ATP6V0C

Summary

ATP6V0C (ATPase H+ transporting V0 subunit c, HGNC:855) is a protein-coding gene on chromosome 16p13.3, encoding V-type proton ATPase 16 kDa proteolipid subunit c (P27449). Proton-conducting pore forming subunit of the V0 complex of vacuolar(H+)-ATPase (V-ATPase), a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that translocates protons. It is a common-essential gene (DepMap: required in 99.8% of cancer cell lines).

This gene encodes a component of vacuolar ATPase (V-ATPase), a multisubunit enzyme that mediates acidification of eukaryotic intracellular organelles. V-ATPase dependent organelle acidification is necessary for such intracellular processes as protein sorting, zymogen activation, receptor-mediated endocytosis, and synaptic vesicle proton gradient generation. V-ATPase is composed of a cytosolic V1 domain and a transmembrane V0 domain. The V1 domain consists of three A and three B subunits, two G subunits plus the C, D, E, F, and H subunits. The V1 domain contains the ATP catalytic site. The V0 domain consists of five different subunits: a, c, c’, c", and d. This gene encodes the V0 subunit c. Alternative splicing results in transcript variants. Pseudogenes have been identified on chromosomes 6 and 17.

Source: NCBI Gene 527 — RefSeq curated summary.

At a glance

• Gene–disease (curated): epilepsy, early-onset, 3, with or without developmental delay (Strong, GenCC) — +1 more curated relationship
• Clinical variants (ClinVar): 51 total — 11 pathogenic, 9 likely-pathogenic
• Phenotypes (HPO): 24
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 99.8% of screened cell lines (common-essential)
• MANE Select transcript: NM_001694

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:855
Approved symbol	ATP6V0C
Name	ATPase H+ transporting V0 subunit c
Location	16p13.3
Locus type	gene with protein product
Status	Approved
Aliases	VATL, Vma3
Ensembl gene	ENSG00000185883
Ensembl biotype	protein_coding
OMIM	108745
Entrez	527

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 5 protein_coding

ENST00000330398, ENST00000564973, ENST00000565223, ENST00000568562, ENST00000930102

RefSeq mRNA: 2 — MANE Select: NM_001694 NM_001198569, NM_001694

CCDS: CCDS10470

Canonical transcript exons

ENST00000330398 — 3 exons

Exon	Start	End
ENSE00001309635	2513952	2514182
ENSE00003529505	2519218	2519401
ENSE00003531696	2519541	2520218

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 99.72.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 499.1678 / max 5828.5248, expressed in 1828 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
152233	359.4028	1828
152234	138.8218	1826
152235	0.9432	349

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
superior frontal gyrus	UBERON:0002661	99.72	gold quality
right frontal lobe	UBERON:0002810	99.59	gold quality
right hemisphere of cerebellum	UBERON:0014890	99.58	gold quality
frontal cortex	UBERON:0001870	99.57	gold quality
primary visual cortex	UBERON:0002436	99.57	gold quality
prefrontal cortex	UBERON:0000451	99.55	gold quality
Brodmann (1909) area 9	UBERON:0013540	99.52	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	99.50	gold quality
cerebellum	UBERON:0002037	99.47	gold quality
cerebellar cortex	UBERON:0002129	99.46	gold quality
cerebellar hemisphere	UBERON:0002245	99.46	gold quality
anterior cingulate cortex	UBERON:0009835	99.45	gold quality
cerebral cortex	UBERON:0000956	99.44	gold quality
pituitary gland	UBERON:0000007	99.35	gold quality
adenohypophysis	UBERON:0002196	99.35	gold quality
hypothalamus	UBERON:0001898	99.32	gold quality
nucleus accumbens	UBERON:0001882	99.26	gold quality
brain	UBERON:0000955	99.22	gold quality
Ammon’s horn	UBERON:0001954	99.20	gold quality
temporal lobe	UBERON:0001871	99.19	gold quality
putamen	UBERON:0001874	99.19	gold quality
metanephros cortex	UBERON:0010533	99.19	gold quality
amygdala	UBERON:0001876	99.18	gold quality
cortex of kidney	UBERON:0001225	99.16	gold quality
caudate nucleus	UBERON:0001873	99.16	gold quality
substantia nigra	UBERON:0002038	99.06	gold quality
lower esophagus mucosa	UBERON:0035834	99.04	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	99.01	gold quality
blood	UBERON:0000178	99.00	gold quality
esophagus mucosa	UBERON:0002469	98.97	gold quality

Single-cell (SCXA)

Detected in 23 experiment(s), a significant marker in 19.

Experiment	Marker?	Max mean expression
E-MTAB-10042	yes	3619.99
E-GEOD-114530	yes	858.82
E-MTAB-11011	yes	557.05
E-HCAD-4	yes	187.66
E-GEOD-76312	yes	104.64
E-HCAD-1	yes	85.24
E-CURD-122	yes	57.23
E-MTAB-8410	yes	50.41
E-MTAB-6701	yes	48.72
E-HCAD-35	yes	48.17
E-GEOD-135922	yes	41.88
E-HCAD-25	yes	35.67
E-HCAD-10	yes	32.16
E-CURD-112	yes	23.69
E-MTAB-10553	yes	23.35

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

21 targeting ATP6V0C, 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-4481	100.00	66.42	1669
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-1299	99.77	71.24	2389
HSA-MIR-1197	99.70	67.75	1027
HSA-MIR-516B-5P	99.56	66.33	1495
HSA-MIR-6128	99.33	67.83	1581
HSA-MIR-4311	99.31	70.47	3041
HSA-MIR-3196	98.96	63.91	326
HSA-MIR-4520-3P	98.75	66.55	963
HSA-MIR-4782-5P	98.35	69.33	1474
HSA-MIR-5706	98.35	69.33	1463
HSA-MIR-484	98.16	66.92	1074
HSA-MIR-3155A	98.16	66.09	965
HSA-MIR-3155B	98.16	66.09	965
HSA-MIR-6773-5P	97.04	64.30	595
HSA-MIR-6724-5P	96.41	63.11	507
HSA-MIR-541-3P	96.07	66.11	1271
HSA-MIR-654-5P	96.07	66.18	1280
HSA-MIR-1251-5P	95.78	64.10	374
HSA-MIR-5684	93.17	64.85	454

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 99.8% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 20)

• 16K expression inhibits beta(1) integrin surface expression and spreading on matrix by a novel mechanism that results in reduced levels of functional beta(1) integrin (PMID:15466867)
• tumor acidity has a role in regulating inhibits the expression of ATP6L mRNA and protein in breast tumor cells (PMID:19299075)
• HRG-1 regulates V-ATPase activity, which is essential for endosomal acidification, heme binding, and receptor trafficking in mammalian cells. (PMID:19875448)
• Novel recessive myoclonic epilepsy candidate gene myoclonic epilepsy , but no mutation was found. (PMID:21087195)
• ATP6L has a protective role against SNP-induced autophagic cell death via inhibition of JNK and p38 in GSH-depleted glial cells. (PMID:21433058)
• data suggest that the bacterial effector VepA targets subunit c of V-ATPase and induces the rupture of host cell lysosomes and subsequent cell death. (PMID:22829766)
• results contribute to the conclusion that LASS2/TMSG1 could regulate V-ATPase activity and intracellular pH through the direct interaction of its homeodomain and the C subunit of V-ATPase (PMID:22991218)
• Results show that inhibition of V-ATPase by archazolid reduces the activity of prometastatic proteases like cathepsin B in vitro and in vivo. (PMID:24166050)
• The consequences of pharmacological inhibition of v-ATPase (by concanamycin) on proliferation, migration, VEGF-receptor 2 (VEGFR2) trafficking and signaling, as well as Notch-mediated transcription in endothelial cells, were examined. (PMID:24254321)
• siRNA knockdown of ATP6V0C resulted in almost complete loss of infectious virus production, suggesting that an human cytomegalovirus microRNA targets a crucial cellular factor required for virus replication. (PMID:24385903)
• A role for ATP6V0C in maintaining constitutive and stress-induced ALP function. (PMID:24695574)
• Data show that 1-acylglycerol-3-phosphate O-acyltransferase 9 (AGPAT9) inhibit cell growth by regulating expression of KLF4/LASS2/V-ATPase proteins in breast cancer. (PMID:26110566)
• RBP2 could induce epithelial-mesenchymal transition in esophageal cancer cells and exert a greater effect on the expression of E-cadherin in lung squamous cells than in esophageal squamous cells. (PMID:26264242)
• Results found that the expression of ATP6V0C was higher in prostate cancer (PC) cell lines with high metastatic potential than that with low metastatic potential, indicating that ATP6V0C enhanced metastatic capacity in prostate cancer cells. Its silencing effectively suppressed the migration and invasion of PC cells through the inhibition of the function of V-ATPase, not through a LASS2/TMSG1-dependent manner. (PMID:29138865)
• ATP6V0C enhances aerobic glycolysis and motility in Esophageal cancer cells. (PMID:31554233)
• Study demonstrated that ATP6L is markedly overexpressed in the poorly differentiated colorectal cancer (CRC) tissues evidently located in the invasive front and metastatic foci. More importantly, in vitro and in vivo data demonstrated that ATP6L can induce the EMT program and promote tumor progression in CRC cells. (PMID:31840304)
• The viral protein U (Vpu)-interacting host protein ATP6V0C down-regulates cell-surface expression of tetherin and thereby contributes to HIV-1 release. (PMID:32291285)
• ATP6V0C variants impair V-ATPase function causing a neurodevelopmental disorder often associated with epilepsy. (PMID:36074901)
• ATP6V0C gene variants were identified in individuals with epilepsy, with or without developmental delay. (PMID:37161035)
• Impaired TFEB-mediated autophagy-lysosome fusion promotes tubular cell cycle G2/M arrest and renal fibrosis by suppressing ATP6V0C expression and interacting with SNAREs. (PMID:38481802)

Cross-species orthologs

10 orthologs

Organism	Symbol	Gene ID
danio_rerio	atp6v0cb	ENSDARG00000036577
danio_rerio	atp6v0ca	ENSDARG00000057853
mus_musculus	Atp6v0c	ENSMUSG00000024121
rattus_norvegicus	Atp6v0c	ENSRNOG00000006542
drosophila_melanogaster	Vha16-3	FBGN0028667
drosophila_melanogaster	Vha16-2	FBGN0028668
drosophila_melanogaster	Vha16-5	FBGN0032294
drosophila_melanogaster	Vha16-1	FBGN0262736
caenorhabditis_elegans		WBGENE00006911
caenorhabditis_elegans		WBGENE00006912

Paralogs (1): ATP6V0B (ENSG00000117410)

Protein

Protein identifiers

V-type proton ATPase 16 kDa proteolipid subunit c — P27449 (reviewed: P27449)

Alternative names: Vacuolar proton pump 16 kDa proteolipid subunit c

All UniProt accessions (3): P27449, H3BMY0, H3BNI4

UniProt curated annotations — full annotation on UniProt →

Function. Proton-conducting pore forming subunit of the V0 complex of vacuolar(H+)-ATPase (V-ATPase), a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that translocates protons. V-ATPase is responsible for acidifying and maintaining the pH of intracellular compartments, and in some cell types, it is targeted to the plasma membrane, where it is responsible for acidifying the extracellular environment.

Subunit / interactions. V-ATPase is a heteromultimeric enzyme made up of two complexes: the ATP-hydrolytic V1 complex and the proton translocation V0 complex. The V1 complex consists of three catalytic AB heterodimers that form a heterohexamer, three peripheral stalks each consisting of EG heterodimers, one central rotor including subunits D and F, and the regulatory subunits C and H. The proton translocation complex V0 consists of the proton transport subunit a, a ring of proteolipid subunits c9c’’, rotary subunit d, subunits e and f, and the accessory subunits ATP6AP1/Ac45 and ATP6AP2/PRR. Interacts with the V0 complex V-ATPase subunit a4 ATP6V0A4. Interacts with LASS2. Interacts with RNF182; this interaction leads to ubiquitination and degradation via the proteasome pathway. (Microbial infection) Interacts with HTLV-1 accessory protein p12I.

Subcellular location. Cytoplasmic vesicle. Clathrin-coated vesicle membrane. Secretory vesicle. Synaptic vesicle membrane.

Post-translational modifications. Ubiquitinated by RNF182, leading to its degradation via the ubiquitin-proteasome pathway.

Disease relevance. Epilepsy, early-onset, 3, with or without developmental delay (EPEO3) [MIM:620465] An autosomal dominant neurologic disorder characterized by various types of seizures with onset in the first months or years of life. Many patients present with febrile seizures and later develop afebrile seizures. Some affected individuals have global developmental delay or regression, impaired intellectual development, poor or absent speech, and motor delay. Additional variable features include hypotonia, gait ataxia, behavioral abnormalities, and anomalies on brain imaging. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the V-ATPase proteolipid subunit family.

RefSeq proteins (2): NP_001185498, NP_001685* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000245	ATPase_proteolipid_csu	Family
IPR002379	ATPase_proteolipid_c-like_dom	Domain
IPR011555	ATPase_proteolipid_su_C_euk	Family
IPR035921	F/V-ATP_Csub_sf	Homologous_superfamily

Pfam: PF00137

UniProt features (45 total): sequence variant 24, helix 9, topological domain 5, transmembrane region 4, chain 1, site 1, mutagenesis site 1

Structure

Experimental structures (PDB)

9 structures.

PDB	Method	Resolution (Å)
6WLW	ELECTRON MICROSCOPY	3
9DET	ELECTRON MICROSCOPY	3
6WM2	ELECTRON MICROSCOPY	3.1
6WM3	ELECTRON MICROSCOPY	3.4
9CF8	ELECTRON MICROSCOPY	3.46
9CFC	ELECTRON MICROSCOPY	3.47
6WM4	ELECTRON MICROSCOPY	3.6
7U4T	ELECTRON MICROSCOPY	3.6
7UNF	ELECTRON MICROSCOPY	4.08

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P27449-F1	88.15	0.63

Functional residue map

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

Catalytic / active sites (1): 139 (essential for proton translocation)

Mutagenesis-validated functional residues (1):

Position	Phenotype
139	severely decreased proton transmembrane transport.

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-1222556	ROS and RNS production in phagocytes
R-HSA-6798695	Neutrophil degranulation
R-HSA-77387	Insulin receptor recycling
R-HSA-917977	Transferrin endocytosis and recycling
R-HSA-9639288	Amino acids regulate mTORC1
R-HSA-983712	Ion channel transport
R-HSA-9857377	Regulation of MITF-M-dependent genes involved in lysosome biogenesis and autophagy

MSigDB gene sets: 332 (showing top): ATF_B, REACTOME_SIGNALING_BY_INSULIN_RECEPTOR, GOBP_REGULATION_OF_AUTOPHAGY, REACTOME_INNATE_IMMUNE_SYSTEM, MYOGENIN_Q6, GOBP_ENDOSOME_ORGANIZATION, GOBP_VACUOLE_ORGANIZATION, GOCC_VACUOLAR_MEMBRANE, GOCC_SECRETORY_GRANULE, GOBP_VESICLE_ORGANIZATION, ENK_UV_RESPONSE_KERATINOCYTE_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, KEGG_LYSOSOME, CREBP1_Q2, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS

GO Biological Process (11): vacuolar acidification (GO:0007035), lysosomal lumen acidification (GO:0007042), regulation of macroautophagy (GO:0016241), positive regulation of Wnt signaling pathway (GO:0030177), endosomal lumen acidification (GO:0048388), intracellular pH reduction (GO:0051452), Golgi lumen acidification (GO:0061795), synaptic vesicle lumen acidification (GO:0097401), proton transmembrane transport (GO:1902600), monoatomic ion transport (GO:0006811), proton motive force-driven ATP synthesis (GO:0015986)

GO Molecular Function (5): ubiquitin protein ligase binding (GO:0031625), proton-transporting ATP synthase activity, rotational mechanism (GO:0046933), proton-transporting ATPase activity, rotational mechanism (GO:0046961), protein binding (GO:0005515), proton transmembrane transporter activity (GO:0015078)

GO Cellular Component (22): Golgi membrane (GO:0000139), vacuolar proton-transporting V-type ATPase, V0 domain (GO:0000220), lysosomal membrane (GO:0005765), plasma membrane (GO:0005886), focal adhesion (GO:0005925), endosome membrane (GO:0010008), membrane (GO:0016020), clathrin-coated vesicle membrane (GO:0030665), phagocytic vesicle membrane (GO:0030670), synaptic vesicle membrane (GO:0030672), proton-transporting V-type ATPase complex (GO:0033176), azurophil granule membrane (GO:0035577), extracellular exosome (GO:0070062), tertiary granule membrane (GO:0070821), ficolin-1-rich granule membrane (GO:0101003), vacuole (GO:0005773), vacuolar membrane (GO:0005774), cytoplasmic vesicle (GO:0031410), proton-transporting two-sector ATPase complex, proton-transporting domain (GO:0033177), proton-transporting V-type ATPase, V0 domain (GO:0033179), synapse (GO:0045202), bounding membrane of organelle (GO:0098588)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Innate Immune System	2
Signaling by Insulin receptor	1
Iron uptake and transport	1
Cellular response to starvation	1
Transport of small molecules	1
MITF-M-dependent gene expression	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular pH reduction	3
bounding membrane of organelle	3
secretory granule membrane	3
proton transmembrane transport	2
proton-transporting two-sector ATPase complex	2
tertiary granule	2
cytoplasm	2
vacuolar acidification	1
regulation of autophagy	1
macroautophagy	1
positive regulation of signal transduction	1
Wnt signaling pathway	1
regulation of Wnt signaling pathway	1
endosome organization	1
regulation of intracellular pH	1
intercellular transport	1
synaptic vesicle maturation	1
establishment of localization in cell	1
neuron cellular homeostasis	1
synaptic vesicle cycle	1
monoatomic cation transmembrane transport	1
transport	1
ATP biosynthetic process	1
ubiquitin-like protein ligase binding	1
proton channel activity	1
proton motive force-driven ATP synthesis	1
ligase activity	1
proton transmembrane transporter activity	1
ATPase-coupled monoatomic cation transmembrane transporter activity	1
ATPase activity, coupled to transmembrane movement of ions, rotational mechanism	1
binding	1
monoatomic cation transmembrane transporter activity	1
Golgi apparatus	1
vacuolar membrane	1
vacuolar proton-transporting V-type ATPase complex	1
proton-transporting V-type ATPase, V0 domain	1
lysosome	1
lytic vacuole membrane	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

2892 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ATP6V0C	ATP6V1A	P38606	964
ATP6V0C	ATP6V1F	Q16864	921
ATP6V0C	ATP6V1C1	P21283	909
ATP6V0C	CERS2	Q96G23	906
ATP6V0C	ATP6V1B2	P21281	876
ATP6V0C	SLC10A2	Q12908	857
ATP6V0C	ATP4A	P20648	850
ATP6V0C	ATP6V0D1	P12953	843
ATP6V0C	ATP12A	P54707	837
ATP6V0C	ATP6V1B1	P15313	832
ATP6V0C	ATP6V1E1	P36543	831
ATP6V0C	ATP6V0A1	Q93050	823
ATP6V0C	ATP6V1D	Q9Y5K8	820
ATP6V0C	TCIRG1	Q13488	792
ATP6V0C	ATP6V0A4	Q9HBG4	791
ATP6V0C	ATP6AP1	Q15904	791

IntAct

264 interactions, top by confidence:

A	B	Type	Score
CERS2	ATP6V0C	psi-mi:“MI:0915”(physical association)	0.730
CERS2	ATP6V0C	psi-mi:“MI:0407”(direct interaction)	0.730
ATP6V0C	ATP6AP2	psi-mi:“MI:0914”(association)	0.730
ATP6V0C	MSR1	psi-mi:“MI:0915”(physical association)	0.720
SMIM3	ATP6V0C	psi-mi:“MI:0915”(physical association)	0.720
ATP6V0C	SMIM3	psi-mi:“MI:0915”(physical association)	0.720
MSR1	ATP6V0C	psi-mi:“MI:0915”(physical association)	0.720
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
ATP6V0C	EDA	psi-mi:“MI:0915”(physical association)	0.670
EDA	ATP6V0C	psi-mi:“MI:0915”(physical association)	0.670
ATP6V0C	RETREG3	psi-mi:“MI:0915”(physical association)	0.670
VMA12	ATP6AP2	psi-mi:“MI:0914”(association)	0.640
ATP6V0C	PSMA3	psi-mi:“MI:0915”(physical association)	0.560
PSMA3	ATP6V0C	psi-mi:“MI:0915”(physical association)	0.560
ATP6V0C	REEP4	psi-mi:“MI:0915”(physical association)	0.560
ATP6V0C	ERGIC3	psi-mi:“MI:0915”(physical association)	0.560
ATP6V0C	FNDC9	psi-mi:“MI:0915”(physical association)	0.560
ATP6V0C	IL7R	psi-mi:“MI:0915”(physical association)	0.560
ATP6V0C	IL10RA	psi-mi:“MI:0915”(physical association)	0.560
ATP6V0C	DIABLO	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (197): EDA (Two-hybrid), MSR1 (Two-hybrid), PSMA3 (Two-hybrid), SMIM3 (Two-hybrid), ATP6V0C (Affinity Capture-MS), ATP6V0C (Proximity Label-MS), ATP6V0C (Two-hybrid), ATP6V0C (Two-hybrid), ATP6V0D1 (Affinity Capture-MS), ATP6V0A2 (Affinity Capture-MS), ATP6V0C (Affinity Capture-MS), ATP6V0C (Affinity Capture-MS), VMA21 (Affinity Capture-MS), ATP6V0C (Affinity Capture-MS), ATP6AP2 (Affinity Capture-MS)

ESM2 similar proteins: A0T0P0, A2ZBW5, C0HLB3, C0HLB4, C0HLB5, C0HLB6, O16110, O18882, O22552, O24011, P0DH92, P0DH93, P0DH94, P11024, P23380, P23956, P23957, P25515, P27449, P31403, P31413, P32842, P50515, P51246, P55277, P59228, P59229, P63081, P63082, P68161, P68162, Q00607, Q03105, Q0IUB5, Q13423, Q17046, Q21898, Q26250, Q40585, Q41773

Diamond homologs: A2ZBW5, C0HLB3, C0HLB4, C0HLB5, C0HLB6, O14046, O16110, O18882, O22552, O24011, P0DH92, P0DH93, P0DH94, P23380, P23956, P23957, P23968, P25515, P27449, P31403, P31413, P32842, P50515, P54642, P55277, P59228, P59229, P63081, P63082, P68161, P68162, Q00607, Q03105, Q0IUB5, Q17046, Q21898, Q24808, Q24810, Q26250, Q2TA24

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
RNF182	“down-regulates quantity by destabilization”	ATP6V0C	polyubiquitination
ATP6V0C	“form complex”	V-ATPase	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 93 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
Regulation of MITF-M-dependent genes involved in lysosome biogenesis and autophagy	5	60.0×	1e-06
Insulin receptor recycling	6	40.8×	1e-06
Transferrin endocytosis and recycling	6	39.5×	1e-06
ROS and RNS production in phagocytes	5	30.0×	4e-05
Ion channel transport	8	13.7×	8e-06

GO biological processes:

GO term	Partners	Fold	FDR
synaptic vesicle lumen acidification	6	70.2×	1e-07
vacuolar acidification	6	55.0×	3e-07
lysosomal lumen acidification	5	42.1×	2e-05
proton transmembrane transport	5	19.5×	6e-04
regulation of macroautophagy	5	18.5×	7e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	11
Likely pathogenic	9
Uncertain significance	26
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (20)

Variant ID	HGVS	Classification
1722927	NM_001694.4(ATP6V0C):c.445G>A (p.Ala149Thr)	Pathogenic
2575302	NM_001694.4(ATP6V0C):c.134_135del (p.Ser45fs)	Pathogenic
2575304	NM_001694.4(ATP6V0C):c.188G>C (p.Gly63Ala)	Pathogenic
2575305	NM_001694.4(ATP6V0C):c.283G>C (p.Ala95Pro)	Pathogenic
2575306	NM_001694.4(ATP6V0C):c.409T>C (p.Phe137Leu)	Pathogenic
2575308	NM_001694.4(ATP6V0C):c.448C>T (p.Leu150Phe)	Pathogenic
2575309	NM_001694.4(ATP6V0C):c.64G>A (p.Ala22Thr)	Pathogenic
2575310	NM_001694.4(ATP6V0C):c.361_373del (p.Thr121fs)	Pathogenic
2575311	NM_001694.4(ATP6V0C):c.260_263+11del	Pathogenic
3903275	NM_001694.4(ATP6V0C):c.296_307del (p.Val99_Ser102del)	Pathogenic
816939	NM_001694.4(ATP6V0C):c.467A>T (p.Ter156Leu)	Pathogenic
1710383	NM_001694.4(ATP6V0C):c.404T>C (p.Leu135Pro)	Likely pathogenic
2500798	NM_001694.4(ATP6V0C):c.424G>T (p.Gly142Cys)	Likely pathogenic
3252882	NM_001694.4(ATP6V0C):c.425G>A (p.Gly142Asp)	Likely pathogenic
3253294	NM_001694.4(ATP6V0C):c.395T>A (p.Ile132Asn)	Likely pathogenic
3340928	NM_001694.4(ATP6V0C):c.158T>G (p.Met53Arg)	Likely pathogenic
3358938	NM_001694.4(ATP6V0C):c.376C>T (p.Arg126Ter)	Likely pathogenic
3772671	NM_001694.4(ATP6V0C):c.263dup (p.Ser89fs)	Likely pathogenic
4073638	NM_001694.4(ATP6V0C):c.146C>T (p.Pro49Leu)	Likely pathogenic
4291797	NM_001694.4(ATP6V0C):c.70del (p.Val24fs)	Likely pathogenic

SpliceAI

590 predictions. Top by Δscore:

Variant	Effect	Δscore
16:2514180:GCG:G	donor_gain	1.0000
16:2519214:ACAGC:A	acceptor_loss	1.0000
16:2519215:CA:C	acceptor_loss	1.0000
16:2519216:A:AC	acceptor_loss	1.0000
16:2519216:A:AG	acceptor_gain	1.0000
16:2519217:G:GA	acceptor_gain	1.0000
16:2519217:G:T	acceptor_loss	1.0000
16:2519217:GC:G	acceptor_gain	1.0000
16:2519217:GCC:G	acceptor_gain	1.0000
16:2519217:GCCC:G	acceptor_gain	1.0000
16:2519217:GCCCT:G	acceptor_gain	1.0000
16:2519398:ACAA:A	donor_gain	1.0000
16:2519400:AA:A	donor_gain	1.0000
16:2519402:G:GG	donor_gain	1.0000
16:2519403:T:A	donor_loss	1.0000
16:2519532:C:CA	acceptor_gain	1.0000
16:2519536:CCCAG:C	acceptor_loss	1.0000
16:2519537:CCAG:C	acceptor_loss	1.0000
16:2519539:AG:A	acceptor_gain	1.0000
16:2519539:AGG:A	acceptor_loss	1.0000
16:2519540:G:GC	acceptor_loss	1.0000
16:2519540:GG:G	acceptor_gain	1.0000
16:2519540:GGA:G	acceptor_gain	1.0000
16:2519540:GGAGC:G	acceptor_gain	1.0000
16:2514182:GGTG:G	donor_loss	0.9900
16:2514183:G:GG	donor_gain	0.9900
16:2514183:GTGAG:G	donor_loss	0.9900
16:2514185:GAGC:G	donor_loss	0.9900
16:2519397:TACAA:T	donor_gain	0.9900
16:2519399:CAA:C	donor_gain	0.9900

AlphaMissense

997 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:2514155:G:C	G18R	1.000
16:2519223:G:C	G29R	1.000
16:2519344:G:A	G69D	1.000
16:2519564:G:A	G96D	1.000
16:2519576:G:A	G100D	1.000
16:2519597:G:A	G107D	1.000
16:2519597:G:T	G107V	1.000
16:2519609:G:A	G111D	1.000
16:2519617:G:T	G114W	1.000
16:2519618:G:A	G114E	1.000
16:2519686:T:C	F137L	1.000
16:2519688:C:A	F137L	1.000
16:2519688:C:G	F137L	1.000
16:2519705:T:A	L143H	1.000
16:2519710:G:C	G145R	1.000
16:2514155:G:T	G18C	0.999
16:2514156:G:A	G18D	0.999
16:2514156:G:T	G18V	0.999
16:2519223:G:T	G29C	0.999
16:2519224:G:A	G29D	0.999
16:2519224:G:T	G29V	0.999
16:2519235:G:C	G33R	0.999
16:2519235:G:T	G33C	0.999
16:2519236:G:A	G33D	0.999
16:2519236:G:T	G33V	0.999
16:2519241:G:C	A35P	0.999
16:2519242:C:A	A35D	0.999
16:2519247:A:C	S37R	0.999
16:2519249:C:A	S37R	0.999
16:2519249:C:G	S37R	0.999

dbSNP variants (sampled 300 via entrez): RS1000014505 (16:2514828 G>C,T), RS1000079139 (16:2515896 G>A), RS1000131528 (16:2516208 G>C), RS1000247388 (16:2512963 AG>A,AGG), RS1000338119 (16:2517303 C>G,T), RS1001460608 (16:2512558 T>C,G), RS1001661839 (16:2516418 C>T), RS1001766817 (16:2520530 G>A,T), RS1001870670 (16:2511837 C>T), RS1002007980 (16:2516668 C>T), RS1002213442 (16:2516269 T>C), RS1002264415 (16:2516437 C>A), RS1002456538 (16:2513991 G>A,C,T), RS1002547240 (16:2517517 C>G), RS1003122848 (16:2511739 G>A,T)

Disease associations

OMIM: gene MIM:108745 | disease phenotypes: MIM:620465

GenCC curated gene-disease

Disease	Classification	Inheritance
epilepsy, early-onset, 3, with or without developmental delay	Strong	Autosomal dominant
genetic developmental and epileptic encephalopathy	Limited	Autosomal dominant

Mondo (2): epilepsy, early-onset, 3, with or without developmental delay (MONDO:0958196), genetic developmental and epileptic encephalopathy (MONDO:0100062)

Orphanet (0):

HPO phenotypes

24 total (24 of 24 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000750	Delayed speech and language development
HP:0001249	Intellectual disability
HP:0001256	Mild intellectual disability
HP:0001263	Global developmental delay
HP:0001344	Absent speech
HP:0002069	Bilateral tonic-clonic seizure
HP:0002121	Generalized non-motor (absence) seizure
HP:0002187	Profound intellectual disability
HP:0002342	Moderate intellectual disability
HP:0002373	Febrile seizure (within the age range of 3 months to 6 years)
HP:0002376	Developmental regression
HP:0002384	Focal impaired awareness seizure
HP:0003593	Infantile onset
HP:0003621	Juvenile onset
HP:0007334	Bilateral tonic-clonic seizure with focal onset
HP:0007359	Focal-onset seizure
HP:0010819	Atonic seizure
HP:0010864	Severe intellectual disability
HP:0011463	Childhood onset
HP:0012469	Infantile spasms
HP:0031165	Multifocal seizures
HP:0032792	Tonic seizure
HP:0032794	Myoclonic seizure

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066929 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: transporter — V-type ATPase

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.61	Kd	2462	nM	CHEMBL3752910
5.57	ED50	2695	nM	CHEMBL3752910

PubChem BioAssay actives

1 with measured affinity, of 2 total; 1 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
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149831: Binding affinity to human ATP6V0C incubated for 45 mins by Kinobead based pull down assay	kd	2.4617	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects cotreatment, increases abundance, increases expression	4
Valproic Acid	increases expression, affects expression	3
Arsenic	increases abundance, increases expression, affects expression, affects cotreatment	2
Particulate Matter	increases abundance, increases expression, affects cotreatment	2
aristolochic acid I	increases expression	1
bisphenol F	increases expression	1
TAK-243	decreases sumoylation	1
triphenyl phosphate	affects expression	1
tris(2-butoxyethyl) phosphate	increases abundance, increases expression	1
arsenite	increases reaction, affects binding	1
manganese chloride	increases abundance, increases expression, affects cotreatment	1
ochratoxin A	increases acetylation, increases expression	1
potassium chromate(VI)	affects cotreatment, increases expression	1
epigallocatechin gallate	affects cotreatment, increases expression	1
CD 437	decreases expression	1
bisphenol B	increases expression	1
licochalcone B	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Azacitidine	increases expression	1
Carmustine	decreases expression	1
Bucladesine	increases expression, affects cotreatment	1
Doxorubicin	decreases expression	1
Estradiol	affects cotreatment, increases expression	1
Flame Retardants	increases abundance, increases expression	1
Gasoline	affects cotreatment, increases abundance, increases expression	1
Ivermectin	decreases expression	1
Manganese	affects cotreatment, increases abundance, increases expression	1
Polycyclic Aromatic Hydrocarbons	increases expression, affects cotreatment, increases abundance	1
Rotenone	increases expression	1
Smoke	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652873	Binding	Binding affinity to human ATP6V0C incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT06719141	PHASE3	RECRUITING	A Study to Investigate LP352 in Children and Adults With Developmental and Epileptic Encephalopathies (DEE)
NCT06908226	PHASE3	ENROLLING_BY_INVITATION	A Study to Investigate LP352 in Children and Adults With Developmental and Epileptic Encephalopathy (DEE)
NCT05626634	PHASE2	COMPLETED	Open-label, Long-term Safety Study of LP352 in Subjects With Developmental and Epileptic Encephalopathy
NCT06700811	PHASE1	RECRUITING	Ketogenic Diet for Prevention of Epileptic Spasms in Infantile Onset Genetic Epilepsies
NCT05364021	PHASE1/PHASE2	COMPLETED	Study to Investigate LP352 in Subjects With Developmental and Epileptic Encephalopathies
NCT06983158	PHASE1/PHASE2	SUSPENDED	A Clinical Trial of CAP-002 Gene Therapy in Pediatric Patients With Syntaxin-Binding Protein 1 (STXBP1) Encephalopathy
NCT04937062	EARLY_PHASE1	ACTIVE_NOT_RECRUITING	Phenylbutyrate for Monogenetic Developmental and Epileptic Encephalopathy
NCT06149663	Not specified	AVAILABLE	Intermediate-Size Expanded Access Protocol (EAP) for LP352
NCT06380192	Not specified	RECRUITING	Developmental and Epileptic Encephalopathy of Genetic Etiology: Natural History Through Reuse of Clinical Data
NCT07396883	Not specified	NOT_YET_RECRUITING	Developmental and Epileptic Encephalopathies Diagnosed Via Long-read Genome Sequencing
NCT07531511	Not specified	NOT_YET_RECRUITING	SLC6A1-NDD Prospective Longitudinal Natural History Study
NCT07585643	Not specified	NOT_YET_RECRUITING	IBIS - Investigating Reliability of BIS and SEDLINE Monitoring in Children With Developmental and Epileptic Encephalopathies (DEE).