Is VAPB p.Ala65= (c.195C>A) pathogenic?

VAPB p.Ala65= (c.195C>A) is classified Likely benign in VAPB (ClinVar, Multiple submitters, 2 submitters; last evaluated 2019-07-11). Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

How common is VAPB p.Ala65= (c.195C>A) in the general population?

VAPB p.Ala65= (c.195C>A) is absent from gnomAD v4.1 (gnomAD).

VAPB p.Ala65=

Q: What condition is associated with VAPB p.Ala65= (c.195C>A)?

VAPB p.Ala65= (c.195C>A) is associated with Inborn genetic diseases, adult-onset proximal spinal muscular atrophy, autosomal dominant, amyotrophic lateral sclerosis type 8 (ClinVar).

c.195C>A · rs1555813003 · VCV534273

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.28	GERP -3, phastCons 0.97
Overall
CADD	7.676	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: VAPB
Protein: p.Ala65=
Coding: c.195C>A
MANE Select: NM_004738
dbSNP: rs1555813003
Type: single nucleotide variant
Location: chr20:58418347 (GRCh38)
Gene constraint: LOEUF 0.699 · pLI 0.52 (gnomAD)
Structure: AlphaFold pLDDT 77.45 · 3 PDB
Residue 65: the msp domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: adult-onset proximal spinal muscular atrophy, autosomal dominant amyotrophic lateral sclerosis type 8

Similar variants

VAPB p.Ala65Thr Uncertain significance ★ ⚠ same residue
VAPB p.Ala65Val 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-ala65 (accessed [today's date]).

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