Is CSTB p.Val41fs (c.121del) pathogenic?

CSTB p.Val41fs (c.121del) is classified Pathogenic in CSTB (ClinVar, Single submitter, 1 submitter; last evaluated 2026-02-04). Very rare (popmax 0.000763%, nfe); Associated with progressive myoclonus epilepsy.

What condition is associated with CSTB p.Val41fs (c.121del)?

CSTB p.Val41fs (c.121del) is associated with progressive myoclonus epilepsy (ClinVar).

How common is CSTB p.Val41fs (c.121del) in the general population?

CSTB p.Val41fs (c.121del) is very rare (popmax 0.000763%, nfe) (gnomAD).

CSTB p.Val41fs

c.121del · rs1257171692 · VCV1455136

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000763%, nfe)

Conditions

progressive myoclonus epilepsy

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 within the last 50 nt of the penultimate exon (2 of 3, 47 nt from its 3' end) — 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 0.14, phastCons 0.023

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000763% European (non-Finnish) · 9/1,180,038 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000558% 9/1,614,194 alleles · very rare exomes 9/1,461,870 · genomes 0/152,324 · 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: CSTB
Protein: p.Val41fs
Coding: c.121del
MANE Select: NM_000100
dbSNP: rs1257171692
Type: Deletion
Location: chr21:43774705 (GRCh38)
Gene constraint: LOEUF 1.681 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 95.81 · 3 PDB
Residue 41: a β-strand

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

Disease context

progressive myoclonus epilepsy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CSTB p.Val41Met Conflicting classifications of pathogenicity ★ ⚠ same residue
CSTB p.Ala49fs Pathogenic ★★ same condition
CSTB p.Asn32del Uncertain significance ★ same condition
CSTB p.Asn84fs Conflicting classifications of pathogenicity ★ same condition
CSTB c.67-1G>C Pathogenic ★★ same condition
CSTB p.Arg68Ter Pathogenic ★★ same condition
CSTB p.Gln22Ter Pathogenic/Likely pathogenic ★★ same condition
CSTB p.Gln46Ter 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/cstb-p-val41fs (accessed [today's date]).

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