Is VCP p.Pro665Ser (c.1993C>T) pathogenic?

VCP p.Pro665Ser (c.1993C>T) is classified Uncertain significance in VCP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-02). AlphaMissense: likely pathogenic (0.9357); Absent from gnomAD v4.1; Associated with frontotemporal dementia and/or amyotrophic lateral sclerosis 6.

What condition is associated with VCP p.Pro665Ser (c.1993C>T)?

VCP p.Pro665Ser (c.1993C>T) is associated with frontotemporal dementia and/or amyotrophic lateral sclerosis 6, inclusion body myopathy with Paget disease of bone and frontotemporal dementia (ClinVar).

How common is VCP p.Pro665Ser (c.1993C>T) in the general population?

VCP p.Pro665Ser (c.1993C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about VCP p.Pro665Ser (c.1993C>T)?

AlphaMissense predicts likely pathogenic (score 0.9357) — an in-silico prediction, not a clinical call.

VCP p.Pro665Ser

Q: How is Frontotemporal dementia with motor neuron disease inherited?

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

c.1993C>T · rs2131029246 · VCV1470708

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9357 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

frontotemporal dementia and/or amyotrophic lateral sclerosis 6

Computational evidence

Protein change
AlphaMissense	0.9357	likely pathogenic
REVEL	0.643	indeterminate
SaProt	LLR -13.24	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 0.88, phastCons 1
Regional constraint	o/e 0.47	unconstrained · MANE · 2,398 bp · p 1.2e-13 · regional, not allelic
Overall
CADD	28.8	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

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.Pro665Ser
Coding: c.1993C>T
MANE Select: NM_007126
dbSNP: rs2131029246
Type: single nucleotide variant
Location: chr9:35059504 (GRCh38)
Gene constraint: LOEUF 0.134 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 83.11 · 144 PDB

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

Disease context

frontotemporal dementia and/or amyotrophic lateral sclerosis 6 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: inclusion body myopathy with Paget disease of bone and frontotemporal dementia

For Frontotemporal dementia with motor neuron disease (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.Arg159Cys Pathogenic/Likely pathogenic ★★ same condition
VCP p.Arg159His Pathogenic ★★ same condition
VCP p.Arg191Gln Pathogenic/Likely pathogenic ★★ same condition
VCP p.Arg191Pro Pathogenic/Likely pathogenic ★★ same condition
VCP p.Arg256Gly 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/vcp-p-pro665ser (accessed [today's date]).

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