VCP

Chr 9AD

valosin containing protein

Also known as: CDC48, FTDALS6, TERA, p97

NCBI Gene: 7415 ENSG00000165280 UniProt: P55072 OMIM: 601023

The encoded protein is an AAA ATPase that forms homohexameric complexes to extract ubiquitinated proteins from membranes and protein complexes, functioning in protein degradation, membrane fusion, DNA repair, and cell cycle regulation. Mutations cause autosomal dominant multisystem disorders including inclusion body myopathy with Paget disease and frontotemporal dementia (IBMPFD), Charcot-Marie-Tooth disease type 2Y, and frontotemporal dementia with or without ALS. Pathogenic variants cause loss of function in this highly constrained gene.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

LOFmechanismADLOEUF 0.133 OMIM phenotypes

Clinical Summary— VCP

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Gene-Disease Validity (ClinGen)

inclusion body myopathy with Paget disease of bone and frontotemporal dementia · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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Clinical Trials

5 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint

0.13LOEUF

pLI 1.000

Z-score 5.52

OE 0.03 (0.01–0.13)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint

5.41Z-score

OE missense 0.28 (0.24–0.33)

126 obs / 448.0 exp

Constrained

Extremely missense-constrained (top ~0.01%)

Observed / Expected Ratios

LoF OE0.03 (0.01–0.13)

0≤0.351.4

Missense OE0.28 (0.24–0.33)

0≤0.61.4

Synonymous OE1.12

0≤1.21.6

LoF obs/exp: 1 / 37.5Missense obs/exp: 126 / 448.0Syn Z: -1.16

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedVCP-related developmental disorderLOFAD

0.4388th %ile

GOF

0.3689th %ile

LOF

0.75top 10%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · LOEUF 0.13

DN1 literature citation

GOF1 literature citation

Literature Evidence

DNThese findings support the idea that VCP is associated with the pathomechanism of SALS and familial ALS with a VCP mutation, presumably acting through a dominant-negative mechanism.PMID:25492614

GOFThese results suggest that VCP disease mutants cause IBMPFD through a gain-of-function mechanism, and that VCP inhibitors have therapeutic value.PMID:28322724

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.