★ same condition
RAG1 p.Leu1025fs Conflicting classifications of pathogenicity ★ same condition
RAG1 p.Ala444Val Pathogenic ★★★ same condition
RAG1 p.Arg108Ter 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-val643fs (accessed [today's date]).

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