VCPKMT

gene

On this page

Also known as VCP-KMT

Summary

VCPKMT (valosin containing protein lysine methyltransferase, HGNC:20352) is a protein-coding gene on chromosome 14q21.3, encoding Protein N-lysine methyltransferase METTL21D (Q9H867). Protein N-lysine methyltransferase that specifically trimethylates ‘Lys-315’ of VCP/p97; this modification may decrease VCP ATPase activity.

Enables ATPase binding activity and protein-lysine N-methyltransferase activity. Involved in negative regulation of ATP-dependent activity and peptidyl-lysine trimethylation. Located in cytosol. Part of protein-containing complex.

Source: NCBI Gene 79609 — RefSeq curated summary.

At a glance

GWAS associations: 3
Clinical variants (ClinVar): 41 total
Druggable target: yes
MANE Select transcript: NM_024558

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20352
Approved symbol	VCPKMT
Name	valosin containing protein lysine methyltransferase
Location	14q21.3
Locus type	gene with protein product
Status	Approved
Aliases	VCP-KMT
Ensembl gene	ENSG00000100483
Ensembl biotype	protein_coding
OMIM	615260
Entrez	79609

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 5 protein_coding, 2 retained_intron, 1 nonsense_mediated_decay

ENST00000395859, ENST00000395860, ENST00000484763, ENST00000491402, ENST00000569518, ENST00000852128, ENST00000922445, ENST00000922446

RefSeq mRNA: 2 — MANE Select: NM_024558 NM_001040662, NM_024558

CCDS: CCDS41951, CCDS9696

Canonical transcript exons

ENST00000395860 — 6 exons

Exon	Start	End
ENSE00001523110	50116069	50116179
ENSE00001914332	50116287	50116572
ENSE00003459354	50112615	50112719
ENSE00003460595	50108637	50109713
ENSE00003591460	50115839	50115911
ENSE00003601272	50114285	50114404

Expression profiles

Bgee: expression breadth ubiquitous, 277 present calls, max score 92.64.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 9.1923 / max 105.5654, expressed in 1732 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
143128	9.1923	1732

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	92.64	gold quality
cartilage tissue	UBERON:0002418	87.77	gold quality
hair follicle	UBERON:0002073	87.42	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	86.44	gold quality
visceral pleura	UBERON:0002401	86.13	gold quality
pleura	UBERON:0000977	85.67	gold quality
upper leg skin	UBERON:0004262	85.49	gold quality
blood	UBERON:0000178	85.46	gold quality
bone marrow	UBERON:0002371	85.18	gold quality
parietal pleura	UBERON:0002400	85.04	gold quality
monocyte	CL:0000576	84.63	gold quality
oral cavity	UBERON:0000167	84.61	gold quality
jejunal mucosa	UBERON:0000399	84.60	gold quality
mononuclear cell	CL:0000842	84.59	gold quality
sperm	CL:0000019	84.49	gold quality
leukocyte	CL:0000738	84.46	gold quality
epithelium of nasopharynx	UBERON:0001951	84.25	gold quality
spleen	UBERON:0002106	84.12	gold quality
blood vessel layer	UBERON:0004797	84.06	gold quality
germinal epithelium of ovary	UBERON:0001304	83.98	gold quality
granulocyte	CL:0000094	83.80	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.76	gold quality
tibia	UBERON:0000979	83.59	gold quality
palpebral conjunctiva	UBERON:0001812	83.30	gold quality
skin of abdomen	UBERON:0001416	82.97	gold quality
Brodmann (1909) area 23	UBERON:0013554	82.77	gold quality
esophagus squamous epithelium	UBERON:0006920	82.38	gold quality
endometrium	UBERON:0001295	82.23	gold quality
cerebellar cortex	UBERON:0002129	82.22	gold quality
cerebellar hemisphere	UBERON:0002245	82.21	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.21

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

74 targeting VCPKMT, 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-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-3686	99.90	70.53	2432

Literature-anchored findings (GeneRIF, showing 3)

METTL21D is the methyltransferase responsible for lysine methylation of VCP. (PMID:22948820)
METTL21D trimethylates Lys-315 in VCP/p97 in a ASPCR1-dependent manner (PMID:23349634)
Structural remodeling of AAA+ ATPase p97 by adaptor protein ASPL facilitates posttranslational methylation by METTL21D. (PMID:36656859)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	vcpkmt	ENSDARG00000060021
mus_musculus	Vcpkmt	ENSMUSG00000049882
rattus_norvegicus	Vcpkmt	ENSRNOG00000065305
caenorhabditis_elegans		WBGENE00016591

Paralogs (5): EEF1AKMT3 (ENSG00000123427), METTL21C (ENSG00000139780), METTL21A (ENSG00000144401), METTL23 (ENSG00000181038), METTL21EP (ENSG00000250878)

Protein

Protein identifiers

Protein N-lysine methyltransferase METTL21D — Q9H867 (reviewed: Q9H867)

Alternative names: Methyltransferase-like protein 21D, VCP lysine methyltransferase, Valosin-containing protein lysine methyltransferase

All UniProt accessions (1): Q9H867

UniProt curated annotations — full annotation on UniProt →

Function. Protein N-lysine methyltransferase that specifically trimethylates ‘Lys-315’ of VCP/p97; this modification may decrease VCP ATPase activity.

Subunit / interactions. Interacts with ALKBH6. Interacts with ASPSCR1 and UBXN6; interaction with ASPSCR1, but not with UBXN6, enhances VCP methylation.

Subcellular location. Cytoplasm.

Similarity. Belongs to the methyltransferase superfamily. METTL21 family.

Isoforms (5)

UniProt ID	Names	Canonical?
Q9H867-4	4	yes
Q9H867-1	1
Q9H867-2	2
Q9H867-3	3
Q9H867-5	5

RefSeq proteins (2): NP_001035752, NP_078834* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR019410	Methyltransf_16	Family
IPR029063	SAM-dependent_MTases_sf	Homologous_superfamily

Pfam: PF10294

Catalyzed reactions (Rhea), 1 shown:

L-lysyl-[protein] + 3 S-adenosyl-L-methionine = N(6),N(6),N(6)-trimethyl-L-lysyl-[protein] + 3 S-adenosyl-L-homocysteine + 3 H(+) (RHEA:54192)

UniProt features (48 total): strand 13, helix 12, splice variant 6, binding site 6, mutagenesis site 3, turn 3, modified residue 2, initiator methionine 1, chain 1, sequence variant 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
4LG1	X-RAY DIFFRACTION	1.8
8HL6	X-RAY DIFFRACTION	1.8
8HL7	X-RAY DIFFRACTION	2.8
7OAT	X-RAY DIFFRACTION	3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H867-F1	93.11	0.86

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 (6): 43; 75–77; 96; 126; 143; 148

Post-translational modifications (2): 2, 8

Mutagenesis-validated functional residues (3):

Position	Phenotype
73	loss of methyltransferase activity.
96	loss of methyltransferase activity.
144	loss of methyltransferase activity.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-8876725	Protein methylation
R-HSA-392499	Metabolism of proteins
R-HSA-597592	Post-translational protein modification

MSigDB gene sets: 139 (showing top): GOBP_NEGATIVE_REGULATION_OF_ATP_DEPENDENT_ACTIVITY, TATTATA_MIR374, LINDGREN_BLADDER_CANCER_CLUSTER_2A_DN, NKX61_01, GOBP_PEPTIDYL_LYSINE_MODIFICATION, ONKEN_UVEAL_MELANOMA_UP, FREAC3_01, NF1_Q6_01, TGCTGAY_UNKNOWN, GATA1_01, GOBP_NEGATIVE_REGULATION_OF_MOLECULAR_FUNCTION, HFH1_01, HNF1_C, GOBP_REGULATION_OF_ATP_DEPENDENT_ACTIVITY, GATA1_02

GO Biological Process (4): peptidyl-lysine methylation (GO:0018022), peptidyl-lysine trimethylation (GO:0018023), negative regulation of ATP-dependent activity (GO:0032780), methylation (GO:0032259)

GO Molecular Function (6): protein-lysine N-methyltransferase activity (GO:0016279), ATPase binding (GO:0051117), protein binding (GO:0005515), methyltransferase activity (GO:0008168), protein methyltransferase activity (GO:0008276), transferase activity (GO:0016740)

GO Cellular Component (3): cytoplasm (GO:0005737), cytosol (GO:0005829), protein-containing complex (GO:0032991)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Post-translational protein modification	1
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
protein methylation	1
peptidyl-lysine modification	1
peptidyl-lysine methylation	1
regulation of ATP-dependent activity	1
negative regulation of molecular function	1
ATP-dependent activity	1
metabolic process	1
protein methyltransferase activity	1
lysine N-methyltransferase activity	1
enzyme binding	1
binding	1
transferase activity, transferring one-carbon groups	1
methyltransferase activity	1
catalytic activity, acting on a protein	1
catalytic activity	1
intracellular anatomical structure	1
cytoplasm	1
cellular_component	1

Protein interactions and networks

STRING

547 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
VCPKMT	VCP	P55072	735
VCPKMT	EEF1AKMT2	Q5JPI9	718
VCPKMT	METTL18	O95568	717
VCPKMT	METTL22	Q9BUU2	717
VCPKMT	EEF2KMT	Q96G04	699
VCPKMT	ETFBKMT	Q8IXQ9	696
VCPKMT	KIN	O60870	658
VCPKMT	EEF1AKMT1	Q8WVE0	627
VCPKMT	CAMKMT	Q7Z624	623
VCPKMT	EEF1AKMT4	P0DPD7	561
VCPKMT	CSKMT	A8MUP2	531
VCPKMT	ATPSCKMT	Q6P4H8	489
VCPKMT	ANTKMT	Q9BQD7	468
VCPKMT	METTL13	Q8N6R0	462
VCPKMT	NTMT1	Q9BV86	434

IntAct

11 interactions, top by confidence:

A	B	Type	Score
VCP	ASPSCR1	psi-mi:“MI:0914”(association)	0.960
CARD9	VCPKMT	psi-mi:“MI:0915”(physical association)	0.560
VCP	PRKN	psi-mi:“MI:0914”(association)	0.530
VCP	UBE4B	psi-mi:“MI:0914”(association)	0.350
UBXN6	POR	psi-mi:“MI:0914”(association)	0.350
UBXN6	ZSWIM8	psi-mi:“MI:0914”(association)	0.350
VCP	COL1A1	psi-mi:“MI:0914”(association)	0.350
CARD9	VCPKMT	psi-mi:“MI:0915”(physical association)	0.000
VCPKMT	CARD9	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (29): VCPKMT (Affinity Capture-MS), VCPKMT (Affinity Capture-MS), VCPKMT (Affinity Capture-MS), VCPKMT (Affinity Capture-MS), VCPKMT (Affinity Capture-MS), CARD9 (Two-hybrid), VCPKMT (Affinity Capture-MS), VCPKMT (Affinity Capture-MS), VCPKMT (Co-fractionation), VCP (Biochemical Activity), VCPKMT (Affinity Capture-MS), VCPKMT (Affinity Capture-RNA), VCPKMT (Affinity Capture-MS), ALDOA (Affinity Capture-MS), ASPSCR1 (Affinity Capture-MS)

ESM2 similar proteins: A2AA28, A2RRH5, A4FV42, A6NDL7, A7MCT6, B0K012, B2RYG8, D3YWP0, D3ZRW8, E1B8U2, J3S6Y1, P21964, P50747, Q0V8R7, Q1JP61, Q2TBI8, Q3SZD4, Q3U2J5, Q4VBE8, Q58DC7, Q5E9Y6, Q5RJL2, Q5VZV1, Q6DJF8, Q6GQ33, Q6P9U1, Q7Z624, Q80WC9, Q86XA0, Q8BNV1, Q8C436, Q8CDZ2, Q8IZ69, Q8N371, Q8R1C6, Q8WU66, Q920N2, Q96AZ1, Q96CB9, Q96RR1

Diamond homologs: A2AA28, A4FV42, A4FV98, A4IGU3, A6NDL7, A6QP81, A7IQW5, D3YWP0, P0CU27, P53970, Q28IN4, Q2KIJ2, Q58DC7, Q5BLD8, Q5RE14, Q5RJL2, Q5VZV1, Q6DJF8, Q86XA0, Q8BLU2, Q8C436, Q8CDZ2, Q8R1C6, Q8WXB1, Q96AZ1, Q9BUU2, Q9CQL0, Q9H867, F4JNX3, O14118, O95568, P40389, P47163, Q4KM84, Q55DL2, Q9CZ09, Q7S634, P0CP44, P0CP45, P64840

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
ASPSCR1	up-regulates	VCPKMT	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	41
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

790 predictions. Top by Δscore:

Variant	Effect	Δscore
14:50112034:A:C	donor_gain	1.0000
14:50112720:C:CC	acceptor_gain	1.0000
14:50114280:CTTA:C	donor_loss	1.0000
14:50114281:TTA:T	donor_loss	1.0000
14:50114282:TACCT:T	donor_loss	1.0000
14:50114283:A:AC	donor_gain	1.0000
14:50114283:ACC:A	donor_loss	1.0000
14:50114284:C:CC	donor_gain	1.0000
14:50114284:C:CT	donor_loss	1.0000
14:50114284:CCT:C	donor_gain	1.0000
14:50114401:AAGA:A	acceptor_gain	1.0000
14:50114402:AGA:A	acceptor_gain	1.0000
14:50114403:GA:G	acceptor_gain	1.0000
14:50114405:C:CC	acceptor_gain	1.0000
14:50114409:T:C	acceptor_gain	1.0000
14:50114409:T:TC	acceptor_gain	1.0000
14:50115909:CCCCT:C	acceptor_gain	1.0000
14:50115910:CCCT:C	acceptor_gain	1.0000
14:50115911:CCT:C	acceptor_gain	1.0000
14:50115913:T:C	acceptor_gain	1.0000
14:50116283:TTA:T	donor_loss	1.0000
14:50116284:TACCC:T	donor_loss	1.0000
14:50116285:A:AC	donor_gain	1.0000
14:50116285:A:C	donor_loss	1.0000
14:50116285:AC:A	donor_gain	1.0000
14:50116286:C:CC	donor_gain	1.0000
14:50116286:CC:C	donor_gain	1.0000
14:50109711:TTT:T	acceptor_gain	0.9900
14:50114283:AC:A	donor_gain	0.9900
14:50114283:ACCT:A	donor_gain	0.9900

AlphaMissense

1492 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:50115911:C:A	W126C	1.000
14:50115911:C:G	W126C	1.000
14:50114339:A:C	C172W	0.999
14:50115854:G:C	C145W	0.999
14:50115855:C:T	C145Y	0.999
14:50115858:T:A	D144V	0.999
14:50115859:C:G	D144H	0.999
14:50116070:A:G	W126R	0.999
14:50116070:A:T	W126R	0.999
14:50116424:C:A	W43C	0.999
14:50116424:C:G	W43C	0.999
14:50116426:A:G	W43R	0.999
14:50116426:A:T	W43R	0.999
14:50114333:T:A	E174D	0.998
14:50114333:T:G	E174D	0.998
14:50114340:C:T	C172Y	0.998
14:50114341:A:G	C172R	0.998
14:50115858:T:C	D144G	0.998
14:50115858:T:G	D144A	0.998
14:50115859:C:A	D144Y	0.998
14:50116159:T:A	D96V	0.998
14:50116159:T:G	D96A	0.998
14:50116309:C:A	G82W	0.998
14:50116317:C:T	G79E	0.998
14:50116318:C:A	G79W	0.998
14:50116422:T:A	D44V	0.998
14:50114328:C:G	R176P	0.997
14:50114379:A:G	L159P	0.997
14:50115856:A:G	C145R	0.997
14:50115862:C:G	A143P	0.997

dbSNP variants (sampled 300 via entrez): RS1000157540 (14:50114135 G>A,C,T), RS1000211212 (14:50113782 C>G), RS1000675672 (14:50107619 A>G), RS1000904974 (14:50113625 C>A,T), RS1000943973 (14:50108753 A>G), RS1001130548 (14:50107450 G>A,C), RS1001137588 (14:50104696 A>G), RS1001155354 (14:50107716 G>A,C,T), RS1001189974 (14:50104456 G>A), RS1001279400 (14:50103825 A>C), RS1001339441 (14:50105102 C>T), RS1001831464 (14:50115278 A>T), RS1002398015 (14:50109924 A>G), RS1002400306 (14:50109093 G>C), RS1002559804 (14:50117370 A>G)

Disease associations

OMIM: gene MIM:615260 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST002380_4	Erythema nodosum in inflammatory bowel disease	7.000000e-06
GCST90013663_76	Alanine aminotransferase levels	1.000000e-08
GCST90013664_72	Aspartate aminotransferase levels	4.000000e-16

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004736	aspartate aminotransferase measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3588742 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Resveratrol	affects cotreatment, increases expression, decreases expression	2
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
o,p’-DDT	decreases expression	1
sodium arsenite	decreases expression	1
potassium chromate(VI)	affects cotreatment, increases expression	1
epigallocatechin gallate	affects cotreatment, increases expression	1
di-n-butylphosphoric acid	affects expression	1
pentabromodiphenyl ether	increases expression	1
cylindrospermopsin	increases expression	1
abrine	increases expression	1
jinfukang	affects cotreatment, decreases expression	1
Acetaminophen	increases expression	1
Air Pollutants	affects expression, increases abundance	1
Cisplatin	affects cotreatment, decreases expression	1
Diethylstilbestrol	affects expression	1
Hydrogen Peroxide	affects expression	1
Ketoconazole	increases expression	1
Methyl Methanesulfonate	increases expression	1
Ozone	affects expression, increases abundance	1
Plant Extracts	affects cotreatment, increases expression	1
Selenium	decreases expression	1
Thiram	increases expression	1
Tobacco Smoke Pollution	increases expression	1
Zearalenone	decreases expression	1
Asbestos, Crocidolite	increases expression	1
Copper Sulfate	increases expression	1
Lactic Acid	increases expression	1
Genistein	decreases expression	1

ChEMBL screening assays

4 unique, capped per target: 4 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3592420	Binding	Inhibition of METTL21D (unknown origin) assessed as incorporation of tritium labeled methyl group from [3H]-SAM to substrate at 1 uM after 1 hr by scintillation proximity assay relative to control	Discovery of A-893, A New Cell-Active Benzoxazinone Inhibitor of Lysine Methyltransferase SMYD2. — ACS Med Chem Lett

Clinical trials (associated diseases)

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

No linked Atlas pages yet — the cross-entity mesh grows as the corpus expands.