Renal tubular acidosis, distal, 3, with or without sensorineural hearing loss

Summary

Renal tubular acidosis, distal, 3, with or without sensorineural hearing loss (MONDO:0011268) is a disease caused by ATP6V0A4 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: ATP6V0A4 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 214

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	renal tubular acidosis, distal, 3, with or without sensorineural hearing loss
Mondo ID	MONDO:0011268
OMIM	602722
DOID	DOID:0061166
UMLS	C5399980
MedGen	1732975
GARD	0015350
Is cancer (heuristic)	no

Also known as: classical distal renal tubular acidosis · classical distal RTA · distal renal tubular acidosis 3, with or without sensorineural hearing loss · renal tubular acidosis, autosomal recessive with preserved hearing · renal tubular acidosis, distal, 3, with or without sensorineural hearing loss · renal tubular acidosis, distal, autosomal recessive · renal tubular acidosis, distal, autosomal recessive, with late-onset sensorineural hearing loss, included · RTADR · type 1 renal tubular acidosis · type 1 RTA

Data availability: 214 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › disorder of acid-base balance › acidosis disorder › renal tubular acidosis › renal tubular acidosis, distal, 3, with or without sensorineural hearing loss

Related subtypes (4): proximal renal tubular acidosis, renal tubular acidosis 3, neuroaxonal dystrophy renal tubular acidosis, hyperkalemic renal tubular acidosis

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

214 retrieved; paginated sample, class counts are floors:

132 uncertain significance, 30 likely pathogenic, 16 pathogenic, 15 pathogenic/likely pathogenic, 8 benign/likely benign, 8 conflicting classifications of pathogenicity, 4 likely benign, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1070788	NM_020632.3(ATP6V0A4):c.1478+2T>G	ATP6V0A4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1074132	NM_020632.3(ATP6V0A4):c.16C>T (p.Arg6Ter)	ATP6V0A4	Pathogenic	criteria provided, multiple submitters, no conflicts
1179181	NM_020632.3(ATP6V0A4):c.52C>T (p.Gln18Ter)	ATP6V0A4	Pathogenic/Likely pathogenic	criteria provided, single submitter
1323841	NM_020632.3(ATP6V0A4):c.1872C>A (p.Tyr624Ter)	ATP6V0A4	Pathogenic	criteria provided, single submitter
1323843	NM_020632.3(ATP6V0A4):c.292-1G>A	ATP6V0A4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1328935	NM_020632.3(ATP6V0A4):c.2257+1G>A	ATP6V0A4	Pathogenic	criteria provided, multiple submitters, no conflicts
1700298	NM_020632.3(ATP6V0A4):c.1185del (p.Tyr396fs)	ATP6V0A4	Pathogenic	criteria provided, multiple submitters, no conflicts
1705668	NM_020632.3(ATP6V0A4):c.1030-2A>C	ATP6V0A4	Pathogenic	criteria provided, single submitter
1802247	NM_020632.3(ATP6V0A4):c.1510C>T (p.Gln504Ter)	ATP6V0A4	Pathogenic	criteria provided, single submitter
2005279	NM_020632.3(ATP6V0A4):c.1187dup (p.Tyr396Ter)	ATP6V0A4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3256909	NM_020632.3(ATP6V0A4):c.977G>A (p.Trp326Ter)	ATP6V0A4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3594360	NM_020632.3(ATP6V0A4):c.727C>T (p.Arg243Ter)	ATP6V0A4	Pathogenic	criteria provided, single submitter
3773929	NM_020632.3(ATP6V0A4):c.1107del (p.Asn370fs)	ATP6V0A4	Pathogenic	criteria provided, multiple submitters, no conflicts
384333	NM_020632.3(ATP6V0A4):c.1231G>T (p.Asp411Tyr)	ATP6V0A4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
450987	NM_020632.3(ATP6V0A4):c.1572G>A (p.Pro524=)	ATP6V0A4	Pathogenic	criteria provided, multiple submitters, no conflicts
450988	NM_020632.3(ATP6V0A4):c.2419C>T (p.Arg807Ter)	ATP6V0A4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4796566	NM_020632.3(ATP6V0A4):c.639+1G>A	ATP6V0A4	Pathogenic	criteria provided, single submitter
5150	NM_020632.3(ATP6V0A4):c.2257C>T (p.Gln753Ter)	ATP6V0A4	Pathogenic	criteria provided, multiple submitters, no conflicts
5152	NM_020632.3(ATP6V0A4):c.1691+1G>A	ATP6V0A4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
5153	NM_020632.3(ATP6V0A4):c.105del (p.Gln36fs)	ATP6V0A4	Pathogenic	no assertion criteria provided
5155	NM_020632.3(ATP6V0A4):c.418-1G>A	ATP6V0A4	Pathogenic	no assertion criteria provided
5156	NM_020632.3(ATP6V0A4):c.829del (p.Thr277fs)	ATP6V0A4	Pathogenic	no assertion criteria provided
5158	NM_020632.3(ATP6V0A4):c.1506T>A (p.Tyr502Ter)	ATP6V0A4	Pathogenic	no assertion criteria provided
5159	NM_020632.3(ATP6V0A4):c.2420G>A (p.Arg807Gln)	ATP6V0A4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
520732	NM_020632.3(ATP6V0A4):c.1987dup (p.Arg663fs)	ATP6V0A4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
623151	NM_020632.3(ATP6V0A4):c.1346G>A (p.Arg449His)	ATP6V0A4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
632498	NM_020632.3(ATP6V0A4):c.2308C>T (p.Arg770Ter)	ATP6V0A4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
802370	NM_020632.3(ATP6V0A4):c.1691+2dup	ATP6V0A4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
956634	NM_020632.3(ATP6V0A4):c.1345C>T (p.Arg449Cys)	ATP6V0A4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
977293	NM_020632.3(ATP6V0A4):c.2137del (p.Glu713fs)	ATP6V0A4	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
ATP6V0A4	Strong	Autosomal recessive	renal tubular acidosis, distal, 3, with or without sensorineural hearing loss	4

Orphanet rare-disease linkage (cohort genes)

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

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ATP6V0A4	HGNC:866	ENSG00000105929	Q9HBG4	V-type proton ATPase 116 kDa subunit a 4	gencc,clinvar
ATP6V1B1	HGNC:853	ENSG00000116039	P15313	V-type proton ATPase subunit B, kidney isoform	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.
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.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

Per-gene assignment

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

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
metanephros cortex	2
adult mammalian kidney	1
renal medulla	1
male germ line stem cell (sensu Vertebrata) in testis	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ATP6V0A4	150	tissue_specific	marker	metanephros cortex, adult mammalian kidney, renal medulla
ATP6V1B1	152	broad	marker	right uterine tube, male germ line stem cell (sensu Vertebrata) in testis, metanephros cortex

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ATP6V1B1	2,172
ATP6V0A4	1,221

Intra-cohort edges

A	B	Sources
ATP6V0A4	ATP6V1B1	biogrid_interaction, string_interaction

Structural data

PDB: 1 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ATP6V0A4	Q9HBG4	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ATP6V1B1	P15313	87.21

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. Enrichment computed across 2 evidence-associated genes (2 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 2 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	380.7×	1e-05	ATP6V0A4, ATP6V1B1
Transferrin endocytosis and recycling	2	368.4×	1e-05	ATP6V0A4, ATP6V1B1
ROS and RNS production in phagocytes	2	335.9×	1e-05	ATP6V0A4, ATP6V1B1
Ion channel transport	2	96.0×	1e-04	ATP6V0A4, ATP6V1B1
Amino acids regulate mTORC1	1	100.2×	0.010	ATP6V1B1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 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	5617.3×	5e-07	ATP6V0A4, ATP6V1B1
regulation of pH	2	1404.3×	5e-06	ATP6V0A4, ATP6V1B1
synaptic vesicle lumen acidification	2	936.2×	8e-06	ATP6V0A4, ATP6V1B1
vacuolar acidification	2	732.7×	1e-05	ATP6V0A4, ATP6V1B1
proton transmembrane transport	2	312.1×	5e-05	ATP6V0A4, ATP6V1B1
ossification	2	227.7×	7e-05	ATP6V0A4, ATP6V1B1
sensory perception of sound	2	100.9×	3e-04	ATP6V0A4, ATP6V1B1
renal sodium ion transport	1	2106.5×	0.001	ATP6V1B1
renal sodium excretion	1	2106.5×	0.001	ATP6V1B1
vacuolar proton-transporting V-type ATPase complex assembly	1	1404.3×	0.002	ATP6V1B1
pH reduction	1	1203.7×	0.002	ATP6V1B1
olfactory behavior	1	936.2×	0.002	ATP6V1B1
chloride ion homeostasis	1	766.0×	0.002	ATP6V1B1
intracellular pH reduction	1	601.9×	0.003	ATP6V0A4
prostaglandin metabolic process	1	421.3×	0.004	ATP6V1B1
potassium ion homeostasis	1	383.0×	0.004	ATP6V1B1
renal water homeostasis	1	255.3×	0.005	ATP6V1B1
adult behavior	1	234.1×	0.005	ATP6V1B1
ATP metabolic process	1	234.1×	0.005	ATP6V1B1
calcium ion homeostasis	1	221.7×	0.005	ATP6V1B1
inner ear morphogenesis	1	150.5×	0.007	ATP6V1B1
regulation of macroautophagy	1	147.8×	0.007	ATP6V1B1
regulation of gene expression	1	41.7×	0.024	ATP6V1B1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ATP6V0A4	0	0
ATP6V1B1	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: 2; 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	2	ATP6V0A4, ATP6V1B1

Undrugged target profiles

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

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.