ATP6V1B2

Summary

ATP6V1B2 (ATPase H+ transporting V1 subunit B2, HGNC:854) is a protein-coding gene on chromosome 8p21.3, encoding V-type proton ATPase subunit B, brain isoform (P21281). 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. It is a common-essential gene (DepMap: required in 97.3% 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, three B, and two G subunits, as well as a C, D, E, F, and H subunit. The V1 domain contains the ATP catalytic site. The protein encoded by this gene is one of two V1 domain B subunit isoforms and is the only B isoform highly expressed in osteoclasts.

Source: NCBI Gene 526 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder (Strong, GenCC) — +5 more curated relationships
• GWAS associations: 7
• Clinical variants (ClinVar): 206 total — 9 pathogenic, 8 likely-pathogenic
• Phenotypes (HPO): 165
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 97.3% of screened cell lines (common-essential)
• MANE Select transcript: NM_001693

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:854
Approved symbol	ATP6V1B2
Name	ATPase H+ transporting V1 subunit B2
Location	8p21.3
Locus type	gene with protein product
Status	Approved
Aliases	VATB, Vma2, HO57
Ensembl gene	ENSG00000147416
Ensembl biotype	protein_coding
OMIM	606939
Entrez	526

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 9 protein_coding, 8 nonsense_mediated_decay, 1 retained_intron

ENST00000276390, ENST00000519667, ENST00000520830, ENST00000521442, ENST00000523478, ENST00000523482, ENST00000718263, ENST00000718264, ENST00000718265, ENST00000718266, ENST00000718267, ENST00000718268, ENST00000891263, ENST00000921231, ENST00000921232, ENST00000958717, ENST00000958718, ENST00000958719

RefSeq mRNA: 1 — MANE Select: NM_001693 NM_001693

CCDS: CCDS6014

Canonical transcript exons

ENST00000276390 — 14 exons

Exon	Start	End
ENSE00000980004	20212782	20212905
ENSE00000980005	20214818	20214968
ENSE00001176898	20197381	20197542
ENSE00003524098	20211177	20211316
ENSE00003525550	20211652	20211753
ENSE00003560109	20210569	20210646
ENSE00003574622	20212102	20212199
ENSE00003585043	20204484	20204539
ENSE00003632966	20210346	20210439
ENSE00003669300	20209433	20209531
ENSE00004034566	20218153	20218282
ENSE00004034570	20216413	20216495
ENSE00004034573	20220263	20221696
ENSE00004034579	20217220	20217324

Expression profiles

Bgee: expression breadth ubiquitous, 300 present calls, max score 99.39.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 79.0268 / max 1208.0655, expressed in 1826 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
87622	78.8434	1826
87626	0.1834	77

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pons	UBERON:0000988	99.39	gold quality
monocyte	CL:0000576	98.93	gold quality
lateral nuclear group of thalamus	UBERON:0002736	98.88	gold quality
mononuclear cell	CL:0000842	98.86	gold quality
leukocyte	CL:0000738	98.85	gold quality
prefrontal cortex	UBERON:0000451	98.72	gold quality
Brodmann (1909) area 10	UBERON:0013541	98.60	gold quality
orbitofrontal cortex	UBERON:0004167	98.57	gold quality
frontal pole	UBERON:0002795	98.55	gold quality
substantia nigra pars compacta	UBERON:0001965	98.51	gold quality
frontal cortex	UBERON:0001870	98.49	gold quality
frontal lobe	UBERON:0016525	98.49	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	98.47	gold quality
superior vestibular nucleus	UBERON:0007227	98.43	gold quality
right frontal lobe	UBERON:0002810	98.39	gold quality
Brodmann (1909) area 9	UBERON:0013540	98.32	gold quality
superior frontal gyrus	UBERON:0002661	98.29	gold quality
postcentral gyrus	UBERON:0002581	98.28	gold quality
blood	UBERON:0000178	98.20	gold quality
parietal lobe	UBERON:0001872	98.20	gold quality
granulocyte	CL:0000094	98.18	gold quality
neocortex	UBERON:0001950	98.18	gold quality
cingulate cortex	UBERON:0003027	98.14	gold quality
anterior cingulate cortex	UBERON:0009835	98.12	gold quality
adult organism	UBERON:0007023	98.06	gold quality
hypothalamus	UBERON:0001898	98.04	gold quality
Brodmann (1909) area 46	UBERON:0006483	98.04	gold quality
cerebral cortex	UBERON:0000956	97.89	gold quality
middle temporal gyrus	UBERON:0002771	97.89	gold quality
cerebellar hemisphere	UBERON:0002245	97.87	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	38.78
E-GEOD-135922	yes	22.71
E-CURD-112	yes	22.55
E-MTAB-8142	yes	19.59
E-MTAB-10042	yes	9.56
E-HCAD-25	yes	8.24
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MEF2A, MITF, NFATC1, ZBTB16

miRNA regulators (miRDB)

97 targeting ATP6V1B2, 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-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-4525	99.94	64.38	675
HSA-MIR-5010-5P	99.94	64.11	705
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-3143	99.93	71.96	3104

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 97.3% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 11)

• This protein has been found differentially expressed in the anterior cingulate cortex from patients with schizophrenia (PMID:20381070)
• The ATP6V1B2 p.Arg506X is a haploinsufficient mutation and resulted in abnormal acidification in lysosomes. (PMID:24913193)
• ATP6V1B2 is somatically mutated in 22% of follicular lymphoma tumors. Mutation hotspots found at Y371 and R400. (PMID:25713363)
• A missense mutation in ATP6V1B2 associated with Zimmermann-Laband syndrome. (PMID:25915598)
• We conclude that the effects of variation in the vacuolar ATPase may point to a new molecular mechanism that influences the long-term development of depression. This mechanism may involve dysfunction specifically in hippocampal circuitry and cognitive impairment that characterizes recurrent and chronic depression. (PMID:27824360)
• 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)
• mutations in the human v-ATPase subunit ATP6V1B2 (also known as Vma2 in yeast) activate autophagic flux and maintain mTOR/TOR in an active state. (PMID:30720463)
• 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)
• atp6v1b2 knockdown zebrafish showed developmental defects in multiple organs and systems. However, Atp6v1b2 c.1516C>T knockin mice displayed obvious cognitive defects but normal hearing and cochlear morphology. Impaired hippocampal CA1 region and weaker interaction between the V1E and B2 subunits in Atp6v1b2(Arg506X//Arg506X) mice were observed. (PMID:31257146)
• EXOME REPORT: Novel mutation in ATP6V1B2 segregating with autosomal dominant epilepsy, intellectual disability and mild gingival and nail abnormalities. (PMID:31655144)
• DOORS syndrome and a recurrent truncating ATP6V1B2 variant. (PMID:32873933)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	atp6v1b2	ENSDARG00000043465
mus_musculus	Atp6v1b2	ENSMUSG00000006273
rattus_norvegicus	Atp6v1b2	ENSRNOG00000011891
drosophila_melanogaster	Vha55	FBGN0005671
caenorhabditis_elegans	spe-5	WBGENE00004959
caenorhabditis_elegans		WBGENE00006921

Paralogs (4): ATP5F1B (ENSG00000110955), ATP6V1A (ENSG00000114573), ATP6V1B1 (ENSG00000116039), ATP5F1A (ENSG00000152234)

Protein

Protein identifiers

V-type proton ATPase subunit B, brain isoform — P21281 (reviewed: P21281)

Alternative names: Endomembrane proton pump 58 kDa subunit, HO57, Vacuolar proton pump subunit B 2

All UniProt accessions (6): P21281, A0A140VK65, E5RGH6, H0YAT8, H0YC04, H0YC45

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. In renal intercalated cells, can partially compensate the lack of ATP6V1B1 and mediate secretion of protons (H+) into the urine under base-line conditions but not in conditions of acid load.

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.

Subcellular location. Apical cell membrane. Melanosome. Cytoplasm. Cytoplasmic vesicle. Secretory vesicle. Synaptic vesicle membrane. Clathrin-coated vesicle membrane.

Tissue specificity. Kidney; localizes to early distal nephron, encompassing thick ascending limbs and distal convoluted tubules (at protein level).

Disease relevance. Zimmermann-Laband syndrome 2 (ZLS2) [MIM:616455] A form of Zimmermann-Laband syndrome, a rare developmental disorder characterized by facial dysmorphism with bulbous nose and thick floppy ears, gingival enlargement, hypoplasia or aplasia of terminal phalanges and nails, hypertrichosis, joint hyperextensibility, and hepatosplenomegaly. Some patients manifest intellectual disability with or without epilepsy. ZLS2 inheritance is autosomal dominant. The disease is caused by variants affecting the gene represented in this entry. Deafness, congenital, with onychodystrophy, autosomal dominant (DDOD) [MIM:124480] An autosomal dominant syndrome characterized mainly by congenital sensorineural hearing loss accompanied by dystrophic or absent nails. Coniform teeth, selective tooth agenesis, and hands and feet abnormalities are present in some patients. The disease is caused by variants affecting the gene represented in this entry.

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

RefSeq proteins (1): NP_001684* (*=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 (57 total): strand 23, helix 19, sequence conflict 8, turn 4, chain 1, binding site 1, sequence variant 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-P21281-F1	86.40	0.63

Functional residue map

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

Ligand- & substrate-binding residues (1): 400

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: 689 (showing top): REACTOME_SIGNALING_BY_INSULIN_RECEPTOR, GOBP_REGULATION_OF_AUTOPHAGY, MODY_HIPPOCAMPUS_POSTNATAL, REACTOME_INNATE_IMMUNE_SYSTEM, GOCC_VACUOLAR_MEMBRANE, GOBP_VESICLE_ORGANIZATION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GAUSSMANN_MLL_AF4_FUSION_TARGETS_A_UP, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_VESICLE_MEDIATED_TRANSPORT, GOCC_RUFFLE, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_MACROAUTOPHAGY, ATGTTAA_MIR302C

GO Biological Process (6): vacuolar acidification (GO:0007035), regulation of macroautophagy (GO:0016241), ATP metabolic process (GO:0046034), synaptic vesicle lumen acidification (GO:0097401), proton transmembrane transport (GO:1902600), monoatomic ion transport (GO:0006811)

GO Molecular Function (5): ATP binding (GO:0005524), proton transmembrane transporter activity (GO:0015078), proton-transporting ATPase activity, rotational mechanism (GO:0046961), nucleotide binding (GO:0000166), protein binding (GO:0005515)

GO Cellular Component (17): vacuolar proton-transporting V-type ATPase, V1 domain (GO:0000221), ruffle (GO:0001726), lysosomal membrane (GO:0005765), cytosol (GO:0005829), plasma membrane (GO:0005886), microvillus (GO:0005902), apical plasma membrane (GO:0016324), clathrin-coated vesicle membrane (GO:0030665), melanosome (GO:0042470), extracellular exosome (GO:0070062), extrinsic component of synaptic vesicle membrane (GO:0098850), cytoplasm (GO:0005737), membrane (GO:0016020), synaptic vesicle membrane (GO:0030672), cytoplasmic vesicle (GO:0031410), proton-transporting V-type ATPase, V1 domain (GO:0033180), synapse (GO:0045202)

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	3
proton transmembrane transport	2
cytoplasm	2
intracellular pH reduction	1
regulation of autophagy	1
macroautophagy	1
purine ribonucleotide metabolic process	1
purine ribonucleoside triphosphate metabolic process	1
intercellular transport	1
synaptic vesicle maturation	1
establishment of localization in cell	1
neuron cellular homeostasis	1
synaptic vesicle cycle	1
monoatomic cation transmembrane transport	1
transport	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
monoatomic cation transmembrane transporter 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
vacuole	1
vacuolar proton-transporting V-type ATPase complex	1
proton-transporting V-type ATPase, V1 domain	1
cell leading edge	1
plasma membrane bounded cell projection	1
lysosome	1
lytic vacuole membrane	1
membrane	1
cell periphery	1
actin filament bundle	1
actin-based cell projection	1
apical part of cell	1
plasma membrane region	1
clathrin-coated vesicle	1
coated vesicle membrane	1
pigment granule	1

Protein interactions and networks

STRING

2384 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ATP6V1B2	ATP6V1C1	P21283	941
ATP6V1B2	ATP6V1H	Q9UI12	877
ATP6V1B2	ATP6V0C	P27449	876
ATP6V1B2	ATP6V1D	Q9Y5K8	866
ATP6V1B2	ATP6V1E1	P36543	866
ATP6V1B2	ATP6V1F	Q16864	866
ATP6V1B2	ATP6V1E2	Q96A05	863
ATP6V1B2	ATP6V1A	P38606	860
ATP6V1B2	ATP6V0A1	Q93050	835
ATP6V1B2	ATP6V1G1	O75348	832
ATP6V1B2	ATP6V0B	Q99437	829
ATP6V1B2	ATP6V1C2	Q8NEY4	815
ATP6V1B2	ATP6V0D1	P12953	806
ATP6V1B2	ATP6V0A4	Q9HBG4	799
ATP6V1B2	TCIRG1	Q13488	797

IntAct

124 interactions, top by confidence:

A	B	Type	Score
MED4	MED19	psi-mi:“MI:0914”(association)	0.900
ATP6V1C2	ATP6V1G1	psi-mi:“MI:0914”(association)	0.640
TCF4	ATP6V1B2	psi-mi:“MI:0915”(physical association)	0.560
ATP6V1B2	TCF4	psi-mi:“MI:0915”(physical association)	0.560
ATP6V1B2	GFAP	psi-mi:“MI:0915”(physical association)	0.560
ATP6V1B2	NEFL	psi-mi:“MI:0915”(physical association)	0.560
ATP6V1B2	WFS1	psi-mi:“MI:0915”(physical association)	0.560
ATP6V1B2	RNF11	psi-mi:“MI:0915”(physical association)	0.560
ATP6V1B2	JPH3	psi-mi:“MI:0915”(physical association)	0.560
ATP6V1B2	HTT	psi-mi:“MI:0915”(physical association)	0.560
ATP6V0A2	B4GALT3	psi-mi:“MI:0914”(association)	0.530
SYNGAP1	IGF2BP3	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

BioGRID (390): TCF4 (Two-hybrid), ATP6V1B2 (Affinity Capture-RNA), ATP6V1B2 (Affinity Capture-MS), ATP6V1B2 (Affinity Capture-MS), ATP6V1B2 (Affinity Capture-MS), ABCF3 (Co-fractionation), ATP5C1 (Co-fractionation), ATP6V0D1 (Co-fractionation), ATP6V1A (Co-fractionation), ATP6V1B2 (Co-fractionation), ATP6V1B2 (Co-fractionation), ATP6V1B2 (Co-fractionation), ATP6V1B2 (Co-fractionation), ATP6V1B2 (Co-fractionation), ATP6V1B2 (Co-fractionation)

ESM2 similar proteins: A0A0J9X1Q5, A2RC97, A3CK48, A4IK94, A7S5D9, A8AUJ7, B5XJH3, E1JIB2, E7FDV5, E9FR69, F4KU78, O25608, O31571, P0DA06, P0DA07, P0DX42, P21281, P31408, P31409, P31410, P45244, P62815, P76092, Q17X32, Q1CSR7, Q1J8S5, Q1JDX0, Q1JIX5, Q1JNS8, Q1MWN4, Q43883, Q48VL3, Q55233, Q5BK17, Q5REW1, Q5XCB9, Q5XE50, Q5XW77, Q65EM1, Q6DLR9

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

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 125 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
Insulin receptor recycling	16	70.0×	2e-24
Regulation of MITF-M-dependent genes involved in lysosome biogenesis and autophagy	9	69.5×	1e-13
Transferrin endocytosis and recycling	15	63.5×	3e-22
ROS and RNS production in phagocytes	14	54.0×	2e-19
Amino acids regulate mTORC1	15	34.5×	1e-17
Ion channel transport	16	17.6×	4e-14
RHOQ GTPase cycle	7	14.6×	3e-05
PTEN Regulation	5	13.1×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
synaptic vesicle lumen acidification	12	109.1×	2e-20
vacuolar acidification	12	85.4×	9e-19
lysosomal lumen acidification	8	52.4×	2e-10
proton transmembrane transport	13	39.4×	2e-15
regulation of macroautophagy	11	31.6×	7e-12
cellular response to amino acid stimulus	5	14.9×	2e-03
intracellular iron ion homeostasis	6	14.2×	4e-04
retrograde transport, endosome to Golgi	6	12.0×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	9
Likely pathogenic	8
Uncertain significance	119
Likely benign	20
Benign	19

Top pathogenic / likely-pathogenic (17)

Variant ID	HGVS	Classification
1334193	NM_001693.4(ATP6V1B2):c.1121A>G (p.Glu374Gly)	Pathogenic
183414	NM_001693.4(ATP6V1B2):c.1454G>C (p.Arg485Pro)	Pathogenic
203442	NM_001693.4(ATP6V1B2):c.1516C>T (p.Arg506Ter)	Pathogenic
3245557	NC_000008.10:g.(?19362692)(20112692_?)del	Pathogenic
3362385	NM_001693.4(ATP6V1B2):c.1192C>G (p.Leu398Val)	Pathogenic
3377165	NM_001693.4(ATP6V1B2):c.1443G>A (p.Trp481Ter)	Pathogenic
3893337	NM_001693.4(ATP6V1B2):c.981G>A (p.Met327Ile)	Pathogenic
4056829	NM_001693.4(ATP6V1B2):c.983A>G (p.Tyr328Cys)	Pathogenic
634920	NM_001693.4(ATP6V1B2):c.1465A>T (p.Lys489Ter)	Pathogenic
2572643	NM_001693.4(ATP6V1B2):c.124C>T (p.Gln42Ter)	Likely pathogenic
3254713	NM_001693.4(ATP6V1B2):c.487C>G (p.Arg163Gly)	Likely pathogenic
3458964	NM_001693.4(ATP6V1B2):c.488G>A (p.Arg163Gln)	Likely pathogenic
372601	NM_001693.4(ATP6V1B2):c.1316_1318del (p.Val439del)	Likely pathogenic
4056414	NM_001693.4(ATP6V1B2):c.1057A>T (p.Ile353Phe)	Likely pathogenic
430256	NM_001693.4(ATP6V1B2):c.925G>A (p.Glu309Lys)	Likely pathogenic
431094	NM_001693.4(ATP6V1B2):c.1120G>C (p.Glu374Gln)	Likely pathogenic
450177	NM_001693.4(ATP6V1B2):c.722C>T (p.Ala241Val)	Likely pathogenic

SpliceAI

1571 predictions. Top by Δscore:

Variant	Effect	Δscore
8:20197538:CCTCA:C	donor_gain	1.0000
8:20197539:CTCA:C	donor_gain	1.0000
8:20197540:TCA:T	donor_gain	1.0000
8:20197541:CA:C	donor_gain	1.0000
8:20197542:AG:A	donor_loss	1.0000
8:20197543:G:C	donor_loss	1.0000
8:20197543:G:GG	donor_gain	1.0000
8:20197544:TGA:T	donor_loss	1.0000
8:20197545:GAG:G	donor_loss	1.0000
8:20209431:A:AG	acceptor_gain	1.0000
8:20209432:G:GA	acceptor_gain	1.0000
8:20209432:GT:G	acceptor_gain	1.0000
8:20209432:GTT:G	acceptor_gain	1.0000
8:20209432:GTTT:G	acceptor_gain	1.0000
8:20209432:GTTTC:G	acceptor_gain	1.0000
8:20209531:GGTA:G	donor_loss	1.0000
8:20209532:G:GG	donor_gain	1.0000
8:20209532:GTAA:G	donor_loss	1.0000
8:20209533:T:A	donor_loss	1.0000
8:20210341:GATA:G	acceptor_loss	1.0000
8:20210430:GA:G	donor_gain	1.0000
8:20210437:TTGGT:T	donor_loss	1.0000
8:20210438:TGGTA:T	donor_loss	1.0000
8:20210439:GGTAA:G	donor_loss	1.0000
8:20210440:G:GC	donor_loss	1.0000
8:20210440:G:GG	donor_gain	1.0000
8:20210441:T:A	donor_loss	1.0000
8:20210557:ACT:A	acceptor_gain	1.0000
8:20210559:T:TA	acceptor_gain	1.0000
8:20210563:TTCTA:T	acceptor_loss	1.0000

AlphaMissense

3328 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:20209490:G:T	G84W	1.000
8:20209491:G:A	G84E	1.000
8:20209497:T:A	V86D	1.000
8:20209527:T:A	V96D	1.000
8:20210572:G:C	R130P	1.000
8:20210584:G:A	G134E	1.000
8:20211210:C:A	P166Q	1.000
8:20211257:A:C	S182R	1.000
8:20211259:T:A	S182R	1.000
8:20211259:T:G	S182R	1.000
8:20211264:C:A	A184D	1.000
8:20211269:G:A	G186R	1.000
8:20211269:G:C	G186R	1.000
8:20211269:G:T	G186W	1.000
8:20211270:G:A	G186E	1.000
8:20211270:G:T	G186V	1.000
8:20211274:G:C	Q187H	1.000
8:20211274:G:T	Q187H	1.000
8:20211276:A:T	K188I	1.000
8:20211282:C:A	P190H	1.000
8:20211282:C:G	P190R	1.000
8:20211303:T:C	L197P	1.000
8:20211659:C:A	A204D	1.000
8:20211671:G:C	R208P	1.000
8:20211743:C:A	A232D	1.000
8:20211751:G:C	G235R	1.000
8:20211752:G:A	G235D	1.000
8:20212117:G:C	A241P	1.000
8:20212172:T:C	L259P	1.000
8:20212182:C:A	N262K	1.000

dbSNP variants (sampled 300 via entrez): RS1000161772 (8:20221636 T>C), RS1000221174 (8:20207217 G>C,T), RS1000274883 (8:20207001 A>G,T), RS1000380579 (8:20200220 G>A,T), RS1000404228 (8:20195798 G>C,T), RS1000435212 (8:20195579 T>C), RS1000436115 (8:20212630 A>G,T), RS1000591389 (8:20197092 C>A,G,T), RS1000643808 (8:20196890 T>C), RS1000647463 (8:20200094 T>G), RS1000768485 (8:20220457 A>C), RS1000785987 (8:20213054 A>C,G), RS1000918649 (8:20215056 A>C), RS1001031956 (8:20209353 A>C,G), RS1001090985 (8:20204074 T>C)

Disease associations

OMIM: gene MIM:606939 | disease phenotypes: MIM:124480, MIM:616455, MIM:135500, MIM:600881

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder	Strong	Autosomal dominant
autosomal dominant deafness - onychodystrophy syndrome	Strong	Autosomal dominant
developmental and epileptic encephalopathy 93	Strong	Autosomal dominant
DOORS syndrome	Strong	Autosomal dominant
Zimmermann-Laband syndrome 2	Strong	Autosomal dominant
Zimmermann-Laband syndrome	Supportive	Autosomal recessive

Mondo (9): autosomal dominant deafness - onychodystrophy syndrome (MONDO:0007420), Zimmermann-Laband syndrome 2 (MONDO:0014646), Zimmermann-Laband syndrome 1 (MONDO:0024526), intellectual disability (MONDO:0001071), cataract 10 multiple types (MONDO:0010948), neurodevelopmental disorder (MONDO:0700092), developmental and epileptic encephalopathy 93 (MONDO:0020632), Zimmermann-Laband syndrome (MONDO:0000200), DOORS syndrome (MONDO:0009079)

Orphanet (5): Deafness-onychodystrophy syndrome (Orphanet:3231), Autosomal dominant deafness-onychodystrophy syndrome (Orphanet:79499), Zimmermann-Laband syndrome (Orphanet:3473), Early onset non-syndromic cataract (Orphanet:91492), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

165 total (30 of 165 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000062	Ambiguous genitalia
HP:0000079	Abnormality of the urinary system
HP:0000121	Nephrocalcinosis
HP:0000126	Hydronephrosis
HP:0000154	Wide mouth
HP:0000158	Macroglossia
HP:0000164	Abnormality of the dentition
HP:0000169	Gingival fibromatosis
HP:0000175	Cleft palate
HP:0000179	Thick lower lip vermilion
HP:0000187	Broad alveolar ridges
HP:0000189	Narrow palate
HP:0000193	Bifid uvula
HP:0000194	Open mouth
HP:0000200	Short lingual frenulum
HP:0000212	Gingival overgrowth
HP:0000218	High palate
HP:0000219	Thin upper lip vermilion
HP:0000248	Brachycephaly
HP:0000252	Microcephaly
HP:0000268	Dolichocephaly
HP:0000269	Prominent occiput
HP:0000280	Coarse facial features
HP:0000286	Epicanthus
HP:0000294	Low anterior hairline
HP:0000316	Hypertelorism
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000348	High forehead

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST000551_3	Major depressive disorder (broad)	7.000000e-07
GCST001979_5	Circulating myeloperoxidase levels (serum)	9.000000e-07
GCST003448_7	Erythrocyte cadmium concentration in never smokers	7.000000e-06
GCST003615_3	Persistent hepatitis B virus infection	3.000000e-12
GCST009391_1688	Metabolite levels	6.000000e-06
GCST009391_767	Metabolite levels	3.000000e-06
GCST009391_780	Metabolite levels	2.000000e-06

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0005243	myeloperoxidase measurement
EFO:0010343	cholesteryl ester 18:0 measurement
EFO:0010392	sphingomyelin 16:1 measurement
EFO:0010394	sphingomyelin 18:1 measurement

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065886	Neurodevelopmental Disorders	F03.625
C563435	Cataract, Congenital Zonular, with Sutural Opacities (supp.)
C563052	Digitorenocerebral Syndrome (supp.)
C536725	Zimmerman Laband syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5641 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 25,001 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL826	ENOXACIN	4	25,001

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: transporter — V-type ATPase

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
enoxacin	Inhibition	5.0	pIC50

ChEMBL bioactivities

3 potent at pChembl≥5 of 3 total, top 3 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.68	Kd	20.89	nM	CHEMBL5653589
7.68	ED50	20.89	nM	CHEMBL5653589
5.00	IC50	1e+04	nM	ENOXACIN

PubChem BioAssay actives

2 with measured affinity, of 6 total; 2 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	2147923: Binding affinity to human ATP6V1B2 incubated for 45 mins by Kinobead based pull down assay	kd	0.0209	uM
1-ethyl-6-fluoro-4-oxo-7-piperazin-1-yl-1,8-naphthyridine-3-carboxylic acid	430759: Inhibition of maltose binding protein-fused human V-ATPase subunit B2 binding to F-actin	ic50	10.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	increases expression, affects cotreatment, decreases expression, increases abundance	3
alpha-Chlorohydrin	decreases expression, decreases reaction	3
Smoke	decreases expression, increases abundance, increases expression	3
bisphenol A	decreases expression, increases expression	2
sodium arsenite	increases expression	2
bisphenol S	affects expression, increases expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
Valproic Acid	increases expression	2
Cadmium Chloride	increases abundance, increases expression	2
aristolochic acid I	increases expression	1
bisphenol F	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	increases abundance, affects cotreatment, decreases expression	1
deoxynivalenol	decreases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, increases expression	1
trichostatin A	affects expression	1
zinc chloride	decreases expression	1
cobaltous chloride	increases expression	1
ochratoxin A	increases expression	1
cupric oxide	increases expression	1
methacrylaldehyde	affects cotreatment, decreases expression, increases abundance	1
diethyl malate	increases expression	1
azoxystrobin	decreases expression	1
chloropicrin	increases expression	1
deguelin	decreases expression	1
fenpyroximate	decreases expression	1
4-chloro-N-((4-(1,1-dimethylethyl)phenyl)methyl)-3-ethyl-1-methyl-1H-pyrazole-5-carboxamide	decreases expression	1
ginsenoside Rb1	decreases expression, decreases reaction	1
2-amino-14,16-dimethyloctadecan-3-ol	decreases expression	1
pyrachlostrobin	decreases expression	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1061614	Binding	Inhibition of maltose binding protein-fused human V-ATPase subunit B2 binding to F-actin	Identification of enoxacin as an inhibitor of osteoclast formation and bone resorption by structure-based virtual screening. — J Med Chem

Cellosaurus cell lines

2 cell lines: 2 induced pluripotent stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A1AZ	CPGHi002-A	Induced pluripotent stem cell	Female
CVCL_A7IF	CPGHi002-A-1	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays