SLC4A7

Summary

SLC4A7 (solute carrier family 4 member 7, HGNC:11033) is a protein-coding gene on chromosome 3p24.1, encoding Sodium bicarbonate cotransporter 3 (Q9Y6M7). Electroneutral sodium- and bicarbonate-dependent cotransporter with a Na(+):HCO3(-) 1:1 stoichiometry. It is a selective cancer dependency (DepMap: 34.7% of cell lines).

This locus encodes a sodium bicarbonate cotransporter. The encoded transmembrane protein appears to transport sodium and bicarbonate ions in a 1:1 ratio, and is thus considered an electroneutral cotransporter. The encoded protein likely plays a critical role in regulation of intracellular pH involved in visual and auditory sensory transmission. Alternatively spliced transcript variants encoding distinct isoforms have been described.

Source: NCBI Gene 9497 — RefSeq curated summary.

At a glance

• Gene–disease (curated): retinitis pigmentosa (Moderate, GenCC) — +1 more curated relationship
• GWAS associations: 58
• Clinical variants (ClinVar): 153 total
• Phenotypes (HPO): 1
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 34.7% of screened cell lines
• MANE Select transcript: NM_001321103

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11033
Approved symbol	SLC4A7
Name	solute carrier family 4 member 7
Location	3p24.1
Locus type	gene with protein product
Status	Approved
Aliases	NBC3, SBC2
Ensembl gene	ENSG00000033867
Ensembl biotype	protein_coding
OMIM	603353
Entrez	9497

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 16 protein_coding, 4 retained_intron, 3 nonsense_mediated_decay

ENST00000295736, ENST00000419036, ENST00000428005, ENST00000428179, ENST00000428386, ENST00000437179, ENST00000437266, ENST00000438530, ENST00000440156, ENST00000445684, ENST00000446700, ENST00000454389, ENST00000455077, ENST00000457377, ENST00000465487, ENST00000475120, ENST00000491211, ENST00000863047, ENST00000935546, ENST00000935547, ENST00000935548, ENST00000935549, ENST00000963935

RefSeq mRNA: 9 — MANE Select: NM_001321103 NM_001258379, NM_001258380, NM_001321103, NM_001321104, NM_001321105, NM_001321106, NM_001321107, NM_001321108, NM_003615

CCDS: CCDS33721, CCDS58819, CCDS58820, CCDS82747, CCDS82748, CCDS82749, CCDS82750, CCDS82751

Canonical transcript exons

ENST00000454389 — 26 exons

Exon	Start	End
ENSE00001075404	27420700	27420787
ENSE00001194926	27411642	27411748
ENSE00001227473	27372723	27376845
ENSE00001633619	27409356	27409530
ENSE00001675628	27421622	27421779
ENSE00001738658	27418486	27418632
ENSE00003468208	27394518	27394769
ENSE00003472488	27398192	27398353
ENSE00003501730	27431298	27431669
ENSE00003523537	27379249	27379356
ENSE00003536247	27452417	27452498
ENSE00003546326	27400764	27400869
ENSE00003549344	27391740	27391808
ENSE00003558022	27404830	27404963
ENSE00003578240	27403139	27403384
ENSE00003600466	27394954	27395115
ENSE00003605600	27448651	27448797
ENSE00003607606	27436388	27436548
ENSE00003619695	27433916	27434104
ENSE00003626723	27389931	27390104
ENSE00003651671	27397684	27397797
ENSE00003664361	27383153	27383250
ENSE00003676732	27424037	27424152
ENSE00003691650	27437388	27437526
ENSE00003790345	27385892	27386023
ENSE00003922889	27484067	27484384

Expression profiles

Bgee: expression breadth ubiquitous, 284 present calls, max score 97.65.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 30.4521 / max 539.1410, expressed in 1787 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
41521	26.4759	1786
41520	3.8029	1491
41517	0.1733	26

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
oocyte	CL:0000023	97.65	gold quality
duodenum	UBERON:0002114	95.81	gold quality
calcaneal tendon	UBERON:0003701	94.73	gold quality
jejunal mucosa	UBERON:0000399	94.15	gold quality
secondary oocyte	CL:0000655	94.13	gold quality
mammary duct	UBERON:0001765	93.84	gold quality
epithelium of mammary gland	UBERON:0003244	93.25	gold quality
sural nerve	UBERON:0015488	92.81	gold quality
frontal pole	UBERON:0002795	92.63	gold quality
blood vessel layer	UBERON:0004797	92.58	gold quality
paraflocculus	UBERON:0005351	92.16	gold quality
Brodmann (1909) area 23	UBERON:0013554	92.13	silver quality
superficial temporal artery	UBERON:0001614	91.57	gold quality
cartilage tissue	UBERON:0002418	91.44	gold quality
jejunum	UBERON:0002115	90.91	gold quality
tendon	UBERON:0000043	89.93	gold quality
colonic epithelium	UBERON:0000397	89.16	gold quality
mucosa of paranasal sinus	UBERON:0005030	89.01	gold quality
middle temporal gyrus	UBERON:0002771	88.96	silver quality
choroid plexus epithelium	UBERON:0003911	88.63	gold quality
pancreatic ductal cell	CL:0002079	88.22	gold quality
gall bladder	UBERON:0002110	88.06	gold quality
cauda epididymis	UBERON:0004360	87.94	gold quality
endometrium	UBERON:0001295	87.91	gold quality
small intestine	UBERON:0002108	87.81	gold quality
muscle layer of sigmoid colon	UBERON:0035805	87.79	gold quality
mammary gland	UBERON:0001911	87.66	gold quality
thoracic mammary gland	UBERON:0005200	87.57	gold quality
right coronary artery	UBERON:0001625	87.53	gold quality
visceral pleura	UBERON:0002401	87.45	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-CURD-119	yes	1336.71
E-MTAB-7316	yes	35.21
E-GEOD-137537	yes	26.03
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): KLF4, SP1

miRNA regulators (miRDB)

277 targeting SLC4A7, 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-3646	100.00	73.56	5283
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-548AW	99.99	72.57	3559

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 34.7% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 23)

• The cystic fibrosis transmembrane conductance regulator interacts with and regulates the activity of the bicarbonate salvage trransporter isoform 3 (PMID:12403779)
• structural and functional study (PMID:14578046)
• NBC3 and CAII interact to maximize the HCO(3)(-) transport rate. Although PKA decreased NBC3 transport activity, it did so independently of the NBC3/CAII interaction and did not involve phosphorylation of NBC3Ct. (PMID:14736710)
• Results suggest that SLC4A7 allelic variants might alter dispositions and/or excretion of drugs and neurotransmitters in brain and periphery in ways that could contribute to differential vulnerabilities to addictions. (PMID:17624982)
• NBCn1 inhibition attenuated cathepsin release and had no net effect on viability of MCF7 cells. (PMID:20542029)
• The present study generated a series of chimeras of human NBCe1-A and human NBCn1-A (SLC4A7). Replacing the fourth extracellular loop (EL4) of human NBCe1-A with EL4 of NBCn1-A creates an electroneutral NBC. (PMID:21224233)
• Data show that DeltaNErbB2 expression elicited Na(+), HCO(3)(-) cotransporter NBCn1 upregulation, Ser(703)-phosphorylation of Na(+)/H(+) exchanger NHE1. (PMID:22120673)
• 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)
• Na(+),HCO(3)(-)-cotransport is a major determinant of pH(i) in breast cancer. (PMID:22907202)
• The SLC4A7 variant rs4973768 is associated with breast cancer risk. (PMID:23117855)
• Upregulation of NBCn1 during human breast carcinogenesis contributes to the characteristic acid distribution within human breast carcinomas. (PMID:24788003)
• We demonstrate, for the first time, that 3 different pHi regulators responsible for acid extruding, i.e. NHE and NBC, and MCT, are functionally co-existed in cultured radial artery smooth muscle cells. (PMID:25241983)
• A meta-analysis of genome-wide association studies of blood pressure and hypertension in Chinese identified three new loci (CACNA1D, CYP21A2, and MED13L) and a newly discovered variant near SLC4A7. (PMID:25249183)
• this is the first work to demonstrate 3’UTR-mediated NBCn1 regulation, shows that p95HER2 regulates NBCn1 expression at multiple levels, and substantiates the central position of p95HER2-NBCn1 signaling in breast cancer. (PMID:27609814)
• the disease-associated T allele of a new hypertension risk variant rs820430 linked increased hypertension risk through higher SLC4A7 expression, and rs820430 functioned as an enhancer of SLC4A7 transcription by allele distinctively increased c-Fos transcription factor binding. (PMID:27784683)
• The finding of a genotypic influence on SLC4A7 expression and pHi regulation in vascular smooth muscle cells provides an insight into the molecular mechanism underlying the association of variation at the SLC4A7 locus with blood pressure (PMID:28087731)
• rs3278 and rs3755652 stimulate an alternative transcription of the SLC4A7 gene, increasing the production of a defective transporter. (PMID:28087757)
• SLC4A7 and bicarbonate-driven cytoplasmic pH homeostasis as an important element of phagocytosis and the associated microbicidal functions in macrophages. (PMID:29779931)
• Increased Alcohol Consumption in Mice Lacking Sodium Bicarbonate Transporter NBCn1. (PMID:32620847)
• The mTORC1-SLC4A7 axis stimulates bicarbonate import to enhance de novo nucleotide synthesis. (PMID:35772404)
• Dynamic localization of the Na+-HCO3- co-transporter NBCn1 to the plasma membrane, centrosomes, spindle and primary cilia. (PMID:37039101)
• Update on the relationship between the SLC4A7 variant rs4973768 and breast cancer risk: a systematic review and meta-analysis. (PMID:37128157)
• Antibodies toward Na[+],HCO3[-]-cotransporter NBCn1/SLC4A7 block net acid extrusion and cause pH-dependent growth inhibition and apoptosis in breast cancer. (PMID:38310186)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	slc4a7	ENSDARG00000073952
mus_musculus	Slc4a7	ENSMUSG00000021733
rattus_norvegicus	Slc4a7	ENSRNOG00000005957
drosophila_melanogaster	Ae2	FBGN0036043
drosophila_melanogaster	Ndae1	FBGN0259111
caenorhabditis_elegans	abts-1	WBGENE00009920
caenorhabditis_elegans		WBGENE00019844

Paralogs (9): SLC4A1 (ENSG00000004939), SLC4A8 (ENSG00000050438), SLC4A4 (ENSG00000080493), SLC4A11 (ENSG00000088836), SLC4A9 (ENSG00000113073), SLC4A3 (ENSG00000114923), SLC4A10 (ENSG00000144290), SLC4A2 (ENSG00000164889), SLC4A5 (ENSG00000188687)

Protein

Protein identifiers

Sodium bicarbonate cotransporter 3 — Q9Y6M7 (reviewed: Q9Y6M7)

Alternative names: Electroneutral Na/HCO(3) cotransporter, Sodium bicarbonate cotransporter 2, Sodium bicarbonate cotransporter 2b, Solute carrier family 4 member 7

All UniProt accessions (4): C9JRP1, Q9Y6M7, E9PFN4, H7C3C4

UniProt curated annotations — full annotation on UniProt →

Function. Electroneutral sodium- and bicarbonate-dependent cotransporter with a Na(+):HCO3(-) 1:1 stoichiometry. Mediates the sodium-dependent bicarbonate transport important for pH recovery after acid load as well as for regulation of steady-state pH in the duodenum and vascular smooth muscle cells. Plays a key role in macrophage acidification, mediating bicarbonate import into the cytoplasm which is crucial for net acid extrusion and maintenance of cytoplasmic pH during phagocytosis. Provides cellular bicarbonate for de novo purine and pyrimidine synthesis and is a key mediator of de novo nucleotide synthesis downstream of mTORC1 signaling in proliferating cells. Plays a key role in macrophage acidification, mediating bicarbonate import into the cytoplasm which is crucial for net acid extrusion and maintenance of cytoplasmic pH during phagocytosis.

Subunit / interactions. Interacts with CFTR through NHERF1/EBP50. Interacts with USH1C. Forms a complex with ATP6V1B1 and NHERF1/EBP50. Interacts in a pH dependent-manner with CA2/carbonic anhydrase 2.

Subcellular location. Basolateral cell membrane. Apical cell membrane. Cell projection. Stereocilium. Cell membrane Cell membrane.

Tissue specificity. Highly expressed in testis and spleen. Also expressed in retina, colon, small intestine, ovary, thymus, prostate, muscle, heart and kidney. Expressed in skeletal muscle and heart muscle.

Activity regulation. Transporter activity is regulated by CA2/carbonic anhydrase 2, cAMP and PKA. Insensitive to stilbene derivatives. Inhibited by 5-(N-ethyl-N-isopropyl)-amiloride (EIPA).

Domain organisation. The PDZ-binding motif mediates interaction with the CFTR, NHERF1/EBP50 complex and probably with USH1C.

Induction. In response to growth factor stimuli, mTORC1 activation, through the RPS6KA1-dependent EIF4B phosphorylation, stimulates SLC4A7 mRNA translation (at protein level). Strongly induced upon macrophage differentiation.

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

Isoforms (14)

UniProt ID	Names	Canonical?
Q9Y6M7-1	1, mNBC3, NBCn1-A	yes
Q9Y6M7-2	2, NBCn1-F
Q9Y6M7-3	3
Q9Y6M7-4	4
Q9Y6M7-5	5
Q9Y6M7-6	6, NBCn1-G
Q9Y6M7-7	7, NBCn1-D
Q9Y6M7-8	8, NBCn1-C
Q9Y6M7-9	9, NBCn1-E
Q9Y6M7-10	10
Q9Y6M7-11	11
Q9Y6M7-12	12, NBCn1-H
Q9Y6M7-13	13
Q9Y6M7-14	14

RefSeq proteins (9): NP_001245308, NP_001245309, NP_001308032, NP_001308033, NP_001308034, NP_001308035, NP_001308036, NP_001308037, NP_003606 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003020	HCO3_transpt_euk	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), 1 shown:

• hydrogencarbonate(in) + Na(+)(in) = hydrogencarbonate(out) + Na(+)(out) (RHEA:70267)

UniProt features (125 total): modified residue 54, topological domain 12, splice variant 12, transmembrane region 11, region of interest 9, compositionally biased region 8, mutagenesis site 7, glycosylation site 7, disulfide bond 2, chain 1, short sequence motif 1, sequence variant 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
9OVR	ELECTRON MICROSCOPY	3.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y6M7-F1	67.85	0.14

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 (54): 1105, 1111, 1201, 1230, 1233, 1239, 1188, 1217, 1220, 1226, 260, 263, 260, 263, 264, 267, 1077, 1106, 1109, 1115 …

Disulfide bonds (2): 766–768, 802–814

Glycosylation sites (7): 171, 269, 398, 406, 776, 786, 791

Mutagenesis-validated functional residues (7):

Position	Phenotype
549	no effect on cell membrane localization. unable to rescue phagocyte deficient acidification phenotype of slc4a7 knockout
811	no effect on cell membrane localization. unable to rescue phagocyte deficient acidification phenotype of slc4a7 knockout
1008–1131	loss of cell membrane localization. unable to rescue phagocyte deficient acidification phenotype of slc4a7 knockout.
1127–1214	loss of cell membrane localization. significant reduction in transport activity.
1135–1136	loss of interaction with ca2. loss of regulation by ca2.
1163–1165	no effect on interaction with ca2. no effect on regulation by ca2.
1214	loss of interaction with atp6v1b1.

Function

Pathways and Gene Ontology

Reactome pathways

13 pathways

ID	Pathway
R-HSA-425381	Bicarbonate transporters
R-HSA-9013405	RHOD GTPase cycle
R-HSA-9013406	RHOQ GTPase cycle
R-HSA-9013407	RHOH GTPase cycle
R-HSA-9013409	RHOJ GTPase cycle
R-HSA-9035034	RHOF GTPase cycle
R-HSA-162582	Signal Transduction
R-HSA-194315	Signaling by Rho GTPases
R-HSA-382551	Transport of small molecules
R-HSA-425393
R-HSA-425407	SLC-mediated transmembrane transport
R-HSA-9012999	RHO GTPase cycle
R-HSA-9716542	Signaling by Rho GTPases, Miro GTPases and RHOBTB3

MSigDB gene sets: 463 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_UP, GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_UP, GOBP_EPITHELIUM_DEVELOPMENT, YAGI_AML_WITH_INV_16_TRANSLOCATION, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, RORA1_01, TGCACTT_MIR519C_MIR519B_MIR519A, GOBP_SODIUM_ION_TRANSMEMBRANE_TRANSPORT, GOBP_NEUROGENESIS, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_NUCLEOSIDE_PHOSPHATE_BIOSYNTHETIC_PROCESS, HASLINGER_B_CLL_WITH_11Q23_DELETION, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_MONOATOMIC_CATION_TRANSPORT

GO Biological Process (14): purine nucleotide biosynthetic process (GO:0006164), pyrimidine nucleotide biosynthetic process (GO:0006221), bicarbonate transport (GO:0015701), regulation of intracellular pH (GO:0051453), transmembrane transport (GO:0055085), auditory receptor cell development (GO:0060117), cellular response to growth factor stimulus (GO:0071363), phagosome acidification (GO:0090383), monoatomic ion transport (GO:0006811), sodium ion transport (GO:0006814), monoatomic anion transport (GO:0006820), inorganic anion transport (GO:0015698), sodium ion transmembrane transport (GO:0035725), monoatomic anion transmembrane transport (GO:0098656)

GO Molecular Function (7): solute:inorganic anion antiporter activity (GO:0005452), monoatomic anion transmembrane transporter activity (GO:0008509), sodium:bicarbonate symporter activity (GO:0008510), protein binding (GO:0005515), bicarbonate transmembrane transporter activity (GO:0015106), secondary active transmembrane transporter activity (GO:0015291), symporter activity (GO:0015293)

GO Cellular Component (6): plasma membrane (GO:0005886), membrane (GO:0016020), basolateral plasma membrane (GO:0016323), apical plasma membrane (GO:0016324), stereocilium (GO:0032420), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
RHO GTPase cycle	5
SLC-mediated transport of inorganic anions	1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1
Transport of small molecules	1
Signaling by Rho GTPases	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transport	4
nucleotide biosynthetic process	2
cellular anatomical structure	2
plasma membrane region	2
purine nucleotide metabolic process	1
purine-containing compound biosynthetic process	1
pyrimidine nucleotide metabolic process	1
pyrimidine-containing compound biosynthetic process	1
regulation of pH	1
intracellular monoatomic cation homeostasis	1
regulation of biological quality	1
cellular process	1
inner ear auditory receptor cell differentiation	1
inner ear receptor cell development	1
response to growth factor	1
cellular response to endogenous stimulus	1
intracellular pH reduction	1
phagosome maturation	1
metal ion transport	1
monoatomic ion transport	1
sodium ion transport	1
monoatomic cation transmembrane transport	1
monoatomic anion transport	1
monoatomic ion transmembrane 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
binding	1
bicarbonate transport	1
transmembrane transporter activity	1
active transmembrane transporter activity	1
secondary active transmembrane transporter activity	1
membrane	1
cell periphery	1
basal plasma membrane	1
apical part of cell	1
stereocilium bundle	1
neuron projection	1

Protein interactions and networks

STRING

1400 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SLC4A7	E9PNW1	E9PNW1	795
SLC4A7	PPP3CB	P16298	795
SLC4A7	ADGRV1	Q8WXG9	788
SLC4A7	CA2	P00918	783
SLC4A7	NEK10	Q6ZWH5	777
SLC4A7	TOX3	O15405	776
SLC4A7	LSP1	P33241	743
SLC4A7	SLC9A1	P19634	736
SLC4A7	USH2A	O75445	714
SLC4A7	COX11	Q9Y6N1	706
SLC4A7	SLC12A2	P55011	678
SLC4A7	SLC9A2	Q9UBY0	661
SLC4A7	SLC26A6	Q9BXS9	638
SLC4A7	SLC9A3	P48764	635
SLC4A7	SLC26A4	O43511	603

IntAct

259 interactions, top by confidence:

A	B	Type	Score
NHERF2	PODXL	psi-mi:“MI:0914”(association)	0.770
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
SNX27	MCC	psi-mi:“MI:0914”(association)	0.700
GPR156	PLD2	psi-mi:“MI:0914”(association)	0.640
YWHAG	BLTP3B	psi-mi:“MI:2364”(proximity)	0.640
SCRIB	SLC4A7	psi-mi:“MI:0407”(direct interaction)	0.620
SLC4A7	SCRIB	psi-mi:“MI:0407”(direct interaction)	0.620
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
YWHAB	BLTP3B	psi-mi:“MI:2364”(proximity)	0.610
SLC4A7	SNX27	psi-mi:“MI:0407”(direct interaction)	0.590
SLC4A7	PDZK1	psi-mi:“MI:0407”(direct interaction)	0.590
SLC4A7	MAST1	psi-mi:“MI:0407”(direct interaction)	0.590
SLC4A7	NHERF2	psi-mi:“MI:0407”(direct interaction)	0.590
YWHAH	BLTP3B	psi-mi:“MI:2364”(proximity)	0.570
CIAO1	SLC4A7	psi-mi:“MI:0915”(physical association)	0.560
KRTAP4-5	SLC4A7	psi-mi:“MI:0915”(physical association)	0.560
MAS1	POTEF	psi-mi:“MI:0914”(association)	0.530
VSIG4	TCAF2	psi-mi:“MI:0914”(association)	0.530
ODAPH	TCAF2	psi-mi:“MI:0914”(association)	0.530
TEX29	TOR1A	psi-mi:“MI:0914”(association)	0.530
RASD2	LRP5	psi-mi:“MI:0914”(association)	0.530
GDE1	GAPDHS	psi-mi:“MI:0914”(association)	0.530
YWHAQ	IGLC7	psi-mi:“MI:0914”(association)	0.530
YWHAZ	BLTP3B	psi-mi:“MI:0914”(association)	0.530
FOXD4	PDHX	psi-mi:“MI:0914”(association)	0.530

BioGRID (346): SLC4A7 (Affinity Capture-MS), SLC4A7 (Affinity Capture-MS), SLC4A7 (Affinity Capture-MS), SLC4A7 (Affinity Capture-MS), SLC4A7 (Affinity Capture-MS), SLC4A7 (Affinity Capture-MS), SLC4A7 (Affinity Capture-MS), SLC4A7 (Affinity Capture-MS), SLC4A7 (Affinity Capture-RNA), SLC4A7 (Affinity Capture-MS), SLC4A7 (Affinity Capture-Western), CFTR (Affinity Capture-Western), SLC4A7 (Reconstituted Complex), SLC4A7 (Proximity Label-MS), SLC4A7 (Proximity Label-MS)

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

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 188 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Activation of BAD and translocation to mitochondria	7	42.3×	4e-08
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	7	37.3×	6e-08
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	7	37.3×	6e-08
Activation of BH3-only proteins	7	27.6×	5e-07
Ras activation upon Ca2+ influx through NMDA receptor	6	27.2×	6e-06
RHO GTPases activate PKNs	8	20.1×	5e-07
Intrinsic Pathway for Apoptosis	7	16.3×	2e-05
RAF activation	6	16.0×	7e-05

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	5	17.3×	3e-03
regulation of postsynaptic membrane neurotransmitter receptor levels	5	14.8×	4e-03
protein targeting	6	13.1×	3e-03
cell-cell adhesion	10	6.0×	3e-03
chemical synaptic transmission	10	4.6×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	107
Likely benign	14
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

4579 predictions. Top by Δscore:

Variant	Effect	Δscore
3:27379355:CA:C	acceptor_gain	1.0000
3:27379357:C:CC	acceptor_gain	1.0000
3:27383250:CCTT:C	acceptor_gain	1.0000
3:27383253:T:C	acceptor_gain	1.0000
3:27383253:T:TC	acceptor_gain	1.0000
3:27385890:A:C	donor_loss	1.0000
3:27385891:C:CT	donor_loss	1.0000
3:27385891:CCT:C	donor_gain	1.0000
3:27385893:T:TA	donor_gain	1.0000
3:27386019:AGAAC:A	acceptor_gain	1.0000
3:27386020:GAAC:G	acceptor_gain	1.0000
3:27386021:AAC:A	acceptor_gain	1.0000
3:27386022:AC:A	acceptor_gain	1.0000
3:27386023:CC:C	acceptor_gain	1.0000
3:27386023:CCTTT:C	acceptor_gain	1.0000
3:27386024:C:CC	acceptor_gain	1.0000
3:27386024:C:CG	acceptor_loss	1.0000
3:27386026:T:C	acceptor_gain	1.0000
3:27386026:T:TC	acceptor_gain	1.0000
3:27386033:G:C	acceptor_gain	1.0000
3:27386033:G:GC	acceptor_gain	1.0000
3:27391805:TAAA:T	acceptor_gain	1.0000
3:27391809:C:CC	acceptor_gain	1.0000
3:27394666:A:AC	donor_gain	1.0000
3:27397680:TTAC:T	donor_loss	1.0000
3:27397681:T:TG	donor_loss	1.0000
3:27398187:GTTAC:G	donor_loss	1.0000
3:27398190:ACC:A	donor_loss	1.0000
3:27398191:C:T	donor_loss	1.0000
3:27398349:CATTC:C	acceptor_gain	1.0000

AlphaMissense

8279 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:27390043:A:G	L1074P	1.000
3:27394550:C:G	G1020R	1.000
3:27394624:G:T	A995D	1.000
3:27394689:A:C	F973L	1.000
3:27394689:A:T	F973L	1.000
3:27394691:A:G	F973L	1.000
3:27394694:A:G	W972R	1.000
3:27394694:A:T	W972R	1.000
3:27394699:A:G	L970P	1.000
3:27395003:T:G	D930A	1.000
3:27395094:A:G	W900R	1.000
3:27395094:A:T	W900R	1.000
3:27403244:A:G	L730P	1.000
3:27403252:A:C	F727L	1.000
3:27403252:A:T	F727L	1.000
3:27403254:A:G	F727L	1.000
3:27403343:C:T	G697D	1.000
3:27403344:C:G	G697R	1.000
3:27403354:T:A	R693S	1.000
3:27403354:T:G	R693S	1.000
3:27403355:C:G	R693T	1.000
3:27404854:T:A	E675V	1.000
3:27404863:A:G	L672P	1.000
3:27404872:C:T	G669D	1.000
3:27404873:C:G	G669R	1.000
3:27404877:G:C	S667R	1.000
3:27404877:G:T	S667R	1.000
3:27404879:T:G	S667R	1.000
3:27404882:C:G	G666R	1.000
3:27404882:C:T	G666R	1.000

dbSNP variants (sampled 300 via entrez): RS1000030089 (3:27446278 C>A), RS1000031601 (3:27389952 A>G), RS1000059051 (3:27484705 G>A,C), RS1000059130 (3:27396038 A>C), RS1000063531 (3:27412029 C>A), RS1000102288 (3:27478033 G>A), RS1000116997 (3:27405462 A>T), RS1000147282 (3:27462909 G>A), RS1000155881 (3:27472123 A>G), RS1000209136 (3:27380210 G>A), RS1000300156 (3:27374119 G>A), RS1000310668 (3:27440617 A>G), RS1000338997 (3:27458761 T>A), RS1000351013 (3:27418423 C>A,G,T), RS1000367966 (3:27484782 GT>G)

Disease associations

OMIM: gene MIM:603353 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
retinitis pigmentosa	Moderate	Autosomal recessive
cone-rod dystrophy	Limited	Autosomal recessive

Mondo (3): inherited retinal dystrophy (MONDO:0019118), retinitis pigmentosa (MONDO:0019200), cone-rod dystrophy (MONDO:0015993)

Orphanet (1): OBSOLETE: Inherited retinal disorder (Orphanet:71862)

HPO phenotypes

1 total (1 of 1 shown, HPO-id order):

HPO	Term
HP:0000556	Retinal dystrophy

GWAS associations

58 associations (top):

Study	Trait	p-value
GCST000678_7	Breast cancer	6.000000e-07
GCST000952_2	Breast cancer	2.000000e-08
GCST001227_5	Systolic blood pressure	2.000000e-06
GCST001228_1	Diastolic blood pressure	4.000000e-09
GCST001236_12	Blood pressure	5.000000e-09
GCST001937_1	Breast cancer	2.000000e-30
GCST002346_13	Breast cancer (early onset)	5.000000e-12
GCST002627_4	Hypertension	1.000000e-06
GCST002630_4	Systolic blood pressure	1.000000e-12
GCST002631_8	Diastolic blood pressure	8.000000e-06
GCST004279_25	Systolic blood pressure	5.000000e-07
GCST004776_13	Systolic blood pressure	3.000000e-06
GCST004777_49	Diastolic blood pressure	3.000000e-10
GCST004948_1	Breast cancer	4.000000e-23
GCST004949_1	Breast cancer	2.000000e-07
GCST004988_260	Breast cancer	5.000000e-57
GCST005979_10	Systolic blood pressure	1.000000e-12
GCST006009_14	Pulse pressure	5.000000e-11
GCST006010_23	Mean arterial pressure	6.000000e-09
GCST006020_17	Diastolic blood pressure	5.000000e-06
GCST006166_52	Diastolic blood pressure x alcohol consumption interaction (2df test)	6.000000e-14
GCST006166_86	Diastolic blood pressure x alcohol consumption interaction (2df test)	2.000000e-16
GCST006167_46	Mean arterial pressure x alcohol consumption interaction (2df test)	3.000000e-15
GCST006168_27	Pulse pressure x alcohol consumption interaction (2df test)	3.000000e-20
GCST006170_34	Systolic blood pressure x alcohol consumption (light vs heavy) interaction (2df test)	4.000000e-08
GCST006172_29	Mean arterial pressure x alcohol consumption (light vs heavy) interaction (2df test)	2.000000e-10
GCST006187_8	Diastolic blood pressure (cigarette smoking interaction)	7.000000e-12
GCST006188_22	Systolic blood pressure (cigarette smoking interaction)	3.000000e-11
GCST006190_25	Diastolic blood pressure x smoking status (ever vs never) interaction (2df test)	1.000000e-08
GCST006190_32	Diastolic blood pressure x smoking status (ever vs never) interaction (2df test)	2.000000e-11

EFO canonical traits (17, from GWAS)

EFO ID	Trait name
EFO:0006335	systolic blood pressure
EFO:0006336	diastolic blood pressure
EFO:0006340	mean arterial pressure
EFO:0005763	pulse pressure measurement
EFO:0004329	alcohol drinking
EFO:0006527	smoking status measurement
EFO:0009882	urinary potassium to creatinine ratio
EFO:0009929	Beta blocking agent use measurement
EFO:0009928	Diuretic use measurement
EFO:0009283	potassium measurement
EFO:0007796	parental longevity
EFO:0009762	healthspan
EFO:1002009	macular telangiectasia type 2
EFO:0004587	lymphocyte count
EFO:0007985	platelet crit
EFO:0007984	platelet component distribution width
EFO:0004309	platelet count

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D000071700	Cone-Rod Dystrophies	C11.270.152; C11.768.585.658.250; C16.320.290.152
D058499	Retinal Dystrophies	C11.768.585.658
D012174	Retinitis Pigmentosa	C11.270.684; C11.768.585.658.500; C16.320.290.684

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3774290 (SINGLE PROTEIN)

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

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

Chemical	Actions (top 5)	PubMed papers
Acetaminophen	affects cotreatment, increases expression, affects expression	4
Valproic Acid	affects expression, decreases expression	4
Tetrachlorodibenzodioxin	affects expression, decreases expression	3
Cyclosporine	increases expression, decreases expression	3
Particulate Matter	decreases expression, increases expression, increases abundance	3
methylmercuric chloride	affects cotreatment, increases expression	2
deoxynivalenol	increases expression	2
potassium chromate(VI)	decreases expression, affects cotreatment	2
Benzo(a)pyrene	affects methylation, increases expression	2
Calcitriol	increases expression	2
Estradiol	increases expression, affects cotreatment, decreases expression	2
Ozone	decreases expression, increases abundance, affects cotreatment	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
bisphenol F	affects cotreatment, decreases expression	1
sotorasib	affects cotreatment, decreases expression	1
testosterone enanthate	affects expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, decreases expression, increases abundance	1
bisphenol A	decreases expression, affects cotreatment	1
lead acetate	increases expression	1
trichostatin A	decreases expression	1
arsenite	affects binding, decreases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
2-amino-9H-pyrido(2,3-b)indole	increases expression	1
sodium arsenite	decreases expression	1
cobaltous chloride	decreases expression	1
nickel chloride	decreases expression	1
perfluorooctanoic acid	increases expression	1
periodate-oxidized adenosine	affects expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3779106	Binding	Inhibition of NBCn1 in human MCF7 cells assessed as decrease in Na(+) -dependent pHi recovery rate at 30 uM	Synthesis of N-cyano-substituted sulfilimine and sulfoximine derivatives of S0859 and their biological evaluation as sodium bicarbonate co-transport inhibitors — Medchemcomm

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D4PU	HCT116-SLC4A7-KO-c10	Cancer cell line	Male
CVCL_D4PV	HCT116-SLC4A7-KO-c20	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00717080	PHASE4	COMPLETED	The Role of Capsular Tension Ring (CTR) in Anterior Capsular Contraction
NCT00000114	PHASE3	COMPLETED	Randomized Trial of Vitamin A and Vitamin E Supplementation for Retinitis Pigmentosa
NCT00000116	PHASE3	COMPLETED	Randomized Trial of DHA for Retinitis Pigmentosa Patients Receiving Vitamin A
NCT00346333	PHASE3	COMPLETED	Clinical Trial of Lutein for Patients With Retinitis Pigmentosa Receiving Vitamin A
NCT01786395	PHASE3	TERMINATED	Phase III Efficacy and Safety Clinical Study of UF-021 for Treatment of Retinitis Pigmentosa
NCT04224207	PHASE3	COMPLETED	Management of Retinitis Pigmentosa by Mesenchymal Stem Cells by Wharton’s Jelly Derived Mesenchymal Stem Cells
NCT04636853	PHASE3	COMPLETED	CB-PRP in Retinitis Pigmentosa and Dry Age-related Macular Degeneration
NCT05537220	PHASE3	ACTIVE_NOT_RECRUITING	Oral N-acetylcysteine for Retinitis Pigmentosa
NCT05800301	PHASE3	COMPLETED	Management of Retinitis Pigmentosa Via Combination of Wharton’s Jelly-derived Mesenchymal Stem Cells and Magnovision
NCT05926583	PHASE3	ACTIVE_NOT_RECRUITING	A Study of AAV5-hRKp.RPGR for the Treatment of Japanese Participants With X-linked Retinitis Pigmentosa
NCT06388200	PHASE3	ACTIVE_NOT_RECRUITING	A Phase 3 Study Of OCU400 Gene Therapy for the Treatment Of Retinitis Pigmentosa
NCT07082855	PHASE3	NOT_YET_RECRUITING	A Multicenter, Randomized, Double-Blind, Controlled Clinical Study of Minocycline for the Treatment of Retinitis Pigmentosa
NCT07290530	PHASE3	NOT_YET_RECRUITING	24-Month Trial of NPI-001 for the Preservation of Photoreceptors in Retinitis Pigmentosa Associated With Usher Syndrome
NCT00100230	PHASE2	COMPLETED	DHA and X-Linked Retinitis Pigmentosa
NCT00447980	PHASE2	COMPLETED	A Study of Encapsulated Cell Technology (ECT) Implant for Participants With Early Stage Retinitis Pigmentosa
NCT00447993	PHASE2	COMPLETED	A Study of Encapsulated Cell Technology (ECT) Implant for Patients With Late Stage Retinitis Pigmentosa
NCT01233609	PHASE2	COMPLETED	Trial of Oral Valproic Acid for Retinitis Pigmentosa
NCT01399515	PHASE2	COMPLETED	Efficacy and Safety of Oral Valproic Acid for Retinitis Pigmentosa
NCT01530659	PHASE2	COMPLETED	Retinal Imaging in CNTF -Releasing Encapsulated Cell Implant Treated Patients for Early-stage Retinitis Pigmentosa
NCT01560715	PHASE2	COMPLETED	Autologous Bone Marrow-Derived Stem Cells Transplantation For Retinitis Pigmentosa
NCT02609165	PHASE2	COMPLETED	Nerve Growth Factor Eye Drops Treatment in Patients With Retinitis Pigmentosa and Cystoid Macular Edema
NCT02661711	PHASE2	COMPLETED	Aflibercept for Macular Oedema With Underlying Retinitis Pigmentosa (AMOUR) Study
NCT02804360	PHASE2	UNKNOWN	Intravitreal Dexamethasone Implant in Retinitis Pigmentosa-related Macular Edema- a Retrospective Study
NCT02837640	PHASE2	UNKNOWN	Studying a Potential Protective Effect of L-Dopa on Retinitis Pigmentosa
NCT03073733	PHASE2	COMPLETED	Safety and Efficacy of Intravitreal Injection of Human Retinal Progenitor Cells in Adults With Retinitis Pigmentosa
NCT04068207	PHASE2	COMPLETED	Minocycline Treatment in Retinitis Pigmentosa
NCT04356716	PHASE2	COMPLETED	Sildenafil for Treatment of Choroidal Ischemia
NCT04604899	PHASE2	COMPLETED	Safety of Repeat Intravitreal Injection of Human Retinal Progenitor Cells (jCell) in Adult Subjects With Retinitis Pigmentosa
NCT04763369	PHASE2	UNKNOWN	Investigation of Therapeutic Efficacy and Safety of UMSCs for the Management of Retinitis Pigmentosa (RP)
NCT04864496	PHASE2	UNKNOWN	Effects of Treatment With N- Acetylcysteine on Visual Outcomes in Patients With Retinitis Pigmentosa
NCT04945772	PHASE2	COMPLETED	Efficacy and Safety of MCO-010 Optogenetic Therapy in Adults With Retinitis Pigmentosa [RESTORE]
NCT05085964	PHASE2	TERMINATED	An Open-Label Extension Study to Evaluate Safety & Tolerability of QR-421a in Subjects With Retinitis Pigmentosa
NCT05392179	PHASE2	COMPLETED	A Study in Subjects With Retinitis Pigmentosa
NCT06627179	PHASE2	RECRUITING	Study to Evaluate Ultevursen in Subjects With Retinitis Pigmentosa (RP) Due to Mutations in Exon 13 of the USH2A Gene
NCT06628947	PHASE2	RECRUITING	A Phase II Study of Intravitreal KIO-301 in Patients With Late-stage Retinitis Pigmentosa
NCT06912633	PHASE2	RECRUITING	Safety of a Single, Intravitreal Injection of 6.0M jCell (Famzeretcel) in Retinitis Pigmentosa (RP)
NCT01773278	PHASE2	RECRUITING	Cholesterol and Antioxidant Treatment in Patients With Smith-Lemli-Opitz Syndrome (SLOS)
NCT03763227	PHASE2	COMPLETED	Intravitreal Ranibizumab (Lucentis®) in the Treatment of Non-leaking Macular Cysts in Retinal Dystrophy
NCT00063765	PHASE1	COMPLETED	Evaluation of Safety of Ciliary Neurotrophic Factor Implants in the Eye
NCT00065455	PHASE1	COMPLETED	Investigating the Effect of Vitamin A Supplementation on Retinitis Pigmentosa