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.

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…

Primary Disease Associations & Inheritance

Charcot-Marie-Tooth disease, type 2YMIM #616687

Frontotemporal dementia and/or amyotrophic lateral sclerosis 6MIM #613954

Inclusion body myopathy with early-onset Paget disease and frontotemporal dementia 1MIM #167320

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · inclusion body myopathy with Paget disease of bone and frontotemporal dementia · AD · ClinGen 2021

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

346

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.13

LOEUF· LoF intol.

LOF

Mechanism· G2P

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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

Background carrier burden — how many people carry a rare variant somewhere in VCP?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 180

481 rare PASS variants

Rare truncating (LoF)

1 in 3,700

47 rare PASS variants

Rare synonymous (reference)

1 in 94

425 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for VCP. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 330	1 in 4,200
South Asian	~43k	1 in 320	1 in 5,800
Remaining (unassigned)	~30k	1 in 150	1 in 2,300
European (Finnish)	~27k	1 in 440	≈ 1 in 8,600
Admixed American	~22k	1 in 240	1 in 1,500
African / African American	~21k	1 in 220	1 in 3,100
East Asian	~20k	1 in 210	1 in 1,800
Ashkenazi Jewish	~13k	1 in 370	none seen
Middle Eastern	~2,884	1 in 140	≈ 1 in 2,800

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 16 of 17 coding exons well covered in gnomAD exomes; exon 1 marginal. Genomes: all 17.? see exons ↓