Autosomal dominant distal renal tubular acidosis

Summary

Autosomal dominant distal renal tubular acidosis (MONDO:0008368) is a disease caused by variants in SLC4A1 and SLC4A3, with 2 cohort genes.

At a glance

• Prevalence: Unknown (Europe)
• Causal genes: SLC4A1 (GenCC Strong), SLC4A3 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 286

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal dominant distal renal tubular acidosis
Mondo ID	MONDO:0008368
OMIM	179800
Orphanet	93608
GARD	0004668
Is cancer (heuristic)	no

Also known as: AD dRTA · autosomal dominant SLC4A1-associated distal renal tubular acidosis · distal renal tubular acidosis (disease), autosomal dominant · DRTA1 · renal tubular acidosis, distal 1 · RTA, classic type · RTA, distal type, autosomal dominant · RTA, gradient type

Data availability: 286 ClinVar variants · 5 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 dominant disease › autosomal dominant distal renal tubular acidosis

Related subtypes (191): autosomal dominant polycystic liver disease, cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1, tuberous sclerosis, Treacher-Collins syndrome, hereditary breast ovarian cancer syndrome, autosomal dominant polycystic kidney disease, Lynch syndrome, branchio-oto-renal syndrome, autosomal dominant Aarskog syndrome, acroosteolysis dominant type, ADULT syndrome, autosomal dominant Alport syndrome, amelogenesis imperfecta type 1B, Townes-Brocks syndrome, nevoid basal cell carcinoma syndrome, blepharophimosis, ptosis, and epicanthus inversus syndrome, autosomal dominant brachyolmia, branchiooculofacial syndrome, pheochromocytoma/paraganglioma syndrome 4, cataract-aberrant oral frenula-growth delay syndrome, cherubism, autosomal dominant chondrodysplasia punctata, autosomal dominant popliteal pterygium syndrome, blepharocheilodontic syndrome, cochleosaccular degeneration-cataract syndrome, renal coloboma syndrome, Beare-Stevenson cutis gyrata syndrome, autosomal dominant vibratory urticaria, neurohypophyseal diabetes insipidus, autosomal dominant Kenny-Caffey syndrome, Rapp-Hodgkin syndrome, Ehlers-Danlos syndrome, classic type, autosomal dominant Ehlers-Danlos syndrome, vascular type, multiple endocrine neoplasia type 1, Coffin-Siris syndrome 1, isolated congenital adermatoglyphia, Flynn-Aird syndrome, Frasier syndrome, hand-foot-genital syndrome, Holt-Oram syndrome, hyperkeratosis-hyperpigmentation syndrome, autosomal dominant ichthyosis vulgaris, hyper-IgE recurrent infection syndrome 1, autosomal dominant, autosomal dominant keratitis, autosomal dominant keratitis-ichthyosis-hearing loss syndrome, LADD syndrome, trichorhinophalangeal syndrome type II, Noonan syndrome with multiple lentigines, microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability, Marfan syndrome, melanoma, cutaneous malignant, susceptibility to, 2, autosomal dominant primary microcephaly, autosomal dominant progressive external ophthalmoplegia, monilethrix, Muir-Torre syndrome, autosomal dominant myoglobinuria, autosomal dominant centronuclear myopathy, nail-patella syndrome, multiple endocrine neoplasia type 2B, autosomal dominant omodysplasia, pheochromocytoma/paraganglioma syndrome 1, Pelger-Huet anomaly, multiple endocrine neoplasia type 2A, piebaldism, autosomal dominant medullary cystic kidney disease with or without hyperuricemia, generalized juvenile polyposis/juvenile polyposis coli, juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, Peutz-Jeghers syndrome, contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A, retinoschisis, autosomal dominant, autosomal dominant Robinow syndrome, scapuloperoneal spinal muscular atrophy, autosomal dominant, autosomal dominant sideroblastic anemia, spondyloepiphyseal dysplasia tarda, autosomal dominant, proximal symphalangism, calcaneonavicular coalition, thanatophoric dysplasia type 1, trichorhinophalangeal syndrome type I, Muckle-Wells syndrome, autosomal dominant hypophosphatemic rickets, von Hippel-Lindau disease, Denys-Drash syndrome, autosomal dominant severe congenital neutropenia, Costello syndrome, EEC syndrome, multiple cutaneous and mucosal venous malformations, diffuse nonepidermolytic palmoplantar keratoderma, Timothy syndrome, pheochromocytoma/paraganglioma syndrome 2, spondyloepimetaphyseal dysplasia with multiple dislocations, Brooke-Spiegler syndrome, macrocephaly-autism syndrome, pheochromocytoma/paraganglioma syndrome 3, Duane-radial ray syndrome, PCWH syndrome, heart-hand syndrome, Slovenian type, congenital stationary night blindness autosomal dominant 3, mandibulofacial dysostosis-microcephaly syndrome, multiple endocrine neoplasia type 4, juvenile cataract-microcornea-renal glucosuria syndrome, Crouzon syndrome-acanthosis nigricans syndrome, Birk-Barel syndrome, thrombophilia due to protein S deficiency, autosomal dominant, dyskeratosis congenita, autosomal dominant 2, dyskeratosis congenita, autosomal dominant 3, colorectal cancer, hereditary nonpolyposis, type 6, colorectal cancer, hereditary nonpolyposis, type 7, brain small vessel disease 2A, autosomal dominant, intellectual disability, autosomal dominant 14, intellectual disability, autosomal dominant 15, intellectual disability, autosomal dominant 16, hypopigmentation-punctate palmoplantar keratoderma syndrome, intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency, postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome, intellectual developmental disorder with microcephaly and with or without ocular malformations or hypogonadotropic hypogonadism, intellectual disability, autosomal dominant 29, intellectual disability, autosomal dominant 30, Houge-Janssens syndrome 2, severe achondroplasia-developmental delay-acanthosis nigricans syndrome, dyskeratosis congenita, autosomal dominant 6, epidermolysis bullosa simplex 6, generalized, with scarring and hair loss, autosomal dominant complex spastic paraplegia, early-onset autosomal dominant Alzheimer disease, muscular dystrophy, limb-girdle, autosomal dominant, Feingold syndrome, Carney complex, neuronopathy, distal hereditary motor, autosomal dominant, autosomal dominant coarctation of aorta, autosomal dominant spondylocostal dysostosis, autosomal dominant hypohidrotic ectodermal dysplasia, Cowden disease, autosomal dominant distal myopathy, autosomal dominant rhegmatogenous retinal detachment, palmoplantar keratoderma-spastic paralysis syndrome, Alagille syndrome due to a JAG1 point mutation, PTEN hamartoma tumor syndrome, gastric adenocarcinoma and proximal polyposis of the stomach, autosomal dominant proximal renal tubular acidosis, autosomal dominant spastic ataxia, Waardenburg syndrome, hereditary retinoblastoma, autosomal dominant hypocalcemia, Li-Fraumeni syndrome, Loeys-Dietz syndrome, hereditary hemorrhagic telangiectasia, hereditary inclusion body myopathy-joint contractures-ophthalmoplegia syndrome, microcephalic osteodysplastic dysplasia, Saul-Wilson type, autosomal dominant intermediate Charcot-Marie-Tooth disease, autosomal dominant cutis laxa, autosomal dominant nonsyndromic hearing loss, autosomal dominant optic atrophy, autosomal dominant Emery-Dreifuss muscular dystrophy, autosomal dominant cerebellar ataxia, autosomal dominant osteopetrosis, autosomal dominant epidermolytic ichthyosis, ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome, distal arthrogryposis type 2B1, neurofibromatosis, autosomal dominant cataract, arthrogryposis, distal, type 2B2, arthrogryposis, distal, type 2B3, Charcot-Marie-Tooth disease, demyelinating, type 1G, Delpire-McNeill syndrome, LAMA5-related multisystemic syndrome, autosomal dominant oculocutaneous albinism, Charcot-Marie-tooth disease, axonal, type 2DD, Pilarowski-Bjornsson syndrome, intellectual disability, autosomal dominant, fatty acyl-CoA reductase 1 upregulation, GUCY2D-related dominant retinopathy, RPE65-related dominant retinopathy, autosomal dominant titinopathy, NOG-related symphalangism spectrum disorder, ALPL-related autosomal dominant hypophosphatasia, MYH10-related neurodevelopmental disorder with congenital anomalies, spastic paraplegia 30A, autosomal dominant, TMEM127-related tumor predisposition, MAX-related tumor predisposition, BMPR1A-related juvenile polyposis syndrome, RP1-related dominant retinopathy, Birt-Hogg-Dube syndrome, inclusion body myopathy and brain white matter abnormalities, KINSSHIP syndrome, autosomal dominant nebulin-related myopathy, IMPG1-related dominant retinopathy, PROM1-related dominant retinopathy, PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome, ALG8-related autosomal dominant polycystic kidney and/or liver disease, NOTCH1-related AOS spectrum disorder, FLNB-associated autosomal dominant filamin related bone disorder, familial antiphospholipid syndrome

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

286 retrieved; paginated sample, class counts are floors:

149 uncertain significance, 60 conflicting classifications of pathogenicity, 28 benign/likely benign, 15 benign, 12 pathogenic/likely pathogenic, 8 pathogenic, 7 likely benign, 7 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
17777	NM_000342.4(SLC4A1):c.[2687_2699dup;2710_2718del]		Pathogenic	no assertion criteria provided
1339451	NM_000342.4(SLC4A1):c.2692G>T (p.Glu898Ter)	SLC4A1	Pathogenic	criteria provided, single submitter
17753	NM_000342.4(SLC4A1):c.1199_1225del (p.Ala400_Ala408del)	SLC4A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17762	NM_000342.3(SLC4A1):c.448C>T (p.Arg150Ter)	SLC4A1	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
17764	NM_000342.4(SLC4A1):c.1765C>T (p.Arg589Cys)	SLC4A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17765	NM_000342.4(SLC4A1):c.1838C>T (p.Ser613Phe)	SLC4A1	Pathogenic	no assertion criteria provided
17766	NM_000342.4(SLC4A1):c.1765C>A (p.Arg589Ser)	SLC4A1	Pathogenic	criteria provided, single submitter
17767	NM_000342.4(SLC4A1):c.2102G>A (p.Gly701Asp)	SLC4A1	Pathogenic/Likely 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
17773	NM_000342.3(SLC4A1):c.1462G>A (p.Val488Met)	SLC4A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17780	NM_000342.3(SLC4A1):c.2279G>A (p.Arg760Gln)	SLC4A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
235293	NM_000342.4(SLC4A1):c.1825G>A (p.Gly609Arg)	SLC4A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3382897	NM_000342.4(SLC4A1):c.2020del (p.Val674fs)	SLC4A1	Pathogenic	criteria provided, single submitter
3582115	NM_000342.4(SLC4A1):c.1242del (p.Phe414fs)	SLC4A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4526886	NM_000342.4(SLC4A1):c.1766_1767delinsAA (p.Arg589Gln)	SLC4A1	Pathogenic	criteria provided, single submitter
544809	NM_000342.4(SLC4A1):c.2423G>A (p.Arg808His)	SLC4A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
620131	NM_000342.4(SLC4A1):c.1030C>T (p.Arg344Ter)	SLC4A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
971626	NM_000342.4(SLC4A1):c.2726T>C (p.Met909Thr)	SLC4A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
994203	NM_000342.4(SLC4A1):c.2169G>A (p.Trp723Ter)	SLC4A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3780627	NC_000002.12:g.42108272_42108298del		Likely pathogenic	criteria provided, single submitter
1163104	NM_000342.4(SLC4A1):c.2260C>T (p.Gln754Ter)	SLC4A1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1275803	NM_000342.4(SLC4A1):c.2716G>T (p.Glu906Ter)	SLC4A1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2433471	NM_000342.4(SLC4A1):c.349+1G>C	SLC4A1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3236234	NM_000342.4(SLC4A1):c.2712C>G (p.Tyr904Ter)	SLC4A1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3236344	NM_000342.4(SLC4A1):c.1816G>A (p.Gly606Arg)	SLC4A1	Likely pathogenic	criteria provided, single submitter
3359164	NM_000342.4(SLC4A1):c.2453A>G (p.Tyr818Cys)	SLC4A1	Likely pathogenic	no assertion criteria provided
1008971	NM_000342.4(SLC4A1):c.1181T>C (p.Leu394Pro)	SLC4A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1017059	NM_000342.4(SLC4A1):c.1400C>T (p.Pro467Leu)	SLC4A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1044950	NM_000342.4(SLC4A1):c.1160G>A (p.Arg387Gln)	SLC4A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 21 · Orphanet: 7 · 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
SLC4A1	Strong	Autosomal dominant	autosomal dominant distal renal tubular acidosis	15
SLC4A3	Strong	Autosomal dominant	autosomal dominant distal renal tubular acidosis	6

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
SLC4A3	Orphanet:51083	Congenital short QT syndrome

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
SLC4A1	HGNC:11027	ENSG00000004939	P02730	Band 3 anion transport protein	gencc,clinvar
SLC4A3	HGNC:11029	ENSG00000114923	P48751	Anion exchange protein 3	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.
SLC4A3	Anion exchange protein 3	Sodium-independent anion exchanger which mediates the electroneutral exchange of chloride for bicarbonate ions across the cell membrane.

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)
SLC4A1	Other/Unknown	no		Anion_exchange, Anion_exchange_1, HCO3_transpt_euk
SLC4A3	Other/Unknown	no		Anion_exchange, Anion_exchange_3, HCO3_transpt_euk

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
bone marrow	1
bone marrow cell	1
trabecular bone tissue	1
apex of heart	1
cardiac atrium	1
right atrium auricular region	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC4A1	161	tissue_specific	marker	trabecular bone tissue, bone marrow, bone marrow cell
SLC4A3	203	ubiquitous	marker	apex of heart, right atrium auricular region, cardiac atrium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SLC4A1	1,598
SLC4A3	859

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SLC4A1	P02730	54
SLC4A3	P48751	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. 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
Bicarbonate transporters	2	1142.0×	8e-06	SLC4A1, SLC4A3
R-HSA-425393	2	129.8×	3e-04	SLC4A1, SLC4A3
Defective SLC4A1 causes hereditary spherocytosis type 4 (HSP4), distal renal tubular acidosis (dRTA) and dRTA with hemolytic anemia (dRTA-HA)	1	5710.0×	6e-04	SLC4A1
SLC-mediated transmembrane transport	2	59.2×	8e-04	SLC4A1, SLC4A3
Erythrocytes take up oxygen and release carbon dioxide	1	634.4×	0.002	SLC4A1
O2/CO2 exchange in erythrocytes	1	634.4×	0.002	SLC4A1
Transport of small molecules	2	25.1×	0.002	SLC4A1, SLC4A3
Erythrocytes take up carbon dioxide and release oxygen	1	439.2×	0.003	SLC4A1
SLC transporter disorders	1	102.0×	0.012	SLC4A1
Disorders of transmembrane transporters	1	69.6×	0.016	SLC4A1
Disease	1	6.5×	0.147	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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
bicarbonate transport	2	802.5×	3e-05	SLC4A1, SLC4A3
regulation of intracellular pH	2	601.9×	3e-05	SLC4A1, SLC4A3
transmembrane transport	2	168.5×	2e-04	SLC4A1, SLC4A3
response to increased oxygen levels	1	8426.0×	5e-04	SLC4A1
pH elevation	1	8426.0×	5e-04	SLC4A1
cardiac muscle cell action potential	1	4213.0×	8e-04	SLC4A3
intracellular monoatomic ion homeostasis	1	2106.5×	0.001	SLC4A1
negative regulation of urine volume	1	2106.5×	0.001	SLC4A1
regulation of cardiac muscle cell action potential	1	1404.3×	0.001	SLC4A3
negative regulation of glycolytic process through fructose-6-phosphate	1	1404.3×	0.001	SLC4A1
pH reduction	1	1203.7×	0.002	SLC4A3
cardiac conduction	1	842.6×	0.002	SLC4A3
plasma membrane phospholipid scrambling	1	766.0×	0.002	SLC4A1
monoatomic anion transport	1	702.2×	0.002	SLC4A1
erythrocyte development	1	263.3×	0.005	SLC4A1
chloride transport	1	227.7×	0.005	SLC4A1
chloride transmembrane transport	1	118.7×	0.010	SLC4A1
transport across blood-brain barrier	1	89.6×	0.012	SLC4A3
blood coagulation	1	86.9×	0.012	SLC4A1
protein localization to plasma membrane	1	54.4×	0.018	SLC4A1

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SLC4A1	0	0
SLC4A3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	SLC4A1, SLC4A3

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)
SLC4A1	0	—
SLC4A3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.