Is VAPB p.Pro35Ser (c.103C>T) pathogenic?

VAPB p.Pro35Ser (c.103C>T) is classified Uncertain significance in VAPB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-30). AlphaMissense: likely pathogenic (0.7996); Very rare (popmax 8.47e-05%, nfe); Associated with adult-onset proximal spinal muscular atrophy, autosomal dominant.

How common is VAPB p.Pro35Ser (c.103C>T) in the general population?

VAPB p.Pro35Ser (c.103C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about VAPB p.Pro35Ser (c.103C>T)?

AlphaMissense predicts likely pathogenic (score 0.7996) — an in-silico prediction, not a clinical call.

VAPB p.Pro35Ser

Q: What condition is associated with VAPB p.Pro35Ser (c.103C>T)?

VAPB p.Pro35Ser (c.103C>T) is associated with adult-onset proximal spinal muscular atrophy, autosomal dominant, amyotrophic lateral sclerosis type 8 (ClinVar).

Q: How is Autosomal dominant adult-onset proximal spinal muscular atrophy inherited?

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

c.103C>T · VCV4792932

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7996 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

adult-onset proximal spinal muscular atrophy, autosomal dominant

Computational evidence

Protein change
AlphaMissense	0.7996	likely pathogenic
REVEL	0.554	indeterminate
SaProt	LLR -11.10	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 2.8, phastCons 1
Regional constraint	o/e 0.67	unconstrained · MANE · 23 kb · p 5.1e-05 · regional, not allelic
Overall
CADD	25.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,030 alleles

Overall 6.2e-05% 1/1,613,980 alleles · very rare exomes 0/1,461,888 · genomes 1/152,092 · 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: VAPB
Protein: p.Pro35Ser
Coding: c.103C>T
MANE Select: NM_004738
Type: single nucleotide variant
Location: chr20:58418255 (GRCh38)
Gene constraint: LOEUF 0.699 · pLI 0.52 (gnomAD)
Structure: AlphaFold pLDDT 77.45 · 3 PDB
Residue 35: the msp domain

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

Disease context

adult-onset proximal spinal muscular atrophy, autosomal dominant — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: amyotrophic lateral sclerosis type 8

For Autosomal dominant adult-onset proximal spinal muscular atrophy (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult, Elderly
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

VAPB p.Pro35= Benign/Likely benign ★★ same residue
VAPB p.Pro35Leu Uncertain significance ★ ⚠ same residue
VAPB p.Pro56Ser Pathogenic ★★ same condition
VAPB p.Ala104Thr Uncertain significance ★★ ⚠ same condition
VAPB p.Arg182Lys Uncertain significance ★★ ⚠ same condition
VAPB p.Asp163Asn Uncertain significance ★★ ⚠ same condition
VAPB p.Asp24Asn Uncertain significance ★★ ⚠ same condition
VAPB p.Asp37Glu 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-pro35ser (accessed [today's date]).

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