ATP6V1B1

protein-coding

ATPase H+ transporting V1 subunit B1, the group of V-type ATPase subunits|ATPase F1/V1 alpha/A and beta/B subunit family

Gene summary

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. [provided by RefSeq, Jul 2008]

Previous symbols:

VPP3
ATP6B1

MANE transcript

NM_001692.4

Inheritance

AR, AD

ClinVar variants

P:160U:265B:243

Top phenotype

Renal tubular acidosis, distal, 2, with progressive sensorineural hearing loss

gnomAD constraint

pLI —, LoF o/e 0.64

Max pathogenic AF

—

Genomic locus

chr2:70,935,900-70,965,431

External References & Databases

Ensembl (ENSG00000116039)

Transcript & Mutation Effects

hg38 • Region Span ~29.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

renal tubular acidosis, distal, 2, with progressive sensorineural hearing lossDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009968

Submitter: Natera

renal tubular acidosis, distal, 2, with progressive sensorineural hearing lossSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009968

Submitter: PanelApp Australia

renal tubular acidosis, distal, 2, with progressive sensorineural hearing lossSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009968

Submitter: Labcorp Genetics (formerly Invitae)

autosomal dominant distal renal tubular acidosisDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008368

Submitter: Natera

renal tubular acidosis, distal, 2, with progressive sensorineural hearing lossSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009968

Submitter: Ambry Genetics

renal tubular acidosis, distal, 2, with progressive sensorineural hearing lossDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009968

Submitter: ClinGen

The relationship between ATP6V1B1 and autosomal recessive renal tubular acidosis with deafness was evaluated using the ClinGen Clinical Validity Framework as of 12/13/2017. Variants in ATP6V1B1 were first reported in humans with this disease as early as 1999 (Karet et al.; PMID: 9916796). Probands with this condition have nephrocalcinosis, reduced urinary acidification, and elevated calciuria. Hearing loss prevalence is about 90 %. 15 variants (missense, nonsense, frameshift, splicing) that have been reported in over 15 probands in 5 publications are included in this curation (PMIDs: 9916796, 28188436, 2884431, 35738466, 35990030). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The majority of patients have loss-of-function variants, with some missense cases. There is one mouse model with a homozygous missense ATP6V1B1 variant resulting in hearing loss, however there is a knockout model in which the mice have renal tubular acidosis and normal hearing (PMIDs: 28934385, 12782355). In addition, there is a third mouse model in which homozygous mutant mice have increased urine pH and deficient renal proton secretion (PMID: 16174750). In summary, ATP6V1B1 is definitively associated with autosomal recessive renal tubular acidosis with deafness. Of note, dominant renal tubular acidosis has been reported in association with two missense variants affecting the same residue, p.Arg394Gln and p.Arg394Gly. Both variants were identified in the heterozygous state in affected probands. Hearing loss was observed in only 36% of reported individuals with heterozygous variants (8/22) (PMID: 39837581). This classification was approved by the ClinGen Hearing Loss Working Group on 12/19/2017. It was re-evaluated by the Hearing Loss GCEP and as a secondary curation by the Tubulopathy GCEP on the meeting date 2/18/2026, and additional genetic and experimental evidence was added (PMIDs: 16174750, 28188436, 2884431, 35738466, 35990030).

renal tubular acidosis, distal, 2, with progressive sensorineural hearing lossDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009968

Submitter: G2P

autosomal recessive distal renal tubular acidosisSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018440

Submitter: Orphanet

Clinical Genomic Database (CGD)

Renal tubular acidosis, distal, 2, with progressive sensorineural hearing lossAR

Manifestation: Audiologic/Otolaryngologic; Renal

Intervention: Renal

Rationale: Individuals can present in infancy with acute with dehydration (which can be lethal), which can be prevented by early recognition

Refs: 9916796; 12414817; 12566520; 16433694; 18798332

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ATP6V1B1 variants in ClinVar

17 Conditions Cataloged

not providedTotal: 628

Renal tubular acidosis with progressive nerve deafnessTotal: 327

Inborn genetic diseasesTotal: 85

not specifiedTotal: 57

ATP6V1B1-related disorderTotal: 47

Renal tubulopathiesTotal: 4

Distal renal tubular acidosisTotal: 3

NephrocalcinosisTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001692.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous		1 clinvar	14 clinvar	232 clinvar	3 clinvar	250
missense		14 clinvar	241 clinvar	7 clinvar	1 clinvar	263
nonsense	17 clinvar	15 clinvar	3 clinvar			35
start loss			3 clinvar			3
frameshift	54 clinvar	26 clinvar				80
splice donor/acceptor (+/-2bp)	6 clinvar	27 clinvar	4 clinvar			37
Total	77	83	265	239	4	668

Highest pathogenic variant AF is 0.00010215153

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 20 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001692.4	RefSeq	NP_001683.2	14	MANE Select
ENST00000234396.10	Ensembl	ENSP00000234396.4	14	MANE Select
ENST00000412314.5	Ensembl	ENSP00000388353.1	14	Standard
ENST00000412314.6	Ensembl	ENSP00000388353.1	14	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

mTOR signaling pathway - Homo sapiens (human)
Synaptic vesicle cycle - Homo sapiens (human)
Phagosome - Homo sapiens (human)
Epithelial cell signaling in Helicobacter pylori infection - Homo sapiens (human)
Oxidative phosphorylation - Homo sapiens (human)

Biological Process

ossification
regulation of pH
excretion
sensory perception of sound
insulin receptor signaling pathway

Molecular Function

ATP binding
proton transmembrane transporter activity
hydrolase activity
protein-containing complex binding

Cellular Component

cytoplasm
cytosol
microvillus
basolateral plasma membrane
apical plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000234396
Coding exons: 14
Length: 29525
Individuals with no LoFs: 125700
Homozygous LoFs: 0
Heterozygous LoFs: 48
Defined: 125748
p: 0.000191

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.232	297	308	0.963	0.0000199	3344
Missense (PolyPhen)		108	124.02	0.87085		1300
Synonymous	0.373	121	126	0.958	0.00000875	1025
Loss of Function	1.77	18	28.2	0.639	0.00000170	291

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00031	0.00031	rare
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00027	0.00027	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00019	0.00019	rare
South Asian	0.00029	0.00029	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Non-catalytic subunit of the peripheral V1 complex of vacuolar ATPase. V-ATPase is responsible for acidifying a variety of intracellular compartments in eukaryotic cells.;
Disease: DISEASE: Renal tubular acidosis, distal, with progressive nerve deafness (dRTA-D) [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. {ECO:0000269|PubMed:12414817, ECO:0000269|PubMed:12579397, ECO:0000269|PubMed:9916796}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.324

Intolerance Scores

LoFtool: 0.264
RVIS EVS: -0.48
RVIS percentile EVS: 22.75

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.692

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	High	Medium	High
Cancer	High	High	High