Is VCP p.Arg95Ser (c.283C>A) pathogenic?

VCP p.Arg95Ser (c.283C>A) is classified Likely pathogenic in VCP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-12). AlphaMissense: likely pathogenic (0.9693); Absent from gnomAD v4.1; Associated with frontotemporal dementia and/or amyotrophic lateral sclerosis 6.

What condition is associated with VCP p.Arg95Ser (c.283C>A)?

VCP p.Arg95Ser (c.283C>A) 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.Arg95Ser (c.283C>A) in the general population?

VCP p.Arg95Ser (c.283C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about VCP p.Arg95Ser (c.283C>A)?

AlphaMissense predicts likely pathogenic (score 0.9693) — an in-silico prediction, not a clinical call.

VCP p.Arg95Ser

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.283C>A · rs121909332 · VCV2954479

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9693 · 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	0.9693	likely pathogenic ✓ concordant with ClinVar
REVEL	0.605	indeterminate
SaProt	LLR -13.49	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	Δ0.77	donor gain · deltas
Pangolin	Δ0.53	gain · loss 0.12 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 10	GERP 1.7, phastCons 1
Regional constraint	o/e 0.52	unconstrained · MANE · 5,547 bp · p 3e-08 · regional, not allelic
Overall
CADD	36.0	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.Arg95Ser
Coding: c.283C>A
MANE Select: NM_007126
dbSNP: rs121909332
Type: single nucleotide variant
Location: chr9:35067910 (GRCh38)
Gene constraint: LOEUF 0.134 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 83.11 · 144 PDB
Residue 95: a UniProt-annotated variant site (in ibmpfd1; cultured cells expressing the mutant protein show a marked general increase in the level of ubiquitin-conjugated proteins and impaired protein degradation through the endoplasmic reticulum-associated degradation (erad) pathway; shows strongly reduced affinity for adp and increased affinity for atp; abolishes enhancement of k-315 methylation by aspscr1; decreased interaction with cav1 and ubxn6); a β-strand

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.Arg95Gly Pathogenic ★ same residue
VCP p.Arg95His Likely pathogenic ★ ⚠ same residue
VCP p.Arg95Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
VCP p.Arg95Pro Conflicting classifications of pathogenicity ★ ⚠ same residue
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

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-arg95ser (accessed [today's date]).

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