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VCP

valosin containing protein
5 disorders 3 causative 2 untyped 9p13.3 gene with protein product
HGNC:12666MonarchNCBI Gene 7415ENSG00000165280UniProt P55072OMIM 601023

Aliases: IBMPFD, p97, CDC48, TERA.

Normal function · from ai-gene-review (P55072, commit 79fe13b38970) · AI-generated, not KB evidence

VCP (valosin-containing protein, also known as p97 or CDC48 in yeast) is a highly conserved, abundant homohexameric AAA+ ATPase (EC 3.6.4.6) that functions as a cofactor-programmable protein unfoldase/segregase. It uses ATP hydrolysis to generate mechanical force that extracts or unfolds ubiquitinated client proteins from membranes, chromatin, ribosomes, and macromolecular complexes. Each protomer contains an N-terminal cofactor-binding domain and two tandem ATPase domains (D1 and D2) that form stacked hexameric rings with a central pore for substrate threading. VCP is a central hub for ubiquitin-dependent protein quality control, with core roles in ERAD (via the VCP-UFD1-NPLOC4 complex), autophagosome maturation, stress granule clearance, DNA damage response (including DPC repair and DSB repair), and mitochondrial/lysosomal quality control. Its functional versatility is determined by a large network of cofactors (UFD1-NPL4, UBX-domain proteins, PLAA, SPRTN, etc.) that specify substrates, subcellular targeting, and outcomes. Mutations cause multisystem proteinopathy (IBMPFD1/MSP1), FTDALS6, and CMT2Y.

VCP/p97 hexamer hydrolyzes ATP to power the extraction (retrotranslocation) of ubiquitinated misfolded proteins from the ER membrane for proteasomal degradation. Acts as the VCP-UFD1-NPLOC4 complex, which recognizes K48-linked polyubiquitin chains on ERAD substrates. VCP threads substrates through its central pore, unfolding them in the process. Recruited to the ER membrane via the Derlin-1/VIMP retrotranslocation channel and cooperates with ER-resident E3 ubiquitin ligases (AMFR/gp78, SYVN1/HRD1, RNF185, MARCH6).
molecular function: ATP hydrolysis activity · directly involved in: ERAD pathway; retrograde protein transport, ER to cytosol; protein unfolding; proteasome-mediated ubiquitin-dependent protein catabolic process · locations: cytosol; endoplasmic reticulum membrane · in complex: VCP-NPL4-UFD1 AAA ATPase complex
VCP/p97 hydrolyzes ATP to promote autophagosome maturation and selective autophagy pathways including lysophagy and stress granule clearance. In lysophagy, VCP is recruited to damaged lysosomes via cofactors UBXD1/UBXN6 and PLAA, a process regulated by PTP4A2-mediated dephosphorylation of VCP Tyr805. VCP also functions in stress granule disassembly via ZFAND1-dependent recruitment. IBMPFD disease mutations specifically impair autophagosome maturation while leaving proteasomal degradation relatively intact.
molecular function: ATP hydrolysis activity · directly involved in: autophagosome maturation; macroautophagy; lysophagy; stress granule disassembly · locations: cytosol; cytoplasmic stress granule
VCP/p97 hydrolyzes ATP to extract ubiquitinated proteins from chromatin during the DNA damage response. Key substrates include: (1) L3MBTL1, whose VCP-mediated extraction from DSB sites unmasks H4K20me2 marks to enable 53BP1 recruitment; (2) trapped PARP1, which is SUMOylated by PIAS4 and ubiquitinated by RNF4 before VCP-mediated removal; (3) DNA-protein crosslinks (DPCs) via SPRTN-dependent recruitment. VCP also participates in CMG helicase disassembly during DNA replication termination. Nuclear localization is actively regulated by VCF1/VCF2 cofactors.
molecular function: ATP hydrolysis activity · directly involved in: double-strand break repair; protein-DNA covalent cross-linking repair; negative regulation of protein localization to chromatin; DNA damage response · locations: nucleus; nucleoplasm; site of double-strand break · in complex: VCP-NPL4-UFD1 AAA ATPase complex
VCP/p97 hydrolyzes ATP to extract ubiquitinated outer mitochondrial membrane (OMM) proteins for proteasomal degradation, a process essential for mitochondrial quality control and mitophagy. Following PINK1/Parkin-mediated ubiquitination of OMM substrates (e.g., mitofusins), VCP extracts these proteins to enable mitophagy progression. This function links VCP to IBMPFD/MSP1 pathology, where disease mutations impair mitochondrial clearance.
molecular function: ATP hydrolysis activity · directly involved in: mitophagy; mitochondria-associated ubiquitin-dependent protein catabolic process · locations: cytosol
VCP/p97 participates in ribosome-associated quality control (RQC) by extracting ubiquitinated nascent polypeptides from stalled 60S ribosomal subunits. Works with the RQC complex (LTN1/Listerin E3 ligase, NEMF, ANKZF1) to process stalled translation products for proteasomal degradation. This function ensures clearance of aberrant translation products that could form toxic aggregates.
molecular function: ATP hydrolysis activity · directly involved in: rescue of stalled cytosolic ribosome; ribosome-associated ubiquitin-dependent protein catabolic process · locations: cytosol
In the knowledge base · computed from kb/ at build time

Disorders

Relationship is the entry's genetic[].relationship_type. untyped means the entry has a genetic record for the gene but does not type it; its free-text association is shown instead.

DisorderRelationshipWhere the gene appears
Adams-Oliver Syndrome causative
mechanism: AOS-Associated VCP Variant Effects; VCP Conformational Coupling Defect; VCP Hypermorphic ATPase Activity
subtype: VCP-Associated AOS
scoped to subtype: VCP-Associated AOS
Amyotrophic Lateral Sclerosis causative
mechanism: Impaired Autophagy
subtype: FTDALS6
scoped to subtype: FTDALS6
Charcot-Marie-Tooth Disease Type 2 causative
mechanism: Impaired Autophagy-Lysosome Function
subtype: CMT2Y
scoped to subtype: CMT2Y
Inclusion body myopathy with Paget disease of bone and frontotemporal dementia untyped
Disease-causing germline variants
mechanism: Defective ubiquitin-containing autophagosome maturation; VCP-dependent proteostasis failure
VCP-Associated Multisystem Proteinopathy untyped
Causative
mechanism: VCP Dysfunction and Proteostasis Failure
ClinGen gene–disease validity · snapshot 2026-10-03 · matched to entries by MONDO

An entry matches when ClinGen's MONDO disease is the entry's own disease term, a subtype term, or an exact-match mapping. An amber status marks an entry ClinGen supports the gene for (Definitive, Strong or Moderate) whose own record does not type it. A Limited, Disputed or Refuted tier on such an entry is not a gap.

ClinGen diseaseMOIClassificationdismech entry
inclusion body myopathy with Paget disease of bone and frontotemporal dementia MONDO:0000507 AD Definitive
2021-12-23
Mechanism modules · computed from kb/

Identity from HGNC (snapshot 2026-10-01). Page layers are described in the gene pages documentation.