Distal renal tubular acidosis

Summary

Distal renal tubular acidosis (MONDO:0015827) is a disease with 6 cohort genes and 1 clinical trial. The dominant Reactome pathway is Insulin receptor recycling (3 cohort genes).

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Cohort genes: 6
• ClinVar variants: 15
• Phenotypes (HPO): 38
• Clinical trials: 1

Clinical features

Signs & symptoms

Clinical features (HPO)

38 HPO clinical features (Orphanet curated; top 38 by frequency):

HPO ID	Term	Frequency
HP:0000121	Nephrocalcinosis	Very frequent (80-99%)
HP:0001996	Chronic metabolic acidosis	Very frequent (80-99%)
HP:0002900	Hypokalemia	Very frequent (80-99%)
HP:0004349	Reduced bone mineral density	Very frequent (80-99%)
HP:0004918	Hyperchloremic metabolic acidosis	Very frequent (80-99%)
HP:0012405	Hypocitraturia	Very frequent (80-99%)
HP:0032066	Decreased serum bicarbonate concentration	Very frequent (80-99%)
HP:0032944	Alkaline urine	Very frequent (80-99%)
HP:0000128	Renal potassium wasting	Frequent (30-79%)
HP:0000787	Nephrolithiasis	Frequent (30-79%)
HP:0001324	Muscle weakness	Frequent (30-79%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0001510	Growth delay	Frequent (30-79%)
HP:0002150	Hypercalciuria	Frequent (30-79%)
HP:0003109	Hyperphosphaturia	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0012608	Hypermagnesiuria	Frequent (30-79%)
HP:0000107	Renal cyst	Occasional (5-29%)
HP:0000114	Proximal tubulopathy	Occasional (5-29%)
HP:0000407	Sensorineural hearing impairment	Occasional (5-29%)
HP:0001944	Dehydration	Occasional (5-29%)
HP:0001959	Polydipsia	Occasional (5-29%)
HP:0002013	Vomiting	Occasional (5-29%)
HP:0002014	Diarrhea	Occasional (5-29%)
HP:0002019	Constipation	Occasional (5-29%)
HP:0002653	Bone pain	Occasional (5-29%)
HP:0002659	Increased susceptibility to fractures	Occasional (5-29%)
HP:0002747	Respiratory insufficiency due to muscle weakness	Occasional (5-29%)
HP:0002748	Rickets	Occasional (5-29%)
HP:0002749	Osteomalacia	Occasional (5-29%)
HP:0003126	Low-molecular-weight proteinuria	Occasional (5-29%)
HP:0003355	Aminoaciduria	Occasional (5-29%)
HP:0004396	Poor appetite	Occasional (5-29%)
HP:0011387	Enlarged vestibular aqueduct	Occasional (5-29%)
HP:0011964	Intermittent painful muscle spasms	Occasional (5-29%)
HP:0012213	Decreased glomerular filtration rate	Occasional (5-29%)
HP:0001878	Hemolytic anemia	Very rare (<1-4%)
HP:0003470	Paralysis	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	distal renal tubular acidosis
Mondo ID	MONDO:0015827
Orphanet	18
SNOMED CT	236461000
UMLS	C1704380
MedGen	853429
GARD	0004667
MedDRA	10045224
NORD	1969
Is cancer (heuristic)	no

Also known as: classic RTA · distal renal tubular acidosis (disease) · dRTA · familial distal primary acidosis · Primary Distal Renal Tubular Acidosis · renal tubular acidosis type 1 · renal tubular acidosis, distal

Data availability: 15 ClinVar variants · 1 GenCC gene-disease record · 1 HPO phenotype.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › urinary system disorder › kidney disorder › distal renal tubular acidosis

Related subtypes (56): renal hypertension, kidney failure, nephritis, impaired renal function disease, nephrocalcinosis, atheroembolism of kidney, renal artery disease, nephrosis, cystic kidney disease, anuria, stricture or kinking of ureter, proteinuria, renal infectious disease, diabetes insipidus, orthostatic proteinuria, kidney hypertrophy, chronic kidney disease, hydronephrosis, renal tubular transport disease, kidney cortex necrosis, kidney papillary necrosis, perinephritis, renal aminoaciduria, autosomal dominant progressive nephropathy with hypertension, nephrolithiasis, X-linked diffuse leiomyomatosis-Alport syndrome, tubulointerstitial nephritis and uveitis syndrome, oligomeganephronia, duplication of urethra, renal tubular dysgenesis, exstrophy-epispadias complex, fetal lower urinary tract obstruction, IgG4-related kidney disease, congenital primary megaureter, renal nutcracker syndrome, renal hypoplasia, renal dysplasia, congenital megacalycosis, glomerular disorder, congenital renal artery stenosis, kidney neoplasm, renal tubule disorder, pyonephrosis, Arnold stickler bourne syndrome, C1q nephropathy, hypertensive nephropathy, atypical Fanconi syndrome-neonatal hyperinsulinism syndrome, idiopathic non-lupus full-house nephropathy, lachiewicz sibley syndrome, crush syndrome, obstructive nephropathy, inherited kidney disorder, acute tubulointerstitial nephritis, kidney cortex disease, non-syndromic supernumerary kidneys, neonatal renal venous thrombosis

Subtypes (2): inherited distal renal tubular acidosis, acquired distal 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

15 retrieved; paginated sample, class counts are floors:

6 pathogenic/likely pathogenic, 5 pathogenic, 3 likely pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1344704	NM_020632.3(ATP6V0A4):c.2446A>G (p.Lys816Glu)	ATP6V0A4	Pathogenic	no assertion criteria provided
1344705	NM_020632.3(ATP6V0A4):c.1312_1315del (p.Asp438fs)	ATP6V0A4	Pathogenic	no assertion criteria provided
623151	NM_020632.3(ATP6V0A4):c.1346G>A (p.Arg449His)	ATP6V0A4	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
280139	NM_001692.4(ATP6V1B1):c.1037C>G (p.Pro346Arg)	ATP6V1B1	Pathogenic	criteria provided, multiple submitters, no conflicts
562411	NM_001692.4(ATP6V1B1):c.497del (p.Thr166fs)	ATP6V1B1	Pathogenic	criteria provided, multiple submitters, no conflicts
17753	NM_000342.4(SLC4A1):c.1199_1225del (p.Ala400_Ala408del)	SLC4A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17763	NM_000342.4(SLC4A1):c.1766G>A (p.Arg589His)	SLC4A1	Pathogenic	criteria provided, multiple submitters, no conflicts
17771	NM_000342.4(SLC4A1):c.2573C>A (p.Ala858Asp)	SLC4A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1343811	NM_182758.4(WDR72):c.764_768del (p.Gly255fs)	WDR72	Pathogenic/Likely pathogenic	no assertion criteria provided
522610	NM_182758.4(WDR72):c.2686C>T (p.Arg896Ter)	WDR72	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1344706	NM_001039362.2(ATP6V1C2):c.503T>C (p.Ile168Thr)	ATP6V1C2	Likely pathogenic	no assertion criteria provided
1344708	NM_003040.4(SLC4A2):c.2107G>A (p.Ala703Thr)	SLC4A2	Likely pathogenic	no assertion criteria provided
1344707	NM_182758.4(WDR72):c.477_485dup (p.Ile159_Cys161dup)	WDR72	Likely pathogenic	no assertion criteria provided
17756	NM_000342.3(SLC4A1):c.118G>A (p.Glu40Lys)	SLC4A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 1 · Orphanet: 10 · 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
ATP6V1C2	Limited	Autosomal recessive	distal renal tubular acidosis

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC4A1	Orphanet:3202	Dehydrated hereditary stomatocytosis
SLC4A1	Orphanet:398088	Hereditary cryohydrocytosis with normal stomatin
SLC4A1	Orphanet:822	Hereditary spherocytosis
SLC4A1	Orphanet:93608	Autosomal dominant distal renal tubular acidosis
SLC4A1	Orphanet:93610	Distal renal tubular acidosis with anemia
SLC4A1	Orphanet:98868	Southeast Asian ovalocytosis
WDR72	Orphanet:100033	Hypomaturation amelogenesis imperfecta
WDR72	Orphanet:402041	Autosomal recessive distal renal tubular acidosis
ATP6V1B1	Orphanet:402041	Autosomal recessive distal renal tubular acidosis
ATP6V0A4	Orphanet:402041	Autosomal recessive distal renal tubular acidosis

Cohort genes → proteins

6 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ATP6V1C2	HGNC:18264	ENSG00000143882	Q8NEY4	V-type proton ATPase subunit C 2	gencc,clinvar
SLC4A1	HGNC:11027	ENSG00000004939	P02730	Band 3 anion transport protein	clinvar
SLC4A2	HGNC:11028	ENSG00000164889	P04920	Anion exchange protein 2	clinvar
WDR72	HGNC:26790	ENSG00000166415	Q3MJ13	WD repeat-containing protein 72	clinvar
ATP6V1B1	HGNC:853	ENSG00000116039	P15313	V-type proton ATPase subunit B, kidney isoform	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)
ATP6V1C2	V-type proton ATPase subunit C 2	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.
SLC4A1	Band 3 anion transport protein	Functions both as a transporter that mediates electroneutral anion exchange across the cell membrane and as a structural protein.
SLC4A2	Anion exchange protein 2	Sodium-independent anion exchanger which mediates the electroneutral exchange of chloride for bicarbonate ions across the cell membrane.
WDR72	WD repeat-containing protein 72	Plays a major role in formation of tooth enamel.
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.
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: 1 · Unknown: 5 · 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
Scaffold/PPI	1	2.9×	0.301
Other/Unknown	5	1.5×	0.301

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ATP6V1C2	Other/Unknown	no		ATPase_V1-cplx_csu, Vac_ATP_synth_c_sf
SLC4A1	Other/Unknown	no		Anion_exchange, Anion_exchange_1, HCO3_transpt_euk
SLC4A2	Other/Unknown	no		Anion_exchange, Anion_exchange_2, HCO3_transpt_euk
WDR72	Scaffold/PPI	no		WD40_rpt, WD40/YVTN_repeat-like_dom_sf, WD40_repeat_CS
ATP6V1B1	Other/Unknown	no		ATPase_F1/V1/A1_a/bsu_nucl-bd, ATPase_F1/V1/A1_a/bsu_N, ATPase_V1-cplx_bsu
ATP6V0A4	Other/Unknown	no		V-ATPase_116kDa_su, V-type_ATPase_116kDa_su_euka

Expression context

Cohort genes with no expression data: 0.

6 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)	6
unknown	0

Top tissues across cohort

Tissue	Cohort genes
metanephros cortex	3
renal medulla	2
lower esophagus mucosa	1
skin of abdomen	1
skin of leg	1
bone marrow	1
bone marrow cell	1
trabecular bone tissue	1
body of stomach	1
muscle layer of sigmoid colon	1
kidney epithelium	1
pancreatic ductal cell	1
male germ line stem cell (sensu Vertebrata) in testis	1
right uterine tube	1
adult mammalian kidney	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ATP6V1C2	181	broad	marker	skin of abdomen, skin of leg, lower esophagus mucosa
SLC4A1	161	tissue_specific	marker	trabecular bone tissue, bone marrow, bone marrow cell
SLC4A2	261	ubiquitous	marker	body of stomach, metanephros cortex, muscle layer of sigmoid colon
WDR72	139	tissue_specific	marker	kidney epithelium, pancreatic ductal cell, renal medulla
ATP6V1B1	152	broad	marker	right uterine tube, male germ line stem cell (sensu Vertebrata) in testis, metanephros cortex
ATP6V0A4	150	tissue_specific	marker	metanephros cortex, adult mammalian kidney, renal medulla

Protein interactions among cohort

Intra-cohort edges: 5.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ATP6V1B1	2,172
SLC4A1	1,598
SLC4A2	1,580
ATP6V0A4	1,221
ATP6V1C2	1,165
WDR72	1,126

Intra-cohort edges

A	B	Sources
ATP6V0A4	ATP6V1B1	biogrid_interaction, string_interaction
ATP6V0A4	ATP6V1C2	string_interaction
ATP6V0A4	SLC4A1	string_interaction
ATP6V1B1	ATP6V1C2	biogrid_interaction, intact, string_interaction
ATP6V1B1	SLC4A1	string_interaction

Structural data

PDB: 3 · AlphaFold-only: 3 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SLC4A1	P02730	54
SLC4A2	P04920	10
ATP6V0A4	Q9HBG4	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ATP6V1B1	P15313	87.21
ATP6V1C2	Q8NEY4	86.29
WDR72	Q3MJ13	67.22

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 16. Enrichment computed across 6 evidence-associated genes (5 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 5 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	3	228.4×	1e-06	ATP6V1C2, ATP6V1B1, ATP6V0A4
Transferrin endocytosis and recycling	3	221.0×	1e-06	ATP6V1C2, ATP6V1B1, ATP6V0A4
ROS and RNS production in phagocytes	3	201.5×	1e-06	ATP6V1C2, ATP6V1B1, ATP6V0A4
Bicarbonate transporters	2	456.8×	3e-05	SLC4A1, SLC4A2
Ion channel transport	3	57.6×	3e-05	ATP6V1C2, ATP6V1B1, ATP6V0A4
Amino acids regulate mTORC1	2	80.1×	6e-04	ATP6V1C2, ATP6V1B1
Defective SLC4A1 causes hereditary spherocytosis type 4 (HSP4), distal renal tubular acidosis (dRTA) and dRTA with hemolytic anemia (dRTA-HA)	1	2284.0×	0.001	SLC4A1
R-HSA-425393	2	51.9×	0.001	SLC4A1, SLC4A2
SLC-mediated transmembrane transport	2	23.7×	0.005	SLC4A1, SLC4A2
Erythrocytes take up oxygen and release carbon dioxide	1	253.8×	0.006	SLC4A1
O2/CO2 exchange in erythrocytes	1	253.8×	0.006	SLC4A1
Erythrocytes take up carbon dioxide and release oxygen	1	175.7×	0.008	SLC4A1
Transport of small molecules	2	10.1×	0.018	SLC4A1, SLC4A2
SLC transporter disorders	1	40.8×	0.028	SLC4A1
Disorders of transmembrane transporters	1	27.9×	0.038	SLC4A1
Disease	1	2.6×	0.328	SLC4A1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 6 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	1872.4×	2e-05	ATP6V1B1, ATP6V0A4
monoatomic anion transport	2	468.1×	1e-04	SLC4A1, SLC4A2
regulation of pH	2	468.1×	1e-04	ATP6V1B1, ATP6V0A4
synaptic vesicle lumen acidification	2	312.1×	2e-04	ATP6V1B1, ATP6V0A4
bicarbonate transport	2	267.5×	2e-04	SLC4A1, SLC4A2
vacuolar acidification	2	244.2×	2e-04	ATP6V1B1, ATP6V0A4
regulation of intracellular pH	2	200.6×	3e-04	SLC4A1, SLC4A2
proton transmembrane transport	2	104.0×	9e-04	ATP6V1B1, ATP6V0A4
regulation of macroautophagy	2	98.5×	9e-04	ATP6V1C2, ATP6V1B1
ossification	2	75.9×	0.001	ATP6V1B1, ATP6V0A4
response to increased oxygen levels	1	2808.7×	0.001	SLC4A1
pH elevation	1	2808.7×	0.001	SLC4A1
transmembrane transport	2	56.2×	0.002	SLC4A1, SLC4A2
negative regulation of CD8-positive, alpha-beta T cell proliferation	1	1404.3×	0.002	SLC4A2
negative regulation of CD8-positive, alpha-beta T cell differentiation	1	936.2×	0.003	SLC4A2
renal sodium ion transport	1	702.2×	0.003	ATP6V1B1
intracellular monoatomic ion homeostasis	1	702.2×	0.003	SLC4A1
negative regulation of urine volume	1	702.2×	0.003	SLC4A1
renal sodium excretion	1	702.2×	0.003	ATP6V1B1
protein localization to plasma membrane	2	36.2×	0.003	SLC4A1, WDR72
sensory perception of sound	2	33.6×	0.003	ATP6V1B1, ATP6V0A4
positive regulation of enamel mineralization	1	561.7×	0.004	SLC4A2
vacuolar proton-transporting V-type ATPase complex assembly	1	468.1×	0.004	ATP6V1B1
negative regulation of glycolytic process through fructose-6-phosphate	1	468.1×	0.004	SLC4A1
pH reduction	1	401.2×	0.005	ATP6V1B1
olfactory behavior	1	312.1×	0.006	ATP6V1B1
plasma membrane phospholipid scrambling	1	255.3×	0.007	SLC4A1
regulation of bone resorption	1	255.3×	0.007	SLC4A2
chloride ion homeostasis	1	255.3×	0.007	ATP6V1B1
amelogenesis	1	234.1×	0.007	SLC4A2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 6

Druggability breadth: 1 of 6 evidence-associated genes (17%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ATP6V1C2	0	0
SLC4A1	0	0
SLC4A2	0	0
WDR72	0	0
ATP6V1B1	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: 6; 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	6	ATP6V1C2, SLC4A1, SLC4A2, WDR72, ATP6V1B1, ATP6V0A4

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ATP6V1C2	0	—
SLC4A1	0	—
SLC4A2	0	—
WDR72	0	—
ATP6V1B1	1	—
ATP6V0A4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03644706	PHASE3	TERMINATED	Study Evaluating Subjects With Distal Renal Tubular Acidosis