VCP

Summary

VCP (valosin containing protein, HGNC:12666) is a protein-coding gene on chromosome 9p13.3, encoding Transitional endoplasmic reticulum ATPase (P55072). Necessary for the fragmentation of Golgi stacks during mitosis and for their reassembly after mitosis. It is a common-essential gene (DepMap: required in 100.0% of cancer cell lines).

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.

Source: NCBI Gene 7415 — RefSeq curated summary.

At a glance

• Gene–disease (curated): inclusion body myopathy with Paget disease of bone and frontotemporal dementia (Definitive, ClinGen) — +9 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 788 total — 17 pathogenic, 25 likely-pathogenic
• Phenotypes (HPO): 228
• Druggable target: yes — 4 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 100.0% of screened cell lines (common-essential)
• MANE Select transcript: NM_007126

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12666
Approved symbol	VCP
Name	valosin containing protein
Location	9p13.3
Locus type	gene with protein product
Status	Approved
Aliases	IBMPFD, p97, CDC48, TERA
Ensembl gene	ENSG00000165280
Ensembl biotype	protein_coding
OMIM	601023
Entrez	7415

Gene structure

Transcript identifiers

Ensembl transcripts: 46 — 25 protein_coding, 9 nonsense_mediated_decay, 8 retained_intron, 4 protein_coding_CDS_not_defined

ENST00000358901, ENST00000417448, ENST00000448530, ENST00000466100, ENST00000479300, ENST00000480327, ENST00000493886, ENST00000676836, ENST00000677257, ENST00000678018, ENST00000678465, ENST00000678650, ENST00000679204, ENST00000679392, ENST00000679449, ENST00000679599, ENST00000679647, ENST00000679800, ENST00000679862, ENST00000679901, ENST00000679902, ENST00000680079, ENST00000680108, ENST00000680520, ENST00000680575, ENST00000680731, ENST00000680834, ENST00000680900, ENST00000680916, ENST00000681125, ENST00000681335, ENST00000681386, ENST00000681537, ENST00000681562, ENST00000681690, ENST00000681789, ENST00000854254, ENST00000854255, ENST00000854256, ENST00000940607, ENST00000940608, ENST00000969525, ENST00000969526, ENST00000969527, ENST00000969528, ENST00000969529

RefSeq mRNA: 3 — MANE Select: NM_007126 NM_001354927, NM_001354928, NM_007126

CCDS: CCDS6573, CCDS94403

Canonical transcript exons

ENST00000358901 — 17 exons

Exon	Start	End
ENSE00001091832	35062217	35062350
ENSE00001091840	35062003	35062138
ENSE00001552285	35056064	35057222
ENSE00001885505	35072337	35072625
ENSE00003480815	35057376	35057530
ENSE00003519681	35061577	35061689
ENSE00003523069	35062978	35063080
ENSE00003550122	35060313	35060525
ENSE00003566556	35067891	35068063
ENSE00003587441	35066675	35066817
ENSE00003597683	35060801	35060923
ENSE00003601474	35065251	35065381
ENSE00003602981	35064154	35064285
ENSE00003632965	35059064	35059219
ENSE00003633833	35059493	35059801
ENSE00003669115	35061015	35061179
ENSE00003685641	35068251	35068362

Expression profiles

Bgee: expression breadth ubiquitous, 294 present calls, max score 98.92.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 179.5954 / max 876.0762, expressed in 1829 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
100558	166.4367	1829
100557	12.4258	1803
100556	0.7329	476

Top tissues by expression

295 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
stromal cell of endometrium	CL:0002255	98.92	gold quality
adrenal tissue	UBERON:0018303	98.91	gold quality
islet of Langerhans	UBERON:0000006	98.83	gold quality
gastrocnemius	UBERON:0001388	98.76	gold quality
right adrenal gland	UBERON:0001233	98.73	gold quality
right adrenal gland cortex	UBERON:0035827	98.72	gold quality
left adrenal gland	UBERON:0001234	98.63	gold quality
muscle of leg	UBERON:0001383	98.63	gold quality
left adrenal gland cortex	UBERON:0035825	98.56	gold quality
hindlimb stylopod muscle	UBERON:0004252	98.54	gold quality
adrenal gland	UBERON:0002369	98.50	gold quality
minor salivary gland	UBERON:0001830	98.45	gold quality
ventricular zone	UBERON:0003053	98.45	gold quality
smooth muscle tissue	UBERON:0001135	98.42	gold quality
adrenal cortex	UBERON:0001235	98.41	gold quality
adenohypophysis	UBERON:0002196	98.41	gold quality
upper lobe of left lung	UBERON:0008952	98.40	gold quality
ectocervix	UBERON:0012249	98.37	gold quality
skin of leg	UBERON:0001511	98.36	gold quality
right lobe of thyroid gland	UBERON:0001119	98.35	gold quality
heart left ventricle	UBERON:0002084	98.35	gold quality
right atrium auricular region	UBERON:0006631	98.33	gold quality
esophagus mucosa	UBERON:0002469	98.30	gold quality
cardiac ventricle	UBERON:0002082	98.28	gold quality
left lobe of thyroid gland	UBERON:0001120	98.27	gold quality
skin of abdomen	UBERON:0001416	98.26	gold quality
apex of heart	UBERON:0002098	98.23	gold quality
body of uterus	UBERON:0009853	98.23	gold quality
endocervix	UBERON:0000458	98.21	gold quality
gall bladder	UBERON:0002110	98.18	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-7249	no	890.64
E-MTAB-7037	no	653.60
E-ENAD-17	no	227.30
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F1, E2F4, ELF2, ESR1, PBX1, PBX2, TBP

miRNA regulators (miRDB)

54 targeting VCP, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6740-5P	100.00	65.64	932
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-4495	99.82	72.08	3080
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-3680-3P	99.75	72.51	3095
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-4422	99.72	72.07	2908
HSA-MIR-10393-3P	99.72	66.56	961
HSA-MIR-6801-5P	99.72	66.50	981
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-4690-5P	99.65	66.24	813
HSA-MIR-586	99.65	70.40	2051
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-3136-3P	99.57	66.59	781
HSA-MIR-7155-3P	99.57	66.48	794
HSA-MIR-3123	99.47	67.15	2693
HSA-MIR-6513-5P	99.43	67.81	1071
HSA-MIR-548AV-3P	99.43	68.50	1721
HSA-MIR-4318	99.38	66.94	1505
HSA-MIR-888-5P	99.30	70.15	1855
HSA-MIR-3973	99.20	69.19	1990

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 100.0% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 40)

• VCP regulates NFKappaB pathway, which is important for metastasis of osteosarcoma (PMID:11927012)
• p97/VCP is essential for degrading membrane-associated ubiquitinated proteins and that profound deficits in its ATPase activity severely affect ER quality control, leading to abnormal ER expansion and cell death (PMID:12351637)
• VCP expression level has prognostic significance for disease-free and overall survival of patients with HCC (PMID:12560433)
• ataxin-3 associates with the ubiquitin- and proteasome-binding factors Rad23 and valosin-containing protein (VCP/p97) (PMID:12944474)
• valosin-containing protein has a role in progression of colorectal carcinomas (PMID:14760088)
• VCP expression analysis is a useful prognosticator for PENs (pancreatic endocrine neoplasms). (PMID:15452376)
• Valosin-containing protein functionally regulates Dorfin through direct interaction (PMID:15456787)
• A 55-year-old German patient with inclusion body myopathy and frontotemporal dementia who harbors a heterozygous R155C missense mutation residing in the N-terminal CDC48 domain of VCP, which is involved in ubiquitin binding. (PMID:15732117)
• VCP/CDC48 is required for transport of T cell-specific adapter protein into the eukaryotic nucleus (PMID:15752563)
• Functional characterizations indicate that VCP is not an Hsp90 substrate, but rather demonstrate the biochemical hallmarks of an Hsp90 co-chaperone (PMID:15883021)
• p97 does not provide the primary driving force for extracting the cholera toxin A1 chain from the endoplasmic reticulum (PMID:15932873)
• p97/valosin-containing protein ATPase activity is regulated by oxidative modification of the evolutionally conserved cysteine 522 residue in Walker A motif (PMID:16234241)
• We identified a novel missense mutation in the VCP gene segregating with this disease in an Austrian family of four affected siblings, who exhibited progressive proximal myopathy and Paget disease of the bone. (PMID:16247064)
• Results suggest that the D2 domain of valosin-containing protein is involved in aggresome formation. (PMID:16386250)
• VCP-Atx-3 association is a potential target for therapeutic intervention and suggest that it might influence the progression of spinocerebellar ataxia type 3. (PMID:16525503)
• VCP is an essential target of Akt signaling (PMID:16551632)
• valosin-containing protein (VCP) is an integral component of the endoplasmic reticulum associated degradation and cellular stress pathways induced by the unfolded protein response, which destroys the CFTR to cause cystic fibrosis (PMID:16621797)
• Our findings are consistent with the hypothesis that the pathology associated with VCP gene mutations is the result of impairment of ubiquitin-based degradation pathways. (PMID:16783167)
• the PUB domain functions as a p97 binding module in human peptide N-glycanase (PMID:16807242)
• These results indicate that VCP is required for maintenance of normal endoplasmic reticulum structure and function and mediates the degradation of some proteins via the ubiquitin (Ub)-proteasome system. (PMID:16914519)
• VCP knockdown by small interfering RNA eventually deconstructed both the ER and Golgi and interdicted protein trafficking through the secretory pathway to the plasma membrane. (PMID:16966435)
• PBX1 plays a crucial role in valosin-containing protein (VCP) expression and function and the PBX-VCP pathway might be important for cell survival under cytokine stress (PMID:17200190)
• results support the hypothesis that components of the retrotranslocation machinery such as VCP do not interact with CFTR in epithelial cells that endogenously express wild-type CFTR since under normal conditions processing of WT protein is efficient (PMID:17272822)
• p97 can exert unfoldase activity in vitro, provided that a single tyrosine residue is introduced into the D1 pore and that the N domain is deleted. (PMID:17346713)
• These findings indicate that ELF2/NERF promotes VCP transcription and that ELF2/NERF-VCP pathway might be important for cell survival and proliferation under cytokine stress. (PMID:17368566)
• Frontotemporal dementia with inclusion body myopathy and Paget’s disease of bone (IBMPFD) is a rare, autosomal dominant disorder caused by mutations in the gene valosin-containing protein (VCP). (PMID:17457594)
• VCP (valosin-containing protein; p97) has a role in the control of N-glycosylation of proteins in the endoplasmic reticulum (PMID:17493577)
• There is no evidence, that common variants in VCP confer a strong risk to the development of sporadic FTD. (PMID:17618707)
• We have found a novel rare variant within the VCP gene, but we did not find a variant that could explain the linkage signal for LOAD on chromosome 9. (PMID:17622780)
• This study demonstrate that VCP is present in both myonuclei and endothelial cell nuclei in normal human muscle tissue. (PMID:17626287)
• Our study demonstrates that VCP mutations are found in patients of Italian background and may lead to a variable clinical phenotype even within the same kinship. (PMID:17763460)
• SVIP is an endogenous inhibitor of ERAD that acts through regulating the assembly of the gp78-p97/VCP-Derlin1 complex. (PMID:17872946)
• We report a novel heterozygous VCP gene mutation (R159C) in a 69-year-old Italian patient presenting with slowly progressive muscle weakness of the distal upper and proximal lower limbs since the age of 50 years, 18 years later FTD supervened. (PMID:17889967)
• A patient with Inclusion body myopathy with Paget disease of bone and frontotemporal dementia carried a novel heterozygous base pair change, 47832C>T, in the VCP gene that resulted in substitution of an arginine residue by cysteine at position 93 (R93C). (PMID:17907600)
• Novel VCP mutations N387H and L198W in six individuals from two families who presented with proximal muscle weakness at a mean age of diagnosis of 40 years, most losing the ability to walk within a few years of onset. (PMID:17935506)
• VCP-containing protein mediates the endoplasmic reticulum degradation of V2 vasopressin receptors. (PMID:18048502)
• Mutations of the valosin-containing protein gene (VCP) at 9p13 cause inclusion body myopathy associated with Paget’s disease of bone and frontotemporal dementia. (PMID:18166610)
• The interaction of EerI with the p97 complex appears to negatively influence a deubiquitinating process that is mediated by p97-associated deubiquitinating enzymes (PMID:18199748)
• The findings demonstrated that monocytic differentiation and G0/G1 growth arrest in human U937 leukemia cells was accompanied by an increase in VCP/p97 expression and a distinct subcellular distribution to be reverted during retrodifferentiation. (PMID:18279508)
• describes the first Italian family with multiple individuals diagnosed as having IBMPFD and carrying the recurrent R155H mutation. (PMID:18341608)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	vcp	ENSDARG00000020008
mus_musculus	Vcp	ENSMUSG00000028452
rattus_norvegicus	Vcp	ENSRNOG00000034242
drosophila_melanogaster	TER94	FBGN0286784
caenorhabditis_elegans		WBGENE00007352
caenorhabditis_elegans		WBGENE00008053

Paralogs (5): PEX6 (ENSG00000124587), PEX1 (ENSG00000127980), NVL (ENSG00000143748), AFG2A (ENSG00000145375), AFG2B (ENSG00000171763)

Protein

Protein identifiers

Transitional endoplasmic reticulum ATPase — P55072 (reviewed: P55072)

Alternative names: 15S Mg(2+)-ATPase p97 subunit, Valosin-containing protein

All UniProt accessions (22): A0A7I2V2Y2, A0A7I2V540, A0A7I2V5G8, A0A7I2YQJ0, A0A7P0T8A3, A0A7P0T8D3, A0A7P0T8D6, A0A7P0T8Q4, A0A7P0T8Q5, A0A7P0T946, P55072, A0A7P0T971, A0A7P0T9X5, A0A7P0TA22, A0A7P0TAQ1, A0A7P0TAW3, A0A7P0TAY0, A0A7P0TBF1, A0A7P0TBK7, A0A7P0Z4C6, A0A7P0Z4D1, C9JUP7

UniProt curated annotations — full annotation on UniProt →

Function. Necessary for the fragmentation of Golgi stacks during mitosis and for their reassembly after mitosis. Involved in the formation of the transitional endoplasmic reticulum (tER). The transfer of membranes from the endoplasmic reticulum to the Golgi apparatus occurs via 50-70 nm transition vesicles which derive from part-rough, part-smooth transitional elements of the endoplasmic reticulum (tER). Vesicle budding from the tER is an ATP-dependent process. The ternary complex containing UFD1, VCP and NPLOC4 binds ubiquitinated proteins and is necessary for the export of misfolded proteins from the ER to the cytoplasm, where they are degraded by the proteasome. The NPLOC4-UFD1-VCP complex regulates spindle disassembly at the end of mitosis and is necessary for the formation of a closed nuclear envelope. Regulates E3 ubiquitin-protein ligase activity of RNF19A. Component of the VCP/p97-AMFR/gp78 complex that participates in the final step of the sterol-mediated ubiquitination and endoplasmic reticulum-associated degradation (ERAD) of HMGCR. Mediates the endoplasmic reticulum-associated degradation of CHRNA3 in cortical neurons as part of the STUB1-VCP-UBXN2A complex. Involved in endoplasmic reticulum stress-induced pre-emptive quality control, a mechanism that selectively attenuates the translocation of newly synthesized proteins into the endoplasmic reticulum and reroutes them to the cytosol for proteasomal degradation. Involved in clearance process by mediating G3BP1 extraction from stress granules. Also involved in DNA damage response: recruited to double-strand breaks (DSBs) sites in a RNF8- and RNF168-dependent manner and promotes the recruitment of TP53BP1 at DNA damage sites. Recruited to stalled replication forks by SPRTN: may act by mediating extraction of DNA polymerase eta (POLH) to prevent excessive translesion DNA synthesis and limit the incidence of mutations induced by DNA damage. Together with SPRTN metalloprotease, involved in the repair of covalent DNA-protein cross-links (DPCs) during DNA synthesis. Involved in interstrand cross-link repair in response to replication stress by mediating unloading of the ubiquitinated CMG helicase complex. Mediates extraction of PARP1 trapped to chromatin: recognizes and binds ubiquitinated PARP1 and promotes its removal. Required for cytoplasmic retrotranslocation of stressed/damaged mitochondrial outer-membrane proteins and their subsequent proteasomal degradation. Essential for the maturation of ubiquitin-containing autophagosomes and the clearance of ubiquitinated protein by autophagy. Acts as a negative regulator of type I interferon production by interacting with RIGI: interaction takes place when RIGI is ubiquitinated via ‘Lys-63’-linked ubiquitin on its CARD domains, leading to recruit RNF125 and promote ubiquitination and degradation of RIGI. May play a role in the ubiquitin-dependent sorting of membrane proteins to lysosomes where they undergo degradation. May more particularly play a role in caveolins sorting in cells. By controlling the steady-state expression of the IGF1R receptor, indirectly regulates the insulin-like growth factor receptor signaling pathway.

Subunit / interactions. Homohexamer. Forms a ring-shaped particle of 12.5 nm diameter, that displays 6-fold radial symmetry. Part of a ternary complex containing STX5A, NSFL1C and VCP. NSFL1C forms a homotrimer that binds to one end of a VCP homohexamer. The complex binds to membranes enriched in phosphatidylethanolamine-containing lipids and promotes Golgi membrane fusion. Binds to a heterodimer of NPLOC4 and UFD1, binding to this heterodimer inhibits Golgi-membrane fusion. Interaction with VCIP135 leads to dissociation of the complex via ATP hydrolysis by VCP. Part of a ternary complex containing NPLOC4, UFD1 and VCP. Interacts with NSFL1C-like protein p37; the complex has membrane fusion activity and is required for Golgi and endoplasmic reticulum biogenesis. Interacts with SELENOS and SYVN1, as well as with DERL1 (via SHP-box motif), DERL2 and DERL3; which probably transfer misfolded proteins from the ER to VCP. Interacts with SVIP and forms a complex with SVIP and DERL1. Component of a complex required to couple retrotranslocation, ubiquitination and deglycosylation composed of NGLY1, SAKS1, AMFR, VCP and RAD23B. Part of a complex composed of STUB1/CHIP, VCP/p97, CHRNA3, and UBXN2A that modulates the ubiquitination and endoplasmic reticulum-associated degradation (ERAD) of CHRNA3. Within the complex UBXN2A acts as a scaffold protein required for the interaction of CHRNA3 with VCP/p97, this interaction also inhibits CHRNA3 ubiquitination by STUB1/CHIP and subsequently ERAD. Interacts with UBXN2A (via UBX domain); the interaction is required for the interaction of CHRNA3 in the STUB1-VCP-UBXN2A complex. Directly interacts with UBXN4 and RNF19A. Interacts with CASR. Interacts with UBE4B and YOD1. Interacts with clathrin. Interacts with RNF103. Interacts with TRIM13 and TRIM21. Component of a VCP/p97-AMFR/gp78 complex that participates in the final step of the endoplasmic reticulum-associated degradation (ERAD) of HMGCR. Interacts directly with AMFR/gp78 (via its VIM). Interacts with RHBDD1 (via C-terminal domain). Interacts with SPRTN; leading to recruitment to stalled replication forks. Interacts with WASHC5. Interacts with UBOX5. Interacts (via N-terminus) with UBXN7, UBXN8, and probably several other UBX domain-containing proteins (via UBX domains); the interactions are mutually exclusive with VIM-dependent interactions such as those with AMFR and SELENOS. Forms a complex with UBQLN1 and UBXN4. Interacts (via the PIM motif) with RNF31 (via the PUB domain). Interacts with RIGI and RNF125; interaction takes place when RIGI is ubiquitinated via ‘Lys-63’-linked ubiquitin on its CARD domains, leading to recruit RNF125 and promote ubiquitination and degradation of RIGI. Interacts with BAG6. Interacts with UBXN10. Interacts with UBXN6; the interaction with UBXN6 is direct and competitive with UFD1. Forms a ternary complex with CAV1 and UBXN6. Interacts with PLAA, UBXN6 and YOD1; may form a complex involved in macroautophagy. Interacts with ANKZF1. Interacts with ubiquitin-binding protein FAF1. Interacts with ZFAND2B (via VIM motif); the interaction is direct. Interacts with ZFAND1 (via its ubiquitin-like region); this interaction occurs in an arsenite-dependent manner. Interacts with CCDC47. Interacts with UBAC2. Interacts with LMBR1L. Interacts with ATXN3. Interacts with TEX264; bridging VCP to covalent DNA-protein cross-links (DPCs). Interacts with FBXL4.

Subcellular location. Cytoplasm. Cytosol. Endoplasmic reticulum. Nucleus. Stress granule.

Post-translational modifications. Phosphorylated by tyrosine kinases in response to T-cell antigen receptor activation. Phosphorylated in mitotic cells. ISGylated. Methylation at Lys-315 catalyzed by VCPKMT is increased in the presence of ASPSCR1. Lys-315 methylation may decrease ATPase activity. UFMylated al Lys-109; UFMylation enhances the interactions between BECN1 and other components of the PtdIns3K complex and thereby promotes cellular autophagy initiation.

Disease relevance. Inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 1 (IBMPFD1) [MIM:167320] An autosomal dominant disease characterized by disabling muscle weakness clinically resembling to limb girdle muscular dystrophy, osteolytic bone lesions consistent with Paget disease, and premature frontotemporal dementia. Clinical features show incomplete penetrance. The disease is caused by variants affecting the gene represented in this entry. Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 (FTDALS6) [MIM:613954] A neurodegenerative disorder characterized by frontotemporal dementia and/or amyotrophic lateral sclerosis in affected individuals. There is high intrafamilial variation. Frontotemporal dementia (FTD) is characterized by frontal and temporal lobe atrophy associated with neuronal loss, gliosis, and dementia. Patients exhibit progressive changes in social, behavioral, and/or language function. Amyotrophic lateral sclerosis (ALS) is characterized by the death of motor neurons in the brain, brainstem, and spinal cord, resulting in fatal paralysis. FTDALS6 is an autosomal dominant form characterized by onset of ALS or FTD in adulthood. Some patients with the disorder may have features of both diseases. The disease is caused by variants affecting the gene represented in this entry. Charcot-Marie-Tooth disease, axonal, type 2Y (CMT2Y) [MIM:616687] An autosomal dominant, axonal form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Neuropathies of the CMT2 group are characterized by signs of axonal degeneration in the absence of obvious myelin alterations, normal or slightly reduced nerve conduction velocities, and progressive distal muscle weakness and atrophy. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The PIM (PUB-interaction motif) motif mediates interaction with the PUB domain of RNF31.

Similarity. Belongs to the AAA ATPase family.

RefSeq proteins (3): NP_001341856, NP_001341857, NP_009057* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003338	CDC4_N-term_subdom	Domain
IPR003593	AAA+_ATPase	Domain
IPR003959	ATPase_AAA_core	Domain
IPR003960	ATPase_AAA_CS	Conserved_site
IPR004201	Cdc48_dom2	Domain
IPR005938	AAA_ATPase_CDC48	Family
IPR009010	Asp_de-COase-like_dom_sf	Homologous_superfamily
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR029067	CDC48_domain_2-like_sf	Homologous_superfamily
IPR041569	AAA_lid_3	Domain
IPR050168	AAA_ATPase_domain	Family

Pfam: PF00004, PF02359, PF02933, PF17862

Enzyme classification (BRENDA):

• EC 3.6.4.6 — vesicle-fusing ATPase (BRENDA: 26 organisms, 48 substrates, 6 inhibitors, 2 Km, 1 kcat entries)

Substrate kinetics (BRENDA)

2 substrates with measured Km, best-characterized 2. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
MGATP2-	0.62	1
ATP	—	0

Catalyzed reactions (Rhea), 1 shown:

• ATP + H2O = ADP + phosphate + H(+) (RHEA:13065)

UniProt features (173 total): helix 44, strand 42, mutagenesis site 23, sequence variant 19, modified residue 18, turn 11, binding site 4, region of interest 3, cross-link 3, sequence conflict 2, initiator methionine 1, chain 1, short sequence motif 1, compositionally biased region 1

Structure

Experimental structures (PDB)

144 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
5B6C	X-RAY DIFFRACTION	1.55
7PUX	X-RAY DIFFRACTION	1.73
3TIW	X-RAY DIFFRACTION	1.8
4KDL	X-RAY DIFFRACTION	1.81
4KDI	X-RAY DIFFRACTION	1.86
5EPP	X-RAY DIFFRACTION	1.88
3EBB	X-RAY DIFFRACTION	1.9
6G2V	X-RAY DIFFRACTION	1.9
6G2Z	X-RAY DIFFRACTION	1.92
4KO8	X-RAY DIFFRACTION	1.98
3QQ8	X-RAY DIFFRACTION	2
3QWZ	X-RAY DIFFRACTION	2
6G2X	X-RAY DIFFRACTION	2.08
10QQ	ELECTRON MICROSCOPY	2.13
6G2Y	X-RAY DIFFRACTION	2.15
3HU3	X-RAY DIFFRACTION	2.2
3QC8	X-RAY DIFFRACTION	2.2
5DYG	X-RAY DIFFRACTION	2.2
5GLF	X-RAY DIFFRACTION	2.25
10QR	ELECTRON MICROSCOPY	2.3
5FTJ	ELECTRON MICROSCOPY	2.3
9MPQ	ELECTRON MICROSCOPY	2.3
4P0A	X-RAY DIFFRACTION	2.3
5FTK	ELECTRON MICROSCOPY	2.4
7LMY	ELECTRON MICROSCOPY	2.4
9Y09	ELECTRON MICROSCOPY	2.4
9YP8	ELECTRON MICROSCOPY	2.4
5X4L	X-RAY DIFFRACTION	2.4
9Y07	ELECTRON MICROSCOPY	2.41
6G30	X-RAY DIFFRACTION	2.42

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P55072-F1	83.11	0.43

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (4): 521–526; 247–253; 348; 384

Post-translational modifications (21): 2, 3, 7, 13, 37, 315, 436, 462, 502, 505, 668, 668, 702, 754, 770, 775, 787, 805, 8, 18 …

Mutagenesis-validated functional residues (23):

Position	Phenotype
52–55	abolishes interaction with nploc4; when associated with a-110.
53	minor effect on affinity for atp and adp.
86	strongly increased affinity for atp. strongly reduced affinity for adp.
109	impaired ufmylation.
110	abolishes interaction with nploc4; when associated with 52-a–a-55. impaired ufmylation.
113–115	severely reduced binding to derl1.
131	severely reduced binding to derl1.
140	severely reduced binding to derl1.
179	no effect on binding to derl1.
183	severely reduced binding to derl1.
251	impairs erad degradation of hmgcr and does not inhibit interaction with rhbdd1; when associated with q-524.
305	defect in ubiquitin-dependent protein degradation by the proteasome; when associated with q-578.
312	does not affect methylation by vcpkmt.
313	does not affect methylation by vcpkmt.
314	does not affect methylation by vcpkmt.
314	strongly impairs methylation by vcpkmt.
315	abolishes methylation by vcpkmt.
316	does not affect methylation by vcpkmt.
317	does not affect methylation by vcpkmt.
318	does not affect methylation by vcpkmt.
524	impairs catalytic activity of rnf19a toward sod1 mutant. does not inhibit interaction with rhbdd1; when associated with
524	impairs erad degradation of hmgcr; when associated with q-251.
578	does not inhibit interaction with rhbdd1. increased interaction with cav1 and ubxn6. impaired autophagic function. defec

Function

Pathways and Gene Ontology

Reactome pathways

55 pathways

ID	Pathway
R-HSA-110320	Translesion Synthesis by POLH
R-HSA-3371511	HSF1 activation
R-HSA-382556	ABC-family protein mediated transport
R-HSA-532668	N-glycan trimming in the ER and Calnexin/Calreticulin cycle
R-HSA-5358346	Hedgehog ligand biogenesis
R-HSA-5362768	Hh mutants are degraded by ERAD
R-HSA-5678895	Defective CFTR causes cystic fibrosis
R-HSA-5689877	Josephin domain DUBs
R-HSA-5689896	Ovarian tumor domain proteases
R-HSA-6798695	Neutrophil degranulation
R-HSA-8866654	E3 ubiquitin ligases ubiquitinate target proteins
R-HSA-8876725	Protein methylation
R-HSA-8951664	Neddylation
R-HSA-9013407	RHOH GTPase cycle
R-HSA-9646399	Aggrephagy
R-HSA-9678110	Attachment and Entry
R-HSA-9694614	Attachment and Entry
R-HSA-9755511	KEAP1-NFE2L2 pathway
R-HSA-9918487	Dengue Virus Genome Translation and Replication
R-HSA-9931269	AMPK-induced ERAD and lysosome mediated degradation of PD-L1(CD274)
R-HSA-9954709	Ribosome Quality Control (RQC) complex extracts and degrades nascent peptide
R-HSA-110313	Translesion synthesis by Y family DNA polymerases bypasses lesions on DNA template
R-HSA-162582	Signal Transduction
R-HSA-1632852	Macroautophagy
R-HSA-1643685	Disease
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System
R-HSA-194315	Signaling by Rho GTPases
R-HSA-2262752	Cellular responses to stress
R-HSA-3371556	Cellular response to heat stress

MSigDB gene sets: 880 (showing top): GOBP_ENDOPLASMIC_RETICULUM_TO_CYTOSOL_TRANSPORT, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, MULLIGHAN_NPM1_SIGNATURE_3_UP, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_REGULATION_OF_PROTEASOMAL_UBIQUITIN_DEPENDENT_PROTEIN_CATABOLIC_PROCESS, GOBP_LYSOSOMAL_TRANSPORT, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOCC_SECRETORY_GRANULE, ENK_UV_RESPONSE_KERATINOCYTE_UP, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GOBP_ENDOSOME_TO_LYSOSOME_TRANSPORT, GOBP_POSITIVE_REGULATION_OF_PROTEIN_CATABOLIC_PROCESS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_VACUOLAR_TRANSPORT

GO Biological Process (51): DNA repair (GO:0006281), double-strand break repair (GO:0006302), ubiquitin-dependent protein catabolic process (GO:0006511), endoplasmic reticulum to Golgi vesicle-mediated transport (GO:0006888), autophagy (GO:0006914), DNA damage response (GO:0006974), proteasomal protein catabolic process (GO:0010498), positive regulation of mitochondrial membrane potential (GO:0010918), macroautophagy (GO:0016236), protein ubiquitination (GO:0016567), viral genome replication (GO:0019079), NAD+ metabolic process (GO:0019674), translesion synthesis (GO:0019985), endoplasmic reticulum unfolded protein response (GO:0030968), retrograde protein transport, ER to cytosol (GO:0030970), positive regulation of protein-containing complex assembly (GO:0031334), positive regulation of proteasomal ubiquitin-dependent protein catabolic process (GO:0032436), endosome to lysosome transport via multivesicular body sorting pathway (GO:0032510), cellular response to heat (GO:0034605), negative regulation of hippo signaling (GO:0035331), stress granule disassembly (GO:0035617), interstrand cross-link repair (GO:0036297), ERAD pathway (GO:0036503), regulation of apoptotic process (GO:0042981), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), establishment of protein localization (GO:0045184), positive regulation of protein catabolic process (GO:0045732), negative regulation of smoothened signaling pathway (GO:0045879), ATP metabolic process (GO:0046034), regulation of synapse organization (GO:0050807), mitotic spindle disassembly (GO:0051228), endoplasmic reticulum stress-induced pre-emptive quality control (GO:0061857), aggresome assembly (GO:0070842), cellular response to misfolded protein (GO:0071218), flavin adenine dinucleotide catabolic process (GO:0072389), positive regulation of canonical Wnt signaling pathway (GO:0090263), autophagosome maturation (GO:0097352), protein-DNA covalent cross-linking repair (GO:0106300), negative regulation of protein localization to chromatin (GO:0120186), cytoplasm protein quality control (GO:0140455)

GO Molecular Function (21): RNA binding (GO:0003723), ATP binding (GO:0005524), lipid binding (GO:0008289), ATP hydrolysis activity (GO:0016887), protein phosphatase binding (GO:0019903), protein domain specific binding (GO:0019904), polyubiquitin modification-dependent protein binding (GO:0031593), ubiquitin protein ligase binding (GO:0031625), deubiquitinase activator activity (GO:0035800), K48-linked polyubiquitin modification-dependent protein binding (GO:0036435), MHC class I protein binding (GO:0042288), identical protein binding (GO:0042802), ADP binding (GO:0043531), ubiquitin-like protein ligase binding (GO:0044389), ubiquitin-modified protein reader activity (GO:0140036), BAT3 complex binding (GO:1904288), ubiquitin-specific protease binding (GO:1990381), nucleotide binding (GO:0000166), protein binding (GO:0005515), hydrolase activity (GO:0016787), protein-containing complex binding (GO:0044877)

GO Cellular Component (28): cytoplasmic ubiquitin ligase complex (GO:0000153), proteasome complex (GO:0000502), extracellular region (GO:0005576), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), lipid droplet (GO:0005811), cytosol (GO:0005829), cytoplasmic stress granule (GO:0010494), protein-containing complex (GO:0032991), VCP-NPL4-UFD1 AAA ATPase complex (GO:0034098), secretory granule lumen (GO:0034774), azurophil granule lumen (GO:0035578), site of double-strand break (GO:0035861), ciliary transition zone (GO:0035869), ciliary basal body (GO:0036064), Derlin-1 retrotranslocation complex (GO:0036513), intracellular membrane-bounded organelle (GO:0043231), perinuclear region of cytoplasm (GO:0048471), extracellular exosome (GO:0070062), ciliary tip (GO:0097542), glutamatergic synapse (GO:0098978), ficolin-1-rich granule lumen (GO:1904813), ATPase complex (GO:1904949), VCP-NSFL1C complex (GO:1990730), synapse (GO:0045202)

Reactome top-level categories

Rollup of top-18 pathways:

Category	Pathways
Deubiquitination	2
Post-translational protein modification	2
Translesion synthesis by Y family DNA polymerases bypasses lesions on DNA template	1
Cellular response to heat stress	1
Transport of small molecules	1
Asparagine N-linked glycosylation	1
Signaling by Hedgehog	1
Hh mutants abrogate ligand secretion	1
ABC transporter disorders	1
Innate Immune System	1
Protein ubiquitination	1
RHO GTPase cycle	1
Selective autophagy	1
SARS-CoV-1 Infection	1
Early SARS-CoV-2 Infection Events	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
cytoplasm	4
cellular response to stress	2
adenyl ribonucleotide binding	2
binding	2
protein binding	2
intracellular membrane-bounded organelle	2
intracellular anatomical structure	2
endoplasmic reticulum membrane	2
membrane protein complex	2
endoplasmic reticulum protein-containing complex	2
cilium	2
DNA metabolic process	1
DNA damage response	1
DNA repair	1
protein ubiquitination	1
modification-dependent protein catabolic process	1
intercellular transport	1
intracellular transport	1
Golgi vesicle transport	1
catabolic process	1
transmembrane transport	1
process utilizing autophagic mechanism	1
protein catabolic process	1
positive regulation of membrane potential	1
regulation of mitochondrial membrane potential	1
autophagosome assembly	1
autophagy	1
protein modification by small protein conjugation	1
viral process	1
viral life cycle	1
purine nucleotide metabolic process	1
nicotinamide nucleotide metabolic process	1
DNA damage tolerance	1
DNA synthesis involved in DNA replication	1
cellular response to unfolded protein	1
response to endoplasmic reticulum stress	1
intracellular signal transduction	1
protein exit from endoplasmic reticulum	1
ERAD pathway	1

Protein interactions and networks

STRING

6773 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
VCP	UFD1	Q92890	999
VCP	NPLOC4	Q8TAT6	999
VCP	ATXN3	P54252	992
VCP	AMFR	P26442	984
VCP	FAF2	Q96CS3	980
VCP	UBE4B	O95155	979
VCP	UBXN4	Q92575	961
VCP	ANKZF1	Q9H8Y5	961
VCP	UBXN6	Q9BZV1	960
VCP	VCPIP1	Q96JH7	951
VCP	SEL1L	Q9UBV2	947
VCP	ATXN3L	Q9H3M9	944
VCP	SYVN1	Q86TM6	940
VCP	TARDBP	Q13148	938
VCP	NSFL1C	Q9UNZ2	937

IntAct

653 interactions, top by confidence:

A	B	Type	Score
VCP	NSFL1C	psi-mi:“MI:0915”(physical association)	0.970
NSFL1C	VCP	psi-mi:“MI:0915”(physical association)	0.970
VCP	NSFL1C	psi-mi:“MI:0407”(direct interaction)	0.970
VCP	NSFL1C	psi-mi:“MI:2364”(proximity)	0.970
ASPSCR1	VCP	psi-mi:“MI:0915”(physical association)	0.960
VCP	ASPSCR1	psi-mi:“MI:0915”(physical association)	0.960
VCP	UBXN6	psi-mi:“MI:0915”(physical association)	0.960
UBXN6	VCP	psi-mi:“MI:0914”(association)	0.960
ASPSCR1	VCP	psi-mi:“MI:0914”(association)	0.960
ASPSCR1	VCP	psi-mi:“MI:2364”(proximity)	0.960
VCP	UBXN6	psi-mi:“MI:2364”(proximity)	0.960
UBXN6	VCP	psi-mi:“MI:2364”(proximity)	0.960
NPLOC4	VCP	psi-mi:“MI:0915”(physical association)	0.950
VCP	UBXN2B	psi-mi:“MI:0915”(physical association)	0.910
UBXN2B	VCP	psi-mi:“MI:0915”(physical association)	0.910
UBXN2B	VCP	psi-mi:“MI:2364”(proximity)	0.910
VCP	VCP	psi-mi:“MI:0915”(physical association)	0.880
VCP	VCP	psi-mi:“MI:0407”(direct interaction)	0.880

BioGRID (2589): VCP (Affinity Capture-MS), VCP (Reconstituted Complex), VCP (Co-fractionation), VCP (Reconstituted Complex), VCP (Co-crystal Structure), VCP (Affinity Capture-MS), VCP (Affinity Capture-MS), VCP (Affinity Capture-Western), AMFR (Two-hybrid), NSFL1C (Two-hybrid), AMFR (Reconstituted Complex), NSFL1C (Reconstituted Complex), VCP (Protein-peptide), VCP (Protein-peptide), VCP (Reconstituted Complex)

ESM2 similar proteins: B4F6J6, D0FH76, F6QV99, O75351, P03974, P18708, P23787, P28737, P46459, P46460, P46461, P46462, P46467, P52917, P54351, P54609, P54774, P54811, P54812, P54815, P55072, Q01853, Q09803, Q0DGP6, Q0VD48, Q3ZBT1, Q503W7, Q505J9, Q54PT2, Q5AG40, Q5R410, Q5R658, Q6GL04, Q75JI3, Q793F9, Q7KN62, Q7ZU99, Q7ZZ25, Q8NBU5, Q8VEJ9

Diamond homologs: A0A061IR73, A0A7N9VSG0, A4G0S4, A6UQT3, A6VHR1, A7YSY2, A9A916, C4QXI8, C4R6C2, D1CDT8, D4A2B7, G1X4S3, G1X7C7, G3GXG9, O05209, O13764, O14325, O15381, O18413, O26824, O28303, O28972, O43933, O60058, O74941, P03974, P23787, P24004, P25694, P32794, P33289, P33760, P34124, P36966, P41836, P46462, P46463, P46468, P54609, P54774

SIGNOR signaling

25 interactions.

A	Effect	B	Mechanism
AKT	up-regulates	VCP	phosphorylation
PTPN3	“down-regulates activity”	VCP	dephosphorylation
VCP	“up-regulates activity”	NPLOC4	binding
VCP	“up-regulates activity”	UFD1	binding
AKT1	up-regulates	VCP	phosphorylation
ELF2	“up-regulates quantity by expression”	VCP	“transcriptional regulation”
VCP	“down-regulates quantity by destabilization”	DDX58	ubiquitination
UBXN8	“down-regulates quantity”	VCP	relocalization
VCP	“up-regulates activity”	NGLY1	binding
SELENOS	“up-regulates activity”	VCP	binding
VCP	“up-regulates activity”	DERL1	binding
PTPRO	“down-regulates activity”	VCP	dephosphorylation
METTL21C	“up-regulates activity”	VCP	methylation
VCP	“down-regulates activity”	AURKA	binding
CB-5083	“down-regulates activity”	VCP	“chemical inhibition”
ML240	“down-regulates activity”	VCP	“chemical inhibition”
2-(2H-Benzo[b][1,4]oxazin-4(3H)-yl)-N-benzyl-5,6,7,8-tetrahydroquinazolin-4-amine	“down-regulates activity”	VCP	“chemical inhibition”
N2,N4-Dibenzylquinazoline-2,4-diamine	“down-regulates activity”	VCP	“chemical inhibition”
VCPIP1	“up-regulates activity”	VCP	binding
VCP	“form complex”	“RQC complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 105 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Aggrephagy	6	21.0×	7e-05
Defective CFTR causes cystic fibrosis	6	18.6×	1e-04
Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha	6	16.6×	2e-04
The role of GTSE1 in G2/M progression after G2 checkpoint	7	15.9×	7e-05
Ubiquitin-Mediated Degradation of Phosphorylated Cdc25A	5	14.4×	1e-03
Activation of NF-kappaB in B cells	5	13.9×	1e-03
AMPK-induced ERAD and lysosome mediated degradation of PD-L1(CD274)	5	13.6×	1e-03
Kinesins	5	12.6×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
ERAD pathway	11	21.4×	1e-09
proteasome-mediated ubiquitin-dependent protein catabolic process	18	10.1×	1e-10
ubiquitin-dependent protein catabolic process	9	7.2×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

788 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	17
Likely pathogenic	25
Uncertain significance	288
Likely benign	340
Benign	37

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1457378	NM_007126.5(VCP):c.472A>G (p.Met158Val)	Pathogenic
1457379	NM_007126.5(VCP):c.469G>A (p.Gly157Arg)	Pathogenic
1457380	NM_007126.5(VCP):c.463C>A (p.Arg155Ser)	Pathogenic
2051539	NM_007126.5(VCP):c.266G>A (p.Arg89Gln)	Pathogenic
217877	NM_007126.5(VCP):c.271A>T (p.Asn91Tyr)	Pathogenic
218306	NM_007126.5(VCP):c.290G>A (p.Gly97Glu)	Pathogenic
2444456	NM_007126.5(VCP):c.1874G>C (p.Arg625Pro)	Pathogenic
30152	NM_007126.5(VCP):c.475C>G (p.Arg159Gly)	Pathogenic
30153	NM_007126.5(VCP):c.1774G>A (p.Asp592Asn)	Pathogenic
4198558	NM_007126.5(VCP):c.1951_1952insTG (p.Lys651fs)	Pathogenic
4539954	NM_007126.5(VCP):c.784A>G (p.Thr262Ala)	Pathogenic
593071	NM_007126.5(VCP):c.277C>T (p.Arg93Cys)	Pathogenic
8468	NM_007126.5(VCP):c.464G>A (p.Arg155His)	Pathogenic
8470	NM_007126.5(VCP):c.695C>A (p.Ala232Glu)	Pathogenic
8471	NM_007126.5(VCP):c.283C>G (p.Arg95Gly)	Pathogenic
8474	NM_007126.5(VCP):c.476G>A (p.Arg159His)	Pathogenic
871718	NM_007126.5(VCP):c.469G>C (p.Gly157Arg)	Pathogenic
1038018	NM_007126.5(VCP):c.577-2A>G	Likely pathogenic
1403085	NM_007126.5(VCP):c.273C>G (p.Asn91Lys)	Likely pathogenic
1496153	NM_007126.5(VCP):c.273C>A (p.Asn91Lys)	Likely pathogenic
1513178	NM_007126.5(VCP):c.284G>A (p.Arg95His)	Likely pathogenic
2028838	NM_007126.5(VCP):c.382G>A (p.Gly128Ser)	Likely pathogenic
218305	NM_007126.5(VCP):c.553G>A (p.Glu185Lys)	Likely pathogenic
2438516	NM_007126.5(VCP):c.478G>A (p.Ala160Thr)	Likely pathogenic
2582678	NM_007126.5(VCP):c.753G>T (p.Lys251Asn)	Likely pathogenic
2582679	NM_007126.5(VCP):c.766C>G (p.Arg256Gly)	Likely pathogenic
2582681	NM_007126.5(VCP):c.1084C>T (p.Arg362Cys)	Likely pathogenic
2582682	NM_007126.5(VCP):c.1622C>A (p.Ser541Tyr)	Likely pathogenic
2584478	NM_007126.5(VCP):c.742G>A (p.Gly248Arg)	Likely pathogenic
2659168	NM_007126.5(VCP):c.166A>G (p.Thr56Ala)	Likely pathogenic

SpliceAI

2347 predictions. Top by Δscore:

Variant	Effect	Δscore
9:35057372:TTACC:T	donor_loss	1.0000
9:35057373:TACC:T	donor_loss	1.0000
9:35057374:A:AC	donor_gain	1.0000
9:35057374:AC:A	donor_gain	1.0000
9:35057375:C:CC	donor_gain	1.0000
9:35057375:CC:C	donor_gain	1.0000
9:35057431:T:TA	donor_gain	1.0000
9:35057526:ACCTC:A	acceptor_gain	1.0000
9:35057527:CCTCC:C	acceptor_gain	1.0000
9:35057528:CTC:C	acceptor_gain	1.0000
9:35057529:TC:T	acceptor_gain	1.0000
9:35057530:CC:C	acceptor_gain	1.0000
9:35057530:CCT:C	acceptor_loss	1.0000
9:35057531:C:CC	acceptor_gain	1.0000
9:35057533:A:AC	acceptor_gain	1.0000
9:35057533:A:C	acceptor_gain	1.0000
9:35057537:T:C	acceptor_gain	1.0000
9:35057537:T:TC	acceptor_gain	1.0000
9:35059060:TCA:T	donor_loss	1.0000
9:35059061:CA:C	donor_loss	1.0000
9:35059062:A:AC	donor_gain	1.0000
9:35059062:A:AT	donor_loss	1.0000
9:35059063:C:CC	donor_gain	1.0000
9:35059216:CATC:C	acceptor_gain	1.0000
9:35059217:ATCC:A	acceptor_loss	1.0000
9:35059220:C:CC	acceptor_gain	1.0000
9:35059220:CTAAA:C	acceptor_loss	1.0000
9:35059221:T:C	acceptor_loss	1.0000
9:35059520:AG:A	donor_gain	1.0000
9:35060307:GCTCA:G	donor_loss	1.0000

AlphaMissense

5307 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:35057406:A:G	L762P	1.000
9:35057416:C:G	A759P	1.000
9:35057417:A:C	F758L	1.000
9:35057417:A:T	F758L	1.000
9:35057418:A:C	F758C	1.000
9:35057418:A:G	F758S	1.000
9:35057419:A:G	F758L	1.000
9:35057451:A:T	V747D	1.000
9:35057454:G:A	S746F	1.000
9:35057463:G:T	A743E	1.000
9:35059116:A:T	I703N	1.000
9:35059125:C:G	R700P	1.000
9:35059128:A:T	I699N	1.000
9:35059131:G:T	A698D	1.000
9:35059132:C:G	A698P	1.000
9:35059146:C:G	R693P	1.000
9:35059164:A:G	L687P	1.000
9:35059167:T:A	D686V	1.000
9:35059167:T:C	D686G	1.000
9:35059168:C:A	D686Y	1.000
9:35059168:C:G	D686H	1.000
9:35059170:G:T	A685D	1.000
9:35059171:C:G	A685P	1.000
9:35059173:C:T	G684E	1.000
9:35059174:C:G	G684R	1.000
9:35059174:C:T	G684R	1.000
9:35059176:G:A	S683F	1.000
9:35059176:G:T	S683Y	1.000
9:35059539:C:G	R653P	1.000
9:35059554:G:T	P648H	1.000

dbSNP variants (sampled 300 via entrez): RS1000062677 (9:35073292 A>G), RS1000496477 (9:35059103 A>C), RS1000604373 (9:35065856 T>A,C), RS1000843787 (9:35068422 A>G), RS1000908156 (9:35055706 T>C), RS1001011267 (9:35065600 A>T), RS1001065261 (9:35061601 C>G), RS1001123172 (9:35071502 A>C,G), RS1001129521 (9:35066516 G>A,C), RS1001219284 (9:35067153 A>T), RS1001784549 (9:35072135 G>A,C,T), RS1001808178 (9:35059950 T>C), RS1001911107 (9:35064910 C>T), RS1002012004 (9:35058798 A>C), RS1002149588 (9:35071135 A>C)

Disease associations

OMIM: gene MIM:601023 | disease phenotypes: MIM:167320, MIM:613954, MIM:227650, MIM:616687, MIM:127750, MIM:608030

GenCC curated gene-disease

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Definitive	Autosomal dominant
inclusion body myopathy with Paget disease of bone and frontotemporal dementia	Definitive	Autosomal dominant
frontotemporal dementia and/or amyotrophic lateral sclerosis 6	Strong	Autosomal dominant
inclusion body myopathy with Paget disease of bone and frontotemporal dementia type 1	Strong	Autosomal dominant
Charcot-Marie-Tooth disease type 2Y	Strong	Autosomal dominant
frontotemporal dementia with motor neuron disease	Supportive	Autosomal dominant
spastic paraplegia-Paget disease of bone syndrome	Supportive	Autosomal dominant
adult-onset distal myopathy due to VCP mutation	Supportive	Autosomal dominant
amyotrophic lateral sclerosis	Supportive	Autosomal dominant
neurodevelopmental disorder	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
inclusion body myopathy with Paget disease of bone and frontotemporal dementia	Definitive	AD

Mondo (15): inclusion body myopathy with Paget disease of bone and frontotemporal dementia (MONDO:0000507), frontotemporal dementia and/or amyotrophic lateral sclerosis 6 (MONDO:0013501), Fanconi anemia (MONDO:0019391), neurodevelopmental disorder (MONDO:0700092), inclusion body myopathy with Paget disease of bone and frontotemporal dementia type 1 (MONDO:0008178), Charcot-Marie-Tooth disease type 2Y (MONDO:0014735), amyotrophic lateral sclerosis (MONDO:0004976), intellectual disability (MONDO:0001071), Alzheimer disease (MONDO:0004975), Lewy body dementia (MONDO:0007488), amyotrophic lateral sclerosis type 6 (MONDO:0011951), complex neurodevelopmental disorder (MONDO:0100038), frontotemporal dementia with motor neuron disease (MONDO:0017161), spastic paraplegia-Paget disease of bone syndrome (MONDO:0018005), adult-onset distal myopathy due to VCP mutation (MONDO:0018006)

Orphanet (9): Frontotemporal dementia with motor neuron disease (Orphanet:275872), Inclusion body myopathy with Paget disease of bone and frontotemporal dementia (Orphanet:52430), Amyotrophic lateral sclerosis (Orphanet:803), Fanconi anemia (Orphanet:84), Autosomal dominant Charcot-Marie-Tooth disease type 2Y (Orphanet:435387), Early-onset autosomal dominant Alzheimer disease (Orphanet:1020), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658), NON RARE IN EUROPE: Alzheimer disease (Orphanet:238616), NON RARE IN EUROPE: Dementia with Lewy body (Orphanet:1648)

HPO phenotypes

228 total (30 of 228 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000020	Urinary incontinence
HP:0000217	Xerostomia
HP:0000474	Thickened nuchal skin fold
HP:0000508	Ptosis
HP:0000518	Cataract
HP:0000605	Supranuclear gaze palsy
HP:0000708	Atypical behavior
HP:0000709	Psychosis
HP:0000710	Hyperorality
HP:0000711	Restlessness
HP:0000712	Emotional lability
HP:0000716	Depression
HP:0000718	Aggressive behavior
HP:0000719	Inappropriate behavior
HP:0000723	Restrictive behavior
HP:0000726	Dementia
HP:0000733	Motor stereotypy
HP:0000734	Disinhibition
HP:0000737	Irritability
HP:0000738	Hallucinations
HP:0000739	Anxiety
HP:0000741	Apathy
HP:0000751	Personality changes
HP:0000757	Lack of insight
HP:0000762	Decreased nerve conduction velocity
HP:0000925	Abnormality of the vertebral column
HP:0001249	Intellectual disability
HP:0001257	Spasticity
HP:0001258	Spastic paraplegia

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST006295_6	Response to quetiapine in schizophrenia	3.000000e-06

MeSH disease descriptors (8)

Descriptor	Name	Tree numbers
D000544	Alzheimer Disease	C10.228.140.380.100; C10.574.945.249; F03.615.400.100
D000690	Amyotrophic Lateral Sclerosis	C10.228.854.139; C10.574.562.250; C10.574.950.050; C10.668.467.250; C18.452.845.800.050
D005199	Fanconi Anemia	C15.378.050.085.080.280; C15.378.190.223.500.500.280; C16.320.077.280; C18.452.284.280
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065886	Neurodevelopmental Disorders	F03.625
C567699	Amyotrophic Lateral Sclerosis 6, Autosomal Recessive (supp.)
C566288	Frontotemporal Dementia With Motor Neuron Disease (supp.)
C563476	Inclusion Body Myopathy With Early-Onset Paget Disease And Frontotemporal Dementia (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1075145 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

4 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 220,947 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL104	CLOTRIMAZOLE	4	56,325
CHEMBL182	GANCICLOVIR	4	138,136
CHEMBL496	HEXACHLOROPHENE	4	26,164
CHEMBL3747513	CB-5083	1	322

PharmGKB: 1 entry (VIP=true, CPIC=false)

Binding affinities (BindingDB)

30 measured of 160 human assays (164 total across all organisms); most potent 30 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
HEXACHLOROPHENE	IC50	98.3 nM
N-[2-(4-butan-2-ylpiperazin-1-yl)ethyl]-1-[3-(1H-indol-2-yl)phenyl]piperidin-4-amine	IC50	110 nM	US-11247985: Phenyl indole allosteric inhibitors of P97 ATPase
1-[3-(1H-indol-2-yl)phenyl]-N-[2-[(3S,5R)-3,4,5-trimethylpiperazin-1-yl]ethyl]piperidin-4-amine	IC50	140 nM	US-11247985: Phenyl indole allosteric inhibitors of P97 ATPase
N-[3-(4-butan-2-ylpiperazin-1-yl)propyl]-1-[3-(1H-indol-2-yl)phenyl]piperidin-4-amine	IC50	640 nM	US-11247985: Phenyl indole allosteric inhibitors of P97 ATPase
(1S,5R)-N-[1-[3-(1H-indol-2-yl)phenyl]piperidin-4-yl]-9-methyl-9-azabicyclo[3.3.1]nonan-3-amine	IC50	1300 nM	US-11247985: Phenyl indole allosteric inhibitors of P97 ATPase
Cephalochromin	IC50	1490 nM
1,3,6-Trimethyl-1H-pyrimido[5,4-e][1,2,4]triazine-5,7-dione	EC50	1610 nM
2-(3-(5,7-dihydroxy-2-(4-hydroxyphenyl)-4-oxo-4H-chromen-8-yl)-4-hydroxyphenyl)-5,7-dihydroxy-4H-chromen-4-one	IC50	1630 nM
2-[[4-(2,4-dichlorobenzyl)oxybenzylidene]amino]guanidine	EC50	1910 nM
4-(4-(2,4-dihydroxyphenyl)thiazol-2-ylamino)benzenesulfonamide	EC50	2300 nM
2-chloranyl-4-[5-[(Z)-2-[(5-methyl-1H-1,2,4-triazol-3-yl)sulfanyl]-3-oxidanyl-3-oxidanylidene-prop-1-enyl]furan-2-yl]benzoic acid	IC50	2350 nM
5-Amino-4-cyano-3-methyl-thiophene-2-carboxylic acid (2-methoxy-naphthalen-1-ylmethylene)-hydrazide	IC50	2580 nM
4-({[4-(2-fluorophenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinolin-8-yl]sulfonyl}amino)benzoic acid	IC50	2580 nM
2-[(6,7-dihydroxy-2-keto-chromen-4-yl)methylthio]-3-(3-methoxyphenyl)quinazolin-4-one	IC50	2720 nM
2-(5-chloranyl-1-ethyl-3-nitro-6-oxidanylidene-pyridazin-4-yl)-2-[5-(trifluoromethyl)-1,3-benzothiazol-2-yl]ethanenitrile	IC50	3870 nM
(1R,19R,21S,22R,23R)-6,7,8,11,12,13,22,23-octahydroxy-3,16-dioxo-2,17,20-trioxatetracyclo[17.3.1.0^{4,9}.0^{10,15}]tricosa-4(9),5,7,10,12,14-hexaen-21-yl 3,4,5-trihydroxybenzoate	IC50	4480 nM
(4Z)-4-[[(7-chloro-4-quinolinyl)hydrazo]methylidene]-2-hydroxy-1-cyclohexa-2,5-dienone	IC50	4730 nM
(5Z)-5-[(2-phenyl-1H-indol-3-yl)methylene]-2-thioxo-thiazolidin-4-one	IC50	4970 nM
MLS000068755	IC50	6150 nM
2-[3-[4-[(4-propan-2-ylcyclohexyl)amino]piperidin-1-yl]phenyl]-1H-indole-5-carbonitrile	IC50	6200 nM	US-11247985: Phenyl indole allosteric inhibitors of P97 ATPase
(6E)-5-azanylidene-6-[(4-oxidanylidenechromen-3-yl)methylidene]-2-pyridin-4-yl-[1,3,4]thiadiazolo[3,2-a]pyrimidin-7-one	IC50	11100 nM
(6Z)-5-imino-3-(isobutylsulfonyl)-6-[(2-methyl-1H-indol-3-yl)methylene]-5,6-dihydro-7H-[1,2,4]thiadiazolo[4,5-a]pyrimidin-7-one	IC50	12300 nM
2-[1-hydroxy-4-[(3-nitrophenyl)sulfonylamino]naphthalen-2-yl]sulfanylacetic acid	IC50	13600 nM
1-[3-(1H-indol-2-yl)phenyl]-N-[2-[4-(2,2,2-trifluoro-1-phenylethyl)piperazin-1-yl]ethyl]piperidin-4-amine	IC50	17000 nM	US-11247985: Phenyl indole allosteric inhibitors of P97 ATPase
(6Z)-5-imino-6-[(2-methyl-1H-indol-3-yl)methylene]-3-(methylthio)-5,6-dihydro-7H-[1,2,4]thiadiazolo[4,5-a]pyrimidin-7-one	IC50	21700 nM
2-N,4-N-dibenzylquinazoline-2,4-diamine;hydrochloride	EC50	30000 nM
4-Isopropyl-2,3-dihydro-1H-6-thia-5,8,10-triaza-cyclopenta[c]fluorene-7-thiol	IC50	42200 nM
GOSSYPOL ACETATE	IC50	50000 nM
3-(2-fluoren-9-ylidenehydrazinyl)benzoic acid	IC50	50000 nM
2-chloranyl-1-[(5E)-5-[[2-(2-chlorophenyl)hydrazinyl]methylidene]pyrrol-3-yl]ethanone	EC50	96900 nM

ChEMBL bioactivities

652 potent at pChembl≥5 of 723 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.46	IC50	0.35	nM	CHEMBL5420815
9.44	IC50	0.36	nM	CHEMBL5414874
8.87	IC50	1.34	nM	CHEMBL5423427
8.44	IC50	3.65	nM	CHEMBL5431792
8.36	IC50	4.39	nM	CHEMBL5420985
8.22	IC50	6	nM	CHEMBL3747448
8.15	IC50	7	nM	CHEMBL4450581
8.15	IC50	7	nM	CHEMBL5206855
8.14	IC50	7.19	nM	CHEMBL5402707
8.13	IC50	7.36	nM	CHEMBL5428666
8.10	IC50	8	nM	CHEMBL4476693
8.10	IC50	7.9	nM	CHEMBL5416704
8.09	IC50	8.07	nM	CHEMBL5430557
8.08	IC50	8.39	nM	CHEMBL5396390
8.07	IC50	8.5	nM	CHEMBL5405131
8.01	IC50	9.7	nM	CHEMBL5407869
7.97	IC50	10.68	nM	CHEMBL5412755
7.96	IC50	11	nM	CB-5083
7.96	IC50	11	nM	CHEMBL2311578
7.96	IC50	11	nM	CHEMBL5399073
7.92	IC50	12.09	nM	CHEMBL5423222
7.92	IC50	12	nM	CHEMBL5441034
7.89	IC50	12.8	nM	CHEMBL5400122
7.86	IC50	13.86	nM	CHEMBL5402810
7.85	IC50	14.1	nM	CHEMBL5415375
7.83	IC50	14.61	nM	CHEMBL5417192
7.82	IC50	15	nM	CHEMBL3746179
7.82	IC50	15	nM	CHEMBL5397160
7.82	IC50	15	nM	CHEMBL4280801
7.82	IC50	15	nM	CHEMBL6064283
7.81	IC50	15.52	nM	CHEMBL5439553
7.80	IC50	15.9	nM	CHEMBL5410189
7.78	IC50	16.64	nM	CHEMBL5428726
7.77	IC50	17	nM	CHEMBL5419713
7.75	IC50	17.8	nM	CHEMBL5410787
7.73	Ki	18.6	nM	CHEMBL4555451
7.73	IC50	18.57	nM	CHEMBL5401866
7.72	IC50	19.24	nM	CHEMBL5422395
7.71	IC50	19.67	nM	CHEMBL5433632
7.70	IC50	20	nM	CHEMBL4280801
7.70	IC50	20	nM	CHEMBL4280125
7.70	IC50	20	nM	CHEMBL2311578
7.70	IC50	20	nM	CHEMBL5402777
7.68	Ki	20.8	nM	CHEMBL4553677
7.68	IC50	21	nM	CHEMBL5414510
7.64	IC50	23	nM	CHEMBL3747049
7.64	IC50	22.78	nM	CHEMBL5425652
7.64	IC50	23	nM	CHEMBL5426088
7.62	IC50	24	nM	CHEMBL2311578
7.62	Ki	24.1	nM	CHEMBL4535337

PubChem BioAssay actives

509 with measured affinity, of 783 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
N-[2-(2-ethoxyethoxy)-5-(1H-imidazol-2-yl)phenyl]-3-(3-fluorophenyl)prop-2-ynamide	1973620: Covalent inhibition of p97 (unknown origin) ATPase activity incubated for 60 mins in presence of ATP by Biomol Green Reagent based microplate reader analysis	ic50	0.0003	uM
3-(3-chlorophenyl)-N-[2-(2-ethoxyethoxy)-5-(1H-imidazol-2-yl)phenyl]prop-2-ynamide	1973620: Covalent inhibition of p97 (unknown origin) ATPase activity incubated for 60 mins in presence of ATP by Biomol Green Reagent based microplate reader analysis	ic50	0.0004	uM
N-[2-(2-ethoxyethoxy)-5-(1H-imidazol-2-yl)phenyl]-3-(4-fluorophenyl)prop-2-ynamide	1973620: Covalent inhibition of p97 (unknown origin) ATPase activity incubated for 60 mins in presence of ATP by Biomol Green Reagent based microplate reader analysis	ic50	0.0013	uM
N-[5-(1H-imidazol-2-yl)-2-[(4-methylphenyl)methoxy]phenyl]-3-phenylprop-2-ynamide	1973620: Covalent inhibition of p97 (unknown origin) ATPase activity incubated for 60 mins in presence of ATP by Biomol Green Reagent based microplate reader analysis	ic50	0.0037	uM
N-[2-(cyclopropylmethoxy)-5-(1H-imidazol-2-yl)phenyl]-3-phenylprop-2-ynamide	1973620: Covalent inhibition of p97 (unknown origin) ATPase activity incubated for 60 mins in presence of ATP by Biomol Green Reagent based microplate reader analysis	ic50	0.0044	uM
1-[4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl]-2-methylindole-4-carboxamide	1266910: Inhibition of human p97 ATPase incubated for 15 mins by ADP Glo luminescence assay	ic50	0.0060	uM
3-[4-[(5-cyclopentylsulfanyl-4-pyridin-3-yl-1,2,4-triazol-3-yl)methoxy]-2-methylphenyl]-N-propan-2-ylprop-2-yn-1-amine	1558387: Inhibition of p97 (unknown origin) assessed as reduction in ATPase activity by biomol green reagent based assay	ic50	0.0070	uM
4-[4-[(2-cyclopentylsulfanyl-3-pyridin-3-ylimidazol-4-yl)methoxy]-2-methylphenyl]-N-propan-2-ylbut-3-yn-1-amine	1846609: Inhibition of p97 (unknown origin) in presence of ATP by Biomol Green Reagent based assay	ic50	0.0070	uM
N-[5-(1H-imidazol-2-yl)-2-[[4-(trifluoromethyl)phenyl]methoxy]phenyl]-3-phenylprop-2-ynamide	1973620: Covalent inhibition of p97 (unknown origin) ATPase activity incubated for 60 mins in presence of ATP by Biomol Green Reagent based microplate reader analysis	ic50	0.0072	uM
N-[2-(cyclopentylmethoxy)-5-(1H-imidazol-2-yl)phenyl]-3-phenylprop-2-ynamide	1973620: Covalent inhibition of p97 (unknown origin) ATPase activity incubated for 60 mins in presence of ATP by Biomol Green Reagent based microplate reader analysis	ic50	0.0074	uM
3-[4-[(5-cyclohex-2-en-1-ylsulfanyl-4-pyridin-3-yl-1,2,4-triazol-3-yl)methoxy]-2,5-difluorophenyl]prop-2-ynyl N-(1-methylpiperidin-4-yl)carbamate	2010034: Inhibition of p97 (unknown origin) ATPase activity by Biomol Green Reagent based microplate reader analysis	ic50	0.0079	uM
3-[2,5-difluoro-4-[[2-(1,2,2,3,3,4,4,5,5-nonadeuteriocyclopentyl)sulfanyl-3-pyridin-3-ylimidazol-4-yl]methoxy]phenyl]prop-2-ynyl N-(1-methylpiperidin-4-yl)carbamate	1558387: Inhibition of p97 (unknown origin) assessed as reduction in ATPase activity by biomol green reagent based assay	ic50	0.0080	uM
N-[5-(1H-imidazol-2-yl)-2-(2-morpholin-4-ylethoxy)phenyl]-3-phenylprop-2-ynamide	1973620: Covalent inhibition of p97 (unknown origin) ATPase activity incubated for 60 mins in presence of ATP by Biomol Green Reagent based microplate reader analysis	ic50	0.0081	uM
N-[5-(1H-imidazol-2-yl)-2-(3-morpholin-4-ylpropoxy)phenyl]-3-phenylprop-2-ynamide	1973620: Covalent inhibition of p97 (unknown origin) ATPase activity incubated for 60 mins in presence of ATP by Biomol Green Reagent based microplate reader analysis	ic50	0.0084	uM
N-[2-ethoxy-5-(1H-imidazol-2-yl)phenyl]-3-phenylprop-2-ynamide	1973620: Covalent inhibition of p97 (unknown origin) ATPase activity incubated for 60 mins in presence of ATP by Biomol Green Reagent based microplate reader analysis	ic50	0.0085	uM
3-[2,5-difluoro-4-[[5-(1,2,2,3,3,4,4,5,5-nonadeuteriocyclopentyl)sulfanyl-4-pyridin-3-yl-1,2,4-triazol-3-yl]methoxy]phenyl]prop-2-ynyl N-(1-methylpiperidin-4-yl)carbamate	2010034: Inhibition of p97 (unknown origin) ATPase activity by Biomol Green Reagent based microplate reader analysis	ic50	0.0097	uM
N-[5-(1H-imidazol-2-yl)-2-propan-2-yloxyphenyl]-3-phenylprop-2-ynamide	1973620: Covalent inhibition of p97 (unknown origin) ATPase activity incubated for 60 mins in presence of ATP by Biomol Green Reagent based microplate reader analysis	ic50	0.0107	uM
3-[4-[(5-cyclohex-2-en-1-ylsulfanyl-4-pyridin-3-yl-1,2,4-triazol-3-yl)methoxy]-2,6-difluorophenyl]prop-2-ynyl N-(1-methylpiperidin-4-yl)carbamate	2010034: Inhibition of p97 (unknown origin) ATPase activity by Biomol Green Reagent based microplate reader analysis	ic50	0.0110	uM
3-[3-cyclopentylsulfanyl-5-[[3-methyl-4-(4-methylsulfonylphenyl)phenoxy]methyl]-1,2,4-triazol-4-yl]pyridine	1711640: Inhibition of recombinant human full length Avi-tagged p97 (1 to 806 residues) expressed in Escherichia coli Rosetta 2(DE3) using 100 uM ATP as substrate incubated for 90 mins by ADP-glo assay	ic50	0.0110	uM
1-[4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl]-2-methylindole-4-carboxamide	1266910: Inhibition of human p97 ATPase incubated for 15 mins by ADP Glo luminescence assay	ic50	0.0110	uM
3-[4-[[5-[(1R)-cyclohex-2-en-1-yl]sulfanyl-4-pyridin-3-yl-1,2,4-triazol-3-yl]methoxy]-2,5-difluorophenyl]prop-2-ynyl N-(1-methylpiperidin-4-yl)carbamate	2010034: Inhibition of p97 (unknown origin) ATPase activity by Biomol Green Reagent based microplate reader analysis	ic50	0.0120	uM
3-(3-bromophenyl)-N-[2-(2-ethoxyethoxy)-5-(1H-imidazol-2-yl)phenyl]prop-2-ynamide	1973620: Covalent inhibition of p97 (unknown origin) ATPase activity incubated for 60 mins in presence of ATP by Biomol Green Reagent based microplate reader analysis	ic50	0.0121	uM
N-[2-(dimethylamino)-5-(1H-imidazol-2-yl)phenyl]-3-phenylprop-2-ynamide	1973620: Covalent inhibition of p97 (unknown origin) ATPase activity incubated for 60 mins in presence of ATP by Biomol Green Reagent based microplate reader analysis	ic50	0.0128	uM
3-(4-chlorophenyl)-N-[2-(2-ethoxyethoxy)-5-(1H-imidazol-2-yl)phenyl]prop-2-ynamide	1973620: Covalent inhibition of p97 (unknown origin) ATPase activity incubated for 60 mins in presence of ATP by Biomol Green Reagent based microplate reader analysis	ic50	0.0139	uM
N-[2-butoxy-5-(1H-imidazol-2-yl)phenyl]-3-phenylprop-2-ynamide	1973620: Covalent inhibition of p97 (unknown origin) ATPase activity incubated for 60 mins in presence of ATP by Biomol Green Reagent based microplate reader analysis	ic50	0.0141	uM
N-[5-(1H-imidazol-2-yl)-2-methoxyphenyl]-3-phenylprop-2-ynamide	1973620: Covalent inhibition of p97 (unknown origin) ATPase activity incubated for 60 mins in presence of ATP by Biomol Green Reagent based microplate reader analysis	ic50	0.0146	uM
N-benzyl-2-[2-methyl-4-(2H-tetrazol-5-yl)indol-1-yl]-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine	1266910: Inhibition of human p97 ATPase incubated for 15 mins by ADP Glo luminescence assay	ic50	0.0150	uM
3-[4-[[5-[(1S)-cyclohex-2-en-1-yl]sulfanyl-4-pyridin-3-yl-1,2,4-triazol-3-yl]methoxy]-2,5-difluorophenyl]prop-2-ynyl N-(1-methylpiperidin-4-yl)carbamate	2010034: Inhibition of p97 (unknown origin) ATPase activity by Biomol Green Reagent based microplate reader analysis	ic50	0.0150	uM
N-[2-(2-ethoxyethoxy)-5-(1H-imidazol-2-yl)phenyl]-3-(3-methoxyphenyl)prop-2-ynamide	1973620: Covalent inhibition of p97 (unknown origin) ATPase activity incubated for 60 mins in presence of ATP by Biomol Green Reagent based microplate reader analysis	ic50	0.0155	uM
N-[2-(2-ethoxyethoxy)-5-(1H-imidazol-2-yl)phenyl]-3-(2-fluorophenyl)prop-2-ynamide	1973620: Covalent inhibition of p97 (unknown origin) ATPase activity incubated for 60 mins in presence of ATP by Biomol Green Reagent based microplate reader analysis	ic50	0.0159	uM
3-(4-chloro-2-fluorophenyl)-N-[2-(2-ethoxyethoxy)-5-(1H-imidazol-2-yl)phenyl]prop-2-ynamide	1973620: Covalent inhibition of p97 (unknown origin) ATPase activity incubated for 60 mins in presence of ATP by Biomol Green Reagent based microplate reader analysis	ic50	0.0166	uM
3-[4-[(5-cyclohex-2-en-1-ylsulfanyl-4-pyridin-3-yl-1,2,4-triazol-3-yl)methoxy]-2,3-difluorophenyl]prop-2-ynyl N-(1-methylpiperidin-4-yl)carbamate	2010034: Inhibition of p97 (unknown origin) ATPase activity by Biomol Green Reagent based microplate reader analysis	ic50	0.0170	uM
N-[2-fluoro-5-(1H-imidazol-2-yl)phenyl]-3-phenylprop-2-ynamide	1973620: Covalent inhibition of p97 (unknown origin) ATPase activity incubated for 60 mins in presence of ATP by Biomol Green Reagent based microplate reader analysis	ic50	0.0178	uM
1-[4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl]-2-methyl-N-prop-2-ynylindole-4-carboxamide	1603027: Inhibition of His-tagged p97 (unknown origin) in presence of ATP and PNP by UV-transparent microplate assay	ki	0.0186	uM
N-[2-(2-ethoxyethoxy)-5-(1H-imidazol-2-yl)phenyl]-3-(3-hydroxyphenyl)prop-2-ynamide	1973620: Covalent inhibition of p97 (unknown origin) ATPase activity incubated for 60 mins in presence of ATP by Biomol Green Reagent based microplate reader analysis	ic50	0.0186	uM
N-[5-(1H-imidazol-2-yl)-2-(2-methoxyethoxy)phenyl]-3-phenylprop-2-ynamide	1973620: Covalent inhibition of p97 (unknown origin) ATPase activity incubated for 60 mins in presence of ATP by Biomol Green Reagent based microplate reader analysis	ic50	0.0192	uM
N-[2-(cyclohexylmethoxy)-5-(1H-imidazol-2-yl)phenyl]-3-phenylprop-2-ynamide	1973620: Covalent inhibition of p97 (unknown origin) ATPase activity incubated for 60 mins in presence of ATP by Biomol Green Reagent based microplate reader analysis	ic50	0.0197	uM
1-[3-(5-fluoro-1H-indol-2-yl)phenyl]-N-[2-(4-propan-2-ylpiperazin-1-yl)ethyl]piperidin-4-amine	1558372: Inhibition of human p97	ic50	0.0200	uM
3-[4-[(5-cyclohex-2-en-1-ylsulfanyl-4-pyridin-3-yl-1,2,4-triazol-3-yl)methoxy]-2-fluorophenyl]prop-2-ynyl N-[2-(4-methylpiperazin-1-yl)ethyl]carbamate	2010034: Inhibition of p97 (unknown origin) ATPase activity by Biomol Green Reagent based microplate reader analysis	ic50	0.0200	uM
1-[3-(5-fluoro-1H-indol-2-yl)phenyl]-N-[[1-(4-methylpiperazin-1-yl)cyclobutyl]methyl]piperidin-4-amine	1423607: Inhibition of recombinant full length human p97 (1 to 806 residues) expressed in Escherichia coli Rosetta 2 (DE3) using 100 uM ATP as substrate after 90 mins by luminescence assay	ic50	0.0200	uM
N-[1-[4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl]-2-methylindol-4-yl]propanamide	1603027: Inhibition of His-tagged p97 (unknown origin) in presence of ATP and PNP by UV-transparent microplate assay	ki	0.0208	uM
3-[4-[(5-cyclohex-2-en-1-ylsulfanyl-4-pyridin-3-yl-1,2,4-triazol-3-yl)methoxy]-2-methylphenyl]prop-2-ynyl N-[2-(4-methylpiperazin-1-yl)ethyl]carbamate	2010034: Inhibition of p97 (unknown origin) ATPase activity by Biomol Green Reagent based microplate reader analysis	ic50	0.0210	uM
3-(2-chlorophenyl)-N-[2-(2-ethoxyethoxy)-5-(1H-imidazol-2-yl)phenyl]prop-2-ynamide	1973620: Covalent inhibition of p97 (unknown origin) ATPase activity incubated for 60 mins in presence of ATP by Biomol Green Reagent based microplate reader analysis	ic50	0.0228	uM
1-[4-(benzylamino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl]-2-methylindole-4-carboxamide	1266910: Inhibition of human p97 ATPase incubated for 15 mins by ADP Glo luminescence assay	ic50	0.0230	uM
3-[4-[(5-cyclohex-2-en-1-ylsulfanyl-4-pyridin-3-yl-1,2,4-triazol-3-yl)methoxy]-2-methylphenyl]prop-2-ynyl N-(1-methylpiperidin-4-yl)carbamate	2010034: Inhibition of p97 (unknown origin) ATPase activity by Biomol Green Reagent based microplate reader analysis	ic50	0.0230	uM
1-[4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl]-N-(2-cyanoethyl)-2-methylindole-4-carboxamide	1603027: Inhibition of His-tagged p97 (unknown origin) in presence of ATP and PNP by UV-transparent microplate assay	ki	0.0241	uM
1-[4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl]-N-but-3-ynyl-2-methylindole-4-carboxamide	1603027: Inhibition of His-tagged p97 (unknown origin) in presence of ATP and PNP by UV-transparent microplate assay	ki	0.0245	uM
4-[4-[(5-cyclopentylsulfanyl-4-pyridin-3-yl-1,2,4-triazol-3-yl)methoxy]-2-methylphenyl]benzenesulfonamide	721967: Inhibition of human recombinant His-GST tagged VCP expressed in baculovirus infected Hi5 cells assessed as ADP formation incubated for 20 mins proir to substrate addition measured after 90 mins by NADH coupled assay	ic50	0.0250	uM
N-[2-(cyclobutylmethoxy)-5-(1H-imidazol-2-yl)phenyl]-3-phenylprop-2-ynamide	1973620: Covalent inhibition of p97 (unknown origin) ATPase activity incubated for 60 mins in presence of ATP by Biomol Green Reagent based microplate reader analysis	ic50	0.0256	uM
N-[1-[4-[(3-hydroxyphenyl)methylamino]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl]-2-methylindol-4-yl]prop-2-enamide	1848094: Inhibition of p97 (unknown origin) using ATP as substrate incubated for 60 mins by ADP-Glo reagent based luminescence assay	ic50	0.0260	uM

CTD chemical–gene interactions

82 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	5
Tobacco Smoke Pollution	affects expression, increases expression, increases metabolic processing	5
NMS-873	affects binding, increases reaction, decreases activity, increases ubiquitination, decreases response to substance	4
Cadmium Chloride	increases degradation, increases glutathionylation, increases reaction, affects localization, decreases expression (+3 more)	4
bisphenol A	decreases expression, decreases methylation, increases expression	3
Silicon Dioxide	affects expression, affects secretion, increases expression	3
TAK-243	affects binding, decreases reaction, increases reaction, decreases sumoylation	2
N2,N4-dibenzylquinazoline-2,4-diamine	decreases activity	2
Air Pollutants	decreases expression, increases abundance, increases expression	2
Arsenic	decreases reaction, affects reaction, increases degradation, affects binding, increases reaction (+1 more)	2
Cadmium	increases abundance, increases expression, increases localization, increases degradation, increases glutathionylation (+2 more)	2
Caffeine	decreases expression, increases phosphorylation	2
Smoke	decreases expression, increases abundance, increases expression	2
Valproic Acid	affects expression, decreases methylation	2
Metribolone	affects binding, increases reaction, increases expression	2
Cyclosporine	affects cotreatment, increases expression, decreases methylation	2
Okadaic Acid	decreases expression, increases expression	2
aristolochic acid I	decreases expression	1
ML240 compound	decreases activity	1
ML241 compound	decreases activity	1
CB-5083	decreases activity	1
FR900359	increases phosphorylation	1
bisphenol F	increases expression	1
ML-792	affects binding, decreases reaction, increases reaction	1
beta-N-methylamino-L-alanine	decreases expression	1
testosterone enanthate	affects expression	1
triphenyl phosphate	affects expression	1
sulforaphane	affects binding	1
potassium chromate(VI)	affects response to substance	1
lead chloride	decreases expression	1

ChEMBL screening assays

120 unique, capped per target: 120 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1102721	Binding	Inhibition of VCP assessed as conversion of ATP to ADP by enzyme coupled glucokinase assay	2-Anilino-4-aryl-1,3-thiazole inhibitors of valosin-containing protein (VCP or p97). — Bioorg Med Chem Lett

Cellosaurus cell lines

79 cell lines: 34 transformed cell line, 25 finite cell line, 20 induced pluripotent stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_1N07	GM22660	Transformed cell line	Female
CVCL_1N08	GM22661	Finite cell line	Female
CVCL_BD14	ND10069	Transformed cell line	Male
CVCL_BE75	ND10666	Transformed cell line	Female
CVCL_BG72	ND11460	Transformed cell line	Male
CVCL_BI17	ND11807	Transformed cell line	Female
CVCL_BK24	ND12329	Transformed cell line	Male
CVCL_BT50	GM21827	Transformed cell line	Female
CVCL_BT51	GM21828	Transformed cell line	Male
CVCL_BT52	GM21829	Finite cell line	Female

Clinical trials (associated diseases)

586 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00542412	PHASE4	COMPLETED	CARE Canadian ALS Riluzole Evaluation
NCT00560287	PHASE4	UNKNOWN	Non-Invasive Ventilation in Amyotrophic Lateral Sclerosis
NCT00613899	PHASE4	COMPLETED	Feasibility of Telesurveillance and Home Cough Assistance for Amyotrophic Lateral Patients (ALS)
NCT04997954	PHASE4	UNKNOWN	EMERALD TRIAL Open Label Extension Study
NCT06849115	PHASE4	COMPLETED	Effects of L-Carnitine in Amyotrophic Lateral Sclerosis Patients With CHCHD10 Mutations
NCT07223723	PHASE4	RECRUITING	A Study to Learn More About the Long-Term Safety of Tofersen (Qalsody) in Chinese Participants With SOD-1 Amyotrophic Lateral Sclerosis (ALS)
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT00021697	PHASE3	COMPLETED	Safety/Efficacy of AVP-923 in the Treatment of Emotional Lability (Uncontrolled Crying & Laughing) in Patients With ALS
NCT00035815	PHASE3	COMPLETED	Insulin-like Growth Factor-1 in Amyotrophic Lateral Sclerosis (ALS) Trial
NCT00047723	PHASE3	COMPLETED	Minocycline to Treat Amyotrophic Lateral Sclerosis
NCT00069186	PHASE3	UNKNOWN	Study of Creatine Monohydrate in Patients With Amyotrophic Lateral Sclerosis
NCT00136110	PHASE3	COMPLETED	Trial of Sodium Valproate in Amyotrophic Lateral Sclerosis
NCT00330681	PHASE3	COMPLETED	Efficacy and Safety Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis (ALS)
NCT00349622	PHASE3	COMPLETED	Clinical Trial Ceftriaxone in Subjects With ALS
NCT00372879	PHASE3	COMPLETED	Clinical Trial of Vitamin E to Treat Muscular Cramps in Patients With ALS
NCT00415519	PHASE3	COMPLETED	Efficacy and Safety Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis (ALS) Who Met Severity Classification III
NCT00424463	PHASE3	COMPLETED	Expanded Controlled Study of Safety and Efficacy of MCI-186 in Patients With Amyotrophic Lateral Sclerosis (ALS)
NCT00839033	PHASE3	TERMINATED	Evaluation of a Mechanical Device During Acute Respiratory Failure in Patients With Neuromuscular Disorders
NCT00868166	PHASE3	COMPLETED	Safety and Efficacy of TRO19622 as add-on Therapy to Riluzole Versus Placebo in Treatment of Patients Suffering From ALS
NCT00965497	PHASE3	COMPLETED	Escitalopram (Lexapro) for Depression MS or ALS
NCT01016522	PHASE3	TERMINATED	Safety and Tolerability of the Ketogenic Diet in Amyotrophic Lateral Sclerosis (ALS)
NCT01160263	PHASE3	COMPLETED	Study of Dopamine and Serotonin Transporters in Patients With Amyotrophic Lateral Sclerosis and Controls
NCT01281189	PHASE3	COMPLETED	Phase 3 Study of Dexpramipexole in ALS
NCT01492686	PHASE3	COMPLETED	Phase 3 Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis
NCT01583088	PHASE3	TERMINATED	Early Stage Amyotrophic Lateral Sclerosis Phrenic Stimulation
NCT01622088	PHASE3	TERMINATED	Phase 3 Extension Study of Dexpramipexole in ALS
NCT02496767	PHASE3	COMPLETED	Ventilatory Investigation of Tirasemtiv and Assessment of Longitudinal Indices After Treatment for a Year
NCT02623699	PHASE3	COMPLETED	An Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of BIIB067 (Tofersen) in Adults With Inherited Amyotrophic Lateral Sclerosis (ALS)
NCT02936635	PHASE3	COMPLETED	A Study for Patients Who Completed VITALITY-ALS (CY 4031)
NCT03127267	PHASE3	RECRUITING	Efficacy and Safety of Masitinib Versus Placebo in the Treatment of ALS Patients
NCT03280056	PHASE3	COMPLETED	Safety and Efficacy of Repeated Administrations of NurOwn® in ALS Patients
NCT03491462	PHASE3	COMPLETED	Arimoclomol in Amyotropic Lateral Sclerosis
NCT03505021	PHASE3	COMPLETED	Effects of Oral Levosimendan (ODM-109) on Respiratory Function in Patients With ALS
NCT03548311	PHASE3	COMPLETED	Clinical Trial of Ultra-high Dose Methylcobalamin for ALS
NCT03690791	PHASE3	UNKNOWN	Efficacy of Cannabinoids in Amyotrophic Lateral Sclerosis or Motor Neurone Disease
NCT03800524	PHASE3	UNKNOWN	Safety and Efficacy of TUDCA as add-on Treatment in Patients Affected by ALS
NCT03836716	PHASE3	TERMINATED	Arimoclomol in Amyotropic Lateral Sclerosis - Open Label Extension Trial
NCT03948178	PHASE3	TERMINATED	Effects of Oral Levosimendan on Respiratory Function in Patients With Amyotrophic Lateral Sclerosis (ALS): Open-Label Extension
NCT04165824	PHASE3	COMPLETED	Safety Study of Oral Edaravone Administered in Subjects With ALS