Autosomal recessive proximal renal tubular acidosis

Summary

Autosomal recessive proximal renal tubular acidosis (MONDO:0011422) is a disease caused by SLC4A4 (GenCC Definitive), with 1 cohort gene and 1 clinical trial.

At a glance

• Prevalence: Unknown (Europe)
• Causal gene: SLC4A4 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 251
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive proximal renal tubular acidosis
Mondo ID	MONDO:0011422
MeSH	C567038
OMIM	604278
Orphanet	93607
DOID	DOID:0061167, DOID:0061195
UMLS	C1970309
MedGen	370883
GARD	0016826
Is cancer (heuristic)	no

Also known as: AR pRTA · proximal renal tubular acidosis with ocular abnormalities and intellectual disability · proximal renal tubular acidosis, autosomal recessive · renal tubular acidosis, proximal, with ocular abnormalities · renal tubular acidosis, proximal, with ocular abnormalities and mental retardation

Data availability: 251 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 recessive disease › autosomal recessive proximal renal tubular acidosis

Related subtypes (218): immunodeficiency-centromeric instability-facial anomalies syndrome, hypercalcemia, infantile, Ochoa syndrome, autosomal recessive Ehlers-Danlos syndrome, vascular type, hydrolethalus syndrome, 3-M syndrome, isolated hyperchlorhidrosis, dacryocystitis-osteopoikilosis syndrome, Hutchinson-Gilford progeria syndrome, achalasia microcephaly syndrome, acrorenal syndrome, autosomal recessive, beta-ketothiolase deficiency, autosomal recessive Alport syndrome, Alstrom syndrome, microphthalmia with limb anomalies, camptodactyly-arthropathy-coxa vara-pericarditis syndrome, Behr syndrome, bifid nose, autosomal recessive, Bloom syndrome, Bowen-Conradi syndrome, camptodactyly with fibrous tissue hyperplasia and skeletal dysplasia, heart defects-limb shortening syndrome, autosomal recessive palmoplantar keratoderma and congenital alopecia, COFS syndrome, craniometaphyseal dysplasia, autosomal recessive, Fraser syndrome, cystic fibrosis, polycystic lipomembranous osteodysplasia with sclerosing leukoencephaly, persistent hyperplastic primary vitreous, autosomal recessive, Donnai-Barrow syndrome, Schöpf-Schulz-Passarge syndrome, cleft lip/palate-ectodermal dysplasia syndrome, Ellis-van Creveld syndrome, Wolcott-Rallison syndrome, autosomal recessive faciodigitogenital syndrome, acromesomelic dysplasia 2B, brittle cornea syndrome, triple-A syndrome, autosomal recessive humeroradial synostosis, multinucleated neurons-anhydramnios-renal dysplasia-cerebellar hypoplasia-hydranencephaly syndrome, hydrocephalus, nonsyndromic, autosomal recessive 1, autosomal recessive hydrocephalus due to congenital stenosis of aqueduct of Sylvius, hypertelorism, microtia, facial clefting syndrome, hypoparathyroidism-retardation-dysmorphism syndrome, Vici syndrome, Johanson-Blizzard syndrome, autosomal recessive Kenny-Caffey syndrome, Papillon-Lefevre disease, Haim-Munk syndrome, Laurence-Moon syndrome, Donohue syndrome, lipase deficiency, combined, autosomal recessive familial Mediterranean fever, thiamine-responsive megaloblastic anemia syndrome, cartilage-hair hypoplasia, Nijmegen breakage syndrome, pseudo-TORCH syndrome, Galloway-Mowat syndrome, mulibrey nanism, myotonia congenita, autosomal recessive, Schwartz-Jampel syndrome, proteosome-associated autoinflammatory syndrome, Netherton syndrome, Niemann-Pick disease type A, oculodentodigital dysplasia, autosomal recessive, odonto-onycho-dermal dysplasia, autosomal recessive omodysplasia, osteoporosis-pseudoglioma syndrome, Shwachman-Diamond syndrome, phenylketonuria, Bjornstad syndrome, Laron syndrome, autosomal recessive polycystic kidney disease, autosomal recessive inherited pseudoxanthoma elasticum, autosomal recessive multiple pterygium syndrome, rapadilino syndrome, short-rib thoracic dysplasia 9 with or without polydactyly, autosomal recessive Robinow syndrome, Sjogren-Larsson syndrome, scapuloperoneal spinal muscular atrophy, autosomal recessive, spondyloepiphyseal dysplasia tarda, autosomal recessive, inherited threoninemia, Pendred syndrome, autosomal recessive spondylocostal dysostosis, Werner syndrome, ABCD syndrome, Naxos disease, autosomal recessive amelia, human HOXA1 syndromes, sickle cell disease, hyper-IgM syndrome type 2, temtamy preaxial brachydactyly syndrome, TH-deficient dopa-responsive dystonia, craniosynostosis syndrome, autosomal recessive, Niemann-Pick disease type B, skin fragility-woolly hair-palmoplantar keratoderma syndrome, CoQ-responsive OXPHOS deficiency, familial adenomatous polyposis 2, Pierson syndrome, palmoplantar keratoderma-XX sex reversal-predisposition to squamous cell carcinoma syndrome, cardiomyopathy-hypotonia-lactic acidosis syndrome, PHARC syndrome, Kahrizi syndrome, cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies, congenital prothrombin deficiency, immunodeficiency 31B, dyskeratosis congenita, autosomal recessive 2, dyskeratosis congenita, autosomal recessive 3, Nestor-Guillermo progeria syndrome, leukoencephalopathy with calcifications and cysts, mitochondrial pyruvate carrier deficiency, branched-chain keto acid dehydrogenase kinase deficiency, dyskeratosis congenita, autosomal recessive 5, hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome, alacrima, achalasia, and intellectual disability syndrome, hyperlipoproteinemia, type 1D, microcephaly and chorioretinopathy 2, congenital stationary night blindness 1G, combined oxidative phosphorylation deficiency 29, hypermanganesemia with dystonia 2, growth retardation, intellectual developmental disorder, hypotonia, and hepatopathy, gnb5-related intellectual disability-cardiac arrhythmia syndrome, autosomal recessive spastic paraplegia type 78, autosomal recessive limb-girdle muscular dystrophy, Bardet-Biedl syndrome, autosomal recessive cerebellar ataxia, neuronopathy, distal hereditary motor, autosomal recessive, UV-sensitive syndrome, Ehlers-Danlos syndrome, kyphoscoliotic type 1, Cockayne syndrome, hyperphenylalaninemia due to tetrahydrobiopterin deficiency, leukoencephalopathy-palmoplantar keratoderma syndrome, autosomal recessive hypohidrotic ectodermal dysplasia, Warburg micro syndrome, autosomal recessive primary microcephaly, autosomal recessive progressive external ophthalmoplegia, Meier-Gorlin syndrome, autosomal recessive sideroblastic anemia, autosomal recessive intermediate Charcot-Marie-Tooth disease, Perrault syndrome, autosomal recessive hypophosphatemic rickets, de Barsy syndrome, leukocyte adhesion deficiency, Senior-Loken syndrome, autosomal recessive spastic ataxia, childhood-onset autosomal recessive myopathy with external ophthalmoplegia, autosomal recessive cerebral atrophy, GM3 synthase deficiency, autosomal recessive distal renal tubular acidosis, pigmentation defects-palmoplantar keratoderma-skin carcinoma syndrome, autosomal recessive brachyolmia, Aicardi-Goutieres syndrome, homocystinuria without methylmalonic aciduria, Niemann-Pick disease type C, nephronophthisis, autosomal recessive osteopetrosis, peroxisome biogenesis disorder, congenital non-bullous ichthyosiform erythroderma, Seckel syndrome, Usher syndrome, autosomal recessive cutis laxa type 1, autosomal recessive cutis laxa type 2, hearing loss, autosomal recessive, microcephaly, growth restriction, and increased sister chromatid exchange 2, encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 1, congenital vertebral-cardiac-renal anomalies syndrome, hair defect with photosensitivity and intellectual disability syndrome, autosomal recessive severe congenital neutropenia, severe combined immunodeficiency due to CARMIL2 deficiency, extraoral halitosis due to methanethiol oxidase deficiency, neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities, mitochondrial complex 2 deficiency, nuclear type 3, mitochondrial complex 2 deficiency, nuclear type 4, mismatch repair cancer syndrome, spondyloepimetaphyseal dysplasia with joint laxity, type 3, Kilquist syndrome, Duane anomaly-myopathy-scoliosis syndrome, autosomal recessive axonal charcot-marie-tooth disease due to copper metabolism defect, immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections-lymphopenia syndrome, optic atrophy-ataxia-peripheral neuropathy-global developmental delay syndrome, congenital myopathy with reduced type 2 muscle fibers, NAD(P)HX dehydratase deficiency, autosomal recessive ocular albinism, ichthyosis linearis circumflexa, eosinophil peroxidase deficiency, hyperphenylalaninemia due to DNAJC12 deficiency, autosomal recessive epidermolytic ichthyosis, Ehlers-Danlos syndrome, classic-like, 2, joint laxity, short stature, and myopia, HELIX syndrome, auditory neuropathy-optic atrophy syndrome, glycosylphosphatidylinositol biosynthesis defect 15, neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures, SCN4A-related myopathy, autosomal recessive, Uner Tan Syndrome, nephropathic cystinosis, Imerslund-Grasbeck syndrome type 1, Imerslund-Grasbeck syndrome type 2, permanent neonatal diabetes mellitus 1, growth hormone insensitivity with immune dysregulation 1, autosomal recessive, Rajab interstitial lung disease with brain calcifications 1, Roberts-SC phocomelia syndrome, neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities, RPE65-related recessive retinopathy, GUCY2D-related recessive retinopathy, autosomal recessive titinopathy, intellectual disability, autosomal recessive, ALPL-related autosomal recessive hypophosphatasia, spastic paraplegia 18b, autosomal recessive, CEP164-related ciliopathy, RP1-related recessive retinopathy, pseudohypoaldosteronism, type IB2, autosomal recessive, pseudohypoaldosteronism, type IB3, autosomal recessive, spastic paraplegia 30B, autosomal recessive, cerebral arteriopathy, autosomal recessive, with subcortical infarcts and leukoencephalopathy 1, brain small vessel disease 2B, autosomal recessive, IMPG1-related recessive retinopathy, PROM1-related recessive retinopathy

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

251 retrieved; paginated sample, class counts are floors:

168 uncertain significance, 28 benign, 26 conflicting classifications of pathogenicity, 9 benign/likely benign, 7 pathogenic, 7 likely benign, 6 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
6472	NM_001098484.3(SLC4A4):c.1661G>A (p.Arg554His)	LOC126807073	Pathogenic	no assertion criteria provided
3242426	NM_001098484.3(SLC4A4):c.2294del (p.Asn765fs)	SLC4A4	Pathogenic	no assertion criteria provided
3590766	NM_001098484.3(SLC4A4):c.277C>T (p.Arg93Ter)	SLC4A4	Pathogenic	criteria provided, single submitter
3590838	NM_001098484.3(SLC4A4):c.*206G>A	SLC4A4	Pathogenic	criteria provided, single submitter
545698	NM_001098484.3(SLC4A4):c.831del (p.Lys277fs)	SLC4A4	Pathogenic	criteria provided, single submitter
6471	NM_001098484.3(SLC4A4):c.1026A>C (p.Arg342Ser)	SLC4A4	Pathogenic	no assertion criteria provided
6473	NM_003759.4(SLC4A4):c.85C>T (p.Gln29Ter)	SLC4A4	Pathogenic	no assertion criteria provided
3590810	NM_001098484.3(SLC4A4):c.1903+2T>A	LOC126807073	Likely pathogenic	criteria provided, single submitter
4526832	NM_001098484.3(SLC4A4):c.1677_1681del (p.Trp560fs)	LOC126807073	Likely pathogenic	criteria provided, single submitter
2576556	NM_001098484.3(SLC4A4):c.1170G>C (p.Arg390Ser)	SLC4A4	Likely pathogenic	criteria provided, single submitter
2683646	NM_001098484.3(SLC4A4):c.1412C>T (p.Ser471Leu)	SLC4A4	Likely pathogenic	criteria provided, single submitter
3590760	NM_001098484.3(SLC4A4):c.160A>T (p.Lys54Ter)	SLC4A4	Likely pathogenic	criteria provided, single submitter
3590781	NM_001098484.3(SLC4A4):c.853del (p.Ser285fs)	SLC4A4	Likely pathogenic	criteria provided, single submitter
713807	NM_001098484.3(SLC4A4):c.1805A>G (p.Lys602Arg)	LOC126807073	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1685128	NM_001098484.3(SLC4A4):c.149G>C (p.Gly50Ala)	SLC4A4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2092051	NM_001098484.3(SLC4A4):c.1209-14G>A	SLC4A4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
349533	NM_001098484.3(SLC4A4):c.390-11C>T	SLC4A4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
349535	NM_001098484.3(SLC4A4):c.520C>T (p.Arg174Trp)	SLC4A4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
349539	NM_001098484.3(SLC4A4):c.942G>C (p.Leu314=)	SLC4A4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
349543	NM_001098484.3(SLC4A4):c.1257G>A (p.Thr419=)	SLC4A4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
349544	NM_001098484.3(SLC4A4):c.1260C>G (p.Pro420=)	SLC4A4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
349547	NM_001098484.3(SLC4A4):c.1942G>A (p.Glu648Lys)	SLC4A4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
349548	NM_001098484.3(SLC4A4):c.2010G>A (p.Ser670=)	SLC4A4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
349549	NM_001098484.3(SLC4A4):c.2243T>C (p.Val748Ala)	SLC4A4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
349550	NM_001098484.3(SLC4A4):c.2311C>T (p.Pro771Ser)	SLC4A4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
349553	NM_001098484.3(SLC4A4):c.2674T>C (p.Phe892Leu)	SLC4A4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
349554	NM_001098484.3(SLC4A4):c.2694+10T>A	SLC4A4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
349558	NM_001098484.3(SLC4A4):c.3177C>T (p.Ser1059=)	SLC4A4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3590816	NM_001098484.3(SLC4A4):c.2241C>T (p.Gly747=)	SLC4A4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
718314	NM_001098484.3(SLC4A4):c.687G>A (p.Lys229=)	SLC4A4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 1 · 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
SLC4A4	Definitive	Autosomal recessive	autosomal recessive proximal renal tubular acidosis	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC4A4	Orphanet:93607	Autosomal recessive proximal renal tubular acidosis

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SLC4A4	HGNC:11030	ENSG00000080493	Q9Y6R1	Electrogenic sodium bicarbonate cotransporter 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC4A4	Electrogenic sodium bicarbonate cotransporter 1	Electrogenic sodium/bicarbonate cotransporter with a Na(+):HCO3(-) stoichiometry varying from 1:2 to 1:3.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLC4A4	Other/Unknown	no		HCO3_transpt_euk, Na/HCO3_transpt, HCO3_transpt-like_TM_dom

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
jejunal mucosa	1
lateral globus pallidus	1
mucosa of sigmoid colon	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC4A4	268	ubiquitous	marker	jejunal mucosa, lateral globus pallidus, mucosa of sigmoid colon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SLC4A4	1,799

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SLC4A4	Q9Y6R1	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective SLC4A4 causes renal tubular acidosis, proximal, with ocular abnormalities and mental retardation (pRTA-OA)	1	5710.0×	0.002	SLC4A4
Bicarbonate transporters	1	1142.0×	0.004	SLC4A4
Developmental Lineage of Pancreatic Ductal Cells	1	228.4×	0.011	SLC4A4
SLC transporter disorders	1	203.9×	0.011	SLC4A4
Disorders of transmembrane transporters	1	139.3×	0.012	SLC4A4
R-HSA-425393	1	129.8×	0.012	SLC4A4
SLC-mediated transmembrane transport	1	59.2×	0.022	SLC4A4
Transport of small molecules	1	25.1×	0.045	SLC4A4
Disease	1	13.1×	0.076	SLC4A4

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
sodium ion export across plasma membrane	1	1053.2×	0.004	SLC4A4
bicarbonate transport	1	802.5×	0.004	SLC4A4
positive regulation of glycolytic process	1	674.1×	0.004	SLC4A4
regulation of intracellular pH	1	601.9×	0.004	SLC4A4
sodium ion transport	1	271.8×	0.006	SLC4A4
regulation of membrane potential	1	230.8×	0.006	SLC4A4
sodium ion transmembrane transport	1	203.0×	0.006	SLC4A4
transport across blood-brain barrier	1	179.3×	0.006	SLC4A4
transmembrane transport	1	168.5×	0.006	SLC4A4

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 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
SLC4A4	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	1	SLC4A4

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SLC4A4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06065852	Not specified	RECRUITING	National Registry of Rare Kidney Diseases