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

Summary

Renal tubular acidosis, distal, 2, with progressive sensorineural hearing loss (MONDO:0009968) is a disease caused by ATP6V1B1 (GenCC Definitive), with 4 cohort genes.

At a glance

• Causal gene: ATP6V1B1 (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 315

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	renal tubular acidosis, distal, 2, with progressive sensorineural hearing loss
Mondo ID	MONDO:0009968
MeSH	C562897
OMIM	267300
Orphanet	93611
SNOMED CT	236532003, 722468005
UMLS	C0403554
MedGen	98336
GARD	0015229
Is cancer (heuristic)	no

Also known as: AR dRTA with deafness · AR dRTA with hearing loss · autosomal recessive distal renal tubular acidosis with deafness · autosomal recessive distal renal tubular acidosis with hearing loss · distal renal tubular acidosis 2 with progressive sensorineural hearing loss · distal renal tubular acidosis co-occurrent with sensorineural deafness · renal tubular acidosis progressive nerve deafness · renal tubular acidosis type 1b · renal tubular acidosis with deafness · renal tubular acidosis, distal, 2, with progressive sensorineural hearing loss · renal tubular acidosis, distal, with progressive nerve deafness

Data availability: 315 ClinVar variants · 6 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal recessive disease › autosomal recessive distal renal tubular acidosis › renal tubular acidosis, distal, 2, with progressive sensorineural hearing loss

Related subtypes (2): renal tubular acidosis, distal, 3, with or without sensorineural hearing loss, renal tubular acidosis, distal, 4, with hemolytic anemia

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

315 retrieved; paginated sample, class counts are floors:

156 uncertain significance, 34 likely pathogenic, 32 likely benign, 28 conflicting classifications of pathogenicity, 24 pathogenic/likely pathogenic, 19 pathogenic, 17 benign, 5 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1071558	NM_001692.4(ATP6V1B1):c.1401_1402dup (p.Phe468fs)	ATP6V1B1	Pathogenic	criteria provided, multiple submitters, no conflicts
12225	NM_001692.4(ATP6V1B1):c.91C>T (p.Arg31Ter)	ATP6V1B1	Pathogenic	criteria provided, multiple submitters, no conflicts
12227	NM_001692.4(ATP6V1B1):c.585+1G>A	ATP6V1B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12228	NM_001692.4(ATP6V1B1):c.242T>C (p.Leu81Pro)	ATP6V1B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12229	NM_001692.4(ATP6V1B1):c.232G>A (p.Gly78Arg)	ATP6V1B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1323856	NM_001692.4(ATP6V1B1):c.67C>T (p.Arg23Ter)	ATP6V1B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1329994	NM_001692.4(ATP6V1B1):c.925G>T (p.Glu309Ter)	ATP6V1B1	Pathogenic	no assertion criteria provided
1406127	NM_001692.4(ATP6V1B1):c.242_245dup (p.Glu82delinsAspTer)	ATP6V1B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1425954	NM_001692.4(ATP6V1B1):c.1349del (p.Gln450fs)	ATP6V1B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1452175	NM_001692.4(ATP6V1B1):c.123C>G (p.Tyr41Ter)	ATP6V1B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1457062	NM_001692.4(ATP6V1B1):c.477C>A (p.Tyr159Ter)	ATP6V1B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1458122	NM_001692.4(ATP6V1B1):c.33dup (p.Leu12fs)	ATP6V1B1	Pathogenic	criteria provided, multiple submitters, no conflicts
1458465	NM_001692.4(ATP6V1B1):c.1258dup (p.Tyr420fs)	ATP6V1B1	Pathogenic	criteria provided, multiple submitters, no conflicts
179259	NM_001692.4(ATP6V1B1):c.785+1G>A	ATP6V1B1	Pathogenic	criteria provided, multiple submitters, no conflicts
1806126	NM_001692.4(ATP6V1B1):c.343_349del (p.Thr115fs)	ATP6V1B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2044793	NM_001692.4(ATP6V1B1):c.1386C>A (p.Tyr462Ter)	ATP6V1B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2203080	NM_001692.4(ATP6V1B1):c.408del (p.Pro137fs)	ATP6V1B1	Pathogenic	criteria provided, multiple submitters, no conflicts
2203081	NM_001692.4(ATP6V1B1):c.687+1G>T	ATP6V1B1	Pathogenic	criteria provided, multiple submitters, no conflicts
2501126	NM_001692.4(ATP6V1B1):c.448C>T (p.Gln150Ter)	ATP6V1B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2585130	NM_001692.4(ATP6V1B1):c.541C>T (p.Gln181Ter)	ATP6V1B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2734207	NM_001692.4(ATP6V1B1):c.823A>C (p.Thr275Pro)	ATP6V1B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
280139	NM_001692.4(ATP6V1B1):c.1037C>G (p.Pro346Arg)	ATP6V1B1	Pathogenic	criteria provided, multiple submitters, no conflicts
2801530	NM_001692.4(ATP6V1B1):c.988G>T (p.Glu330Ter)	ATP6V1B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2865159	NM_001692.4(ATP6V1B1):c.481del (p.Glu161fs)	ATP6V1B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3066230	NM_001692.4(ATP6V1B1):c.893dup (p.Glu299fs)	ATP6V1B1	Pathogenic	criteria provided, single submitter
3586876	NM_001692.4(ATP6V1B1):c.687+1G>A	ATP6V1B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4759247	NM_001692.4(ATP6V1B1):c.841dup (p.Tyr281fs)	ATP6V1B1	Pathogenic	criteria provided, single submitter
520772	NM_001692.4(ATP6V1B1):c.1155dup (p.Ile386fs)	ATP6V1B1	Pathogenic	criteria provided, multiple submitters, no conflicts
521461	NM_001692.4(ATP6V1B1):c.340C>T (p.Arg114Ter)	ATP6V1B1	Pathogenic	criteria provided, multiple submitters, no conflicts
554499	NM_001692.4(ATP6V1B1):c.943C>T (p.Arg315Ter)	ATP6V1B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
ATP6V1B1	Definitive	Autosomal recessive	renal tubular acidosis, distal, 2, with progressive sensorineural hearing loss	6
SLC12A7	No Known Disease Relationship	Unknown	renal tubular acidosis, distal, 2, with progressive sensorineural hearing loss

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ATP6V1B1	Orphanet:402041	Autosomal recessive distal renal tubular acidosis
ATP6V0A4	Orphanet:402041	Autosomal recessive distal renal tubular acidosis

Cohort genes → proteins

4 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ATP6V1B1	HGNC:853	ENSG00000116039	P15313	V-type proton ATPase subunit B, kidney isoform	gencc,clinvar
SLC12A7	HGNC:10915	ENSG00000113504	Q9Y666	Solute carrier family 12 member 7	gencc
ATP6V1B1-AS1	HGNC:51118	ENSG00000239322		ATP6V1B1 antisense RNA 1	clinvar
ATP6V0A4	HGNC:866	ENSG00000105929	Q9HBG4	V-type proton ATPase 116 kDa subunit a 4	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ATP6V1B1	V-type proton ATPase subunit B, kidney isoform	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.
SLC12A7	Solute carrier family 12 member 7	Mediates electroneutral potassium-chloride cotransport when activated by cell swelling.
ATP6V0A4	V-type proton ATPase 116 kDa subunit a 4	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.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 4 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	4	1.8×	0.097

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ATP6V1B1	Other/Unknown	no		ATPase_F1/V1/A1_a/bsu_nucl-bd, ATPase_F1/V1/A1_a/bsu_N, ATPase_V1-cplx_bsu
SLC12A7	Other/Unknown	no		KCL_cotranspt, AA-permease/SLC12A_dom, SLC12A_fam
ATP6V1B1-AS1	Other/Unknown	no
ATP6V0A4	Other/Unknown	no		V-ATPase_116kDa_su, V-type_ATPase_116kDa_su_euka

Expression context

Cohort genes with no expression data: 0.

3 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
metanephros cortex	3
male germ line stem cell (sensu Vertebrata) in testis	2
right uterine tube	1
apex of heart	1
heart left ventricle	1
stromal cell of endometrium	1
tonsil	1
adult mammalian kidney	1
renal medulla	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ATP6V1B1	152	broad	marker	right uterine tube, male germ line stem cell (sensu Vertebrata) in testis, metanephros cortex
SLC12A7	140	ubiquitous	marker	apex of heart, heart left ventricle, metanephros cortex
ATP6V1B1-AS1	105		yes	male germ line stem cell (sensu Vertebrata) in testis, tonsil, stromal cell of endometrium
ATP6V0A4	150	tissue_specific	marker	metanephros cortex, adult mammalian kidney, renal medulla

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ATP6V1B1	2,172
SLC12A7	1,474
ATP6V0A4	1,221
ATP6V1B1-AS1	0

Intra-cohort edges

A	B	Sources
ATP6V0A4	ATP6V1B1	biogrid_interaction, string_interaction

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ATP6V0A4	Q9HBG4	2
SLC12A7	Q9Y666	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ATP6V1B1	P15313	87.21

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. Enrichment computed across 4 evidence-associated genes (3 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Insulin receptor recycling	2	253.8×	8e-05	ATP6V1B1, ATP6V0A4
Transferrin endocytosis and recycling	2	245.6×	8e-05	ATP6V1B1, ATP6V0A4
ROS and RNS production in phagocytes	2	223.9×	8e-05	ATP6V1B1, ATP6V0A4
Ion channel transport	2	64.0×	7e-04	ATP6V1B1, ATP6V0A4
Cation-coupled Chloride cotransporters	1	543.8×	0.003	SLC12A7
Amino acids regulate mTORC1	1	66.8×	0.022	ATP6V1B1
R-HSA-425393	1	43.3×	0.029	SLC12A7
SLC-mediated transmembrane transport	1	19.7×	0.056	SLC12A7
Transport of small molecules	1	8.4×	0.115	SLC12A7

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
renal tubular secretion	2	3744.9×	2e-06	ATP6V1B1, ATP6V0A4
chloride ion homeostasis	2	1021.3×	1e-05	ATP6V1B1, SLC12A7
regulation of pH	2	936.2×	1e-05	ATP6V1B1, ATP6V0A4
synaptic vesicle lumen acidification	2	624.1×	2e-05	ATP6V1B1, ATP6V0A4
potassium ion homeostasis	2	510.7×	3e-05	ATP6V1B1, SLC12A7
vacuolar acidification	2	488.5×	3e-05	ATP6V1B1, ATP6V0A4
proton transmembrane transport	2	208.1×	1e-04	ATP6V1B1, ATP6V0A4
ossification	2	151.8×	2e-04	ATP6V1B1, ATP6V0A4
sensory perception of sound	2	67.3×	1e-03	ATP6V1B1, ATP6V0A4
renal sodium ion transport	1	1404.3×	0.002	ATP6V1B1
renal sodium excretion	1	1404.3×	0.002	ATP6V1B1
vacuolar proton-transporting V-type ATPase complex assembly	1	936.2×	0.003	ATP6V1B1
pH reduction	1	802.5×	0.003	ATP6V1B1
olfactory behavior	1	624.1×	0.003	ATP6V1B1
intracellular pH reduction	1	401.2×	0.005	ATP6V0A4
prostaglandin metabolic process	1	280.9×	0.007	ATP6V1B1
cell volume homeostasis	1	200.6×	0.009	SLC12A7
renal water homeostasis	1	170.2×	0.010	ATP6V1B1
adult behavior	1	156.0×	0.010	ATP6V1B1
ATP metabolic process	1	156.0×	0.010	ATP6V1B1
calcium ion homeostasis	1	147.8×	0.010	ATP6V1B1
potassium ion import across plasma membrane	1	122.1×	0.011	SLC12A7
inner ear morphogenesis	1	100.3×	0.013	ATP6V1B1
regulation of macroautophagy	1	98.5×	0.013	ATP6V1B1
cellular response to glucose stimulus	1	89.2×	0.013	SLC12A7
chloride transmembrane transport	1	79.1×	0.015	SLC12A7
monoatomic ion transport	1	52.0×	0.021	SLC12A7
potassium ion transmembrane transport	1	45.3×	0.023	SLC12A7
regulation of gene expression	1	27.8×	0.037	ATP6V1B1
chemical synaptic transmission	1	25.8×	0.038	SLC12A7

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 4

Druggability breadth: 1 of 4 evidence-associated genes (25%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ATP6V1B1	0	0
SLC12A7	0	0
ATP6V1B1-AS1	0	0
ATP6V0A4	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
ATP6V1B1	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	4	ATP6V1B1, SLC12A7, ATP6V1B1-AS1, ATP6V0A4

Undrugged target profiles

4 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
ATP6V1B1	1	—
SLC12A7	0	—
ATP6V1B1-AS1	0	—
ATP6V0A4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.