Is VAPB p.Cys41fs (c.122_123del) pathogenic?

VAPB p.Cys41fs (c.122123del) is classified Uncertain significance in VAPB (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-06). No gnomAD frequency available for this variant; Associated with amyotrophic lateral sclerosis type 8.

What condition is associated with VAPB p.Cys41fs (c.122_123del)?

VAPB p.Cys41fs (c.122_123del) is associated with amyotrophic lateral sclerosis type 8, adult-onset proximal spinal muscular atrophy, autosomal dominant (ClinVar).

How common is VAPB p.Cys41fs (c.122_123del) in the general population?

VAPB p.Cys41fs (c.122_123del) is no gnomAD frequency available for this variant (gnomAD).

VAPB p.Cys41fs

c.122_123del · rs2516032933 · VCV2942488

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

amyotrophic lateral sclerosis type 8

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 2 of 6
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.9	GERP 1.7, phastCons 1

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: VAPB
Protein: p.Cys41fs
Coding: c.122_123del
MANE Select: NM_004738
dbSNP: rs2516032933
Type: Microsatellite
Location: chr20:58418269 (GRCh38)
Gene constraint: LOEUF 0.699 · pLI 0.52 (gnomAD)
Structure: AlphaFold pLDDT 77.45 · 3 PDB
Residue 41: a β-strand; the msp domain

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

Disease context

amyotrophic lateral sclerosis type 8 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: adult-onset proximal spinal muscular atrophy, autosomal dominant

Similar variants

VAPB p.Cys41Arg Uncertain significance ★ ⚠ same residue
VAPB p.Glu186del Uncertain significance ★ same condition
VAPB p.Ser160del Conflicting classifications of pathogenicity ★ same condition
VAPB c.59-11_59-10del Likely benign ★ same condition
VAPB c.59-16_59-15del Likely benign ★ same condition
VAPB p.Pro56Ser Pathogenic ★★ same condition
VAPB p.Ala104Thr Uncertain significance ★★ ⚠ same condition
VAPB p.Arg182Lys Uncertain significance ★★ ⚠ 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/vapb-p-cys41fs (accessed [today's date]).

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