Is VCP p.Arg155Pro (c.464G>C) pathogenic?

VCP p.Arg155Pro (c.464G>C) is classified Conflicting classifications of pathogenicity in VCP (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2022-09-27). AlphaMissense: likely pathogenic (0.9834); Absent from gnomAD v4.1; Associated with frontotemporal dementia and/or amyotrophic lateral sclerosis 6.

How common is VCP p.Arg155Pro (c.464G>C) in the general population?

VCP p.Arg155Pro (c.464G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about VCP p.Arg155Pro (c.464G>C)?

AlphaMissense predicts likely pathogenic (score 0.9834) — an in-silico prediction, not a clinical call.

VCP p.Arg155Pro

Q: What condition is associated with VCP p.Arg155Pro (c.464G>C)?

VCP p.Arg155Pro (c.464G>C) is associated with frontotemporal dementia and/or amyotrophic lateral sclerosis 6, inclusion body myopathy with Paget disease of bone and frontotemporal dementia, inclusion body myopathy with Paget disease of bone and frontotemporal dementia type 1 (ClinVar).

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.464G>C · rs121909329 · VCV8472

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9834 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

frontotemporal dementia and/or amyotrophic lateral sclerosis 6

Computational evidence

Protein change
AlphaMissense	0.9834	likely pathogenic
REVEL	0.825	moderately pathogenic-leaning
SaProt	LLR -12.90	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	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	33.0	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.Arg155Pro
Coding: c.464G>C
MANE Select: NM_007126
dbSNP: rs121909329
Type: single nucleotide variant
Location: chr9:35065363 (GRCh38)
Gene constraint: LOEUF 0.134 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 83.11 · 144 PDB
Residue 155: a UniProt-annotated variant site (in ibmpfd1; also in one patient without evidence of paget disease of the bone); a UniProt-annotated variant site (in ftdals6 and ibmpfd1; properly assembles into a hexameric structure; 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; shows normal atpase activity according to pubmed:16321991 while according to pubmed:25878907 and pubmed:25125609 shows increased atpase activity; no defect in ubiquitin-dependent protein degradation by the proteasome; impaired autophagic function; defective maturation of ubiquitin-containing autophagosomes; decreased interaction with cav1 and ubxn6; decreased endosome to lysosome transport via multivesicular body sorting pathway of cav1; decreases the arsenite-induced stress granules (sgs) clearance process); a UniProt-annotated variant site (in ibmpfd1); a UniProt-annotated variant site (in ibmpfd1; impaired autophagic function)

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

For Frontotemporal dementia with motor neuron disease (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

VCP p.Arg155Cys Pathogenic/Likely pathogenic ★★ same residue
VCP p.Arg155Gly Pathogenic/Likely pathogenic ★★ same residue
VCP p.Arg155His Pathogenic ★★ ⚠ same residue
VCP p.Arg155Ser Pathogenic ★ ⚠ same residue
VCP p.Arg155= Benign ★ same residue
VCP p.Arg159Cys Pathogenic/Likely pathogenic ★★ same condition
VCP p.Arg159His Pathogenic ★★ same condition
VCP p.Arg191Gln 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-arg155pro (accessed [today's date]).

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