ATP6V1A

Summary

ATP6V1A (ATPase H+ transporting V1 subunit A, HGNC:851) is a protein-coding gene on chromosome 3q13.31, encoding V-type proton ATPase catalytic subunit A (P38606). Catalytic subunit of the V1 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 99.0% 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. Additional isoforms of many of the V1 and V0 subunit proteins are encoded by multiple genes or alternatively spliced transcript variants. This encoded protein is one of two V1 domain A subunit isoforms and is found in all tissues. Transcript variants derived from alternative polyadenylation exist.

Source: NCBI Gene 523 — RefSeq curated summary.

At a glance

• Gene–disease (curated): developmental and epileptic encephalopathy 93 (Definitive, GenCC) — +3 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 462 total — 17 pathogenic, 10 likely-pathogenic
• Phenotypes (HPO): 154
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 99.0% of screened cell lines (common-essential)
• MANE Select transcript: NM_001690

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:851
Approved symbol	ATP6V1A
Name	ATPase H+ transporting V1 subunit A
Location	3q13.31
Locus type	gene with protein product
Status	Approved
Aliases	Vma1, VA68
Ensembl gene	ENSG00000114573
Ensembl biotype	protein_coding
OMIM	607027
Entrez	523

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 15 protein_coding, 4 protein_coding_CDS_not_defined, 1 retained_intron, 1 nonsense_mediated_decay

ENST00000273398, ENST00000461496, ENST00000462855, ENST00000470455, ENST00000475322, ENST00000496747, ENST00000703904, ENST00000703907, ENST00000703908, ENST00000703909, ENST00000703910, ENST00000703911, ENST00000703912, ENST00000703913, ENST00000899948, ENST00000899949, ENST00000899950, ENST00000899951, ENST00000929060, ENST00000948559, ENST00000948560

RefSeq mRNA: 1 — MANE Select: NM_001690 NM_001690

CCDS: CCDS2976

Canonical transcript exons

ENST00000273398 — 15 exons

Exon	Start	End
ENSE00001194950	113809335	113812056
ENSE00003481403	113789732	113789840
ENSE00003530282	113794872	113794994
ENSE00003547778	113795090	113795204
ENSE00003577207	113788713	113788875
ENSE00003579698	113803583	113803677
ENSE00003608093	113805354	113805525
ENSE00003638527	113786232	113786383
ENSE00003648315	113795876	113795939
ENSE00003665460	113798243	113798446
ENSE00003990271	113778741	113778835
ENSE00003990273	113784224	113784438
ENSE00003990275	113781050	113781178
ENSE00003990276	113747035	113747113
ENSE00003990281	113784696	113784833

Expression profiles

Bgee: expression breadth ubiquitous, 300 present calls, max score 99.73.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 55.6613 / max 904.2777, expressed in 1820 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
37973	50.1843	1816
37974	2.3766	989
37971	1.8542	1045
37972	1.2461	694

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
Brodmann (1909) area 23	UBERON:0013554	99.73	gold quality
middle temporal gyrus	UBERON:0002771	99.67	gold quality
endothelial cell	CL:0000115	99.37	gold quality
pons	UBERON:0000988	99.37	gold quality
choroid plexus epithelium	UBERON:0003911	99.19	gold quality
nephron tubule	UBERON:0001231	99.18	gold quality
orbitofrontal cortex	UBERON:0004167	98.99	gold quality
cerebellar vermis	UBERON:0004720	98.91	gold quality
lateral nuclear group of thalamus	UBERON:0002736	98.89	gold quality
renal medulla	UBERON:0000362	98.80	gold quality
pancreatic ductal cell	CL:0002079	98.79	gold quality
frontal pole	UBERON:0002795	98.79	gold quality
superior vestibular nucleus	UBERON:0007227	98.79	gold quality
kidney epithelium	UBERON:0004819	98.76	gold quality
superior frontal gyrus	UBERON:0002661	98.68	gold quality
substantia nigra pars compacta	UBERON:0001965	98.62	gold quality
postcentral gyrus	UBERON:0002581	98.58	gold quality
parietal lobe	UBERON:0001872	98.55	gold quality
tongue squamous epithelium	UBERON:0006919	98.49	gold quality
renal glomerulus	UBERON:0000074	98.48	gold quality
Brodmann (1909) area 46	UBERON:0006483	98.45	gold quality
esophagus squamous epithelium	UBERON:0006920	98.35	gold quality
metanephric glomerulus	UBERON:0004736	98.29	gold quality
Brodmann (1909) area 10	UBERON:0013541	98.27	gold quality
gingival epithelium	UBERON:0001949	98.26	gold quality
germinal epithelium of ovary	UBERON:0001304	98.24	gold quality
pigmented layer of retina	UBERON:0001782	98.23	gold quality
retina	UBERON:0000966	98.21	gold quality
visceral pleura	UBERON:0002401	98.17	gold quality
entorhinal cortex	UBERON:0002728	98.17	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-CURD-114	yes	592.62
E-HCAD-13	yes	23.70
E-ENAD-27	no	831.64
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): YY1

miRNA regulators (miRDB)

162 targeting ATP6V1A, 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-5692A	100.00	74.40	6850
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-3613-3P	100.00	76.36	7965
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-126-5P	100.00	72.71	3180
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-495-3P	99.96	72.81	4197

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 99.0% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 14)

• there is an important role for physical association between aldolase and the A, B and E subunits of V-ATPase in the regulation of the proton pump (PMID:17576770)
• This protein has been found differentially expressed in the dorsolateral prefrontal cortex from patients with schizophrenia. (PMID:19110265)
• This protein has been found differentially expressed in the Wernicke’s Area from patients with schizophrenia. (PMID:19405953)
• These data introduce Rab11b as a crucial regulator and Rip11 as mediator of acidosis-induced V-ATPase traffic in duct cells of submandibular gland. (PMID:20717956)
• Data show that the cAMP/PKA/CREB signaling pathway initiates acidosis-induced V-ATPase trafficking in salivary ducts via regulation of Rab11b expression. (PMID:22561749)
• V1A subunit of V-ATPase has a role in the progression and prognosis of gastric cancer. (PMID:25652905)
• We report biallelic mutations in ATP6V1E1 and ATP6V1A, respectively encoding the E1 and A subunits of the V1 domain of V-ATPase, as a cause of distinct metabolic and multisystemic cutis laxa entities. (PMID:28065471)
• In conclusion, YY1 may play an important regulatory role in ATP6V1A expression with potential mechanistic and clinical implications in gastric cancer. (PMID:28592880)
• This study provides evidence that de novo heterozygous ATP6V1A mutations cause a developmental encephalopathy with a pathomechanism that involves perturbations of lysosomal homeostasis and neuronal connectivity. (PMID:29668857)
• Expanding the clinical and molecular spectrum of ATP6V1A related metabolic cutis laxa. (PMID:33320377)
• Phenotypic and genetic spectrum of ATP6V1A encephalopathy: a disorder of lysosomal homeostasis. (PMID:35675510)
• Hypoxia promotes EV secretion by impairing lysosomal homeostasis in HNSCC through negative regulation of ATP6V1A by HIF-1alpha. (PMID:36748335)
• ATP6V1A variants are associated with childhood epilepsy with favorable outcome. (PMID:37574426)
• Expanding the Spectrum of Autosomal Dominant ATP6V1A-Related Disease: Case Report and Literature Review. (PMID:39336810)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	atp6v1aa	ENSDARG00000034534
danio_rerio	atp6v1ab	ENSDARG00000076318
mus_musculus	Atp6v1a	ENSMUSG00000052459
rattus_norvegicus	Atp6v1a	ENSRNOG00000001992
drosophila_melanogaster	Vha68-3	FBGN0032464
drosophila_melanogaster	Vha68-2	FBGN0263598
drosophila_melanogaster	Vha68-1	FBGN0265262
caenorhabditis_elegans		WBGENE00013025

Paralogs (4): ATP5F1B (ENSG00000110955), ATP6V1B1 (ENSG00000116039), ATP6V1B2 (ENSG00000147416), ATP5F1A (ENSG00000152234)

Protein

Protein identifiers

V-type proton ATPase catalytic subunit A — P38606 (reviewed: P38606)

Alternative names: V-ATPase 69 kDa subunit, Vacuolar ATPase isoform VA68, Vacuolar proton pump subunit alpha

All UniProt accessions (6): P38606, A0A994J477, A0A994J738, C9JA17, C9JVW8, F8WDJ3

UniProt curated annotations — full annotation on UniProt →

Function. Catalytic subunit of the V1 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, is targeted to the plasma membrane, where it is responsible for acidifying the extracellular environment. In aerobic conditions, involved in intracellular iron homeostasis, thus triggering the activity of Fe(2+) prolyl hydroxylase (PHD) enzymes, and leading to HIF1A hydroxylation and subsequent proteasomal degradation. May play a role in neurite development and synaptic connectivity. (Microbial infection) Plays an important role in virion uncoating during Rabies virus replication after membrane fusion. Specifically, participates in the dissociation of incoming viral matrix M proteins uncoating through direct interaction.

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 WFS1. Interacts with alpha-crystallin B chain/CRYAB and with MTOR, forming a ternary complex. (Microbial infection) Interacts with Rabies virus protein M; this interaction promotes virion uncoating.

Subcellular location. Cytoplasm. Cytosol. Cytoplasmic vesicle. Secretory vesicle. Clathrin-coated vesicle membrane. Lysosome.

Tissue specificity. High expression in the skin.

Post-translational modifications. Phosphorylation at Ser-384 by AMPK down-regulates its enzyme activity.

Disease relevance. Cutis laxa, autosomal recessive, 2D (ARCL2D) [MIM:617403] A form of cutis laxa, a disorder characterized by an excessive congenital skin wrinkling, a large fontanelle with delayed closure, a typical facial appearance with downslanting palpebral fissures, and a general connective tissue weakness. Most ARCL2D patients exhibit severe hypotonia as well as cardiovascular and neurologic involvement. The disease is caused by variants affecting the gene represented in this entry. Epileptic encephalopathy, infantile or early childhood, 3 (IECEE3) [MIM:618012] A form of epileptic encephalopathy, a heterogeneous group of severe childhood onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. IECEE3 is an autosomal dominant form characterized by onset of seizures in the first years of life. The severity of the phenotype is highly variable: some patients may be non-verbal and non-ambulatory with spastic quadriparesis and poor eye contact, whereas others have moderate intellectual disability. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. ATP hydrolysis occurs at the interface between the nucleotide-binding domains of subunits A and B. ATP hydrolysis triggers a conformational change in the subunits D and F, which induces a shift of subunit d. The c-ring is subsequently rotated and results in a continuous proton translocation across the membrane.

Similarity. Belongs to the ATPase alpha/beta chains family.

Isoforms (2)

UniProt ID	Names	Canonical?
P38606-1	1	yes
P38606-2	2

RefSeq proteins (1): NP_001681* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000194	ATPase_F1/V1/A1_a/bsu_nucl-bd	Domain
IPR004100	ATPase_F1/V1/A1_a/bsu_N	Domain
IPR005725	ATPase_V1-cplx_asu	Family
IPR020003	ATPase_a/bsu_AS	Active_site
IPR022878	V-ATPase_asu	Family
IPR023366	ATP_synth_asu-like_sf	Homologous_superfamily
IPR024034	ATPase_F1/V1_b/a_C	Homologous_superfamily
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR031686	ATP-synth_a_Xtn	Domain
IPR036121	ATPase_F1/V1/A1_a/bsu_N_sf	Homologous_superfamily
IPR055190	ATP-synt_VA_C	Domain

Pfam: PF00006, PF02874, PF16886, PF22919

Catalyzed reactions (Rhea), 1 shown:

• ATP + H2O + 4 H(+)(in) = ADP + phosphate + 5 H(+)(out) (RHEA:57720)

UniProt features (86 total): strand 39, helix 19, sequence variant 8, turn 8, sequence conflict 3, modified residue 3, mutagenesis site 2, chain 1, binding site 1, splice variant 1, initiator methionine 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
6WLZ	ELECTRON MICROSCOPY	2.9
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-P38606-F1	90.85	0.74

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 (1): 250–257

Post-translational modifications (3): 136, 384, 2

Mutagenesis-validated functional residues (2):

Position	Phenotype
256	complete loss of interaction with rabies virus protein m; when associated with q-279.
279	complete loss of interaction with rabies virus protein m; when associated with q-256.

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-1222556	ROS and RNS production in phagocytes
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: 675 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_UP, GSE45365_NK_CELL_VS_BCELL_UP, REACTOME_SIGNALING_BY_INSULIN_RECEPTOR, GOBP_REGULATION_OF_AUTOPHAGY, TAATAAT_MIR126, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_ENDOSOME_ORGANIZATION, GOBP_VACUOLE_ORGANIZATION, RORA1_01, GOCC_VACUOLAR_MEMBRANE, GOCC_SECRETORY_GRANULE, GOBP_VESICLE_ORGANIZATION, GOBP_INTRACELLULAR_IRON_ION_HOMEOSTASIS, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, TGACCTY_ERR1_Q2

GO Biological Process (13): intracellular iron ion homeostasis (GO:0006879), vacuolar acidification (GO:0007035), lysosomal lumen acidification (GO:0007042), regulation of macroautophagy (GO:0016241), cellular response to increased oxygen levels (GO:0036295), ATP metabolic process (GO:0046034), 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), homeostatic process (GO:0042592)

GO Molecular Function (5): ATP binding (GO:0005524), ATP hydrolysis activity (GO:0016887), proton-transporting ATPase activity, rotational mechanism (GO:0046961), nucleotide binding (GO:0000166), protein binding (GO:0005515)

GO Cellular Component (23): Golgi membrane (GO:0000139), vacuolar proton-transporting V-type ATPase, V1 domain (GO:0000221), nucleoplasm (GO:0005654), lysosomal membrane (GO:0005765), cytosol (GO:0005829), plasma membrane (GO:0005886), microvillus (GO:0005902), endosome membrane (GO:0010008), membrane (GO:0016020), apical plasma membrane (GO:0016324), proton-transporting two-sector ATPase complex (GO:0016469), secretory granule (GO:0030141), clathrin-coated vesicle membrane (GO:0030665), proton-transporting V-type ATPase complex (GO:0033176), extracellular exosome (GO:0070062), extrinsic component of synaptic vesicle membrane (GO:0098850), cytoplasm (GO:0005737), lysosome (GO:0005764), transport vesicle (GO:0030133), cytoplasmic vesicle (GO:0031410), proton-transporting V-type ATPase, V1 domain (GO:0033180), transmembrane transporter complex (GO:1902495), ATPase complex (GO:1904949)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Innate Immune System	1
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
cellular anatomical structure	4
intracellular pH reduction	3
bounding membrane of organelle	2
cytoplasm	2
endomembrane system	2
intracellular monoatomic cation homeostasis	1
inorganic ion homeostasis	1
vacuolar acidification	1
regulation of autophagy	1
macroautophagy	1
response to increased oxygen levels	1
cellular response to oxygen levels	1
purine ribonucleotide metabolic process	1
purine ribonucleoside triphosphate metabolic process	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
proton transmembrane transport	1
monoatomic cation transmembrane transport	1
transport	1
biological_process	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
ribonucleoside triphosphate phosphatase activity	1
ATP-dependent 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
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
Golgi apparatus	1
vacuole	1
vacuolar proton-transporting V-type ATPase complex	1
proton-transporting V-type ATPase, V1 domain	1
nuclear lumen	1

Protein interactions and networks

STRING

2708 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ATP6V1A	ATP6V0C	P27449	964
ATP6V1A	ATP6V1E1	P36543	928
ATP6V1A	ATP6V1C1	P21283	928
ATP6V1A	ATP6V1D	Q9Y5K8	872
ATP6V1A	ATP6V1B2	P21281	860
ATP6V1A	ATP6V0B	Q99437	855
ATP6V1A	ATP6V0A1	Q93050	841
ATP6V1A	ATP6V1F	Q16864	834
ATP6V1A	ATP6V1C2	Q8NEY4	806
ATP6V1A	ATP6AP1	Q15904	800
ATP6V1A	ATP6V0A2	Q9Y487	797
ATP6V1A	ATP6V0A4	Q9HBG4	787
ATP6V1A	ATP6V1H	Q9UI12	774
ATP6V1A	TCIRG1	Q13488	773
ATP6V1A	ATP6V0D1	P12953	752

IntAct

198 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
ATP6V1C2	ATP6V1G1	psi-mi:“MI:0914”(association)	0.640
	PMPCB	psi-mi:“MI:0914”(association)	0.640
SLC12A2	CLGN	psi-mi:“MI:0914”(association)	0.640
M	ATP6V1A	psi-mi:“MI:0407”(direct interaction)	0.630
ATP6V1A	M	psi-mi:“MI:0915”(physical association)	0.630
M	ATP6V1A	psi-mi:“MI:0915”(physical association)	0.630
SYNGAP1	IGF2BP3	psi-mi:“MI:0914”(association)	0.530
SYNGAP1	SEC16A	psi-mi:“MI:0914”(association)	0.530
ATP6V0A1	ATP6V1G1	psi-mi:“MI:0914”(association)	0.530
ATP6V1A	ATP6V1G1	psi-mi:“MI:0914”(association)	0.530
ATP6V1B2	ATP6V1G1	psi-mi:“MI:0914”(association)	0.530
ATP6V1G2	ATP6V1B1	psi-mi:“MI:0914”(association)	0.530
TCIRG1	AP3D1	psi-mi:“MI:0914”(association)	0.530
ATP6V1A	M	psi-mi:“MI:0915”(physical association)	0.500
CFTR	PLEKHG3	psi-mi:“MI:0914”(association)	0.480

BioGRID (395): ATP6V1A (Affinity Capture-MS), ATP6V1A (Affinity Capture-MS), ATP6V1A (Affinity Capture-MS), ATP6V1A (Affinity Capture-MS), ATP5C1 (Co-fractionation), ATP6V0D1 (Co-fractionation), ATP6V1A (Co-fractionation), ATP6V1A (Co-fractionation), ATP6V1A (Co-fractionation), ATP6V1A (Co-fractionation), ATP6V1A (Co-fractionation), ATP6V1A (Co-fractionation), ATP6V1A (Co-fractionation), ATP6V1A (Co-fractionation), ATP6V1A (Co-fractionation)

ESM2 similar proteins: A0B9K2, A0PZC6, A0RXK1, A2SST5, A3CS71, A3DHP0, A4FXD4, A5I557, A6UP54, A6UT35, A6VFZ2, A7FWQ7, A7GGL4, A7IAU8, A9A2R0, A9AAQ4, B1IJM8, B1KXT6, B2TP91, B2UWY4, O23654, O27036, P09469, P11592, P22662, P31404, P38606, P48414, Q0SSI2, Q0TPW7, Q0W363, Q12WL1, Q184E7, Q29048, Q2FP52, Q2NF87, Q38676, Q38677, Q39291, Q46FH3

Diamond homologs: A0B9K2, A0PZC6, A0RXK1, A2BKX6, A2RC97, A2SST5, A3CK48, A3CS71, A3DHP0, A4FXD4, A4YI05, A5I557, A5UKB2, A6UP54, A6UT35, A6VFZ2, A7FWQ7, A7GGL4, A7IAU8, A8AC29, A8AUJ7, A9A2R0, A9AAQ4, B0K5J0, B0K8E8, B0R755, B1ICC9, B1IJM8, B1KXT6, B2TP91, B2UWY4, B5E552, B5XJH3, B6YV14, B8CZG8, B8ZK31, C1CES2, C1CXU3, C3MQL5, C3MW93

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
YY1	“up-regulates quantity by expression”	ATP6V1A	“transcriptional regulation”
“bafilomycin A1”	“down-regulates activity”	ATP6V1A	“chemical inhibition”
ATP6V1A	“form complex”	V-ATPase	binding
mTORC1	“up-regulates quantity by expression”	ATP6V1A

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 207 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	9	42.9×	2e-11
Insulin receptor recycling	14	37.8×	9e-17
Transferrin endocytosis and recycling	14	36.6×	9e-17
ROS and RNS production in phagocytes	13	31.0×	2e-14
Amino acids regulate mTORC1	13	18.5×	2e-11
RHOH GTPase cycle	5	10.9×	8e-03
Ion channel transport	14	9.5×	3e-08
RHOQ GTPase cycle	6	7.7×	9e-03

GO biological processes:

GO term	Partners	Fold	FDR
synaptic vesicle lumen acidification	11	58.5×	5e-15
vacuolar acidification	11	45.8×	1e-13
lysosomal lumen acidification	7	26.8×	1e-06
proton transmembrane transport	12	21.3×	1e-10
membrane fusion	6	21.3×	5e-05
regulation of macroautophagy	12	20.2×	2e-10
intracellular iron ion homeostasis	6	8.3×	1e-02
transport across blood-brain barrier	7	7.1×	7e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	17
Likely pathogenic	10
Uncertain significance	223
Likely benign	160
Benign	22

Top pathogenic / likely-pathogenic (27)

Variant ID	HGVS	Classification
1512702	NM_001690.4(ATP6V1A):c.955C>T (p.Pro319Ser)	Pathogenic
1722511	NM_001690.4(ATP6V1A):c.1088G>T (p.Gly363Val)	Pathogenic
1722512	NM_001690.4(ATP6V1A):c.1068G>T (p.Glu356Asp)	Pathogenic
1802126	NM_001690.4(ATP6V1A):c.954G>A (p.Met318Ile)	Pathogenic
2423902	NC_000003.11:g.(?113010404)(114099634_?)del	Pathogenic
2570676	NM_001690.4(ATP6V1A):c.1294T>A (p.Phe432Ile)	Pathogenic
3767996	NM_001690.4(ATP6V1A):c.1234C>T (p.Pro412Ser)	Pathogenic
417773	NM_001690.4(ATP6V1A):c.215G>A (p.Gly72Asp)	Pathogenic
443681	GRCh37/hg19 3q13.2-13.31(chr3:112590339-116461450)x1	Pathogenic
4690191	NM_001690.4(ATP6V1A):c.954G>T (p.Met318Ile)	Pathogenic
4780871	NM_001690.4(ATP6V1A):c.941A>G (p.Asn314Ser)	Pathogenic
4819942	NM_001690.4(ATP6V1A):c.959T>C (p.Val320Ala)	Pathogenic
545524	NM_001690.4(ATP6V1A):c.298G>T (p.Asp100Tyr)	Pathogenic
545525	NM_001690.4(ATP6V1A):c.1045G>A (p.Asp349Asn)	Pathogenic
545527	NM_001690.4(ATP6V1A):c.1112A>G (p.Asp371Gly)	Pathogenic
562807	GRCh37/hg19 3q13.2-13.31(chr3:111894832-116930109)x1	Pathogenic
929399	GRCh37/hg19 3q13.2-13.32(chr3:113233952-118525556)x1	Pathogenic
1029520	NM_001690.4(ATP6V1A):c.1649T>C (p.Met550Thr)	Likely pathogenic
1172608	NM_001690.4(ATP6V1A):c.790T>C (p.Ser264Pro)	Likely pathogenic
1803505	NM_001690.4(ATP6V1A):c.634C>T (p.Arg212Cys)	Likely pathogenic
2627987	NM_001690.4(ATP6V1A):c.299A>T (p.Asp100Val)	Likely pathogenic
3256729	NM_001690.4(ATP6V1A):c.841G>A (p.Gly281Arg)	Likely pathogenic
3363195	NM_001690.4(ATP6V1A):c.1068G>C (p.Glu356Asp)	Likely pathogenic
3377061	NM_001690.4(ATP6V1A):c.958G>A (p.Val320Ile)	Likely pathogenic
4073686	NM_001690.4(ATP6V1A):c.935T>C (p.Val312Ala)	Likely pathogenic
4536633	NM_001690.4(ATP6V1A):c.1069G>C (p.Ala357Pro)	Likely pathogenic
584428	NM_001690.4(ATP6V1A):c.1123C>A (p.Pro375Thr)	Likely pathogenic

SpliceAI

2362 predictions. Top by Δscore:

Variant	Effect	Δscore
3:113778739:A:AG	acceptor_gain	1.0000
3:113778740:G:GG	acceptor_gain	1.0000
3:113778740:GGT:G	acceptor_gain	1.0000
3:113778740:GGTA:G	acceptor_gain	1.0000
3:113778832:CCTG:C	donor_gain	1.0000
3:113778832:CCTGG:C	donor_loss	1.0000
3:113778833:CTGG:C	donor_loss	1.0000
3:113778834:TGGTA:T	donor_loss	1.0000
3:113778836:G:GC	donor_loss	1.0000
3:113778836:G:GG	donor_gain	1.0000
3:113778837:T:G	donor_loss	1.0000
3:113781048:A:AG	acceptor_gain	1.0000
3:113781048:AGT:A	acceptor_gain	1.0000
3:113781049:G:GG	acceptor_gain	1.0000
3:113781049:GTG:G	acceptor_gain	1.0000
3:113784829:CCTCT:C	donor_gain	1.0000
3:113784830:CTCT:C	donor_gain	1.0000
3:113784834:G:GG	donor_gain	1.0000
3:113786222:A:AG	acceptor_gain	1.0000
3:113786223:T:G	acceptor_gain	1.0000
3:113786227:TATA:T	acceptor_loss	1.0000
3:113786228:A:AG	acceptor_gain	1.0000
3:113786228:ATAG:A	acceptor_gain	1.0000
3:113786229:T:G	acceptor_gain	1.0000
3:113786229:TAG:T	acceptor_loss	1.0000
3:113786230:A:AG	acceptor_gain	1.0000
3:113786230:AG:A	acceptor_gain	1.0000
3:113786230:AGGAT:A	acceptor_gain	1.0000
3:113786231:G:GT	acceptor_gain	1.0000
3:113786231:GG:G	acceptor_gain	1.0000

AlphaMissense

4055 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:113781121:G:A	G52R	1.000
3:113781121:G:C	G52R	1.000
3:113781122:G:A	G52E	1.000
3:113784311:A:T	D100V	1.000
3:113784313:G:C	G101R	1.000
3:113784314:G:A	G101D	1.000
3:113788724:G:A	G243E	1.000
3:113788744:G:A	G250R	1.000
3:113788744:G:C	G250R	1.000
3:113788745:G:A	G250E	1.000
3:113788750:T:A	F252I	1.000
3:113788750:T:C	F252L	1.000
3:113788751:T:G	F252C	1.000
3:113788752:T:A	F252L	1.000
3:113788752:T:G	F252L	1.000
3:113788753:G:C	G253R	1.000
3:113788754:G:A	G253D	1.000
3:113788758:T:G	C254W	1.000
3:113788759:G:A	G255R	1.000
3:113788759:G:C	G255R	1.000
3:113788760:G:A	G255E	1.000
3:113788760:G:T	G255V	1.000
3:113788762:A:C	K256Q	1.000
3:113788772:T:A	I259K	1.000
3:113788784:T:C	L263P	1.000
3:113788825:T:C	C277R	1.000
3:113788826:G:A	C277Y	1.000
3:113788827:T:G	C277W	1.000
3:113788828:G:C	G278R	1.000
3:113788828:G:T	G278C	1.000

dbSNP variants (sampled 300 via entrez): RS1000150925 (3:113793620 A>G), RS1000156275 (3:113751539 A>G), RS1000236012 (3:113754456 C>T), RS1000292230 (3:113787077 G>A), RS1000345504 (3:113780126 A>T), RS1000358130 (3:113747010 G>A,C,T), RS1000375226 (3:113793294 C>T), RS1000376185 (3:113800258 C>A,T), RS1000410539 (3:113761094 TTTC>T), RS1000420703 (3:113780444 T>C), RS1000423516 (3:113751267 A>G), RS1000490269 (3:113748540 G>A), RS1000503247 (3:113786733 A>G), RS1000577827 (3:113774350 T>C), RS1000578975 (3:113786877 G>A)

Disease associations

OMIM: gene MIM:607027 | disease phenotypes: MIM:618012, MIM:617403, MIM:300672

GenCC curated gene-disease

Disease	Classification	Inheritance
developmental and epileptic encephalopathy 93	Definitive	Autosomal dominant
autosomal recessive cutis laxa type 2D	Strong	Autosomal recessive
autosomal recessive cutis laxa type 2, classic type	Supportive	Autosomal recessive
undetermined early-onset epileptic encephalopathy	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
autosomal recessive cutis laxa type 2D	Limited	AR

Mondo (6): developmental and epileptic encephalopathy 93 (MONDO:0020632), autosomal recessive cutis laxa type 2D (MONDO:0027451), developmental and epileptic encephalopathy, 2 (MONDO:0010396), vascular disorder (MONDO:0005385), autosomal recessive cutis laxa type 2, classic type (MONDO:0009054), undetermined early-onset epileptic encephalopathy (MONDO:0018614)

Orphanet (3): Early infantile developmental and epileptic encephalopathy (Orphanet:1934), West syndrome (Orphanet:3451), CDKL5-deficiency disorder (Orphanet:505652)

HPO phenotypes

154 total (30 of 154 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000023	Inguinal hernia
HP:0000028	Cryptorchidism
HP:0000054	Micropenis
HP:0000218	High palate
HP:0000252	Microcephaly
HP:0000253	Progressive microcephaly
HP:0000272	Malar flattening
HP:0000278	Retrognathia
HP:0000298	Mask-like facies
HP:0000316	Hypertelorism
HP:0000319	Smooth philtrum
HP:0000325	Triangular face
HP:0000343	Long philtrum
HP:0000348	High forehead
HP:0000369	Low-set ears
HP:0000400	Macrotia
HP:0000411	Protruding ear
HP:0000414	Bulbous nose
HP:0000431	Wide nasal bridge
HP:0000455	Broad nasal tip
HP:0000463	Anteverted nares
HP:0000486	Strabismus
HP:0000494	Downslanted palpebral fissures
HP:0000504	Abnormality of vision
HP:0000508	Ptosis
HP:0000518	Cataract
HP:0000540	Hypermetropia
HP:0000546	Retinal degeneration

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST001942_7	Prostate cancer	4.000000e-13

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D014652	Vascular Diseases	C14.907
C564064	CDKL5 deficiency disorder (supp.)
C562632	Cutis Laxa, Autosomal Recessive, Type IIA (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295756 (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
5.79	Kd	1607	nM	CHEMBL5653589
5.79	ED50	1607	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 3 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-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147922: Binding affinity to human ATP6V1A incubated for 45 mins by Kinobead based pull down assay	kd	1.6071	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases methylation, increases expression	4
bisphenol A	increases expression, decreases expression, decreases methylation	3
Cadmium Chloride	increases expression	3
cobaltous chloride	decreases expression, increases expression	2
alpha-Chlorohydrin	decreases reaction, decreases expression	2
Estradiol	affects cotreatment, increases expression	2
Rotenone	increases expression	2
Tretinoin	decreases expression, increases expression	2
Cyclosporine	decreases expression	2
Aflatoxin B1	increases expression, decreases methylation, affects cotreatment	2
aristolochic acid I	increases expression	1
testosterone enanthate	affects expression	1
triphenyl phosphate	affects expression	1
uranyl acetate	affects expression	1
deoxynivalenol	decreases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, decreases expression	1
trichostatin A	affects expression	1
sodium arsenite	increases expression	1
nickel sulfate	decreases expression	1
cupric oxide	increases expression	1
tamibarotene	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
ginsenoside Rb1	decreases expression, decreases reaction	1
bisphenol B	increases expression	1
jinfukang	decreases expression	1
bisphenol AF	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Temozolomide	decreases expression	1
Arsenic Trioxide	increases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4118981	Binding	Binding affinity to ATP6V1A in human NCI-H358 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — Bioorg Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03537742	PHASE2	COMPLETED	Cardiac Allograft Vasculopathy Inhibition With Alirocumab
NCT07075185	PHASE1	RECRUITING	A Study to Evaluate a Novel Gene Therapy in Patients With Relapsed and Refractory Multiple Myeloma
NCT00384540	Not specified	COMPLETED	Cardiac Allograft Vasculopathy and Dobutamine Stress Echocardiography / Brain Natriuretic Peptide Coupling
NCT01642680	Not specified	COMPLETED	Optimal Timing of Physical Activity in Cancer Treatment
NCT03882580	Not specified	UNKNOWN	Reporting, Evaluating, Preventing and Treating the Cardiotoxicity Induced by Anticancer Drugs During a Specific Cardio-oncology Consult and Follow up in Routine Care
NCT04051086	Not specified	UNKNOWN	Quantification of Elastin Markers Synthesis in Williams-Beuren Syndrome and 7q11.23 Micro-duplication Syndrome
NCT05251129	Not specified	WITHDRAWN	Statin InTensity to Prevent Coronary Artery Vasculopathy After Heart Transplantation
NCT05485467	Not specified	COMPLETED	The Role of CD34 + Stem Cells and Biomarkers in the Development of CAV in HTX Patients
NCT06392347	Not specified	NOT_YET_RECRUITING	Evaluation of Accelerated Sampling Techniques for Vessel Wall Imaging
NCT06818760	Not specified	RECRUITING	Remote Monitoring in Pregnant Women With Congenital Heart Disease Using Wrist Wearables