Is VCP p.Ala232Glu (c.695C>A) pathogenic?

VCP p.Ala232Glu (c.695C>A) is classified Pathogenic in VCP (ClinVar, Single submitter, 2 submitters; last evaluated 2020-08-01). AlphaMissense: likely pathogenic (0.9731); Absent from gnomAD v4.1; Associated with inclusion body myopathy with Paget disease of bone and frontotemporal dementia type 1.

How common is VCP p.Ala232Glu (c.695C>A) in the general population?

VCP p.Ala232Glu (c.695C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about VCP p.Ala232Glu (c.695C>A)?

AlphaMissense predicts likely pathogenic (score 0.9731) — an in-silico prediction, not a clinical call.

VCP p.Ala232Glu

Q: What condition is associated with VCP p.Ala232Glu (c.695C>A)?

VCP p.Ala232Glu (c.695C>A) is associated with inclusion body myopathy with Paget disease of bone and frontotemporal dementia type 1 (ClinVar).

Q: How is Inclusion body myopathy with Paget disease of bone and frontotemporal dementia inherited?

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

c.695C>A · rs121909331 · VCV8470

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9731 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

inclusion body myopathy with Paget disease of bone and frontotemporal dementia type 1

Computational evidence

Protein change
AlphaMissense	0.9731	likely pathogenic ✓ concordant with ClinVar
REVEL	0.489	indeterminate
SaProt	LLR -14.42	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>A here scores Δ0.97 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.25	constrained · MANE · 5,151 bp · p 1.5e-44 · regional, not allelic
Overall
CADD	25.5	PHRED · no single calibrated threshold — expert panels disagree

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

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: VCP
Protein: p.Ala232Glu
Coding: c.695C>A
MANE Select: NM_007126
dbSNP: rs121909331
Type: single nucleotide variant
Location: chr9:35064167 (GRCh38)
Gene constraint: LOEUF 0.134 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 83.11 · 144 PDB
Residue 232: an α-helix; a UniProt-annotated variant site (in ibmpfd1; increased atpase activity; no defect in ubiquitin-dependent protein degradation by the proteasome; impaired autophagic function; defect in maturation of ubiquitin-containing autophagosomes; decreased interaction with cav1 and ubxn6)

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

Disease context

inclusion body myopathy with Paget disease of bone and frontotemporal dementia type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Inclusion body myopathy with Paget disease of bone and frontotemporal dementia (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

VCP p.Arg155Cys Pathogenic/Likely pathogenic ★★ same condition
VCP p.Arg155Gly Pathogenic/Likely pathogenic ★★ same condition
VCP p.Arg155His Pathogenic ★★ ⚠ same condition
VCP p.Arg159His Pathogenic ★★ same condition
VCP p.Arg191Gln Pathogenic/Likely pathogenic ★★ same condition
VCP p.Arg256Gly Likely pathogenic ★★ same condition
VCP p.Arg93Cys Pathogenic ★★ same condition
VCP c.*63G>A 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/vcp-p-ala232glu (accessed [today's date]).

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