SLC4A1

Summary

SLC4A1 (solute carrier family 4 member 1 (Diego blood group), HGNC:11027) is a protein-coding gene on chromosome 17q21.31, encoding Band 3 anion transport protein (P02730). Functions both as a transporter that mediates electroneutral anion exchange across the cell membrane and as a structural protein.

The protein encoded by this gene is part of the anion exchanger (AE) family and is expressed in the erythrocyte plasma membrane, where it functions as a chloride/bicarbonate exchanger involved in carbon dioxide transport from tissues to lungs. The protein comprises two domains that are structurally and functionally distinct. The N-terminal 40kDa domain is located in the cytoplasm and acts as an attachment site for the red cell skeleton by binding ankyrin. The glycosylated C-terminal membrane-associated domain contains 12-14 membrane spanning segments and carries out the stilbene disulphonate-sensitive exchange transport of anions. The cytoplasmic tail at the extreme C-terminus of the membrane domain binds carbonic anhydrase II. The encoded protein associates with the red cell membrane protein glycophorin A and this association promotes the correct folding and translocation of the exchanger. This protein is predominantly dimeric but forms tetramers in the presence of ankyrin. Many mutations in this gene are known in man, and these mutations can lead to two types of disease: destabilization of red cell membrane leading to hereditary spherocytosis, and defective kidney acid secretion leading to distal renal tubular acidosis. Other mutations that do not give rise to disease result in novel blood group antigens, which form the Diego blood group system. Southeast Asian ovalocytosis (SAO, Melanesian ovalocytosis) results from the heterozygous presence of a deletion in the encoded protein and is common in areas where Plasmodium falciparum malaria is endemic. One null mutation in this gene is known, resulting in very severe anemia and nephrocalcinosis.

Source: NCBI Gene 6521 — RefSeq curated summary.

At a glance

• Gene–disease (curated): southeast Asian ovalocytosis (Strong, GenCC) — +6 more curated relationships
• GWAS associations: 38
• Clinical variants (ClinVar): 1,012 total — 87 pathogenic, 113 likely-pathogenic
• Phenotypes (HPO): 81
• MANE Select transcript: NM_000342

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11027
Approved symbol	SLC4A1
Name	solute carrier family 4 member 1 (Diego blood group)
Location	17q21.31
Locus type	gene with protein product
Status	Approved
Aliases	RTA1A, CD233, FR, SW, WR, EMPB3
Ensembl gene	ENSG00000004939
Ensembl biotype	protein_coding
OMIM	109270
Entrez	6521

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 2 protein_coding, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000262418, ENST00000399246, ENST00000471005, ENST00000498270

RefSeq mRNA: 1 — MANE Select: NM_000342 NM_000342

CCDS: CCDS11481

Canonical transcript exons

ENST00000262418 — 20 exons

Exon	Start	End
ENSE00000390705	44257350	44257544
ENSE00000390707	44255207	44255296
ENSE00000390709	44253118	44253371
ENSE00000390711	44251159	44251332
ENSE00000732375	44255673	44255846
ENSE00000732380	44254496	44254662
ENSE00000732382	44251419	44251588
ENSE00002258053	44248390	44250538
ENSE00003478893	44258413	44258623
ENSE00003498888	44259163	44259344
ENSE00003500694	44262852	44262934
ENSE00003530044	44262636	44262726
ENSE00003564794	44261575	44261636
ENSE00003572104	44260635	44260815
ENSE00003593472	44257986	44258180
ENSE00003617087	44259809	44259932
ENSE00003631323	44257659	44257807
ENSE00003637867	44260404	44260539
ENSE00003694254	44259497	44259581
ENSE00003846760	44268054	44268135

Expression profiles

Bgee: expression breadth ubiquitous, 161 present calls, max score 99.66.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 14.9814 / max 7626.1754, expressed in 163 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
166357	12.9211	147
166356	1.6490	47
166347	0.1794	15
166346	0.0749	13
166348	0.0590	11
166354	0.0564	14
166353	0.0280	5
166344	0.0137	5

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
trabecular bone tissue	UBERON:0002483	99.66	gold quality
bone marrow	UBERON:0002371	98.19	gold quality
bone marrow cell	CL:0002092	98.13	gold quality
renal medulla	UBERON:0000362	96.14	gold quality
bone element	UBERON:0001474	96.10	gold quality
blood	UBERON:0000178	95.29	gold quality
type B pancreatic cell	CL:0000169	93.56	gold quality
adult mammalian kidney	UBERON:0000082	93.35	gold quality
olfactory bulb	UBERON:0002264	92.94	gold quality
monocyte	CL:0000576	90.72	gold quality
mononuclear cell	CL:0000842	90.26	gold quality
nephron tubule	UBERON:0001231	90.15	gold quality
kidney	UBERON:0002113	88.67	gold quality
vena cava	UBERON:0004087	88.13	gold quality
metanephros cortex	UBERON:0010533	87.18	gold quality
leukocyte	CL:0000738	85.98	gold quality
kidney epithelium	UBERON:0004819	84.51	gold quality
diaphragm	UBERON:0001103	83.69	gold quality
lateral globus pallidus	UBERON:0002476	82.50	gold quality
metanephros	UBERON:0000081	81.43	gold quality
left ventricle myocardium	UBERON:0006566	80.72	gold quality
tongue squamous epithelium	UBERON:0006919	80.72	gold quality
cortex of kidney	UBERON:0001225	80.36	gold quality
substantia nigra pars compacta	UBERON:0001965	80.21	gold quality
cardiac muscle of right atrium	UBERON:0003379	80.06	gold quality
cardia of stomach	UBERON:0001162	79.25	gold quality
substantia nigra pars reticulata	UBERON:0001966	79.06	gold quality
body of tongue	UBERON:0011876	78.75	gold quality
tongue	UBERON:0001723	78.67	gold quality
pericardium	UBERON:0002407	78.36	gold quality

Single-cell (SCXA)

Detected in 16 experiment(s), a significant marker in 13.

Experiment	Marker?	Max mean expression
E-GEOD-149689	yes	3664.91
E-CURD-122	yes	1651.96
E-MTAB-9067	yes	1588.90
E-MTAB-9221	yes	1454.63
E-MTAB-10042	yes	1097.86
E-MTAB-7407	yes	996.20
E-GEOD-130473	yes	811.69
E-MTAB-8205	yes	708.81
E-CURD-112	yes	74.25
E-HCAD-9	yes	11.68
E-MTAB-9388	yes	8.40
E-HCAD-10	yes	5.40
E-GEOD-75367	no	4645.80
E-CURD-98	no	1151.96
E-MTAB-9467	no	2.84

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): KLF1, PPARG, THRA, ZNF362

miRNA regulators (miRDB)

62 targeting SLC4A1, 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-9-5P	100.00	72.28	2361
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-6759-5P	99.99	66.54	785
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-182-5P	99.87	74.03	2589
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-6887-3P	99.66	67.83	1778
HSA-MIR-7106-5P	99.53	67.47	3574
HSA-MIR-6833-5P	99.50	68.93	1161
HSA-MIR-504-3P	99.30	67.18	1745
HSA-MIR-4641	99.28	66.64	744
HSA-MIR-133A-3P	99.27	71.53	1270
HSA-MIR-133B	99.27	71.53	1270
HSA-MIR-6878-3P	99.24	64.23	920
HSA-MIR-6734-3P	99.15	66.27	1627

Literature-anchored findings (GeneRIF, showing 40)

• function as anion exchanger (PMID:11831035)
• REVIEW. Involvement in erythrocyte and kidney disorders. (PMID:11844997)
• clarification of sidedness of lysine 743 residue (PMID:11876646)
• R589H distal renal tubular acidosis(dRTA)mutation creates a severe trafficking defect in kAE1 but not in erythroid AE1 [kAE1] (PMID:11934690)
• extracellular loop 4 binds carbonic anhydrase IV (PMID:11994299)
• Band 3 is an anchor protein for and a target for SHP-2 tyrosine phosphatase in human erythrocytes. (PMID:12070037)
• G701D mutation of anion exchanger 1 gene causes autosomal recessive distal renal tubular acidosis. (PMID:12087557)
• Sulfate transport by band-3 protein in adult human erythrocytes was shown to be modulated by oxygen pressure. (PMID:12101015)
• substrate-dependent reversal of anion transport site orientation in the human red blood cell anion-exchange protein, AE-1 (PMID:12149479)
• Ca2+ promotes erythrocyte band 3 tyrosine phosphorylation via dissociation of phosphotyrosine phosphatase from band 3. (PMID:12175337)
• mutant kAE1 proteins exhibited impaired trafficking from the endoplasmic reticulum to the plasma membrane as determined by immunolocalization, cell-surface biotinylation, oligosaccharide processing and pulse-chase experiments (PMID:12227829)
• an examination of the topology in the c-terminal domain of this protein (PMID:12446737)
• Functional alteration of band 3 is due to its oxidative modification originated as a consequence of the exposure to hypobaric hypoxia and further reoxygenation. (PMID:12466935)
• role of the N-terminal region of the transmembrane domain (PMID:12482865)
• the NH(2) terminus of cdb3 is proximal to but not required for the cdb3-ankyrin interaction (PMID:12482869)
• The first spectral and kinetic evidence is presented for the existence of an apparent high-affinity, chloride-binding, allosteric modifier site which functions to convert band 3 (AE1) from a symmetrical to an asymmetrical dimeric conformational state. (PMID:12578372)
• human red cell anion exchanger transport function and surface trafficking is enhanced by glycophorin A (PMID:12813056)
• data increase the minimal extent of a functionally defined carbonic anhydrase 2 binding site in anion exchanger 1 (PMID:12933803)
• Anion exchanger 1 mutations are associated with distal renal tubular acidosis (PMID:12938018)
• Band 3 is cleaved by caspase 3 at the N-terminal cytoplasmic domain (PMID:14570914)
• band 3 in the red cell can take up two different structures: one with high anion transport activity when glycophorin A is present and one with lower anion transport activity when glycophorin A is absent (PMID:14604989)
• Palmitoylation is not required for trafficking of anion exchanger 1 to the plasma membrane. (PMID:14640982)
• A novel mutation in the AE1 gene was identified in association with autosomal dominant distal renal tubular acidosis. We suggest that RTA be considered a diagnostic possibility in all children with failure to thrive and nephrocalcinosis. (PMID:14654610)
• Neither mutation was associated with altered susceptibility to asymptomatic Plasmodium falciparum or P. vivax infection. Contribution of these erythrocyte polymorphisms to susceptibility to clinical malaria morbidity requires further study. (PMID:14695625)
• dominant dRTA is associated with non-polarized trafficking of the protein, with no significant effect on anion transport function in vitro, which remains an unusual mechanism of human disease. (PMID:14734552)
• Patients with familial autosomal dominant distal renal tubular acidosis associated with the SLC4A1 mutation. (PMID:14736961)
• Amino acid segment Asp893-Val911 at the hydrophilic carboxyl (C)-terminus of human erythrocyte membrane band 3 protein interacts with glycophorin A C-terminus Lys101-Asn130 and is able to cleave it at the Leu118-Ser119 bond. (PMID:14769040)
• old RBCs display higher Tyr-phosphorylation levels of band 3 than younger cells under hypertonic conditions, at least in part due to the reduced cell volume of old RBCs, a condition of lowered threshold for activation of volume-sensitive PTKs (PMID:15039022)
• Current research addressing this central question in the pathobiology of inherited dRTA associated with mutations in the SLC4A1 gene. Review. (PMID:15067510)
• The cdB3 interaction is strongly dependent on pH and the number of negative and positive charges of the peptide and at the effector binding site, respectively (PMID:15087282)
• measured the distance between the C201 residues in adjacent dimerized cytoplasmic domains of AE1 (PMID:15121092)
• the binding of autologous IgG to band 3 dimers (AIgGB) is much greater with hypoxic erythrocytes from newborns as compared to that from adults (PMID:15182940)
• Two novel compound heterozygous SLC4A1 G701D/S773P and SAO/R602H mutations were identified in Thai patients with autosomal recessive distal renal tubular acidosis. (PMID:15211439)
• an autosomal recessive distal renal tubular acidosis mutant (S773P) of the human kidney anion exchanger (kAE1) has trafficking defects (PMID:15252044)
• Quantitative analysis of erythrocyte membrane proteins revealed decrease in band 3 protein from patients with homozygous and heterozygous forms of beta-thalassemia. (PMID:15310273)
• host membrane proteins such as AE1 contribute to the adhesion of malaria-infected erythrocytes to CD36 (PMID:15478802)
• conformational change (in a region of the protein involved in the enhanced adhesiveness of Plasmodium falciparum-infected erythrocytes) induced by malaria infection (PMID:15500919)
• E681OH AE1 has a second Cl- binding/transport site that is distinct from the Cl- transport site in the native protein (PMID:15653731)
• examination of interaction with tumor suppressor p16 (PMID:15811326)
• Missense mutation in a case of hereditary spherocytosis. (PMID:15813913)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	slc4a1a	ENSDARG00000012881
danio_rerio	slc4a1b	ENSDARG00000024560
mus_musculus	Slc4a1	ENSMUSG00000006574
rattus_norvegicus	Slc4a1	ENSRNOG00000020951
drosophila_melanogaster	Ae2	FBGN0036043
drosophila_melanogaster	Ndae1	FBGN0259111
caenorhabditis_elegans	abts-1	WBGENE00009920
caenorhabditis_elegans		WBGENE00019844

Paralogs (9): SLC4A7 (ENSG00000033867), SLC4A8 (ENSG00000050438), SLC4A4 (ENSG00000080493), SLC4A11 (ENSG00000088836), SLC4A9 (ENSG00000113073), SLC4A3 (ENSG00000114923), SLC4A10 (ENSG00000144290), SLC4A2 (ENSG00000164889), SLC4A5 (ENSG00000188687)

Protein

Protein identifiers

Band 3 anion transport protein — P02730 (reviewed: P02730)

Alternative names: Anion exchange protein 1, Solute carrier family 4 member 1

All UniProt accessions (2): P02730, A0A0A0MS98

UniProt curated annotations — full annotation on UniProt →

Function. Functions both as a transporter that mediates electroneutral anion exchange across the cell membrane and as a structural protein. Component of the ankyrin-1 complex of the erythrocyte membrane; required for normal flexibility and stability of the erythrocyte membrane and for normal erythrocyte shape via the interactions of its cytoplasmic domain with cytoskeletal proteins, glycolytic enzymes, and hemoglobin. Functions as a transporter that mediates the 1:1 exchange of inorganic anions across the erythrocyte membrane. Mediates chloride-bicarbonate exchange in the kidney, and is required for normal acidification of the urine. (Microbial infection) Acts as a receptor for P.falciparum (isolate 3D7) MSP9 and thus, facilitates merozoite invasion of erythrocytes. Acts as a receptor for P.falciparum (isolate 3D7) MSP1 and thus, facilitates merozoite invasion of erythrocytes.

Subunit / interactions. A dimer in solution, but in its membrane environment, it exists primarily as a mixture of dimers and tetramers and spans the membrane asymmetrically. Component of the ankyrin-1 complex in the erythrocyte, composed of ANK1, RHCE, RHAG, SLC4A1, EPB42, GYPA, GYPB and AQP1. Interacts with STOM; this interaction positively regulates SLC4A1 activity. Interacts with GYPA; a GYPA monomer is bound at each end of the SLC4A1 dimer forming a heterotetramer. Three SLC4A1 dimers (Band 3-I, Band 3-II and Band 3-III) participates in the ankyrin-1 complex. Interacts (via the cytoplasmic domain) with EPB42; this interaction is mediated by the SLC4A1 Band 3-I dimer. Interacts (via the cytoplasmic domain) directly with ANK1; this interaction is mediated by the SLC4A1 Band 3-II and Band 3-III dimers. Interacts with TMEM139. (Microbial infection) Interacts (via N-terminus) with P.falciparum (isolate K1) aldolase FBPA; the interaction inhibits FBPA catalytic activity. (Microbial infection) Interacts (via the 5ABC region) with P.falciparum (isolate 3D7) MSP9/ABRA (via N-terminus). (Microbial infection) Interacts (via the 5ABC region) with P.falciparum (isolate 3D7) MSP1 p42 subunit.

Subcellular location. Cell membrane. Basolateral cell membrane.

Tissue specificity. Detected in erythrocytes (at protein level). Expressed in kidney (at protein level).

Post-translational modifications. Phosphorylated on Tyr-8 and Tyr-21 most likely by SYK. PP1-resistant phosphorylation that precedes Tyr-359 and Tyr-904 phosphorylation. Phosphorylated on Tyr-359 and Tyr-904 most likely by LYN. PP1-inhibited phosphorylation that follows Tyr-8 and Tyr-21 phosphorylation. N-glycosylated.

Disease relevance. Ovalocytosis, Southeast Asian (SAO) [MIM:166900] An autosomal dominant hematologic disorder characterized by ovalocytic erythrocytes that are rigid and exhibit reduced expression of many erythrocyte antigens. Clinical manifestations include mild hemolysis, intermittent jaundice and gallstones. However, the disorder is most often asymptomatic. The disease is caused by variants affecting the gene represented in this entry. Spherocytosis 4 (SPH4) [MIM:612653] An autosomal dominant form of spherocytosis, a group of hematologic disorders characterized by the presence of numerous abnormally shaped erythrocytes which are generally spheroidal. Affected individuals have anemia, jaundice, and splenomegaly. Clinical severity is variable. Some individuals are asymptomatic, whereas others have severe hemolytic anemia requiring erythrocyte transfusion. The disease is caused by variants affecting the gene represented in this entry. Renal tubular acidosis, distal, 1 (DRTA1) [MIM:179800] An autosomal dominant disease characterized by reduced ability to acidify urine, variable hyperchloremic hypokalemic metabolic acidosis, nephrocalcinosis, and nephrolithiasis. It is due to functional failure of alpha-intercalated cells of the cortical collecting duct of the distal nephron, where vectorial proton transport is required for urinary acidification. The disease is caused by variants affecting the gene represented in this entry. Renal tubular acidosis, distal, 4, with hemolytic anemia (DRTA4) [MIM:611590] An autosomal recessive disease characterized by the association of hemolytic anemia with distal renal tubular acidosis, the reduced ability to acidify urine resulting in variable hyperchloremic hypokalemic metabolic acidosis, nephrocalcinosis, and nephrolithiasis. The disease is caused by variants affecting the gene represented in this entry. Cryohydrocytosis (CHC) [MIM:185020] An autosomal dominant disorder of red cell membrane permeability characterized by cold-induced changes in cell volume, resulting in cold-sensitive stomatocytosis, and increased erythrocyte osmotic fragility and autohemolysis at 4 degrees Celsius. Patients present with mild to moderate hemolytic anemia, splenomegaly, fatigue, and pseudohyperkalemia due to a potassium leak from the erythrocytes. The disease is caused by variants affecting distinct genetic loci, including the gene represented in this entry.

Activity regulation. Phenyl isothiocyanate inhibits anion transport in vitro.

Polymorphism. SLC4A1 is responsible for the Diego blood group system [MIM:110500]. The molecular basis of the Di(a)=Di1/Di(b)/Di2 blood group antigens is a single variation in position 854; Leu-854 corresponds to Di(a) and Pro-854 to Di(b). The molecular basis of the Wr(a)=Di3/Wr(b)/Di4 blood group antigens is a single variation in position 658; Lys-658 corresponds to Wr(a) and Glu-658 to Wr(b). The blood group antigens Wd(a)=Di5 (Waldner-type) has Met-557; Rb(a)=Di6 has Leu-548 and WARR=Di7 has Ile-552. SLC4A1 is responsible for the Swann blood group system (SW) [MIM:601550]. Sw(a+) has a Gln or a Trp at position 646 and Sw(a-) has an Arg. SLC4A1 is responsible for the Froese blood group system (FR) [MIM:601551]. FR(a+) has a Lys at position 480 and FR(a-) has a Glu. Genetic variations in SLC4A1 are involved in resistance to malaria [MIM:611162].

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

Isoforms (2)

UniProt ID	Names	Canonical?
P02730-1	1, eAE1, Erythrocyte	yes
P02730-2	2, kAE1, Kidney

RefSeq proteins (1): NP_000333* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001717	Anion_exchange	Family
IPR002977	Anion_exchange_1	Family
IPR003020	HCO3_transpt_euk	Family
IPR011531	HCO3_transpt-like_TM_dom	Domain
IPR013769	Band3_cytoplasmic_dom	Domain
IPR016152	PTrfase/Anion_transptr	Homologous_superfamily
IPR018241	Anion_exchange_CS	Conserved_site

Pfam: PF00955, PF07565

Catalyzed reactions (Rhea), 1 shown:

• hydrogencarbonate(in) + chloride(out) = hydrogencarbonate(out) + chloride(in) (RHEA:72363)

UniProt features (205 total): sequence variant 79, helix 47, strand 23, topological domain 12, transmembrane region 12, modified residue 8, region of interest 7, mutagenesis site 4, sequence conflict 3, turn 2, site 2, chain 1, intramembrane region 1, compositionally biased region 1, lipid moiety-binding region 1, glycosylation site 1, splice variant 1

Structure

Experimental structures (PDB)

54 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
4KY9	X-RAY DIFFRACTION	2.23
7UZU	ELECTRON MICROSCOPY	2.3
7UZ3	ELECTRON MICROSCOPY	2.35
7V0K	ELECTRON MICROSCOPY	2.4
9MND	ELECTRON MICROSCOPY	2.4
7UZV	ELECTRON MICROSCOPY	2.5
1HYN	X-RAY DIFFRACTION	2.6
7V0M	ELECTRON MICROSCOPY	2.7
7V0T	ELECTRON MICROSCOPY	2.7
8CSV	ELECTRON MICROSCOPY	2.7
8CSY	ELECTRON MICROSCOPY	2.7
8CS9	ELECTRON MICROSCOPY	2.74
7V07	ELECTRON MICROSCOPY	2.8
9MOS	ELECTRON MICROSCOPY	2.88
8CTE	ELECTRON MICROSCOPY	2.9
8T6V	ELECTRON MICROSCOPY	2.95
8T3U	ELECTRON MICROSCOPY	2.97
7TY6	ELECTRON MICROSCOPY	2.98
7TY4	ELECTRON MICROSCOPY	2.99
8T3R	ELECTRON MICROSCOPY	2.99
8T45	ELECTRON MICROSCOPY	2.99
7V0U	ELECTRON MICROSCOPY	3
7V0Y	ELECTRON MICROSCOPY	3
8CRR	ELECTRON MICROSCOPY	3
8CRT	ELECTRON MICROSCOPY	3
7TYA	ELECTRON MICROSCOPY	3.07
9MNG	ELECTRON MICROSCOPY	3.11
8T44	ELECTRON MICROSCOPY	3.12
8T6U	ELECTRON MICROSCOPY	3.13
8T47	ELECTRON MICROSCOPY	3.16

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P02730-F1	82.49	0.49

Antibody-complex structures (SAbDab): 1 — 4YZF

Functional residue map

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

Catalytic / active sites (2): 590 (important for anion transport); 681 (important for anion-proton cotransport)

Post-translational modifications (9): 1, 8, 21, 46, 185, 350, 359, 904, 843

Glycosylation sites (1): 642

Mutagenesis-validated functional residues (4):

Position	Phenotype
85	impairs expression at the cell membrane.
283	impairs expression at the cell membrane.
642	loss of n-glycosylation site.
681	impairs expression at the cell membrane.

Function

Pathways and Gene Ontology

Reactome pathways

11 pathways

ID	Pathway
R-HSA-1237044	Erythrocytes take up carbon dioxide and release oxygen
R-HSA-1247673	Erythrocytes take up oxygen and release carbon dioxide
R-HSA-425381	Bicarbonate transporters
R-HSA-5619050	Defective SLC4A1 causes hereditary spherocytosis type 4 (HSP4), distal renal tubular acidosis (dRTA) and dRTA with hemolytic anemia (dRTA-HA)
R-HSA-1480926	O2/CO2 exchange in erythrocytes
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: 387 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, RNGTGGGC_UNKNOWN, GOBP_NUCLEOSIDE_DIPHOSPHATE_METABOLIC_PROCESS, GOBP_MYELOID_CELL_HOMEOSTASIS, PAX4_01, GOBP_MYELOID_CELL_DEVELOPMENT, MODULE_64, GOBP_ERYTHROCYTE_HOMEOSTASIS, GOBP_PLASMA_MEMBRANE_ORGANIZATION, GOBP_CARBOHYDRATE_DERIVATIVE_CATABOLIC_PROCESS, IVANOVA_HEMATOPOIESIS_MATURE_CELL, GOBP_INORGANIC_ANION_TRANSPORT, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, AP2_Q3, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS

GO Biological Process (18): monoatomic anion transport (GO:0006820), chloride transport (GO:0006821), intracellular monoatomic ion homeostasis (GO:0006873), blood coagulation (GO:0007596), bicarbonate transport (GO:0015701), plasma membrane phospholipid scrambling (GO:0017121), negative regulation of urine volume (GO:0035811), response to increased oxygen levels (GO:0036296), pH elevation (GO:0045852), erythrocyte development (GO:0048821), regulation of intracellular pH (GO:0051453), transmembrane transport (GO:0055085), protein localization to plasma membrane (GO:0072659), chloride transmembrane transport (GO:1902476), negative regulation of glycolytic process through fructose-6-phosphate (GO:1904539), monoatomic ion transport (GO:0006811), inorganic anion transport (GO:0015698), monoatomic anion transmembrane transport (GO:0098656)

GO Molecular Function (12): solute:inorganic anion antiporter activity (GO:0005452), monoatomic anion transmembrane transporter activity (GO:0008509), bicarbonate transmembrane transporter activity (GO:0015106), chloride transmembrane transporter activity (GO:0015108), hemoglobin binding (GO:0030492), ankyrin binding (GO:0030506), protein homodimerization activity (GO:0042803), protein-membrane adaptor activity (GO:0043495), chloride:bicarbonate antiporter activity (GO:0140900), protein binding (GO:0005515), cytoskeletal protein binding (GO:0008092), antiporter activity (GO:0015297)

GO Cellular Component (10): plasma membrane (GO:0005886), cytoplasmic side of plasma membrane (GO:0009898), membrane (GO:0016020), basolateral plasma membrane (GO:0016323), Z disc (GO:0030018), cortical cytoskeleton (GO:0030863), extracellular exosome (GO:0070062), blood microparticle (GO:0072562), ankyrin-1 complex (GO:0170014), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
O2/CO2 exchange in erythrocytes	2
Transport of small molecules	2
SLC-mediated transport of inorganic anions	1
SLC transporter disorders	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	4
monoatomic anion transport	2
regulation of pH	2
monoatomic anion transmembrane transport	2
protein binding	2
monoatomic ion transport	1
inorganic anion transport	1
monoatomic ion homeostasis	1
intracellular chemical homeostasis	1
hemostasis	1
wound healing	1
coagulation	1
plasma membrane organization	1
phospholipid translocation	1
regulation of urine volume	1
response to oxygen levels	1
erythrocyte differentiation	1
myeloid cell development	1
intracellular monoatomic cation homeostasis	1
regulation of biological quality	1
cellular process	1
protein localization to membrane	1
protein localization to cell periphery	1
chloride transport	1
negative regulation of glycolytic process	1
glycolytic process through fructose-6-phosphate	1
monoatomic ion transmembrane transport	1
antiporter activity	1
monoatomic ion transmembrane transporter activity	1
bicarbonate transport	1
transmembrane transporter activity	1
monoatomic anion transmembrane transporter activity	1
chloride transmembrane transport	1
cytoskeletal protein binding	1
identical protein binding	1
protein dimerization activity	1
protein-macromolecule adaptor activity	1
solute:inorganic anion antiporter activity	1
chloride transmembrane transporter activity	1

Protein interactions and networks

STRING

1366 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SLC4A1	ANK1	P16157	983
SLC4A1	GYPA	P02724	941
SLC4A1	ANK3	Q12955	928
SLC4A1	ANK2	Q01484	909
SLC4A1	EPB42	P16452	893
SLC4A1	EPB41	P11171	890
SLC4A1	ATP6V0A4	Q9HBG4	843
SLC4A1	ATP6V1B1	P15313	836
SLC4A1	SPTA1	P02549	794
SLC4A1	GYPB	P06028	769
SLC4A1	SLC26A4	O43511	751
SLC4A1	SLC4A1AP	Q9BWU0	749
SLC4A1	RHCG	Q9UBD6	731
SLC4A1	OSGEP	Q9NPF4	719
SLC4A1	CA2	P00918	675

IntAct

70 interactions, top by confidence:

A	B	Type	Score
ATP1B1	SLC4A1	psi-mi:“MI:0915”(physical association)	0.670
ATP1B1	SLC4A1	psi-mi:“MI:0914”(association)	0.670
SLC4A1	ATP1B1	psi-mi:“MI:0403”(colocalization)	0.670
SLC4A1	ATP1B1	psi-mi:“MI:0407”(direct interaction)	0.670
GYPA	SLC4A1	psi-mi:“MI:0403”(colocalization)	0.660
GYPA	SLC4A1	psi-mi:“MI:0915”(physical association)	0.660
SLC4A1	GYPA	psi-mi:“MI:0403”(colocalization)	0.660
GAPDH	SLC4A1	psi-mi:“MI:0407”(direct interaction)	0.620
STOM	SLC4A1	psi-mi:“MI:0915”(physical association)	0.610
SLC4A1	CDKN2A	psi-mi:“MI:0915”(physical association)	0.600
CDKN2A	SLC4A1	psi-mi:“MI:0915”(physical association)	0.600
SLC4A1	CDKN2A	psi-mi:“MI:0403”(colocalization)	0.600
	SLC4A1	psi-mi:“MI:0407”(direct interaction)	0.560

BioGRID (162): SLC4A1AP (Two-hybrid), KAT2B (Affinity Capture-Western), SLC4A1 (Affinity Capture-Western), SLC4A1 (Co-fractionation), SLC4A1 (Co-fractionation), HADHB (Co-fractionation), VDAC2 (Co-fractionation), VDAC3 (Co-fractionation), ANK1 (Affinity Capture-Western), CFHR5 (Two-hybrid), TMEM60 (Two-hybrid), ADAM33 (Two-hybrid), BMP10 (Two-hybrid), SLC4A1 (Co-crystal Structure), SLC4A1 (Reconstituted Complex)

ESM2 similar proteins: A0A0G2K1Q8, A0A494BA31, B1MTL0, B2RXE2, D3ZBP4, E9Q3M5, F1MH07, O18917, O62667, O88269, P02730, P04919, P04920, P13808, P15575, P16283, P23347, P23348, P23562, P48746, P48751, Q14940, Q14AT5, Q2Y0W8, Q32LP4, Q5DTL9, Q5RB85, Q5RD44, Q60825, Q6IFT6, Q6IWH7, Q6RI88, Q6RVG2, Q6SJP2, Q6U841, Q80ZA5, Q8JZR6, Q8K4V2, Q8NG04, Q8TDZ2

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

8 interactions.

A	Effect	B	Mechanism
SLC4A1	“form complex”	“Ankyrin complex”	binding
SLC4A1	“form complex”	“4.1 complex”	binding
SYK	up-regulates	SLC4A1	phosphorylation
SYK	unknown	SLC4A1	phosphorylation
LYN	unknown	SLC4A1	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

1012 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	87
Likely pathogenic	113
Uncertain significance	459
Likely benign	157
Benign	43

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1285098	NM_000342.4(SLC4A1):c.37G>T (p.Glu13Ter)	Pathogenic
1330539	NM_000342.4(SLC4A1):c.1059dup (p.Pro354fs)	Pathogenic
1330736	NM_000342.4(SLC4A1):c.2057+1G>C	Pathogenic
1331054	NM_000342.4(SLC4A1):c.2501A>C (p.His834Pro)	Pathogenic
1339451	NM_000342.4(SLC4A1):c.2692G>T (p.Glu898Ter)	Pathogenic
1676953	NM_000342.4(SLC4A1):c.370C>T (p.Gln124Ter)	Pathogenic
1676960	NM_000342.4(SLC4A1):c.1610dup (p.Ser538fs)	Pathogenic
1676961	NM_000342.4(SLC4A1):c.1267_1268insG (p.Phe423fs)	Pathogenic
17758	NM_000342.3(SLC4A1):c.2464_2465insCACCCAGATG (p.Val822Alafs)	Pathogenic
17761	NM_000342.3(SLC4A1):c.988C>T (p.Gln330Ter)	Pathogenic
17762	NM_000342.3(SLC4A1):c.448C>T (p.Arg150Ter)	Pathogenic
17763	NM_000342.4(SLC4A1):c.1766G>A (p.Arg589His)	Pathogenic
17765	NM_000342.4(SLC4A1):c.1838C>T (p.Ser613Phe)	Pathogenic
17766	NM_000342.4(SLC4A1):c.1765C>A (p.Arg589Ser)	Pathogenic
17772	NM_000342.4(SLC4A1):c.2545GTG[1] (p.Val850del)	Pathogenic
17778	NM_000342.4(SLC4A1):c.2317T>C (p.Ser773Pro)	Pathogenic
17779	NM_000342.4(SLC4A1):c.1805G>C (p.Arg602Pro)	Pathogenic
2002718	NM_000342.4(SLC4A1):c.554C>G (p.Ser185Ter)	Pathogenic
2027697	NM_000342.4(SLC4A1):c.1786_1787insGCTCCCTCTCCCGTCTCCCGCTCACTCTCCCGTCTCCCGCTCCCTCTCCCGGCACCCTCGCCCGCACCCCGCACCCACGCCCTCGCCAGCCGCGCNNNNNNNNNNAAAAAAAAAAAAAAAAAAAAAAGAACAGCTCCT (p.Ser595_Tyr596insCysSerLeuSerArgLeuProLeuThrLeuProSerProAlaProSerProGlyThrLeuAlaArgThrProHisProArgProArgGlnProArgXaaXaaXaaXaaLysLysLysLysLysLysLysAsnSerSer)	Pathogenic
2036485	NM_000342.4(SLC4A1):c.1173dup (p.Tyr392fs)	Pathogenic
2116827	NM_000342.4(SLC4A1):c.1943G>A (p.Trp648Ter)	Pathogenic
2135727	NM_000342.4(SLC4A1):c.1957del (p.Leu653fs)	Pathogenic
2138052	NM_000342.4(SLC4A1):c.823dup (p.His275fs)	Pathogenic
218182	NM_000342.4(SLC4A1):c.2191T>C (p.Ser731Pro)	Pathogenic
218184	NM_000342.4(SLC4A1):c.2060T>C (p.Leu687Pro)	Pathogenic
2576283	NM_000342.4(SLC4A1):c.2386G>A (p.Gly796Arg)	Pathogenic
2690493	NM_000342.4(SLC4A1):c.515dup (p.Val173fs)	Pathogenic
2696008	NM_000342.4(SLC4A1):c.1032_1033insT (p.Arg345Ter)	Pathogenic
2736602	NM_000342.4(SLC4A1):c.106+1G>A	Pathogenic
2738214	NM_000342.4(SLC4A1):c.2487del (p.Thr830fs)	Pathogenic

SpliceAI

3097 predictions. Top by Δscore:

Variant	Effect	Δscore
17:44250534:TCCAG:T	acceptor_gain	1.0000
17:44250535:CCAG:C	acceptor_gain	1.0000
17:44250535:CCAGC:C	acceptor_gain	1.0000
17:44250536:CAG:C	acceptor_gain	1.0000
17:44250536:CAGC:C	acceptor_gain	1.0000
17:44250537:AG:A	acceptor_gain	1.0000
17:44250538:GC:G	acceptor_loss	1.0000
17:44250539:C:CC	acceptor_gain	1.0000
17:44250540:T:C	acceptor_loss	1.0000
17:44251155:TCAC:T	donor_loss	1.0000
17:44251156:CA:C	donor_loss	1.0000
17:44251157:A:AC	donor_gain	1.0000
17:44251158:C:CA	donor_gain	1.0000
17:44251158:C:CG	donor_loss	1.0000
17:44251158:CA:C	donor_gain	1.0000
17:44251158:CACA:C	donor_gain	1.0000
17:44251160:CA:C	donor_gain	1.0000
17:44251161:A:AC	donor_gain	1.0000
17:44251162:C:CC	donor_gain	1.0000
17:44251176:T:A	donor_gain	1.0000
17:44251330:CAC:C	acceptor_gain	1.0000
17:44251331:ACCT:A	acceptor_loss	1.0000
17:44251334:T:A	acceptor_loss	1.0000
17:44251411:T:TA	donor_gain	1.0000
17:44251418:CCCG:C	donor_gain	1.0000
17:44251545:C:CT	acceptor_gain	1.0000
17:44251584:CAGGC:C	acceptor_gain	1.0000
17:44251587:GCCTG:G	acceptor_loss	1.0000
17:44251588:CCTG:C	acceptor_loss	1.0000
17:44251589:C:A	acceptor_loss	1.0000

AlphaMissense

5887 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:44251513:C:T	G796E	0.999
17:44251514:C:A	G796W	0.999
17:44251514:C:G	G796R	0.999
17:44251514:C:T	G796R	0.999
17:44253143:A:C	S762R	0.999
17:44253143:A:T	S762R	0.999
17:44253145:T:G	S762R	0.999
17:44253262:A:G	W723R	0.999
17:44253262:A:T	W723R	0.999
17:44257999:G:C	F423L	0.999
17:44257999:G:T	F423L	0.999
17:44258001:A:G	F423L	0.999
17:44258018:A:G	L417P	0.999
17:44258024:G:T	A415D	0.999
17:44251477:C:G	R808P	0.998
17:44251522:A:G	L793P	0.998
17:44251524:G:C	F792L	0.998
17:44251524:G:T	F792L	0.998
17:44251526:A:G	F792L	0.998
17:44251531:C:T	G790D	0.998
17:44251532:C:G	G790R	0.998
17:44254611:A:G	W648R	0.998
17:44254611:A:T	W648R	0.998
17:44257380:G:C	F532L	0.998
17:44257380:G:T	F532L	0.998
17:44257382:A:G	F532L	0.998
17:44257396:A:G	L527P	0.998
17:44257404:G:C	F524L	0.998
17:44257404:G:T	F524L	0.998
17:44257406:A:G	F524L	0.998

dbSNP variants (sampled 300 via entrez): RS1000055615 (17:44266584 A>T), RS1000118471 (17:44255611 G>A,C,T), RS1000312644 (17:44248310 C>G), RS1000461619 (17:44261870 G>A), RS1000596266 (17:44248631 C>T), RS1000810826 (17:44265208 C>G), RS1000863113 (17:44265351 G>A), RS1001107479 (17:44253652 T>C), RS1001475628 (17:44267874 C>T), RS1001781328 (17:44267703 C>T), RS1001858271 (17:44256126 A>G), RS1001900148 (17:44262467 A>G), RS1002359554 (17:44250310 C>A,T), RS1002543047 (17:44256388 G>C), RS1002564671 (17:44264828 G>A,T)

Disease associations

OMIM: gene MIM:109270 | disease phenotypes: MIM:166900, MIM:179800, MIM:185020, MIM:611590, MIM:612653, MIM:611162, MIM:613071

GenCC curated gene-disease

Disease	Classification	Inheritance
southeast Asian ovalocytosis	Strong	Autosomal dominant
autosomal dominant distal renal tubular acidosis	Strong	Autosomal dominant
cryohydrocytosis	Strong	Autosomal dominant
renal tubular acidosis, distal, 4, with hemolytic anemia	Strong	Autosomal recessive
hereditary spherocytosis type 4	Strong	Autosomal dominant
dehydrated hereditary stomatocytosis	Supportive	Autosomal dominant
hereditary spherocytosis	Supportive	Autosomal dominant

Mondo (14): southeast Asian ovalocytosis (MONDO:0008165), autosomal dominant distal renal tubular acidosis (MONDO:0008368), cryohydrocytosis (MONDO:0008494), renal tubular acidosis, distal, 4, with hemolytic anemia (MONDO:0012700), hereditary spherocytosis type 4 (MONDO:0012981), malaria, susceptibility to (MONDO:0021024), autosomal recessive distal renal tubular acidosis (MONDO:0018440), hemolytic anemia (MONDO:0003664), distal renal tubular acidosis (MONDO:0015827), bronchiectasis with or without elevated sweat chloride 3 (MONDO:0013112), renal tubular acidosis (MONDO:0001909), hereditary spherocytosis (MONDO:0019350), inherited distal renal tubular acidosis (MONDO:1060161), dehydrated hereditary stomatocytosis (MONDO:0017910)

Orphanet (10): Hereditary cryohydrocytosis with normal stomatin (Orphanet:398088), Malaria (Orphanet:673), Hereditary spherocytosis (Orphanet:822), Autosomal dominant distal renal tubular acidosis (Orphanet:93608), Distal renal tubular acidosis with anemia (Orphanet:93610), Southeast Asian ovalocytosis (Orphanet:98868), Autosomal recessive distal renal tubular acidosis (Orphanet:402041), Distal renal tubular acidosis (Orphanet:18), Idiopathic bronchiectasis (Orphanet:60033), Constitutional hemolytic anemia due to acanthocytosis (Orphanet:98366)

HPO phenotypes

81 total (30 of 81 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000121	Nephrocalcinosis
HP:0000787	Nephrolithiasis
HP:0000952	Jaundice
HP:0000969	Edema
HP:0000980	Pallor
HP:0001017	Anemic pallor
HP:0001046	Intermittent jaundice
HP:0001081	Cholelithiasis
HP:0001251	Ataxia
HP:0001254	Lethargy
HP:0001324	Muscle weakness
HP:0001433	Hepatosplenomegaly
HP:0001508	Failure to thrive
HP:0001510	Growth delay
HP:0001723	Restrictive cardiomyopathy
HP:0001744	Splenomegaly
HP:0001878	Hemolytic anemia
HP:0001900	Increased circulating hemoglobin concentration
HP:0001901	Polycythemia
HP:0001903	Anemia
HP:0001907	Thromboembolism
HP:0001923	Reticulocytosis
HP:0001930	Nonspherocytic hemolytic anemia
HP:0001942	Metabolic acidosis
HP:0001945	Fever
HP:0001947	Renal tubular acidosis
HP:0001972	Macrocytic anemia
HP:0001978	Extramedullary hematopoiesis

GWAS associations

38 associations (top):

Study	Trait	p-value
GCST001762_311	Obesity-related traits	1.000000e-06
GCST004605_22	Mean corpuscular hemoglobin concentration	5.000000e-76
GCST004615_111	Hemoglobin concentration	5.000000e-10
GCST004619_190	Reticulocyte fraction of red cells	3.000000e-32
GCST004621_192	Red cell distribution width	2.000000e-22
GCST004622_54	Reticulocyte count	2.000000e-30
GCST004628_21	Immature fraction of reticulocytes	1.000000e-16
GCST004630_215	Mean corpuscular hemoglobin	1.000000e-22
GCST005992_24	Mean corpuscular hemoglobin concentration	2.000000e-18
GCST006804_113	Red cell distribution width	3.000000e-17
GCST008103_24	Bipolar disorder	2.000000e-08
GCST008972_32	Urate levels	5.000000e-09
GCST010083_265	Hemoglobin levels	2.000000e-17
GCST012126_13	hemolysis of donated blood (osmotic)	5.000000e-08
GCST012135_13	hemolysis of donated blood (osmotic)	4.000000e-08
GCST90000025_588	Appendicular lean mass	1.000000e-18
GCST90002384_413	Hemoglobin	1.000000e-14
GCST90002384_414	Hemoglobin	2.000000e-09
GCST90002385_416	High light scatter reticulocyte count	3.000000e-40
GCST90002385_417	High light scatter reticulocyte count	3.000000e-15
GCST90002386_189	High light scatter reticulocyte percentage of red cells	5.000000e-40
GCST90002386_190	High light scatter reticulocyte percentage of red cells	2.000000e-17
GCST90002387_32	Immature fraction of reticulocytes	4.000000e-18
GCST90002388_499	Lymphocyte count	4.000000e-14
GCST90002389_235	Lymphocyte percentage of white cells	6.000000e-13
GCST90002390_113	Mean corpuscular hemoglobin	1.000000e-52
GCST90002391_91	Mean corpuscular hemoglobin concentration	5.000000e-188
GCST90002391_92	Mean corpuscular hemoglobin concentration	2.000000e-12
GCST90002396_621	Mean reticulocyte volume	1.000000e-53
GCST90002396_622	Mean reticulocyte volume	7.000000e-09

EFO canonical traits (12, from GWAS)

EFO ID	Trait name
EFO:0004528	mean corpuscular hemoglobin concentration
EFO:0004509	hemoglobin measurement
EFO:0007986	reticulocyte count
EFO:0009188	Red cell distribution width
EFO:0004527	mean corpuscular hemoglobin
EFO:0004531	urate measurement
EFO:0009473	hemolysis
EFO:0004980	appendicular lean mass
EFO:0004587	lymphocyte count
EFO:0007993	lymphocyte percentage of leukocytes
EFO:0010701	mean reticulocyte volume
EFO:0007990	neutrophil percentage of leukocytes

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D000141	Acidosis, Renal Tubular	C12.050.351.968.419.815.093; C12.200.777.419.815.093; C12.950.419.815.093; C16.320.831.093; C18.452.076.176.210
D000743	Anemia, Hemolytic	C15.378.050.141
D013103	Spherocytosis, Hereditary	C15.378.050.141.150.785; C16.320.070.785
C567772	Bronchiectasis With Or Without Elevated Sweat Chloride 3 (supp.)
C535827	Pseudohyperkalemia Cardiff (supp.)
C567208	Spherocytosis, Type 4 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs45545233	Efficacy	3	atenolol;metoprolol	Hypertension

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs45545233	SLC4A1	3	0.00	1	atenolol;metoprolol

GtoPdb / IUPHAR curated pharmacology

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

Target class: transporter — Anion exchangers

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Resveratrol	affects activity, increases activity, increases expression	2
Chlorides	decreases reaction, increases transport, affects transport	2
aristolochic acid I	increases expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
sodium arsenite	increases expression	1
4,4’-dinitro-2,2’-stilbenedisulfonic acid	decreases reaction, increases transport	1
benzo(e)pyrene	increases methylation	1
tebuconazole	decreases expression	1
CGP 52608	increases reaction, affects binding	1
Acetaminophen	decreases expression	1
Benzo(a)pyrene	affects methylation	1
Diethylhexyl Phthalate	increases expression	1
Dipyridamole	increases transport, decreases reaction	1
Endosulfan	decreases expression	1
Furans	decreases reaction, increases expression	1
Glucose	decreases reaction, increases expression	1
Methapyrilene	increases methylation	1
Niflumic Acid	decreases reaction, increases transport	1
Potassium	affects transport	1
Silicon Dioxide	decreases expression	1
Sodium	affects transport	1
Sulfates	decreases transport	1
Tretinoin	decreases expression	1
Valproic Acid	increases methylation	1
Paclitaxel	increases expression	1
4,4’-Diisothiocyanostilbene-2,2’-Disulfonic Acid	affects binding, decreases reaction, increases transport	1
Copper Sulfate	increases expression	1
tert-Butylhydroperoxide	increases degradation	1
Selenious Acid	increases uptake	1

Cellosaurus cell lines

1 cell lines: 1 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_C0FI	MUSIi019-A	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05777993	PHASE4	ENROLLING_BY_INVITATION	A Study to Provide Continued Access to Mitapivat for Participants Who Previously Completed an Agios-Sponsored Mitapivat Study
NCT00001729	PHASE3	COMPLETED	Combination Drug Therapy for Patients With Hepatitis C
NCT03548220	PHASE3	COMPLETED	A Study to Evaluate Efficacy and Safety of AG-348 in Not Regularly Transfused Adult Participants With Pyruvate Kinase Deficiency (PKD)
NCT03559699	PHASE3	COMPLETED	A Study Evaluating the Efficacy and Safety of AG-348 in Regularly Transfused Adult Participants With Pyruvate Kinase Deficiency (PKD)
NCT03644706	PHASE3	TERMINATED	Study Evaluating Subjects With Distal Renal Tubular Acidosis
NCT01842451	PHASE2	COMPLETED	A Phase 2 Study to Evaluate the Safety, Efficacy, Pharmacokinetics, and Pharmacodynamics of VX-135 and Daclatasvir in Subjects With Genotype 1 Chronic Hepatitis C Chronic Hepatitis C
NCT00110617	PHASE2	COMPLETED	Study of Deferasirox Relative to Subcutaneous Deferoxamine in Sickle Cell Disease Patients
NCT01579110	PHASE2	UNKNOWN	Efficacy and Safety of Levamisole Combined With Standard Prednisolone in Warm Antibody Autoimmune Hemolytic Anemia.
NCT01642979	PHASE2	UNKNOWN	Safety and Efficacy of Levamisole Combined With Cyclosporine A in Patients With Classic Paroxysmal Nocturnal Hemoglobinuria
NCT01760096	PHASE2	UNKNOWN	Safety and Efficacy of Levamisole Combined With Cyclosporine A in Patients With Subclinical Paroxysmal Nocturnal Hemoglobinuria and PNH in the Setting of Another Bone Marrow Failure Syndromes(PNH-2013)
NCT05004259	PHASE1	COMPLETED	The Safety of Repurposing Daratumumab for Relapsed or Refractory Autoimmune Antibody Mediated Hemolytic Anemia
NCT06684041	PHASE1	COMPLETED	A Safety, Tolerability, Pharmacokinetic/Pharmacodynamic Study, and QT Interval Study of HRS-5965 Capsules in Healthy Subjects
NCT07040787	PHASE1	COMPLETED	Investigation of Drug-drug Interaction of HRS-5965 With Clopidogrel and Clarithromycin in Healthy Subjects
NCT04372498	PHASE1/PHASE2	COMPLETED	Senicapoc and Dehydrated Stomatocytosis
NCT01141621	Not specified	TERMINATED	The Dallas Hereditary Spherocytosis Cohort Study
NCT01276561	Not specified	WITHDRAWN	Single Incision Versus Standard Laparoscopic Splenectomy
NCT04451785	Not specified	COMPLETED	Hereditary Spherocytosis and Vascular Function
NCT06065852	Not specified	RECRUITING	National Registry of Rare Kidney Diseases
NCT03513328	PHASE1/PHASE2	COMPLETED	Conditioning Regimen for Allogeneic Hematopoietic Stem-Cell Transplantation
NCT04610866	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Long-term Mitapivat Dosing in Subjects With Stable Sickle Cell Disease: An Extension of a Phase I Pilot Study of Mitapivat
NCT00842621	Not specified	COMPLETED	Long Term Effects of Erythrocyte Lysis
NCT00971984	Not specified	COMPLETED	Demographic, Clinical and Laboratory Characteristics of Children With Alpha Thalassemia in Northern Israel
NCT02111590	Not specified	COMPLETED	Immunoglobulin Dosage and Administration Form in CIDP and MMN
NCT03006718	Not specified	COMPLETED	SCD-PROMIS: A Software Platform to Enhance Self-efficacy and Patient-provider Engagement for Patients With Sickle Cell Pain
NCT04721262	Not specified	COMPLETED	Ferumoxytol Enhanced Hyperfine Low Field Strength MRI
NCT04964323	Not specified	TERMINATED	Pyruvate Kinase (PK) Deficiency Global Longitudinal Registry: Patient-Reported Outcomes (PRO)
NCT06708728	Not specified	NOT_YET_RECRUITING	Study of Acquired Hemolytic Anemia in Adult Hospitalized Patients