Is VCP p.Arg155= (c.465T>G) pathogenic?

VCP p.Arg155= (c.465T>G) is classified Benign in VCP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-19). Ultra-rare (popmax 0.0583%, amr); Associated with frontotemporal dementia and/or amyotrophic lateral sclerosis 6.

What condition is associated with VCP p.Arg155= (c.465T>G)?

VCP p.Arg155= (c.465T>G) 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.Arg155= (c.465T>G) in the general population?

VCP p.Arg155= (c.465T>G) is ultra-rare (popmax 0.0583%, amr) (gnomAD).

VCP p.Arg155=

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.465T>G · rs765140312 · VCV1167708

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0583%, amr)

Conditions

frontotemporal dementia and/or amyotrophic lateral sclerosis 6

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1	GERP -3.7, phastCons 0.001
Overall
CADD	7.738	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0583% Admixed American · 35/59,994 alleles

Filtering AF 0.0431% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0378%

Overall 0.00242% 39/1,614,056 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0583%	1,714
European (non-Finnish)	0.000339%	295,011

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: VCP
Protein: p.Arg155=
Coding: c.465T>G
MANE Select: NM_007126
dbSNP: rs765140312
Type: single nucleotide variant
Location: chr9:35065362 (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

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.Arg155Pro Conflicting classifications of pathogenicity ★ ⚠ 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-arg155 (accessed [today's date]).

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