SLC4A4

Summary

SLC4A4 (solute carrier family 4 member 4, HGNC:11030) is a protein-coding gene on chromosome 4q13.3, encoding Electrogenic sodium bicarbonate cotransporter 1 (Q9Y6R1). Electrogenic sodium/bicarbonate cotransporter with a Na(+):HCO3(-) stoichiometry varying from 1:2 to 1:3. It is a selective cancer dependency (DepMap: 12.5% of cell lines).

This gene encodes a sodium bicarbonate cotransporter (NBC) involved in the regulation of bicarbonate secretion and absorption and intracellular pH. Mutations in this gene are associated with proximal renal tubular acidosis. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 8671 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autosomal recessive proximal renal tubular acidosis (Definitive, GenCC)
• GWAS associations: 14
• Clinical variants (ClinVar): 658 total — 6 pathogenic, 8 likely-pathogenic
• Phenotypes (HPO): 19
• Cancer dependency (DepMap): dependent in 12.5% of screened cell lines
• MANE Select transcript: NM_001098484

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11030
Approved symbol	SLC4A4
Name	solute carrier family 4 member 4
Location	4q13.3
Locus type	gene with protein product
Status	Approved
Aliases	NBC1, HNBC1, NBC2, pNBC, hhNMC, kNBC1, KNBC, NBCe1
Ensembl gene	ENSG00000080493
Ensembl biotype	protein_coding
OMIM	603345
Entrez	8671

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 16 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000264485, ENST00000340595, ENST00000351898, ENST00000425175, ENST00000512686, ENST00000514331, ENST00000638464, ENST00000639096, ENST00000649996, ENST00000698522, ENST00000895605, ENST00000895606, ENST00000895607, ENST00000895608, ENST00000895609, ENST00000895610, ENST00000962280

RefSeq mRNA: 3 — MANE Select: NM_001098484 NM_001098484, NM_001134742, NM_003759

CCDS: CCDS3549, CCDS43236, CCDS47071

Canonical transcript exons

ENST00000264485 — 26 exons

Exon	Start	End
ENSE00000720481	71546350	71546528
ENSE00000720498	71547648	71547720
ENSE00000720527	71557712	71557885
ENSE00000720528	71560093	71560254
ENSE00000720530	71563793	71563889
ENSE00000851009	71532062	71532175
ENSE00000851010	71534227	71534388
ENSE00001170623	71497501	71497692
ENSE00001170630	71486948	71487018
ENSE00001170640	71472699	71472970
ENSE00001170647	71255220	71255399
ENSE00001170749	71236576	71236649
ENSE00002086782	71567788	71572083
ENSE00002496968	71555140	71555208
ENSE00003468057	71357008	71357187
ENSE00003475934	71567004	71567083
ENSE00003502980	71447646	71447733
ENSE00003510337	71349912	71350072
ENSE00003525302	71453495	71453669
ENSE00003578531	71397577	71397653
ENSE00003586527	71440616	71440773
ENSE00003591738	71339370	71339505
ENSE00003598200	71450389	71450543
ENSE00003647521	71451188	71451301
ENSE00003649874	71466444	71466577
ENSE00003799589	71187259	71187401

Expression profiles

Bgee: expression breadth ubiquitous, 268 present calls, max score 98.90.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 15.1396 / max 1080.2761, expressed in 1028 samples.

FANTOM5 promoters (21 alternative TSS)

Promoter ID	TPM avg	Samples expressed
48030	12.2541	935
48034	0.8820	432
48036	0.2596	92
48032	0.2181	88
48047	0.1749	16
48038	0.1585	52
48031	0.1492	67
48033	0.1489	70
48027	0.1337	6
48041	0.1077	29

Top tissues by expression

293 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
jejunal mucosa	UBERON:0000399	98.90	gold quality
lateral globus pallidus	UBERON:0002476	98.69	gold quality
mucosa of sigmoid colon	UBERON:0004993	98.42	gold quality
colonic mucosa	UBERON:0000317	98.24	gold quality
pancreatic ductal cell	CL:0002079	98.20	gold quality
medial globus pallidus	UBERON:0002477	98.17	gold quality
globus pallidus	UBERON:0001875	98.05	gold quality
nephron tubule	UBERON:0001231	97.96	gold quality
body of pancreas	UBERON:0001150	97.78	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	97.75	gold quality
duodenum	UBERON:0002114	97.30	gold quality
kidney epithelium	UBERON:0004819	96.94	gold quality
pancreas	UBERON:0001264	96.30	gold quality
bronchial epithelial cell	CL:0002328	95.70	gold quality
substantia nigra pars reticulata	UBERON:0001966	95.61	gold quality
renal glomerulus	UBERON:0000074	95.58	gold quality
substantia nigra pars compacta	UBERON:0001965	95.27	gold quality
CA1 field of hippocampus	UBERON:0003881	95.23	gold quality
metanephric glomerulus	UBERON:0004736	95.19	gold quality
adult organism	UBERON:0007023	95.15	gold quality
parietal pleura	UBERON:0002400	94.85	gold quality
renal medulla	UBERON:0000362	94.83	gold quality
medulla oblongata	UBERON:0001896	94.54	gold quality
rectum	UBERON:0001052	94.36	gold quality
epithelial cell of pancreas	CL:0000083	94.29	gold quality
inferior olivary complex	UBERON:0002127	94.16	gold quality
pigmented layer of retina	UBERON:0001782	94.00	gold quality
retina	UBERON:0000966	93.98	gold quality
superior vestibular nucleus	UBERON:0007227	93.86	gold quality
germinal epithelium of ovary	UBERON:0001304	93.79	gold quality

Single-cell (SCXA)

Detected in 11 experiment(s), a significant marker in 11.

Experiment	Marker?	Max mean expression
E-GEOD-81547	yes	3590.92
E-CURD-119	yes	3046.43
E-MTAB-5061	yes	983.88
E-GEOD-83139	yes	939.10
E-ENAD-27	yes	615.05
E-GEOD-81608	yes	265.80
E-HCAD-35	yes	86.99
E-HCAD-25	yes	24.65
E-GEOD-125970	yes	21.81
E-GEOD-84465	yes	13.02
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FOXA2, JUN, NFKB1, TP53

miRNA regulators (miRDB)

245 targeting SLC4A4, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-548AT-5P	99.96	70.83	2666

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 12.5% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• An in vitro transcription/translation analysis in the presence of canine pancreatic microsomal membranes shows that pNBC1 contains 10 transmembrane domains with cytoplasmic localization of the N- and C-termini. (PMID:12534288)
• phosphorylation of Ser1026 mediates the cAMP-dependent shift in the stoichiometry of pNBC1, whereas Thr49 plays an essential role in the cAMP-induced increase in basolateral membrane conductance (PMID:12730338)
• expression of kNBC-1 but not of pNBC-1 was detected in both normal human kidney and renal cell carcinoma tissues (PMID:14559244)
• carbonic anhydrase IV binds EC4 of NBC1, and this interaction is essential for full NBC1 activity (PMID:14567693)
• the electrogenic NBCe1 renders the cell membrane potential an effective regulator of intracellular H(+) buffering and acid/base-coupled metabolite transport (PMID:15123668)
• First direct evidence that a complex of an electrogenic sodium bicarbonate cotransporter (human kNBC1) with carbonic anhydrase II functions as a transport metabolon. (PMID:15218065)
• a carboxyl-terminal motif with the sequence QQPFLS, which spans amino acid residues 1010-1015, and specifically the amino acid residue Phe (position 1013) are essential for the exclusive targeting of NBC1 to the basolateral membrane (PMID:15273250)
• Early activation of NBC1 activity by 10% CO2 was mediated by NBC1 phosphorylation. (PMID:15366422)
• The expression of two missense mutations of NBC1 in MDCK cells and X. laevis oocytes to determine the distribution of the mutant proteins in polarized cells is reported. (PMID:15713912)
• asymmetry of distribution of kNBC1 charged amino acids involved in ion recognition in putative outward-facing and inward-facing conformations (PMID:15817634)
• NBC1 may have a role in proximal renal tubular acidosis and ocular abnormalities (PMID:15930088)
• PMA inhibition of hkNBCe1 is mediated by Ca-dependent PKC and PMA does not induce downregulation of cotransporter surface expression. ANG II inhibition of hkNBCe1 is mediated by both PKCepsilon and downregulation of cotransporter surface expression. (PMID:16159892)
• NBC1 targets to the basolateral membrane of OK cells by a default mechanism and the COOH terminus plays a role on NBC1 stability in the basolateral membrane. (PMID:16622177)
• CA II does not enhance NBCe1-A activity (PMID:16687407)
• Pathophysiology of proximal renal tubular acidosis(pRTA0 caused by R881C mutation is likely due to deficit of NBCe1-A at proximal tubule basolateral membrane, rather than defect in transport activity of individual molecules. (PMID:16707554)
• Existence of an electrogenic sodium bicarbonate cotransporter in the basolateral membrane of respiratory epithelial cells that mediates bicarbonate entry from the interstitium. (PMID:16857349)
• We propose that the phenylalanine-leucine motif in the COOH-terminal tail of NBC1 is essential for the targeting of NBC1 to the basolateral membrane but is distinct from the membrane-targeting di-leucine motif identified in other membrane proteins. (PMID:17182531)
• Of the NBC1 mutations, G486R, like T485S, is a partial loss of function mutation without major trafficking abnormalities, while L522P causes the clinical phenotypes mainly through its inability to reach the plasma membranes. (PMID:17661077)
• No mutation was found in the coding regions and intron-exon boundaries of the genes for CA II, CA IV, CA XIV, kNCB1, NHE3, NHE8, NHRF1, NHRF2 and SLC26A6 amplified from genomic DNA of family members with pRTA. (PMID:17881426)
• Autosomal recessive pRTA with ocular abnormalities’ is, for instance, attributable to homozygous mutations in the gene for kNBC-1 (PMID:18223262)
• analysis of the SLC4A4 human mutation and structural model (PMID:18441326)
• NBCe1-A-Q29X mutation that causes proximal renal tubular acidosis treated in a targeted and specific manner (PMID:18614622)
• NBC1 expressed in Hek293 is inhibited by cAMP but not by cholinergic stimulation, as opposed to the findings in native intestinal tissue. (PMID:19102757)
• NBCe1-A Transmembrane Segment 1 Lines the Ion Translocation Pathway. (PMID:19158093)
• it is proposed that specific orientation & precise location of the FL motif in the primary sequence of NBC1 are strict requirements for the alpha-helical structure of the C-terminal cytoplasmic domain & for targeting of NBC1 to the basolateral membrane (PMID:19294449)
• Amino acid subsitution in this protein produces an increase in chloride transport. (PMID:19336397)
• the pRTA residues in NBCe1-A are buried in the protein complex/lipid bilayer where they perform important structural roles. (PMID:20197274)
• C-terminal transmembrane region of NBCe1-A is tightly folded with unique structural and functional features. (PMID:20837482)
• NBCe1 (SLC4A4) is electrogenic because it has an apparent Na+:HCO stoichiometry of 1:2 or 1:3, whereas NBCn1 (SLC4A7) is electroneutral because it has an apparent stoichiometry of 1:1. (PMID:21224233)
• Identify a novel homozygous nonsense mutation (W516X) in the kidney-type electrogenic sodium bicarbonate cotransporter 1 in a patient with isolated proximal renal tubular acidosis. (PMID:21228764)
• among four SNPs, only the K558R variant, which is predicted to lie in transmembrane segment 5, significantly reduces the NBCe1A activity without changing the trafficking behavior or the apparent extracellular Na(+) affinity. (PMID:21234596)
• IRBIT opposes the effects of WNKs and SPAK by recruiting PP1 to the complex to dephosphorylate CFTR and NBCe1-B, restoring their cell surface expression, in addition to stimulating their activities (PMID:21317537)
• the present results suggested that PTH stimulated intestinal HCO(3)(-) secretion, particularly in the ileum, by inducing the basolateral HCO(3)(-) uptake via NBCe1. (PMID:21621518)
• Slc4a4/NBCe1 is a key element in a feedforward mechanism linking excitatory synaptic transmission to fast modulation of glycolysis in astrocytes. (PMID:21976511)
• study finds that NBCe1-B is equally stimulated by autoinhibitory domain removal and coexpression of IRBIT with full-length NBCe1-B. (PMID:22012331)
• Simultaneous switching of the putative transmembrane segment (TM6) and TM12 of NBCe1 for those from NBCn1 severely impairs the expression of the transporter at the plasma membrane. (PMID:22383045)
• the regulation of anion fluxes in insulin-producing cells may involve both SLC4A4 and TMEM16A (PMID:22415075)
• Data identified IGF1, SLC4A4, WWOX, and SFMBT1 as hypertension susceptibility genes by gene based association scan and gene expression analysis. (PMID:22479346)
• novel role of STCH in the regulation of pHi through site-specific interactions with NBCe1-B and NHE1 and subsequent modulation of membrane transporter expression. (PMID:23303189)
• features of NBCe1-like activity in renal preparations are influenced by yet-to-be-identified renal factors (PMID:23324180)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	slc4a4a	ENSDARG00000013730
danio_rerio	slc4a4b	ENSDARG00000044808
mus_musculus	Slc4a4	ENSMUSG00000060961
rattus_norvegicus	Slc4a4	ENSRNOG00000003134
drosophila_melanogaster	Ae2	FBGN0036043
drosophila_melanogaster	Ndae1	FBGN0259111
caenorhabditis_elegans	abts-1	WBGENE00009920
caenorhabditis_elegans		WBGENE00019844

Paralogs (9): SLC4A1 (ENSG00000004939), SLC4A7 (ENSG00000033867), SLC4A8 (ENSG00000050438), SLC4A11 (ENSG00000088836), SLC4A9 (ENSG00000113073), SLC4A3 (ENSG00000114923), SLC4A10 (ENSG00000144290), SLC4A2 (ENSG00000164889), SLC4A5 (ENSG00000188687)

Protein

Protein identifiers

Electrogenic sodium bicarbonate cotransporter 1 — Q9Y6R1 (reviewed: Q9Y6R1)

Alternative names: Na(+)/HCO3(-) cotransporter, Solute carrier family 4 member 4, kNBC1

All UniProt accessions (5): Q9Y6R1, A0A1W2PNW8, A0A1W2PRU6, A0A8V8TNB1, A5JJ20

UniProt curated annotations — full annotation on UniProt →

Function. Electrogenic sodium/bicarbonate cotransporter with a Na(+):HCO3(-) stoichiometry varying from 1:2 to 1:3. May regulate bicarbonate influx/efflux at the basolateral membrane of cells and regulate intracellular pH.

Subunit / interactions. Homodimer. Interacts with CA2/carbonic anhydrase 2 and CA4/carbonic anhydrase 4 which may regulate transporter activity. Isoform 1 but not isoform 2 interacts with AHCYL1 (via PEST domain when phosphorylated); the interaction increases SLC4A4 isoform 1 activity. Interacts with AHCYL2.

Subcellular location. Basolateral cell membrane. Cell membrane.

Tissue specificity. Expressed in the corneal endothelium cells (at protein level). Expressed in pancreas and to a lower extent in heart, skeletal muscle, liver, parotid salivary glands, prostate, colon, stomach, thyroid, brain and spinal cord. Specifically expressed in kidney at the level of proximal tubules.

Post-translational modifications. Phosphorylation of Ser-1026 by PKA increases the binding of CA2 and changes the Na(+):HCO3(-) stoichiometry of the transporter from 3:1 to 2:1. Phosphorylated in presence of STK39 and dephosphorylated in presence of PP1 phosphatase; phosphorylation seems to inhibit SLC4A4 activity. N-glycosylated. May not be necessary for the transporter basic functions.

Disease relevance. Proximal renal tubular acidosis-ocular anomaly syndrome (PRTAO) [MIM:604278] An extremely rare autosomal recessive syndrome characterized by short stature, profound proximal renal tubular acidosis, intellectual disability, bilateral glaucoma, cataracts and bandkeratopathy. The disease is caused by variants affecting the gene represented in this entry. Loss of interaction with and stimulation by CA4 is the cause of retinitis pigmentosa type 17 (RP17).

Similarity. Belongs to the anion exchanger (TC 2.A.31) family.

Isoforms (5)

UniProt ID	Names	Canonical?
Q9Y6R1-1	1, hcNBC, hhNBC, hNBC1, pNBC, pNCB1, pNBC-1, NBC1b	yes
Q9Y6R1-2	2, hkNBC, hkNBCe1, kNBC, kNBC1, kNBC-1, NBC1a
Q9Y6R1-3	3
Q9Y6R1-4	4
Q9Y6R1-5	5

RefSeq proteins (3): NP_001091954, NP_001128214, NP_003750 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003020	HCO3_transpt_euk	Family
IPR003024	Na/HCO3_transpt	Family
IPR011531	HCO3_transpt-like_TM_dom	Domain
IPR013769	Band3_cytoplasmic_dom	Domain
IPR016152	PTrfase/Anion_transptr	Homologous_superfamily

Pfam: PF00955, PF07565

Catalyzed reactions (Rhea), 2 shown:

• 2 hydrogencarbonate(out) + Na(+)(out) = 2 hydrogencarbonate(in) + Na(+)(in) (RHEA:72215)
• 3 hydrogencarbonate(out) + Na(+)(out) = 3 hydrogencarbonate(in) + Na(+)(in) (RHEA:72219)

UniProt features (167 total): mutagenesis site 73, modified residue 19, sequence conflict 17, topological domain 14, transmembrane region 12, region of interest 8, sequence variant 8, splice variant 6, compositionally biased region 4, glycosylation site 2, disulfide bond 2, chain 1, intramembrane region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
6CAA	ELECTRON MICROSCOPY	3.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y6R1-F1	70.77	0.16

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (19): 30, 49, 61, 65, 68, 223, 232, 233, 245, 249, 254, 256, 257, 262, 1026, 1029, 1034, 1044, 1069

Disulfide bonds (2): 583–585, 630–642

Glycosylation sites (2): 597, 617

Mutagenesis-validated functional residues (73):

Position	Phenotype
721	moderate reduction of the sodium-dependent ion transport activity.
724	strong reduction of the sodium-dependent ion transport activity.
725	strong reduction of the sodium-dependent ion transport activity.
728	strong reduction of the sodium-dependent ion transport activity.
729	strong reduction of the sodium-dependent ion transport activity.
743	prevents membrane targeting.
749	moderate reduction of the sodium-dependent ion transport activity.
752	prevents membrane targeting.
766	moderate reduction of the sodium-dependent ion transport activity.
767	alters interaction with ca4.
775	moderate reduction of the sodium-dependent ion transport activity.
798	abolishes transporter activity.
798	severely reduces transporter activity. confers anion exchange activity; when associated with sst-527–529-gfs; s-842; t-
798	strong reduction of the sodium-dependent ion transport activity.
802	abolishes transporter activity.
808–809	strong reduction of the sodium-dependent ion transport activity.
814–815	moderate reduction of the sodium-dependent ion transport activity.
820	moderate reduction of the sodium-dependent ion transport activity.
822	moderate reduction of the sodium-dependent ion transport activity.
842	confers anion exchange activity; when associated with sst-527–529-gfs; d-798; t-844 and r-847.
844	confers anion exchange activity; when associated with sst-527–529-gfs; d-798; s-842 and r-847.
845	strongly reduces transporter activity.
847	abolishes transporter activity. confers anion exchange activity; when associated with sst-527–529-gfs; d-798; s-842 and
851	prevents membrane targeting.
853	moderate reduction of the sodium-dependent ion transport activity.

Function

Pathways and Gene Ontology

Reactome pathways

9 pathways

ID	Pathway
R-HSA-425381	Bicarbonate transporters
R-HSA-5619054	Defective SLC4A4 causes renal tubular acidosis, proximal, with ocular abnormalities and mental retardation (pRTA-OA)
R-HSA-9925563	Developmental Lineage of Pancreatic Ductal Cells
R-HSA-1643685	Disease
R-HSA-382551	Transport of small molecules
R-HSA-425393
R-HSA-425407	SLC-mediated transmembrane transport
R-HSA-5619102	SLC transporter disorders
R-HSA-5619115	Disorders of transmembrane transporters

MSigDB gene sets: 512 (showing top): GOBP_EPITHELIUM_DEVELOPMENT, GOBP_NUCLEOSIDE_DIPHOSPHATE_METABOLIC_PROCESS, GOBP_REGULATION_OF_BLOOD_PRESSURE, GOBP_CIRCULATORY_SYSTEM_PROCESS, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_EPITHELIAL_CELL_DEVELOPMENT, NKX25_02, GOBP_SODIUM_ION_TRANSMEMBRANE_TRANSPORT, MODULE_64, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_REGULATION_OF_SYSTEMIC_ARTERIAL_BLOOD_PRESSURE, GOBP_CARBOHYDRATE_DERIVATIVE_CATABOLIC_PROCESS, GOCC_CELL_SURFACE, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, HNF1_Q6

GO Biological Process (13): sodium ion transport (GO:0006814), bicarbonate transport (GO:0015701), sodium ion transmembrane transport (GO:0035725), sodium ion export across plasma membrane (GO:0036376), regulation of membrane potential (GO:0042391), positive regulation of glycolytic process (GO:0045821), regulation of intracellular pH (GO:0051453), transmembrane transport (GO:0055085), transport across blood-brain barrier (GO:0150104), monoatomic ion transport (GO:0006811), monoatomic anion transport (GO:0006820), inorganic anion transport (GO:0015698), monoatomic anion transmembrane transport (GO:0098656)

GO Molecular Function (6): solute:inorganic anion antiporter activity (GO:0005452), monoatomic anion transmembrane transporter activity (GO:0008509), sodium:bicarbonate symporter activity (GO:0008510), symporter activity (GO:0015293), identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (6): cytosol (GO:0005829), plasma membrane (GO:0005886), cell surface (GO:0009986), membrane (GO:0016020), basolateral plasma membrane (GO:0016323), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
SLC-mediated transport of inorganic anions	1
SLC transporter disorders	1
Developmental Cell Lineages of the Exocrine Pancreas	1
Transport of small molecules	1
Disorders of transmembrane transporters	1
Disease	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transport	4
cellular anatomical structure	3
monoatomic ion transmembrane transport	2
regulation of biological quality	2
metal ion transport	1
sodium ion transport	1
monoatomic cation transmembrane transport	1
sodium ion transmembrane transport	1
export across plasma membrane	1
glycolytic process	1
regulation of glycolytic process	1
positive regulation of purine nucleotide catabolic process	1
positive regulation of carbohydrate metabolic process	1
positive regulation of ATP metabolic process	1
regulation of pH	1
intracellular monoatomic cation homeostasis	1
cellular process	1
vascular transport	1
monoatomic ion transport	1
monoatomic anion transport	1
antiporter activity	1
monoatomic ion transmembrane transporter activity	1
monoatomic anion transmembrane transport	1
solute:sodium symporter activity	1
monoatomic cation:bicarbonate symporter activity	1
secondary active transmembrane transporter activity	1
protein binding	1
binding	1
cytoplasm	1
membrane	1
cell periphery	1
basal plasma membrane	1
plasma membrane region	1
extracellular vesicle	1

Protein interactions and networks

STRING

1712 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SLC4A4	AHCYL1	O43865	962
SLC4A4	CA2	P00918	880
SLC4A4	SLC9A3	P48764	789
SLC4A4	CA4	P22748	747
SLC4A4	SLC9A1	P19634	743
SLC4A4	SLC26A6	Q9BXS9	741
SLC4A4	SLC12A2	P55011	677
SLC4A4	SLC26A3	P40879	637
SLC4A4	SLC26A4	O43511	623
SLC4A4	CFTR	P13569	621
SLC4A4	SLC12A1	Q13621	618
SLC4A4	SLC9A2	Q9UBY0	617
SLC4A4	DCTN1	Q14203	616
SLC4A4	SLC26A9	Q7LBE3	611
SLC4A4	SLC1A3	P43003	583

IntAct

17 interactions, top by confidence:

A	B	Type	Score
CA4	SLC4A4	psi-mi:“MI:0403”(colocalization)	0.460
CA4	SLC4A4	psi-mi:“MI:0915”(physical association)	0.460
SCRIB	SLC4A4	psi-mi:“MI:0915”(physical association)	0.400
SLC4A4	ATP2A2	psi-mi:“MI:0915”(physical association)	0.400
APP	ESYT2	psi-mi:“MI:0914”(association)	0.350
PRNP	CARNS1	psi-mi:“MI:0914”(association)	0.350
PRNP	WDR91	psi-mi:“MI:0914”(association)	0.350
	SHTN1	psi-mi:“MI:0914”(association)	0.350
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350
CACNA1C	SNRPGP15	psi-mi:“MI:0914”(association)	0.350
KLHL22	TRAV18	psi-mi:“MI:0914”(association)	0.350
SLC4A4	SAP18	psi-mi:“MI:0914”(association)	0.350
SLC4A8	PSMA7	psi-mi:“MI:0914”(association)	0.350
SLC4A4	glpF	psi-mi:“MI:0915”(physical association)	0.000
SLC4A4	SREBF2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (70): SLC4A4 (Affinity Capture-MS), SLC4A4 (Affinity Capture-MS), SLC4A4 (Proximity Label-MS), SLC4A4 (Affinity Capture-MS), SLC4A4 (Proximity Label-MS), SLC4A4 (Affinity Capture-MS), SLC4A4 (Affinity Capture-MS), SLC4A4 (Affinity Capture-MS), SLC4A4 (Affinity Capture-MS), SLC4A4 (Proximity Label-MS), SLC4A4 (Affinity Capture-MS), SLC4A4 (Affinity Capture-MS), SLC4A4 (Co-fractionation), SLC4A4 (Co-fractionation), SLC4A4 (Co-fractionation)

ESM2 similar proteins: A0A096X8J7, B1MTL0, E9Q3M5, G3X939, M5A7P9, O13134, O18917, O88343, P04919, P13808, P16283, P19334, P23347, P23348, P23562, P23685, P26433, P32418, P32847, P34586, P48746, P48751, P48765, P48766, P48767, P48994, P70414, P90895, Q01728, Q28362, Q2Y0W8, Q32LP4, Q4U116, Q5DTL9, Q5RB85, Q5RD44, Q6RI88, Q6RVG2, Q6SJP2, Q6U841

Diamond homologs: A0A096X8J7, A0A494BA31, B1MTL0, E9Q3M5, O13134, O18917, O88343, P02730, P04919, P04920, P13808, P15575, P16283, P23347, P23348, P23562, P32847, P48746, P48751, Q2Y0W8, Q32LP4, Q4U116, Q5DTL9, Q5RB85, Q5RD44, Q6RI88, Q6RVG2, Q6SJP2, Q6U841, Q80ZA5, Q8BTY2, Q8JZR6, Q8K4V2, Q96Q91, Q9BY07, Q9GKY1, Q9GL77, Q9JI66, Q9R1N3, Q9XSZ4

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
STK39	“down-regulates activity”	SLC4A4	phosphorylation
AHCYL1	“up-regulates activity”	SLC4A4	binding
PKA	“up-regulates activity”	SLC4A4	phosphorylation
PP1	“up-regulates activity”	SLC4A4	dephosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

658 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	8
Uncertain significance	384
Likely benign	111
Benign	67

Top pathogenic / likely-pathogenic (14)

Variant ID	HGVS	Classification
3242426	NM_001098484.3(SLC4A4):c.2294del (p.Asn765fs)	Pathogenic
3590766	NM_001098484.3(SLC4A4):c.277C>T (p.Arg93Ter)	Pathogenic
3590838	NM_001098484.3(SLC4A4):c.*206G>A	Pathogenic
545698	NM_001098484.3(SLC4A4):c.831del (p.Lys277fs)	Pathogenic
6471	NM_001098484.3(SLC4A4):c.1026A>C (p.Arg342Ser)	Pathogenic
6473	NM_003759.4(SLC4A4):c.85C>T (p.Gln29Ter)	Pathogenic
191191	NM_001098484.3(SLC4A4):c.842A>T (p.Asp281Val)	Likely pathogenic
2576556	NM_001098484.3(SLC4A4):c.1170G>C (p.Arg390Ser)	Likely pathogenic
2633027	NM_001098484.3(SLC4A4):c.2017G>T (p.Glu673Ter)	Likely pathogenic
2683646	NM_001098484.3(SLC4A4):c.1412C>T (p.Ser471Leu)	Likely pathogenic
3590760	NM_001098484.3(SLC4A4):c.160A>T (p.Lys54Ter)	Likely pathogenic
3590781	NM_001098484.3(SLC4A4):c.853del (p.Ser285fs)	Likely pathogenic
4278969	NM_001098484.3(SLC4A4):c.1015G>A (p.Glu339Lys)	Likely pathogenic
4721003	NM_001098484.3(SLC4A4):c.551-2A>G	Likely pathogenic

SpliceAI

11152 predictions. Top by Δscore:

Variant	Effect	Δscore
2:74218642:A:AC	donor_gain	1.0000
2:74218643:C:CC	donor_gain	1.0000
2:74224838:ACCT:A	donor_gain	1.0000
2:74224839:CCTC:C	donor_gain	1.0000
2:74224841:T:TA	donor_gain	1.0000
2:74224853:T:TA	donor_gain	1.0000
2:74224878:T:TA	donor_gain	1.0000
2:74227126:CAGAA:C	acceptor_gain	1.0000
2:74227127:AGAA:A	acceptor_gain	1.0000
2:74227129:AAC:A	acceptor_loss	1.0000
2:74227130:ACTA:A	acceptor_loss	1.0000
2:74227131:C:CA	acceptor_loss	1.0000
2:74227131:C:CC	acceptor_gain	1.0000
2:74227515:A:AC	donor_gain	1.0000
2:74227516:C:CC	donor_gain	1.0000
2:74227804:CCTTA:C	donor_loss	1.0000
2:74227805:CTTAC:C	donor_loss	1.0000
2:74227806:TTAC:T	donor_loss	1.0000
2:74227806:TTACC:T	donor_loss	1.0000
2:74227807:TACC:T	donor_loss	1.0000
2:74227808:ACCTG:A	donor_loss	1.0000
2:74227809:C:A	donor_loss	1.0000
2:74227879:C:CC	acceptor_gain	1.0000
2:74231230:CCTCA:C	donor_loss	1.0000
2:74231231:CTCA:C	donor_loss	1.0000
2:74231231:CTCAC:C	donor_loss	1.0000
2:74231232:TCA:T	donor_loss	1.0000
2:74231233:CAC:C	donor_loss	1.0000
2:74231234:A:AT	donor_loss	1.0000
2:74231234:ACCTT:A	donor_loss	1.0000

AlphaMissense

7182 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:71339451:T:C	L112P	1.000
4:71339489:T:A	W125R	1.000
4:71339489:T:C	W125R	1.000
4:71339490:G:C	W125S	1.000
4:71339491:G:C	W125C	1.000
4:71339491:G:T	W125C	1.000
4:71339505:G:T	R130M	1.000
4:71349913:T:A	W131R	1.000
4:71349913:T:C	W131R	1.000
4:71349922:T:C	F134L	1.000
4:71349924:T:A	F134L	1.000
4:71349924:T:G	F134L	1.000
4:71349955:T:A	W145R	1.000
4:71349955:T:C	W145R	1.000
4:71349957:G:C	W145C	1.000
4:71349957:G:T	W145C	1.000
4:71350004:T:C	L161P	1.000
4:71440671:T:C	L288P	1.000
4:71440676:G:A	G290R	1.000
4:71440676:G:C	G290R	1.000
4:71440676:G:T	G290W	1.000
4:71440677:G:A	G290E	1.000
4:71440719:G:C	R304T	1.000
4:71440719:G:T	R304M	1.000
4:71440773:G:T	R322M	1.000
4:71447647:T:C	F323L	1.000
4:71447648:T:C	F323S	1.000
4:71447649:C:A	F323L	1.000
4:71447649:C:G	F323L	1.000
4:71447660:T:C	L327P	1.000

dbSNP variants (sampled 300 via entrez): RS1000002177 (4:71292060 T>A,C), RS1000004008 (4:71151505 T>G), RS1000005153 (4:71334972 G>A), RS10000084 (4:71462234 A>G), RS1000009416 (4:71078853 C>G,T), RS1000014853 (4:71110242 T>C), RS1000015661 (4:71417761 CT>C), RS1000016923 (4:71500879 T>A,C), RS10000279 (4:71120704 A>C), RS1000029470 (4:71287931 C>T), RS1000030762 (4:71362296 C>T), RS1000036927 (4:71529423 G>T), RS1000046629 (4:71418049 C>A,T), RS1000046781 (4:71064871 C>A,G,T), RS1000049966 (4:71117084 C>T)

Disease associations

OMIM: gene MIM:603345 | disease phenotypes: MIM:604278, MIM:616239

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal recessive proximal renal tubular acidosis	Definitive	Autosomal recessive

Mondo (2): autosomal recessive proximal renal tubular acidosis (MONDO:0011422), combined oxidative phosphorylation defect type 24 (MONDO:0014547)

Orphanet (2): Autosomal recessive proximal renal tubular acidosis (Orphanet:93607), Combined oxidative phosphorylation defect type 24 (Orphanet:444458)

HPO phenotypes

19 total (19 of 19 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000501	Glaucoma
HP:0000518	Cataract
HP:0000585	Band keratopathy
HP:0001249	Intellectual disability
HP:0001510	Growth delay
HP:0001942	Metabolic acidosis
HP:0001995	Hyperchloremic acidosis
HP:0002049	Proximal renal tubular acidosis
HP:0002514	Cerebral calcification
HP:0002900	Hypokalemia
HP:0004322	Short stature
HP:0004910	Bicarbonate-wasting renal tubular acidosis
HP:0005546	Increased red cell osmotic resistance
HP:0011463	Childhood onset
HP:0025708	Early young adult onset
HP:0032066	Decreased serum bicarbonate concentration
HP:0410288	Hyperamylasemia
HP:4000010	Impaired renal tubular reabsorption of bicarbonate

GWAS associations

14 associations (top):

Study	Trait	p-value
GCST001536_4	Immune reponse to smallpox (secreted TNF-alpha)	5.000000e-07
GCST002037_16	Post-traumatic stress disorder (asjusted for relatedness)	3.000000e-06
GCST002304_19	Fractional exhaled nitric oxide (childhood)	9.000000e-07
GCST002304_2	Fractional exhaled nitric oxide (childhood)	9.000000e-07
GCST002498_15	Age-related nuclear cataracts	8.000000e-06
GCST002500_51	QT interval	8.000000e-10
GCST004863_133	Mosquito bite size	6.000000e-06
GCST006288_522	Heel bone mineral density	5.000000e-10
GCST006979_435	Heel bone mineral density	1.000000e-18
GCST007268_8	Diastolic blood pressure	2.000000e-11
GCST010002_394	Refractive error	2.000000e-11
GCST010002_8	Refractive error	8.000000e-09
GCST010919_18	QT interval	4.000000e-08
GCST90007009_6	Gut microbiota relative abundance (Faecalibacterium)	7.000000e-06

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0004645	response to vaccine
EFO:0004873	cytokine measurement
EFO:0005536	nitric oxide exhalation measurement
EFO:0004682	QT interval
EFO:0008378	mosquito bite reaction size measurement
EFO:0009270	heel bone mineral density
EFO:0006336	diastolic blood pressure
EFO:0007874	gut microbiome measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C567038	Renal Tubular Acidosis, Proximal, With Ocular Abnormalities And Mental Retardation (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: transporter — Sodium-dependent HCO₃^- transporters

CTD chemical–gene interactions

40 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Aflatoxin B1	decreases expression, decreases methylation	3
trichostatin A	increases expression	2
Acetaminophen	decreases expression	2
Arsenic	affects methylation, increases methylation	2
Benzo(a)pyrene	affects methylation, decreases expression, decreases methylation	2
Tobacco Smoke Pollution	decreases expression, increases methylation	2
Cyclosporine	decreases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	decreases expression	1
FR900359	affects phosphorylation	1
methyleugenol	decreases expression	1
triphenyl phosphate	affects expression	1
pirinixic acid	affects binding, increases activity, increases expression	1
bisphenol A	affects cotreatment, decreases methylation	1
antibiotic G 418	increases expression	1
sodium arsenite	affects methylation	1
butyraldehyde	decreases expression	1
nickel sulfate	decreases expression	1
bicalutamide	decreases expression	1
CGP 52608	affects binding, increases reaction	1
abrine	decreases expression	1
(+)-JQ1 compound	decreases expression	1
Temozolomide	decreases expression	1
Zoledronic Acid	decreases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Doxorubicin	decreases expression	1
N-Nitrosopyrrolidine	decreases expression	1
Selenium	decreases expression	1
Silicon Dioxide	decreases expression	1
Sodium	increases transport	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D4TX	HuH7-SLC4A4-KO-c2	Cancer cell line	Male
CVCL_D4TY	HuH7-SLC4A4-KO-c4	Cancer cell line	Male

Clinical trials (associated diseases)

1 trials via MONDO — disease-level, not drug-specific.

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