ATP6V0A4

Summary

ATP6V0A4 (ATPase H+ transporting V0 subunit a4, HGNC:866) is a protein-coding gene on chromosome 7q34, encoding V-type proton ATPase 116 kDa subunit a 4 (Q9HBG4). 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.

This gene encodes a component of vacuolar ATPase (V-ATPase), a multisubunit enzyme that mediates acidification of intracellular compartments of eukaryotic cells. V-ATPase dependent 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 is one of four genes in man and mouse that encode different isoforms of the a subunit. Alternatively spliced transcript variants encoding the same protein have been described. Mutations in this gene are associated with renal tubular acidosis associated with preserved hearing.

Source: NCBI Gene 50617 — RefSeq curated summary.

At a glance

• Gene–disease (curated): renal tubular acidosis, distal, 3, with or without sensorineural hearing loss (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 4
• Clinical variants (ClinVar): 652 total — 30 pathogenic, 40 likely-pathogenic
• Phenotypes (HPO): 15
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_020632

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:866
Approved symbol	ATP6V0A4
Name	ATPase H+ transporting V0 subunit a4
Location	7q34
Locus type	gene with protein product
Status	Approved
Aliases	RDRTA2, VPP2, RTADR, a4, Vph1, Stv1
Ensembl gene	ENSG00000105929
Ensembl biotype	protein_coding
OMIM	605239
Entrez	50617

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 15 protein_coding, 1 retained_intron, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000310018, ENST00000353492, ENST00000393054, ENST00000471085, ENST00000478480, ENST00000479909, ENST00000483139, ENST00000644341, ENST00000645515, ENST00000647427, ENST00000868981, ENST00000868982, ENST00000868983, ENST00000868984, ENST00000868985, ENST00000868986, ENST00000868987, ENST00000941116

RefSeq mRNA: 3 — MANE Select: NM_020632 NM_020632, NM_130840, NM_130841

CCDS: CCDS5849

Canonical transcript exons

ENST00000310018 — 22 exons

Exon	Start	End
ENSE00000833427	138755689	138755782
ENSE00000977801	138756458	138756540
ENSE00000977806	138739540	138739633
ENSE00000977807	138734136	138734254
ENSE00000977809	138728761	138728862
ENSE00000977810	138721897	138722025
ENSE00000977812	138709624	138709795
ENSE00001138682	138759752	138759878
ENSE00001355409	138786158	138786260
ENSE00001355412	138798034	138798196
ENSE00001389558	138732877	138733093
ENSE00001415476	138745123	138745280
ENSE00002335521	138715764	138715881
ENSE00003463806	138762340	138762434
ENSE00003497880	138762900	138763025
ENSE00003524140	138768780	138768874
ENSE00003526958	138749167	138749317
ENSE00003632283	138752625	138752837
ENSE00003635321	138769173	138769251
ENSE00003667882	138747425	138747564
ENSE00003819148	138706294	138706717
ENSE00003821405	138771131	138771264

Expression profiles

Bgee: expression breadth ubiquitous, 150 present calls, max score 94.60.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.6789 / max 118.9661, expressed in 182 samples.

FANTOM5 promoters (12 alternative TSS)

Promoter ID	TPM avg	Samples expressed
86460	0.3652	138
86464	0.0907	17
86462	0.0656	25
86459	0.0547	23
86458	0.0352	14
86463	0.0253	8
86461	0.0117	7
86455	0.0109	2
86465	0.0075	4
86466	0.0067	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
metanephros cortex	UBERON:0010533	94.60	gold quality
adult mammalian kidney	UBERON:0000082	94.17	gold quality
renal medulla	UBERON:0000362	90.98	gold quality
kidney	UBERON:0002113	88.35	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	85.22	gold quality
nephron tubule	UBERON:0001231	84.71	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.44	gold quality
parotid gland	UBERON:0001831	83.32	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	81.74	gold quality
cortex of kidney	UBERON:0001225	80.96	gold quality
skin of leg	UBERON:0001511	79.41	gold quality
kidney epithelium	UBERON:0004819	79.33	gold quality
cartilage tissue	UBERON:0002418	79.15	gold quality
saliva-secreting gland	UBERON:0001044	78.67	gold quality
metanephros	UBERON:0000081	77.61	gold quality
skin of abdomen	UBERON:0001416	77.19	gold quality
zone of skin	UBERON:0000014	76.71	gold quality
oral cavity	UBERON:0000167	76.43	gold quality
minor salivary gland	UBERON:0001830	76.09	gold quality
buccal mucosa cell	CL:0002336	74.95	gold quality
lower esophagus mucosa	UBERON:0035834	74.72	gold quality
mouth mucosa	UBERON:0003729	73.26	gold quality
metanephric glomerulus	UBERON:0004736	72.45	silver quality
renal glomerulus	UBERON:0000074	71.42	silver quality
mucosa of paranasal sinus	UBERON:0005030	71.22	silver quality
upper leg skin	UBERON:0004262	69.94	gold quality
tonsil	UBERON:0002372	69.81	gold quality
esophagus mucosa	UBERON:0002469	69.20	gold quality
esophagus squamous epithelium	UBERON:0006920	68.89	gold quality
epithelium of bronchus	UBERON:0002031	67.21	silver quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-CURD-119	yes	35.61
E-CURD-114	yes	10.87
E-ANND-3	yes	6.02

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

21 targeting ATP6V0A4, 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-4795-3P	100.00	74.62	4024
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-205-5P	99.81	70.05	1557
HSA-MIR-374C-5P	99.80	72.06	2910
HSA-MIR-655-3P	99.80	72.19	2909
HSA-MIR-3617-5P	99.75	69.41	1968
HSA-MIR-641	99.75	69.35	1975
HSA-MIR-580-3P	99.67	69.23	1841
HSA-MIR-6722-3P	99.45	67.62	1919
HSA-MIR-372-5P	99.41	69.11	2299
HSA-MIR-16-2-3P	99.29	70.60	1954
HSA-MIR-195-3P	99.29	70.61	1954
HSA-MIR-6734-3P	99.15	66.27	1627
HSA-MIR-1909-3P	99.03	66.56	1662
HSA-MIR-6780A-3P	98.42	67.49	1518
HSA-MIR-4275	97.96	68.42	1549
HSA-MIR-144-5P	97.66	69.90	531
HSA-MIR-6506-3P	96.01	68.49	80
HSA-MIR-339-3P	94.34	67.96	97

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 20)

• stability and function of the metabolon composed of H+ATPase and glycolytic components can be compromised by either loss of required PFK-1 binding (G820R) or loss of pump protein (R807Q) (PMID:18632794)
• the a4 isoform may be responsible for targeting V-ATPases to the plasma membrane of MB231 cells and that cell surface V-ATPases play a significant role in breast cancer invasion (PMID:19366680)
• Mutations in ATP6V0A4 present enlarged vestibular aqueduct and early onset sensorial hearing loss. (PMID:19639346)
• Novel compound heterozygous ATP6V0A4 mutations in an infant with distal renal tubular acidosis. (PMID:20221774)
• There is the first evidence presented with progressive hearing loss associated with ATP6VOA4 mutation in a chinese patient. (PMID:22093743)
• This study demonistrated that expression identifies subtypes of oligodendrogliomas, pilocytic astrocytomas and gangliogliomas and may contribute to refine characterization of these tumors. (PMID:22460948)
• Case Report: novel ATP6V0A4 gene mutation confirmed autosomal recessive distal renal tubular acidosis with normal hearing. (PMID:22854161)
• Mutations of the ATP6V0A4 gene is associated with primary distal renal tubular acidosis. (PMID:23729491)
• The function of vacuolar ATPase (V-ATPase) a subunit isoforms in invasiveness of MCF10a and MCF10CA1a human breast cancer cells. (PMID:24072707)
• Four mutations in the ATP6V0A4 gene were obesrved one single nucleotide deletion in exon 13, the nonsensein exon 3, and the missense changes in exon 17 and in exon 19. (PMID:24252324)
• Two from different families carrying ATP6V0A4 mutations manifested early onset moderate mixed HL and moderate SNHL (PMID:24975934)
• For the remaining patients, two mutations in the ATP6V0A4 gene, one of them being novel, were found in three Tunisian cases. (PMID:25285676)
• e have described patients with severe distal renal tubular acidosis and a novel splicing mutation in the ATP6V0A4 gene in a family originating from the Siliana region in northwestern Tunisia (PMID:25572248)
• Functional analysis of selected regulated proteins revealed that knockdown of HNRPD, PHB2 and UB2V2 can increase HCMV replication, while knockdown of A4 and KSRP resulted in decreased HCMV replication. (PMID:25910425)
• ITM2A expression is positively regulated by PKA-CREB signaling and ITM2A expression interferes with autophagic flux by interacting with vacuolar ATPase. (PMID:25951193)
• The aim of this work was to analyze the prevalence of genetic defects in SLC4A1, ATP6V0A4, and ATP6V1B1 genes and to assess the clinical phenotype of distal renal tubular acidosis patients that are eventually typical of the different genetic forms of the disease. (PMID:28233610)
• Distal renal acidosis patient carries two novel mutations, one in each of the genes ATP6V0A4 and ATP6V1B1. (PMID:29024829)
• The p. P137S and p. R302W mutations in ATP6V1B1 and p. S473F and p. R807X in ATP6V0A4, were novel disease-causing mutations of distal renal tubular acidosis. (PMID:30230413)
• a novel heterozygous intronic mutation (c.639 + 1G>A) in the ATP6V0A4 gene was identified along with a heterozygous nonsense variant (c.580C>T, p.Arg194*). (PMID:30256676)
• Identification of seven exonic variants in the SLC4A1, ATP6V1B1, and ATP6V0A4 genes that alter RNA splicing by minigene assay. (PMID:34157794)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	si:ch73-173p19.2	ENSDARG00000103971
mus_musculus	Atp6v0a4	ENSMUSG00000038600
rattus_norvegicus	Atp6v0a4	ENSRNOG00000013428

Paralogs (3): ATP6V0A1 (ENSG00000033627), TCIRG1 (ENSG00000110719), ATP6V0A2 (ENSG00000185344)

Protein

Protein identifiers

V-type proton ATPase 116 kDa subunit a 4 — Q9HBG4 (reviewed: Q9HBG4)

Alternative names: Vacuolar proton translocating ATPase 116 kDa subunit a isoform 4, Vacuolar proton translocating ATPase 116 kDa subunit a kidney isoform

All UniProt accessions (5): Q9HBG4, A0A2R8Y6X9, A0A2R8Y7G6, A0A2R8YE46, A0A2R8YGN5

UniProt curated annotations — full annotation on UniProt →

Function. 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, is targeted to the plasma membrane, where it is responsible for acidifying the extracellular environment. Involved in normal vectorial acid transport into the urine by the kidney.

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 V1 complex V-ATPase subunit A ATP6V1A. Interacts with the V0 complex V-ATPase subunit c ATP6V0C.

Subcellular location. Apical cell membrane. Basolateral cell membrane.

Tissue specificity. Expressed in adult and fetal kidney. Found in the inner ear.

Disease relevance. Renal tubular acidosis, distal, 3, with or without sensorineural hearing loss (DRTA3) [MIM:602722] An autosomal recessive disease characterized by reduced ability to acidify urine, variable hyperchloremic hypokalemic metabolic acidosis, nephrocalcinosis, and nephrolithiasis. It is due to functional failure of alpha-intercalated cells of the cortical collecting duct of the distal nephron, where vectorial proton transport is required for urinary acidification. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the V-ATPase 116 kDa subunit family.

RefSeq proteins (3): NP_065683, NP_570855, NP_570856 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002490	V-ATPase_116kDa_su	Family
IPR026028	V-type_ATPase_116kDa_su_euka	Family

Pfam: PF01496

UniProt features (30 total): sequence variant 10, topological domain 9, transmembrane region 8, chain 1, region of interest 1, sequence conflict 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
9DET	ELECTRON MICROSCOPY	3
7UNF	ELECTRON MICROSCOPY	4.08

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9HBG4-F1	83.39	0.39

Function

Pathways and Gene Ontology

Reactome pathways

4 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-983712	Ion channel transport

MSigDB gene sets: 179 (showing top): GOBP_EXCRETION, REACTOME_SIGNALING_BY_INSULIN_RECEPTOR, REACTOME_INNATE_IMMUNE_SYSTEM, GOCC_VACUOLAR_MEMBRANE, GOBP_SENSORY_PERCEPTION_OF_MECHANICAL_STIMULUS, GOBP_VESICLE_ORGANIZATION, KEGG_LYSOSOME, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_MONOATOMIC_CATION_TRANSPORT, GATA6_01, GOBP_VACUOLAR_ACIDIFICATION, ZIC1_01, GOMF_PROTON_TRANSMEMBRANE_TRANSPORTER_ACTIVITY, GOBP_OSSIFICATION, GOBP_REGULATION_OF_PH

GO Biological Process (9): ossification (GO:0001503), regulation of pH (GO:0006885), vacuolar acidification (GO:0007035), sensory perception of sound (GO:0007605), intracellular pH reduction (GO:0051452), renal tubular secretion (GO:0097254), synaptic vesicle lumen acidification (GO:0097401), proton transmembrane transport (GO:1902600), monoatomic ion transport (GO:0006811)

GO Molecular Function (3): proton-transporting ATPase activity, rotational mechanism (GO:0046961), ATPase binding (GO:0051117), protein binding (GO:0005515)

GO Cellular Component (17): vacuolar proton-transporting V-type ATPase, V0 domain (GO:0000220), lysosomal membrane (GO:0005765), endosome (GO:0005768), plasma membrane (GO:0005886), endosome membrane (GO:0010008), basolateral plasma membrane (GO:0016323), apical plasma membrane (GO:0016324), vacuolar proton-transporting V-type ATPase complex (GO:0016471), phagocytic vesicle membrane (GO:0030670), synaptic vesicle membrane (GO:0030672), brush border membrane (GO:0031526), proton-transporting V-type ATPase complex (GO:0033176), apical part of cell (GO:0045177), extracellular exosome (GO:0070062), brush border (GO:0005903), membrane (GO:0016020), proton-transporting V-type ATPase, V0 domain (GO:0033179)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Innate Immune System	1
Signaling by Insulin receptor	1
Iron uptake and transport	1
Transport of small molecules	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
vacuolar membrane	2
plasma membrane region	2
apical part of cell	2
proton-transporting V-type ATPase complex	2
cellular anatomical structure	2
multicellular organismal process	1
monoatomic cation homeostasis	1
biological regulation	1
intracellular pH reduction	1
sensory perception of mechanical stimulus	1
regulation of intracellular pH	1
renal system process	1
excretion	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
proton transmembrane transporter activity	1
ATPase-coupled monoatomic cation transmembrane transporter activity	1
ATPase activity, coupled to transmembrane movement of ions, rotational mechanism	1
enzyme binding	1
binding	1
vacuolar proton-transporting V-type ATPase complex	1
proton-transporting V-type ATPase, V0 domain	1
lysosome	1
lytic vacuole membrane	1
endomembrane system	1
cytoplasmic vesicle	1
membrane	1
cell periphery	1
endosome	1
cytoplasmic vesicle membrane	1
bounding membrane of organelle	1
basal plasma membrane	1
endocytic vesicle membrane	1
phagocytic vesicle	1

Protein interactions and networks

STRING

1168 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ATP6V0A4	ATP6V1B1	P15313	990
ATP6V0A4	ATP12A	P54707	902
ATP6V0A4	ATP4A	P20648	902
ATP6V0A4	SLC4A1	P02730	843
ATP6V0A4	ATP6V1C2	Q8NEY4	840
ATP6V0A4	ATP6V1B2	P21281	799
ATP6V0A4	ATP6V0D1	P12953	799
ATP6V0A4	ATP6V1E2	Q96A05	795
ATP6V0A4	ATP6V1C1	P21283	795
ATP6V0A4	ATP6V0D2	Q8N8Y2	793
ATP6V0A4	ATP6V0C	P27449	791
ATP6V0A4	ATP6V1G3	Q96LB4	788
ATP6V0A4	ATP6V1A	P38606	787
ATP6V0A4	ATP6V1F	Q16864	764
ATP6V0A4	ATP6V0B	Q99437	764

IntAct

8 interactions, top by confidence:

A	B	Type	Score
ATP6V0A4	APOE	psi-mi:“MI:0915”(physical association)	0.560
ATP6V0A4	ATP6AP2	psi-mi:“MI:0914”(association)	0.530
Npc1	ESYT2	psi-mi:“MI:0914”(association)	0.350
ATP6V0A4	ATP6V0C	psi-mi:“MI:0914”(association)	0.350

BioGRID (45): ATP6V0A4 (Affinity Capture-MS), ATP6V1B1 (Affinity Capture-Western), ATP6V0A4 (Reconstituted Complex), ATP6V0A4 (Affinity Capture-RNA), PFKM (Affinity Capture-Western), PFKM (Reconstituted Complex), ATP6V0A4 (Affinity Capture-MS), ATP6V0A4 (Affinity Capture-MS), ATP6AP1 (Affinity Capture-MS), IGFN1 (Affinity Capture-MS), CCDC115 (Affinity Capture-MS), ATP6V0D1 (Affinity Capture-MS), VMA21 (Affinity Capture-MS), FKBP5 (Affinity Capture-MS), TMEM199 (Affinity Capture-MS)

ESM2 similar proteins: A0A452G813, A0A8V0ZB02, A1L3G9, A2AWR3, A9LIW2, B6HTR9, D3ZNF5, F4I248, F4JCY2, O35379, O57428, O94886, O94911, P08983, Q059Y8, Q06538, Q09427, Q09428, Q09429, Q17JQ7, Q3KTM2, Q3TWI9, Q4R7U0, Q4V8U5, Q5GH22, Q5GH60, Q5GH68, Q5R826, Q5R9A7, Q5T3F8, Q5YCC5, Q6NP91, Q6PP77, Q6UR05, Q7Q5R7, Q7Z3F1, Q7Z402, Q8C428, Q8CBX0, Q8CG09

Diamond homologs: A1A5G6, B2MZD0, G5EEK9, G5EGP4, O13742, O29106, O57721, O97681, P15920, P25286, P30628, P32563, P37296, Q01290, Q13488, Q29466, Q54E04, Q57675, Q5JDS2, Q5R422, Q8AVM5, Q8RWZ7, Q8W4S4, Q920R6, Q93050, Q9HBG4, Q9I8D0, Q9SJT7, Q9UWW3, Q9UXU2, Q9Y487, Q9Z1G4, Q9YEA0, O27041, Q9HND8, O83544

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	30
Likely pathogenic	40
Uncertain significance	267
Likely benign	133
Benign	110

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1074131	NM_020632.3(ATP6V0A4):c.154_157del (p.Val52fs)	Pathogenic
1074132	NM_020632.3(ATP6V0A4):c.16C>T (p.Arg6Ter)	Pathogenic
1323841	NM_020632.3(ATP6V0A4):c.1872C>A (p.Tyr624Ter)	Pathogenic
1328935	NM_020632.3(ATP6V0A4):c.2257+1G>A	Pathogenic
1344704	NM_020632.3(ATP6V0A4):c.2446A>G (p.Lys816Glu)	Pathogenic
1344705	NM_020632.3(ATP6V0A4):c.1312_1315del (p.Asp438fs)	Pathogenic
1700298	NM_020632.3(ATP6V0A4):c.1185del (p.Tyr396fs)	Pathogenic
1705668	NM_020632.3(ATP6V0A4):c.1030-2A>C	Pathogenic
1802247	NM_020632.3(ATP6V0A4):c.1510C>T (p.Gln504Ter)	Pathogenic
2767196	NM_020632.3(ATP6V0A4):c.195_196dup (p.Arg66fs)	Pathogenic
2779421	NM_020632.3(ATP6V0A4):c.2390_2391del (p.Glu797fs)	Pathogenic
280715	NM_020632.3(ATP6V0A4):c.334C>T (p.Gln112Ter)	Pathogenic
3034523	NM_020632.3(ATP6V0A4):c.338del (p.Asn113fs)	Pathogenic
3381029	NM_020632.3(ATP6V0A4):c.2004del (p.Lys668fs)	Pathogenic
3594360	NM_020632.3(ATP6V0A4):c.727C>T (p.Arg243Ter)	Pathogenic
3773929	NM_020632.3(ATP6V0A4):c.1107del (p.Asn370fs)	Pathogenic
422991	NM_020632.3(ATP6V0A4):c.1006_1007del (p.Lys336fs)	Pathogenic
450987	NM_020632.3(ATP6V0A4):c.1572G>A (p.Pro524=)	Pathogenic
4771504	NM_020632.3(ATP6V0A4):c.826del (p.Gln276fs)	Pathogenic
4796566	NM_020632.3(ATP6V0A4):c.639+1G>A	Pathogenic
5150	NM_020632.3(ATP6V0A4):c.2257C>T (p.Gln753Ter)	Pathogenic
5153	NM_020632.3(ATP6V0A4):c.105del (p.Gln36fs)	Pathogenic
5155	NM_020632.3(ATP6V0A4):c.418-1G>A	Pathogenic
5156	NM_020632.3(ATP6V0A4):c.829del (p.Thr277fs)	Pathogenic
5158	NM_020632.3(ATP6V0A4):c.1506T>A (p.Tyr502Ter)	Pathogenic
520733	NM_020632.3(ATP6V0A4):c.777del (p.Met259fs)	Pathogenic
802371	NM_020632.3(ATP6V0A4):c.369_373del (p.Glu123fs)	Pathogenic
955469	NM_020632.3(ATP6V0A4):c.2258-1G>A	Pathogenic
973549	NM_020632.3(ATP6V0A4):c.2140-61_2257+166del	Pathogenic
977293	NM_020632.3(ATP6V0A4):c.2137del (p.Glu713fs)	Pathogenic

SpliceAI

3872 predictions. Top by Δscore:

Variant	Effect	Δscore
7:138709791:CAGTT:C	acceptor_gain	1.0000
7:138709796:C:CC	acceptor_gain	1.0000
7:138715762:A:AC	donor_gain	1.0000
7:138715763:C:CC	donor_gain	1.0000
7:138715882:C:CC	acceptor_gain	1.0000
7:138721856:CAAA:C	donor_gain	1.0000
7:138721859:A:AC	donor_gain	1.0000
7:138721860:C:CC	donor_gain	1.0000
7:138721871:T:TA	donor_gain	1.0000
7:138733091:TAT:T	acceptor_gain	1.0000
7:138733092:ATCT:A	acceptor_loss	1.0000
7:138733093:TC:T	acceptor_loss	1.0000
7:138733094:C:CA	acceptor_loss	1.0000
7:138733094:C:CC	acceptor_gain	1.0000
7:138733100:G:GC	acceptor_gain	1.0000
7:138733115:A:C	acceptor_gain	1.0000
7:138734134:A:AC	donor_gain	1.0000
7:138734135:C:CC	donor_gain	1.0000
7:138734135:CA:C	donor_gain	1.0000
7:138734250:CAAAT:C	acceptor_gain	1.0000
7:138734251:AAAT:A	acceptor_gain	1.0000
7:138734251:AAATC:A	acceptor_loss	1.0000
7:138734252:AAT:A	acceptor_gain	1.0000
7:138734252:AATCT:A	acceptor_loss	1.0000
7:138734253:AT:A	acceptor_gain	1.0000
7:138734253:ATCTG:A	acceptor_loss	1.0000
7:138734254:TCT:T	acceptor_loss	1.0000
7:138734255:C:CC	acceptor_gain	1.0000
7:138734255:CT:C	acceptor_loss	1.0000
7:138734256:T:A	acceptor_loss	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000008958 (7:138745577 C>T), RS1000076270 (7:138722388 C>A,G,T), RS1000132665 (7:138712203 G>A), RS1000154953 (7:138773318 T>C), RS1000157181 (7:138777949 C>T), RS1000171722 (7:138790891 G>A), RS1000205377 (7:138797011 C>T), RS1000212134 (7:138737911 G>A), RS1000263907 (7:138757082 A>G), RS1000295545 (7:138719477 G>T), RS1000297689 (7:138726229 T>C), RS1000344856 (7:138715382 G>T), RS1000351177 (7:138796459 T>C), RS1000373827 (7:138763579 G>T), RS1000374192 (7:138795818 T>G)

Disease associations

OMIM: gene MIM:605239 | disease phenotypes: MIM:602722, MIM:255995, MIM:267300

GenCC curated gene-disease

Disease	Classification	Inheritance
renal tubular acidosis, distal, 3, with or without sensorineural hearing loss	Strong	Autosomal recessive
autosomal recessive distal renal tubular acidosis	Supportive	Autosomal recessive

Mondo (6): renal tubular acidosis, distal, 3, with or without sensorineural hearing loss (MONDO:0011268), autosomal recessive distal renal tubular acidosis (MONDO:0018440), distal renal tubular acidosis (MONDO:0015827), Bailey-Bloch congenital myopathy (MONDO:0009722), renal tubular acidosis, distal, 2, with progressive sensorineural hearing loss (MONDO:0009968), sensorineural hearing loss disorder (MONDO:0020678)

Orphanet (4): Autosomal recessive distal renal tubular acidosis (Orphanet:402041), Distal renal tubular acidosis (Orphanet:18), Native American myopathy (Orphanet:168572), Autosomal recessive distal renal tubular acidosis with deafness (Orphanet:93611)

HPO phenotypes

15 total (16 of 15 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000121	Nephrocalcinosis
HP:0001508	Failure to thrive
HP:0001510	Growth delay
HP:0001942	Metabolic acidosis
HP:0001944	Dehydration
HP:0002013	Vomiting
HP:0002150	Hypercalciuria
HP:0002748	Rickets
HP:0002900	Hypokalemia
HP:0003593	Infantile onset
HP:0003623	Neonatal onset
HP:0008341	Distal renal tubular acidosis
HP:0008619	Bilateral sensorineural hearing impairment
HP:0011463	Childhood onset
HP:0000407	Sensorineural hearing impairment

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST000982_5	F-cell distribution in sickle cell anaemia	6.000000e-06
GCST009368_52	HDL cholesterol levels x long total sleep time interaction (2df test)	3.000000e-08
GCST009368_81	HDL cholesterol levels x long total sleep time interaction (2df test)	4.000000e-10
GCST012442_43	Age-related hearing impairment	1.000000e-10

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004576	fetal hemoglobin measurement
EFO:0004612	high density lipoprotein cholesterol measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
C538343	Native American myopathy (supp.)
C562897	Renal Tubular Acidosis, Distal, with Progressive Nerve Deafness (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: transporter — V-type ATPase

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression	3
sodium arsenite	increases expression	2
Panobinostat	affects cotreatment, increases expression	2
Benzo(a)pyrene	affects methylation, decreases methylation	2
Estradiol	decreases expression	2
Nickel	decreases expression	2
Aflatoxin B1	increases methylation	2
aristolochic acid I	increases expression	1
propionaldehyde	increases expression	1
trichostatin A	increases expression	1
tris(2-butoxyethyl) phosphate	increases expression	1
beta-lapachone	decreases expression, increases expression	1
perfluorooctanoic acid	increases expression, affects cotreatment	1
benzo(e)pyrene	decreases methylation	1
potassium chromate(VI)	increases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
(+)-JQ1 compound	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Zoledronic Acid	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Cosmetics	affects cotreatment, increases expression	1
Endosulfan	decreases expression	1
Etoposide	affects response to substance	1
Flame Retardants	affects cotreatment, increases expression	1
Folic Acid	increases expression	1
Methapyrilene	decreases methylation	1
Plant Extracts	affects cotreatment, decreases expression	1
Plasticizers	affects cotreatment, increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03644706	PHASE3	TERMINATED	Study Evaluating Subjects With Distal Renal Tubular Acidosis
NCT01655212	PHASE3	TERMINATED	Congenital Cytomegalovirus: Efficacy of Antiviral Treatment in a Randomized Controlled Trial
NCT02005822	PHASE3	COMPLETED	Congenital Cytomegalovirus: Efficacy of Antiviral Treatment
NCT03374514	PHASE3	UNKNOWN	Cochlear Electrical Impedance and the Effect of Topical Dexamethasone on Cochlear Implant Surgery
NCT02497690	PHASE2	COMPLETED	Effectiveness of Therapy Via Telemedicine Following Cochlear Implants
NCT03107871	PHASE2	ACTIVE_NOT_RECRUITING	Randomized Controlled Trial of Valganciclovir for Cytomegalovirus Infected Hearing Impaired Infants
NCT04120116	PHASE2	COMPLETED	FX-322 in Adults With Stable Sensorineural Hearing Loss
NCT05061758	PHASE2	WITHDRAWN	A Trial of LY3056480 in Patients With SNLH
NCT07364747	PHASE2	RECRUITING	Protective Effect of Acetylcysteine Against Cisplatinum-Induced Ototoxicity: A Randomized Controlled Trial
NCT02259595	PHASE1	COMPLETED	Study to Determine the Safety, Tolerability, and Pharmacokinetic Profile of HPN-07 and HPN-07 Plus NAC
NCT06065852	Not specified	RECRUITING	National Registry of Rare Kidney Diseases
NCT02693704	PHASE2/PHASE3	COMPLETED	Evaluation of a Binaural Spatialization Method for Hearing Aids
NCT02882477	PHASE2/PHASE3	UNKNOWN	Treatment of Wolfram Syndrome Type 2 With the Chelator Deferiprone and Incretin Based Therapy
NCT01267994	PHASE1/PHASE2	COMPLETED	A Clinical Trial of Anakinra for Steroid-Resistant Autoimmune Inner Ear Disease
NCT01902914	PHASE1/PHASE2	UNKNOWN	Effectiveness of P02 Digital Hearing Aids
NCT02038972	PHASE1/PHASE2	COMPLETED	Safety of Autologous Stem Cell Infusion for Children With Acquired Hearing Loss
NCT02616172	PHASE1/PHASE2	SUSPENDED	Autologous Bone Marrow Harvest and Transplant for Sensorineural Hearing Loss
NCT03616223	PHASE1/PHASE2	COMPLETED	FX-322 in Sensorineural Hearing Loss
NCT04129775	PHASE1/PHASE2	COMPLETED	OTO-413 in Subjects With Speech-in-Noise Hearing Impairment
NCT04462198	PHASE1/PHASE2	COMPLETED	Phase I/IIa Study Evaluating Safety and Efficacy of an Intratympanic Dose of PIPE-505 in Subjects With Hearing Loss
NCT07032038	PHASE1/PHASE2	NOT_YET_RECRUITING	First In Human Randomised Trial of Rincell-1 in Adults With a Cochlear Implant
NCT06025097	EARLY_PHASE1	COMPLETED	Intra-Tympanic Steroid With PRP Combination in Sensorineural Hearing Loss and Tinnitus.
NCT06707389	EARLY_PHASE1	NOT_YET_RECRUITING	Autologous Blood Monocyte Vesicles for the Treatment of Sudden Deafness
NCT07472023	EARLY_PHASE1	ENROLLING_BY_INVITATION	Regenerative Medicine and Stem Cell-Based Interventions for Inner Ear Trauma, Tinnitus, and Sensorineural Hearing Loss
NCT00023036	Not specified	COMPLETED	Clinical and Genetic Analysis of Enlarged Vestibular Aqueducts
NCT00023049	Not specified	COMPLETED	Genetic Analysis of Hereditary Disorders of Hearing and Balance
NCT00261768	Not specified	COMPLETED	Efficacy of Digital Noise Reduction Strategies: A Hearing Aid Trial
NCT00589511	Not specified	COMPLETED	Nucleus Freedom Cochlear Implant System Pediatric Post-approval Study
NCT00678899	Not specified	COMPLETED	Evaluation of the Nucleus Hybrid™ L24 Cochlear Implant System
NCT00787189	Not specified	COMPLETED	Study of Low Level Laser Therapy and Word Recognition in Hearing Impaired Individuals
NCT01184248	Not specified	COMPLETED	The Effect of Sound Stimulation on Pure-tone Hearing Threshold
NCT01434446	Not specified	COMPLETED	The Effect of Sound Stimulation on Hearing Ability
NCT01749592	Not specified	COMPLETED	Single-sided Deafness and Cochlear Implants
NCT01781039	Not specified	COMPLETED	Investigation of Anatomical Correlates of Speech Discrimination
NCT02082431	Not specified	COMPLETED	Determine the Incidence of Long QT Amongst a Large Cohort of Subjects Diagnosed With Unilateral or Bilateral Sensorineural Hearing Loss.
NCT02093806	Not specified	UNKNOWN	Clinical Applications of Round Window Imaging Anatomy in Cochlear Implant Surgery
NCT02252601	Not specified	UNKNOWN	Evaluation of the High Frequency Digit Triplet Test in Cystic Fibrosis
NCT02584361	Not specified	UNKNOWN	Cochlear Implant and Vestibular Function.
NCT02638883	Not specified	COMPLETED	Implantation of the Cochlear™ Nucleus® Hybrid S Round Window (S-RW) in Adults
NCT02689349	Not specified	COMPLETED	Esteem New Subject Enrollment Post Approval Study