VCP

Chr 9AD

valosin containing protein

Also known as: CDC48, FTDALS6, TERA, p97

NCBI Gene: 7415 ENSG00000165280 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.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a member of the AAA ATPase family of proteins. The encoded protein plays a role in protein degradation, intracellular membrane fusion, DNA repair and replication, regulation of the cell cycle, and activation of the NF-kappa B pathway. This protein forms a homohexameric complex that interacts with a variety of cofactors and extracts ubiquitinated proteins from lipid membranes or protein complexes. Mutations in this gene cause IBMPFD (inclusion body myopathy with paget disease of bone and frontotemporal dementia), ALS (amyotrophic lateral sclerosis) and Charcot-Marie-Tooth disease in human patients. [provided by RefSeq, Aug 2017]

GeneReviews OMIM ResearchGenerating clinical summary…

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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ClinVar Variants

51 unique Pathogenic / Likely Pathogenic· 288 VUS of 789 total submissions

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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 →

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GeneReview available — VCP

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

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 OE?0.03 (0.01–0.13)

0≤0.351.4

Missense OE?0.28 (0.24–0.33)

0≤0.61.4

Synonymous OE?1.12

0≤1.21.6

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

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

moderateVCP-related neurodevelopmental disorderLOFAD

This gene — mechanism propensity

0.4388th %ile

GOF

0.3689th %ile

LOF

0.75top 10%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, gain-of-function and dominant-negative). 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

GOF1 literature citation · 96% of P/LP are missense

DN1 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.1

GOFThese results suggest that VCP disease mutants cause IBMPFD through a gain-of-function mechanism, and that VCP inhibitors have therapeutic value.2

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

References

ClinVar Variant Classifications

789 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic17

Likely Pathogenic34

VUS288

Likely Benign355

Benign37

Conflicting37

Pathogenic

Likely Pathogenic

288

VUS

355

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	16	0	0	17
Likely Pathogenic	1	33	0	0	34
VUS	5	240	37	6	288
Likely Benign	2	1	163	189	355
Benign	0	0	31	6	37
Conflicting	—				37
Total	9	290	231	201	768

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

72 pathogenic / likely-pathogenic (of 83) ClinVar copy-number / structural variants overlap VCP — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →