ATP6V1B1

Summary

ATP6V1B1 (ATPase H+ transporting V1 subunit B1, HGNC:853) is a protein-coding gene on chromosome 2p13.3, encoding V-type proton ATPase subunit B, kidney isoform (P15313). Non-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.

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 B subunit isoforms and is found in the kidney. Mutations in this gene cause distal renal tubular acidosis associated with sensorineural deafness.

Source: NCBI Gene 525 — RefSeq curated summary.

At a glance

• Gene–disease (curated): renal tubular acidosis, distal, 2, with progressive sensorineural hearing loss (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 3
• Clinical variants (ClinVar): 870 total — 55 pathogenic, 49 likely-pathogenic
• Phenotypes (HPO): 4
• Druggable target: yes
• MANE Select transcript: NM_001692

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:853
Approved symbol	ATP6V1B1
Name	ATPase H+ transporting V1 subunit B1
Location	2p13.3
Locus type	gene with protein product
Status	Approved
Aliases	VATB, RTA1B, Vma2
Ensembl gene	ENSG00000116039
Ensembl biotype	protein_coding
OMIM	192132
Entrez	525

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 9 protein_coding, 3 retained_intron

ENST00000234396, ENST00000412314, ENST00000432098, ENST00000433895, ENST00000454446, ENST00000463380, ENST00000495118, ENST00000872155, ENST00000872156, ENST00000872157, ENST00000872158, ENST00000872159

RefSeq mRNA: 1 — MANE Select: NM_001692 NM_001692

CCDS: CCDS1912

Canonical transcript exons

ENST00000234396 — 14 exons

Exon	Start	End
ENSE00000760765	70943658	70943713
ENSE00001129685	70935900	70936072
ENSE00001864049	70964958	70965431
ENSE00003476362	70958046	70958144
ENSE00003481069	70961596	70961693
ENSE00003507792	70963572	70963654
ENSE00003535178	70964438	70964542
ENSE00003556574	70958333	70958426
ENSE00003579111	70962777	70962900
ENSE00003599995	70963162	70963312
ENSE00003601295	70964736	70964865
ENSE00003649801	70959939	70960078
ENSE00003657373	70959018	70959095
ENSE00003664875	70960921	70961022

Expression profiles

Bgee: expression breadth ubiquitous, 152 present calls, max score 95.48.

FANTOM5 (CAGE): breadth broad, TPM avg 2.4651 / max 335.7360, expressed in 262 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
20856	2.3535	259
20857	0.1116	27

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right uterine tube	UBERON:0001302	95.48	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	95.00	gold quality
metanephros cortex	UBERON:0010533	92.95	gold quality
adult mammalian kidney	UBERON:0000082	91.90	gold quality
skin of leg	UBERON:0001511	90.74	gold quality
minor salivary gland	UBERON:0001830	90.13	gold quality
skin of abdomen	UBERON:0001416	88.25	gold quality
saliva-secreting gland	UBERON:0001044	87.99	gold quality
mouth mucosa	UBERON:0003729	85.78	gold quality
zone of skin	UBERON:0000014	85.61	gold quality
cortex of kidney	UBERON:0001225	84.85	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	84.52	gold quality
kidney	UBERON:0002113	83.28	gold quality
metanephros	UBERON:0000081	83.09	gold quality
endocervix	UBERON:0000458	78.78	gold quality
body of pancreas	UBERON:0001150	76.12	gold quality
tendon of biceps brachii	UBERON:0008188	75.04	gold quality
omental fat pad	UBERON:0010414	74.32	gold quality
peritoneum	UBERON:0002358	74.28	gold quality
stromal cell of endometrium	CL:0002255	74.18	gold quality
adipose tissue of abdominal region	UBERON:0007808	73.26	gold quality
body of uterus	UBERON:0009853	72.53	gold quality
smooth muscle tissue	UBERON:0001135	72.16	gold quality
cerebellar hemisphere	UBERON:0002245	72.09	gold quality
cerebellar cortex	UBERON:0002129	71.96	gold quality
parotid gland	UBERON:0001831	71.82	gold quality
right hemisphere of cerebellum	UBERON:0014890	71.72	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	71.65	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	70.98	gold quality
left coronary artery	UBERON:0001626	70.97	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-CURD-119	yes	18.45
E-HCAD-10	yes	16.61
E-MTAB-7303	no	83.62
E-ANND-3	no	2.50

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

15 targeting ATP6V1B1, 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-4803	99.98	71.99	3117
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-6752-3P	99.72	66.71	1587
HSA-MIR-4651	99.06	67.57	2002
HSA-MIR-608	98.93	67.83	2013
HSA-MIR-935	98.82	69.36	1072
HSA-MIR-4664-5P	98.17	65.07	1020
HSA-MIR-6819-5P	97.96	66.59	1071
HSA-MIR-6737-5P	97.75	66.54	1044
HSA-MIR-6812-5P	97.56	65.39	1059
HSA-MIR-4296	96.35	63.55	1233
HSA-MIR-4265	96.18	64.68	557
HSA-MIR-4322	96.18	64.85	539
HSA-MIR-2277-5P	84.91	61.40	23

Literature-anchored findings (GeneRIF, showing 28)

• Here, we describe the molecular findings of the first two Greek Cypriot families with recessive dRTA and the long-term clinical findings in four of five affected members. (PMID:16433694)
• This report describes a new mutation in the ATP6V1B1 gene responsible for distal renal tubular acidosis. (PMID:17216496)
• Two siblings with distal renal tubular acidosis and sensorineural deafness having mutation in the first coding exon of the ATP6V1B1 gene , resulting in a non functional protein, are reported. The parents were found to be carriers for the mutation. (PMID:19478356)
• A mutation in ATP6V1B1 is associated with enlarged vestibular aqueduct and early onset of sensorial hearing loss. (PMID:19639346)
• two novel mutations of a heterozygous 15 base-pair deletion (c.756_770del) in exon 7 and a heterozygous 1 base-pair insertion (c.1242_1243insC) in exon 12 in distal renal tubular acidosis and hearing loss (PMID:20233014)
• This study indicated that a significant percentage of the children with DRTA had sensorineural hearing loss and mutation in ATP6V1B1 gene. (PMID:20622307)
• Only two ATP6V1B1 mutations are found in a Cypriot population with distal renal tubular acidosis. (PMID:20805693)
• Data indicate that direct sequencing of the ATP6V1B1 gene showed one patient harbors two homozygous mutations and the other one is a compound heterozygous. (PMID:22509993)
• Mutations of the ATP6V1B1 gene is associated with primary distal renal tubular acidosis. (PMID:23729491)
• Rare and family-specific variants in ATP6V1B1 are responsible for distal renal tubular acidosis and sensorineural hearing loss syndrome in Turkey. (PMID:23923981)
• Three ATP6V1B1 mutations were observed: one frameshift mutation in exon 12; a G to C single nucleotide substitution, on the acceptor splicing site in intron 2, and one novel missense mutation in exon 11. (PMID:24252324)
• Two probands from different kindreds with mutations in ATP6V1B1 presented early onset profound sensorineural hearing loss (PMID:24975934)
• demonstration of renal acidification defects and nephrolithiasis in heterozygous carriers of a mutant B1 subunit that cannot be attributable to negative dominance; propose that heterozygosity may lead to mild real acidification defects due to haploinsufficiency (PMID:25164082)
• Two founder mutations in the ATP6V1B1 gene were found in 16/27 dRTA cases. (PMID:25285676)
• ATP6V1B1 genetic mutations were detected in more than half of the families studied. Mutations in this gene therefore seem to be the most common causative factors in hearing loss associated with distal renal tubular acidosis in these families. (PMID:25498251)
• Our data indicate that recurrent stone formers with the vacuolar H(+)-ATPase B1 subunit p.E161K SNP exhibit a urinary acidification deficit with an increased prevalence of calcium phosphate-containing kidney stones (PMID:26453614)
• A novel c.1169dupC frameshift mutation of ATP6V1B1 gene was identified in one family and the c.1155dupC North African mutation in 2 other families. Both mutations are located in exon 12 of ATP6V1B1 gene in Moroccan patients with recessive form of distal renal tubular acidosis associated with precocious hearing loss. (PMID:27140593)
• 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)
• RhCG and H+ATPases are located within the same cellular protein complex in the kidney and this interaction is required for maximal urinary acidification by H+-ATPases, a prerequisite for efficient NH3 secretion and urine excretion of NH4+. (PMID:29054531)
• Both B1 and B2 subunits of the V-ATPase are detectable in human urinary exosomes, and acid and alkali loading or distal renal tubular acidosis cause changes in the B1 but not B2 subunit abundance in urinary exosomes. (PMID:29310826)
• ATP6V1B1 is expressed in the early distal nephron. The physiological importance of H(+)-ATPase expression in these segments remains to be delineated. (PMID:29993276)
• 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)
• In patient one, Two novel heterozygous missense mutations of the ATP6V1B1 gene (c.409C>T, p.Pro137Ser; c.904C>T, p.Arg302Trp) were identified. In patient III 2 novel heterozygous duplications (c.1504dupT, p.Tyr502Leufs*22; c.2351dupT, p.Phe785Ilefs*28) were found. (PMID:30256676)
• Serum autoantibodies to subunit B1 and subunit B2 of v-H(+) -ATPase in renal tubular acidosis patients may be responsible for impaired urinary acidification. (PMID:30821427)
• Our study indicates the importance contribution of ATP6V1B1 gene mutations to the pathogenesis of the dRTA in the Algerian population and will contribute to introducing principles to predict the characteristics of the dRTA in patients. (PMID:31733597)
• Identification of seven exonic variants in the SLC4A1, ATP6V1B1, and ATP6V0A4 genes that alter RNA splicing by minigene assay. (PMID:34157794)
• Genetic heterogeneity in GJB2, COL4A3, ATP6V1B1 and EDNRB variants detected among hearing impaired families in Morocco. (PMID:35301649)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
mus_musculus	Atp6v1b1	ENSMUSG00000006269
rattus_norvegicus	Atp6v1b1	ENSRNOG00000013573
caenorhabditis_elegans	spe-5	WBGENE00004959
caenorhabditis_elegans		WBGENE00006921

Paralogs (4): ATP5F1B (ENSG00000110955), ATP6V1A (ENSG00000114573), ATP6V1B2 (ENSG00000147416), ATP5F1A (ENSG00000152234)

Protein

Protein identifiers

V-type proton ATPase subunit B, kidney isoform — P15313 (reviewed: P15313)

Alternative names: Endomembrane proton pump 58 kDa subunit, Vacuolar proton pump subunit B 1

All UniProt accessions (4): C9JL73, C9JNS9, P15313, C9JZ02

UniProt curated annotations — full annotation on UniProt →

Function. Non-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. Essential for the proper assembly and activity of V-ATPase. In renal intercalated cells, mediates secretion of protons (H+) into the urine thereby ensuring correct urinary acidification. Required for optimal olfactory function by mediating the acidification of the nasal olfactory epithelium.

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. Forms a complex with NHERF1 and SCL4A7.

Subcellular location. Apical cell membrane. Basolateral cell membrane.

Tissue specificity. Kidney; localizes to early distal nephron, encompassing thick ascending limbs and distal convoluted tubules (at protein level). Expressed in the cochlea and endolymphatic sac.

Disease relevance. Renal tubular acidosis, distal, 2, with progressive sensorineural hearing loss (DRTA2) [MIM:267300] An autosomal recessive disease characterized by the association of renal distal tubular acidosis with sensorineural hearing loss. Distal renal tubular acidosis is 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.

Domain organisation. The PDZ-binding motif mediates interactions with NHERF1 and SCL4A7.

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

RefSeq proteins (1): NP_001683* (*=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
IPR005723	ATPase_V1-cplx_bsu	Family
IPR020003	ATPase_a/bsu_AS	Active_site
IPR022879	V-ATPase_su_B/beta	Family
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR055190	ATP-synt_VA_C	Domain

Pfam: PF00006, PF02874, PF22919

UniProt features (20 total): sequence variant 13, sequence conflict 3, chain 1, short sequence motif 1, mutagenesis site 1, binding site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P15313-F1	87.21	0.69

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): 394

Mutagenesis-validated functional residues (1):

Position	Phenotype
513	loss of interactions with nherf1 and scl4a7.

Function

Pathways and Gene Ontology

Reactome pathways

5 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

MSigDB gene sets: 232 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_UP, RNGTGGGC_UNKNOWN, GOBP_EXCRETION, REACTOME_SIGNALING_BY_INSULIN_RECEPTOR, GOBP_REGULATION_OF_AUTOPHAGY, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_BEHAVIOR, MORF_MSH3, GOCC_VACUOLAR_MEMBRANE, GOBP_SENSORY_PERCEPTION_OF_MECHANICAL_STIMULUS, GOBP_VESICLE_ORGANIZATION, GOBP_ADULT_BEHAVIOR, GOBP_POTASSIUM_ION_HOMEOSTASIS, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, TGACCTY_ERR1_Q2

GO Biological Process (23): ossification (GO:0001503), renal water homeostasis (GO:0003091), renal sodium ion transport (GO:0003096), prostaglandin metabolic process (GO:0006693), regulation of pH (GO:0006885), vacuolar acidification (GO:0007035), sensory perception of sound (GO:0007605), regulation of gene expression (GO:0010468), regulation of macroautophagy (GO:0016241), adult behavior (GO:0030534), renal sodium excretion (GO:0035812), olfactory behavior (GO:0042048), inner ear morphogenesis (GO:0042472), pH reduction (GO:0045851), ATP metabolic process (GO:0046034), chloride ion homeostasis (GO:0055064), calcium ion homeostasis (GO:0055074), potassium ion homeostasis (GO:0055075), vacuolar proton-transporting V-type ATPase complex assembly (GO:0070072), renal tubular secretion (GO:0097254), synaptic vesicle lumen acidification (GO:0097401), proton transmembrane transport (GO:1902600), monoatomic ion transport (GO:0006811)

GO Molecular Function (6): ATP binding (GO:0005524), proton transmembrane transporter activity (GO:0015078), protein-containing complex binding (GO:0044877), proton-transporting ATPase activity, rotational mechanism (GO:0046961), nucleotide binding (GO:0000166), protein binding (GO:0005515)

GO Cellular Component (15): vacuolar proton-transporting V-type ATPase, V1 domain (GO:0000221), cytoplasm (GO:0005737), cytosol (GO:0005829), microvillus (GO:0005902), basolateral plasma membrane (GO:0016323), apical plasma membrane (GO:0016324), lateral plasma membrane (GO:0016328), vacuolar proton-transporting V-type ATPase complex (GO:0016471), extracellular exosome (GO:0070062), extrinsic component of synaptic vesicle membrane (GO:0098850), plasma membrane (GO:0005886), membrane (GO:0016020), proton-transporting two-sector ATPase complex (GO:0016469), proton-transporting V-type ATPase, V1 domain (GO:0033180), transmembrane transporter complex (GO:1902495)

Reactome top-level categories

Rollup of top-5 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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
renal system process	3
monoatomic cation homeostasis	3
inorganic ion homeostasis	3
binding	2
plasma membrane region	2
proton-transporting V-type ATPase complex	2
membrane protein complex	2
multicellular organismal process	1
multicellular organismal-level water homeostasis	1
sodium ion transport	1
prostanoid metabolic process	1
biological regulation	1
intracellular pH reduction	1
sensory perception of mechanical stimulus	1
gene expression	1
regulation of macromolecule biosynthetic process	1
regulation of autophagy	1
macroautophagy	1
behavior	1
sodium ion homeostasis	1
renal tubular secretion	1
chemosensory behavior	1
ear morphogenesis	1
embryonic morphogenesis	1
inner ear development	1
regulation of pH	1
purine ribonucleotide metabolic process	1
purine ribonucleoside triphosphate metabolic process	1
monoatomic anion homeostasis	1
proton-transporting V-type ATPase complex assembly	1
excretion	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
monoatomic cation transmembrane transporter activity	1
proton transmembrane 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
nucleoside phosphate binding	1

Protein interactions and networks

STRING

1937 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ATP6V1B1	ATP6V0A4	Q9HBG4	990
ATP6V1B1	TCIRG1	Q13488	979
ATP6V1B1	ATP4A	P20648	921
ATP6V1B1	ATP12A	P54707	917
ATP6V1B1	ATP6V0A1	Q93050	900
ATP6V1B1	ATP6V1C1	P21283	863
ATP6V1B1	ATP6V1E2	Q96A05	863
ATP6V1B1	ATP6V1C2	Q8NEY4	860
ATP6V1B1	ATP6V1E1	P36543	851
ATP6V1B1	CA2	P00918	839
ATP6V1B1	SLC4A1	P02730	836
ATP6V1B1	ATP6V1H	Q9UI12	833
ATP6V1B1	ATP6V0C	P27449	832
ATP6V1B1	ATP6V1D	Q9Y5K8	830
ATP6V1B1	ATP6V1F	Q16864	799

IntAct

63 interactions, top by confidence:

A	B	Type	Score
ATP6V1B1		psi-mi:“MI:0915”(physical association)	0.560
ATP6V1B1	HSPB1	psi-mi:“MI:0915”(physical association)	0.560
ATP6V1B1	TTR	psi-mi:“MI:0915”(physical association)	0.560
ATP6V1B1	WFS1	psi-mi:“MI:0915”(physical association)	0.560
DNALI1	ATP6V1B1	psi-mi:“MI:0915”(physical association)	0.560
ATP6V1B1	BAG6	psi-mi:“MI:0915”(physical association)	0.560
KLF11	ATP6V1B1	psi-mi:“MI:0915”(physical association)	0.560
DNAJB6	ATP6V1B1	psi-mi:“MI:0915”(physical association)	0.560
ATP6V1B1	KIF1B	psi-mi:“MI:0915”(physical association)	0.560
ATP6V1B1	RNF11	psi-mi:“MI:0915”(physical association)	0.560
ATP6V1B1	ATXN1	psi-mi:“MI:0915”(physical association)	0.560
ATP6V1B1	TARDBP	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (172): ATP6V1C1 (Affinity Capture-MS), ATP6V1B2 (Affinity Capture-MS), ATP6V1E2 (Affinity Capture-MS), ATP6V1E1 (Affinity Capture-MS), CCT6B (Affinity Capture-MS), CCT2 (Affinity Capture-MS), ATP6V1A (Affinity Capture-MS), DMXL1 (Affinity Capture-MS), ATP6V0A2 (Affinity Capture-MS), ATP6V0A1 (Affinity Capture-MS), ATP6V1D (Affinity Capture-MS), ATP6V0D1 (Affinity Capture-MS), ATP6V1F (Affinity Capture-MS), ATP6V1G1 (Affinity Capture-MS), ATP6V1G2 (Affinity Capture-MS)

ESM2 similar proteins: A2RC98, A3CK49, A4YI06, A8AUJ8, B1ICC8, B2IP44, B5E551, B5XJH4, B8CZG7, B8ZK30, C1CES1, P0DA08, P0DA09, P11574, P11593, P15313, P16140, P21281, P22550, P31407, P31408, P31411, P48413, P62814, P62815, Q08637, Q19626, Q1J8S4, Q1JDW9, Q1JIX4, Q1JNS7, Q38680, Q38681, Q40078, Q40079, Q43432, Q48VL2, Q59PT0, Q5R5V5, Q5XE49

Diamond homologs: A2BKX5, A2RC98, A2SST6, A3CK49, A3CS72, A5UKB1, A6UT36, A7IAU7, A8AUJ8, B0K5I9, B0K8E7, B1ICC8, B2IP44, B2TP90, B2UWY3, B5E551, B5XJH4, B5YFA1, B6YV15, B8E137, B8GFQ7, B8ZK30, B9LS42, C1CES1, C5A337, O06505, O27035, O29100, O32467, O57729, P0DA08, P0DA09, P11574, P11593, P15313, P16140, P21281, P22550, P22663, P31401

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
ATP6V1B1	“form complex”	V-ATPase	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 35 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	124.4×	1e-08
Insulin receptor recycling	7	98.7×	4e-11
Transferrin endocytosis and recycling	7	95.5×	4e-11
ROS and RNS production in phagocytes	7	87.1×	6e-11
Ion channel transport	7	24.9×	3e-07

GO biological processes:

GO term	Partners	Fold	FDR
synaptic vesicle lumen acidification	6	170.2×	3e-10
vacuolar acidification	6	133.2×	7e-10
proton transmembrane transport	6	56.7×	1e-07
regulation of macroautophagy	6	53.8×	1e-07

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	55
Likely pathogenic	49
Uncertain significance	262
Likely benign	385
Benign	45

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1070677	NM_001692.4(ATP6V1B1):c.1149C>A (p.Tyr383Ter)	Pathogenic
1071557	NM_001692.4(ATP6V1B1):c.825del (p.Ala276fs)	Pathogenic
1071558	NM_001692.4(ATP6V1B1):c.1401_1402dup (p.Phe468fs)	Pathogenic
1072671	NM_001692.4(ATP6V1B1):c.1303dup (p.Glu435fs)	Pathogenic
12225	NM_001692.4(ATP6V1B1):c.91C>T (p.Arg31Ter)	Pathogenic
1329994	NM_001692.4(ATP6V1B1):c.925G>T (p.Glu309Ter)	Pathogenic
1350336	NM_001692.4(ATP6V1B1):c.190del (p.Glu64fs)	Pathogenic
1376028	NM_001692.4(ATP6V1B1):c.1391_1392dup (p.Arg465fs)	Pathogenic
1400673	NM_001692.4(ATP6V1B1):c.175-1G>A	Pathogenic
1429656	NM_001692.4(ATP6V1B1):c.1178C>A (p.Ser393Ter)	Pathogenic
1452280	NM_001692.4(ATP6V1B1):c.1204dup (p.Glu402fs)	Pathogenic
1452630	NM_001692.4(ATP6V1B1):c.603_612del (p.Cys201fs)	Pathogenic
1458122	NM_001692.4(ATP6V1B1):c.33dup (p.Leu12fs)	Pathogenic
1458465	NM_001692.4(ATP6V1B1):c.1258dup (p.Tyr420fs)	Pathogenic
1459453	NM_001692.4(ATP6V1B1):c.1126C>T (p.Gln376Ter)	Pathogenic
179259	NM_001692.4(ATP6V1B1):c.785+1G>A	Pathogenic
2009682	NM_001692.4(ATP6V1B1):c.1241del (p.Asn414fs)	Pathogenic
2084596	NM_001692.4(ATP6V1B1):c.1248+1G>A	Pathogenic
2092192	NM_001692.4(ATP6V1B1):c.612_616del (p.Leu206fs)	Pathogenic
2099318	NM_001692.4(ATP6V1B1):c.245del (p.Glu82fs)	Pathogenic
2203080	NM_001692.4(ATP6V1B1):c.408del (p.Pro137fs)	Pathogenic
2203081	NM_001692.4(ATP6V1B1):c.687+1G>T	Pathogenic
2203082	NM_001692.4(ATP6V1B1):c.1397C>A (p.Ser466Ter)	Pathogenic
2707640	NM_001692.4(ATP6V1B1):c.853A>T (p.Lys285Ter)	Pathogenic
2751688	NM_001692.4(ATP6V1B1):c.319G>T (p.Glu107Ter)	Pathogenic
2758524	NM_001692.4(ATP6V1B1):c.577del (p.His193fs)	Pathogenic
2782834	NM_001692.4(ATP6V1B1):c.777del (p.Asn259fs)	Pathogenic
280139	NM_001692.4(ATP6V1B1):c.1037C>G (p.Pro346Arg)	Pathogenic
2813310	NM_001692.4(ATP6V1B1):c.246_247insC (p.Val83fs)	Pathogenic
2847265	NM_001692.4(ATP6V1B1):c.112dup (p.Arg38fs)	Pathogenic

SpliceAI

3198 predictions. Top by Δscore:

Variant	Effect	Δscore
2:70936069:GTCA:G	donor_gain	1.0000
2:70936073:G:GG	donor_gain	1.0000
2:70958040:T:A	acceptor_gain	1.0000
2:70958042:CCA:C	acceptor_loss	1.0000
2:70958043:CAG:C	acceptor_loss	1.0000
2:70958044:A:AC	acceptor_loss	1.0000
2:70958044:A:AG	acceptor_gain	1.0000
2:70958045:G:GA	acceptor_gain	1.0000
2:70958045:GTT:G	acceptor_gain	1.0000
2:70958141:TCAGG:T	donor_loss	1.0000
2:70958143:AGG:A	donor_loss	1.0000
2:70958145:GT:G	donor_loss	1.0000
2:70958330:CAGGT:C	acceptor_loss	1.0000
2:70958331:A:T	acceptor_loss	1.0000
2:70958332:G:A	acceptor_loss	1.0000
2:70958332:GGT:G	acceptor_gain	1.0000
2:70958417:G:GT	donor_gain	1.0000
2:70958422:GCTGG:G	donor_gain	1.0000
2:70958425:GG:G	donor_gain	1.0000
2:70958426:GG:G	donor_gain	1.0000
2:70959012:CCTCA:C	acceptor_loss	1.0000
2:70959013:CTCAG:C	acceptor_loss	1.0000
2:70959014:TCAGG:T	acceptor_loss	1.0000
2:70959015:CAG:C	acceptor_loss	1.0000
2:70959016:AGGTC:A	acceptor_gain	1.0000
2:70959017:GGTC:G	acceptor_gain	1.0000
2:70959017:GGTCG:G	acceptor_gain	1.0000
2:70959093:ATG:A	donor_gain	1.0000
2:70959094:TG:T	donor_gain	1.0000
2:70959094:TGG:T	donor_loss	1.0000

AlphaMissense

3367 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:70963616:G:A	G369R	1.000
2:70963616:G:C	G369R	1.000
2:70958104:G:A	G78E	0.999
2:70958140:T:A	V90D	0.999
2:70959021:G:C	R124P	0.999
2:70959033:G:A	G128D	0.999
2:70960019:A:C	S176R	0.999
2:70960021:C:A	S176R	0.999
2:70960021:C:G	S176R	0.999
2:70960026:C:A	A178D	0.999
2:70960031:G:C	G180R	0.999
2:70960032:G:A	G180D	0.999
2:70960032:G:T	G180V	0.999
2:70960036:G:C	Q181H	0.999
2:70960036:G:T	Q181H	0.999
2:70960044:C:A	P184H	0.999
2:70960044:C:G	P184R	0.999
2:70960065:T:C	L191P	0.999
2:70960925:C:A	A197D	0.999
2:70960940:G:C	R202P	0.999
2:70961020:G:A	G229R	0.999
2:70961020:G:C	G229R	0.999
2:70961020:G:T	G229W	0.999
2:70961611:G:C	A235P	0.999
2:70961676:C:A	N256K	0.999
2:70961676:C:G	N256K	0.999
2:70962785:G:C	R265P	0.999
2:70962806:C:A	A272E	0.999
2:70962809:T:C	L273P	0.999
2:70962817:G:C	A276P	0.999

dbSNP variants (sampled 300 via entrez): RS1000171223 (2:70945436 A>C), RS1000559497 (2:70943805 C>T), RS1000711717 (2:70949508 C>G), RS1000822789 (2:70956097 C>G), RS1000872799 (2:70962460 C>G,T), RS1000890034 (2:70957522 C>G), RS1000945972 (2:70962223 C>T), RS1001171457 (2:70956365 C>T), RS1001281431 (2:70960684 G>A), RS1001639236 (2:70938337 G>A), RS1001691569 (2:70938126 C>A), RS1001979601 (2:70937058 G>A,T), RS1002030509 (2:70936707 C>G), RS1002682559 (2:70946949 C>T), RS1002734657 (2:70946683 G>A)

Disease associations

OMIM: gene MIM:192132 | disease phenotypes: MIM:267300, MIM:276900, MIM:602722, MIM:174200

GenCC curated gene-disease

Disease	Classification	Inheritance
renal tubular acidosis, distal, 2, with progressive sensorineural hearing loss	Definitive	Autosomal recessive
autosomal recessive distal renal tubular acidosis	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
renal tubular acidosis, distal, 2, with progressive sensorineural hearing loss	Definitive	AR

Mondo (11): renal tubular acidosis, distal, 2, with progressive sensorineural hearing loss (MONDO:0009968), Usher syndrome (MONDO:0019501), hearing loss disorder (MONDO:0005365), urogenital tract malformation (MONDO:0019356), nephrocalcinosis (MONDO:0001567), nephrolithiasis (MONDO:0008171), distal renal tubular acidosis (MONDO:0015827), renal tubular acidosis, distal, 3, with or without sensorineural hearing loss (MONDO:0011268), polydactyly, postaxial, type A1 (MONDO:0008266), renal tubular acidosis (MONDO:0001909), autosomal recessive distal renal tubular acidosis (MONDO:0018440)

Orphanet (5): Usher syndrome (Orphanet:886), Urogenital tract malformation (Orphanet:83001), Distal renal tubular acidosis (Orphanet:18), Rare genetic deafness (Orphanet:96210), Autosomal recessive distal renal tubular acidosis with deafness (Orphanet:93611)

HPO phenotypes

4 total (5 of 4 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000407	Sensorineural hearing impairment
HP:0000787	Nephrolithiasis
HP:0001947	Renal tubular acidosis
HP:0008341	Distal renal tubular acidosis

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST002481_1	Acne (severe)	5.000000e-06
GCST008971_49	Urate levels	8.000000e-09
GCST008972_184	Urate levels	9.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004531	urate measurement

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D000141	Acidosis, Renal Tubular	C12.050.351.968.419.815.093; C12.200.777.419.815.093; C12.950.419.815.093; C16.320.831.093; C18.452.076.176.210
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341
D009397	Nephrocalcinosis	C12.050.351.968.419.590; C12.200.777.419.590; C12.950.419.590; C18.452.174.130.560
D053040	Nephrolithiasis	C12.050.351.968.419.600; C12.050.351.968.967.249; C12.200.777.419.600; C12.200.777.967.249; C12.950.419.600; C12.950.967.249
D052245	Usher Syndromes	C09.218.458.341.186.500.500; C09.218.458.341.887.886; C10.597.751.418.341.186.500.500; C10.597.751.418.341.887.886; C10.597.751.941.162.625.500; C11.768.585.658.500.813; C11.966.075.375.500; C16.131.077.299.500; C16.320.290.684.500; C23.888.592.763.393.341.887.886
C562897	Renal Tubular Acidosis, Distal, with Progressive Nerve Deafness (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3217 (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

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

pChembl	Type	Value	Unit	Molecule
7.00	IC50	100	nM	CHEMBL291117
6.43	IC50	370	nM	CHEMBL41588
6.36	IC50	440	nM	CHEMBL449696
5.88	IC50	1320	nM	CHEMBL288419
5.52	IC50	3000	nM	CHEMBL39485

PubChem BioAssay actives

5 with measured affinity, of 5 total; 5 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
methyl (2E,4E)-5-(1H-indol-2-yl)-2-methoxypenta-2,4-dienoate	213628: Compound was tested for inhibition of V-ATPase from human kidney cortex(hK)	ic50	0.1000	uM
(2Z,4E)-5-(5,6-dichloro-1H-indol-2-yl)-2-methoxy-N-[3-(4-pyrimidin-2-ylpiperazin-1-yl)propyl]penta-2,4-dienamide	213628: Compound was tested for inhibition of V-ATPase from human kidney cortex(hK)	ic50	0.3700	uM
(2Z,4E)-5-(5,6-dichloro-1H-indol-2-yl)-2-methoxy-N-(2,2,6,6-tetramethylpiperidin-4-yl)penta-2,4-dienamide	213628: Compound was tested for inhibition of V-ATPase from human kidney cortex(hK)	ic50	0.4400	uM
(2Z,4E)-5-(5,6-dichloro-1H-indol-2-yl)-2-methoxy-N-[(1S,5R)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl]penta-2,4-dienamide	213628: Compound was tested for inhibition of V-ATPase from human kidney cortex(hK)	ic50	1.3200	uM
(2Z,4E)-5-(5,6-dichloro-1H-indol-2-yl)-N-[3-(diethylamino)propyl]-2-methoxypenta-2,4-dienamide	213628: Compound was tested for inhibition of V-ATPase from human kidney cortex(hK)	ic50	3.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases methylation, increases methylation, affects methylation, decreases expression	3
Aflatoxin B1	affects methylation, decreases expression	2
bisphenol A	decreases methylation	1
sodium arsenite	increases expression	1
butyraldehyde	decreases expression	1
benzo(e)pyrene	increases methylation	1
beta-methylcholine	affects expression	1
pentanal	decreases expression	1
jinfukang	decreases expression, affects cotreatment	1
Resveratrol	affects cotreatment, decreases expression	1
Zoledronic Acid	decreases expression	1
Acetaminophen	decreases expression	1
Arsenic	affects methylation	1
Vehicle Emissions	increases abundance, increases expression	1
Cisplatin	affects cotreatment, decreases expression	1
Clozapine	decreases expression	1
Diethylhexyl Phthalate	decreases expression	1
Estradiol	affects cotreatment, decreases expression	1
Haloperidol	decreases expression	1
Hydralazine	affects cotreatment, increases expression	1
Methapyrilene	increases methylation	1
Nickel	decreases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Rotenone	increases expression	1
Smoke	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Tretinoin	decreases expression	1
Triclosan	increases expression	1
Valproic Acid	affects cotreatment, increases expression	1
Okadaic Acid	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
CHEMBL813071	Binding	Compound was tested for inhibition of V-ATPase from human kidney cortex(hK)	5-(5,6-Dichloro-2-indolyl)-2-methoxy-2,4-pentadienamides: novel and selective inhibitors of the vacuolar H+-ATPase of osteoclasts with bone antiresorptive activity. — J Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00205881	PHASE4	COMPLETED	Bilateral Benefit in Adult Users of the HiRes 90K Bionic Ear System
NCT00331539	PHASE4	UNKNOWN	Relationship Between Auto NRT and Behavioural T & C Levels With the Nucleus Freedom Cochlear Implant
NCT00424307	PHASE4	UNKNOWN	Bilateral Cochlear Implant Benefit in Young Children
NCT00765635	PHASE4	COMPLETED	Chlorobutanol, Potassium Carbonate, and Irrigation in Cerumen Removal
NCT03321006	PHASE4	COMPLETED	Treating Hearing Loss to Improve Mood and Cognition in Older Adults
NCT07290530	PHASE3	NOT_YET_RECRUITING	24-Month Trial of NPI-001 for the Preservation of Photoreceptors in Retinitis Pigmentosa Associated With Usher Syndrome
NCT01499901	PHASE3	WITHDRAWN	Comparison of the Bilateral Sequential and Simultaneous Cochlear Implantation in the Deaf Children
NCT02561091	PHASE3	COMPLETED	AM-111 in the Treatment of Acute Inner Ear Hearing Loss
NCT03331627	PHASE3	COMPLETED	Safety and Efficacy of STR001-IT and STR001-ER in Patients With SSHL
NCT05532657	PHASE3	ACTIVE_NOT_RECRUITING	ACHIEVE Brain Health Follow-Up Study
NCT02065011	PHASE2	ACTIVE_NOT_RECRUITING	A Study to Determine the Long-Term Safety, Tolerability and Biological Activity of SAR421869 in Patients With Usher Syndrome Type 1B
NCT00013455	PHASE2	COMPLETED	Quantifying Auditory Perceptual Learning Following Hearing Aid Fitting
NCT00323427	PHASE2	COMPLETED	Clinical Trial of the Living Well With Hearing Loss Workshop
NCT00552786	PHASE2	COMPLETED	Antioxidation Medication for Noise-induced Hearing Loss
NCT00802425	PHASE2	COMPLETED	Efficacy of AM-111 in Patients With Acute Sensorineural Hearing Loss
NCT01139281	PHASE2	COMPLETED	The Protective Effect of Ginkgo Biloba Extract on Cisplatin-induced Ototoxicity in Humans
NCT01451853	PHASE2	UNKNOWN	SPI-1005 for Prevention and Treatment of Chemotherapy Induced Hearing Loss
NCT01588925	PHASE2	COMPLETED	Hearing Preservation Using Dexamethasone and Hyaluronic Acid for Cochlear Implantation
NCT01773278	PHASE2	RECRUITING	Cholesterol and Antioxidant Treatment in Patients With Smith-Lemli-Opitz Syndrome (SLOS)
NCT02832128	PHASE2	COMPLETED	Evaluating Possible Improvement in Speech and Hearing Tests After 28 Days of Dosing of the Study Drug AUT00063 Compared to Placebo (QuicKfire)
NCT04915183	PHASE2	RECRUITING	Atorvastatin to Reduce Cisplatin-Induced Hearing Loss Among Individuals With Head and Neck Cancer
NCT05258773	PHASE2	COMPLETED	Evaluation of the Presence of SENS-401 in the Perilymph
NCT06340633	PHASE2	RECRUITING	SPI-1005 in Adults Receiving Cochlear Implant
NCT00582946	PHASE1	COMPLETED	Wide-Bandwidth Open Canal Hearing Aid For Better Multitalker Speech Understanding
NCT00584155	PHASE1	WITHDRAWN	Protection From Cisplatin Ototoxicity by Lactated Ringers
NCT01206829	PHASE1	UNKNOWN	Hearing Impairment, Cognitive Therapy and Coping
NCT01256229	PHASE1	COMPLETED	Outcomes In Children With Developmental Delay And Deafness
NCT01343394	PHASE1	WITHDRAWN	Safety of Autologous Human Umbilical Cord Blood Mononuclear Fraction to Treat Acquired Hearing Loss in Children
NCT01452607	PHASE1	COMPLETED	Study to Evaluate the Safety and Pharmacokinetics of SPI-1005
NCT02259595	PHASE1	COMPLETED	Study to Determine the Safety, Tolerability, and Pharmacokinetic Profile of HPN-07 and HPN-07 Plus NAC
NCT04041440	PHASE1	COMPLETED	Speech Recognition Training in Children With Hearing Loss
NCT07218913	PHASE1	RECRUITING	Testing the Addition of Pedmark to Cisplatin Chemotherapy for Reducing Drug-Induced Ear Damage in Men With Stage II-III Metastatic Testicular Germ Cell Tumors
NCT06065852	Not specified	RECRUITING	National Registry of Rare Kidney Diseases
NCT01505062	PHASE1/PHASE2	TERMINATED	Study of SAR421869 in Participants With Retinitis Pigmentosa Associated With Usher Syndrome Type 1B
NCT04355689	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Safety and Efficacy of NPI-001 Tablets for RP Associated With Usher Syndrome
NCT06789445	PHASE1/PHASE2	RECRUITING	A Study to Investigate the Safety of OpCT-001 in Adults Who Have Primary Photoreceptor Disease (CLARICO)
NCT00004345	Not specified	TERMINATED	Study of Dietary N-3 Fatty Acids in Patients With Retinitis Pigmentosa and Usher Syndrome
NCT00016471	Not specified	COMPLETED	A Genetic Analysis of Usher Syndrome in Ashkenazi Jews
NCT00106743	Not specified	COMPLETED	Natural History and Genetic Studies of Usher Syndrome
NCT01954953	Not specified	UNKNOWN	Clinical and Genetic Examination of Usher Syndrome Patients’ Cohort in Europe