SLC4A2

Summary

SLC4A2 (solute carrier family 4 member 2, HGNC:11028) is a protein-coding gene on chromosome 7q36.1, encoding Anion exchange protein 2 (P04920). Sodium-independent anion exchanger which mediates the electroneutral exchange of chloride for bicarbonate ions across the cell membrane.

This gene encodes a member of the anion exchanger family of membrane transport proteins. The encoded protein regulates intracellular pH, biliary bicarbonate secretion, and chloride uptake. Reduced expression of this gene may be associated with primary biliary cirrhosis (PBC) in human patients, while differential expression of this gene may be associated with malignant hepatocellular carcinoma, colon and gastric cancers.

Source: NCBI Gene 6522 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hereditary spherocytosis type 4 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 3
• Clinical variants (ClinVar): 218 total — 2 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 16
• MANE Select transcript: NM_003040

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11028
Approved symbol	SLC4A2
Name	solute carrier family 4 member 2
Location	7q36.1
Locus type	gene with protein product
Status	Approved
Aliases	HKB3, BND3L, NBND3
Ensembl gene	ENSG00000164889
Ensembl biotype	protein_coding
OMIM	109280
Entrez	6522

Gene structure

Transcript identifiers

Ensembl transcripts: 20 — 9 protein_coding, 8 retained_intron, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000392826, ENST00000413384, ENST00000460010, ENST00000461735, ENST00000463414, ENST00000466368, ENST00000469355, ENST00000469467, ENST00000472204, ENST00000480107, ENST00000482697, ENST00000482950, ENST00000483786, ENST00000485713, ENST00000488420, ENST00000490898, ENST00000493040, ENST00000494125, ENST00000494298, ENST00000677246

RefSeq mRNA: 4 — MANE Select: NM_003040 NM_001199692, NM_001199693, NM_001199694, NM_003040

CCDS: CCDS56520, CCDS56521, CCDS5917

Canonical transcript exons

ENST00000413384 — 23 exons

Exon	Start	End
ENSE00001088291	151070181	151070346
ENSE00001088294	151075255	151075508
ENSE00001088301	151067874	151068054
ENSE00001088303	151066851	151066993
ENSE00001088305	151064848	151064966
ENSE00001088308	151070457	151070571
ENSE00001088310	151069947	151070082
ENSE00001088312	151066517	151066761
ENSE00001088314	151074675	151074841
ENSE00001088316	151064202	151064367
ENSE00001088317	151074039	151074293
ENSE00001088318	151075606	151075775
ENSE00001088319	151076013	151076186
ENSE00001088320	151074399	151074488
ENSE00001088326	151071390	151071605
ENSE00001088329	151071072	151071297
ENSE00001201478	151064526	151064767
ENSE00001753937	151059589	151059762
ENSE00001923865	151076287	151076523
ENSE00002372694	151071689	151071837
ENSE00003540808	151061925	151062038
ENSE00003575563	151071942	151072136
ENSE00003606816	151070727	151070911

Expression profiles

Bgee: expression breadth ubiquitous, 261 present calls, max score 98.41.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 22.9303 / max 222.4560, expressed in 1803 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
82039	13.8445	1792
82040	2.6239	1294
82044	2.0944	417
82041	2.0503	589
82043	1.0427	240
82047	0.6819	304
82042	0.3031	148
82046	0.2132	107
82045	0.0763	38

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
body of stomach	UBERON:0001161	98.41	gold quality
metanephros cortex	UBERON:0010533	97.91	gold quality
muscle layer of sigmoid colon	UBERON:0035805	97.46	gold quality
endocervix	UBERON:0000458	97.34	gold quality
right lobe of liver	UBERON:0001114	97.23	gold quality
mucosa of transverse colon	UBERON:0004991	97.17	gold quality
body of uterus	UBERON:0009853	97.13	gold quality
stomach	UBERON:0000945	96.88	gold quality
lower esophagus	UBERON:0013473	96.85	gold quality
lower esophagus muscularis layer	UBERON:0035833	96.85	gold quality
stromal cell of endometrium	CL:0002255	96.83	gold quality
body of pancreas	UBERON:0001150	96.83	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	96.82	gold quality
left uterine tube	UBERON:0001303	96.75	gold quality
right ovary	UBERON:0002118	96.69	gold quality
lower esophagus mucosa	UBERON:0035834	96.62	gold quality
pigmented layer of retina	UBERON:0001782	96.49	gold quality
upper lobe of left lung	UBERON:0008952	96.43	gold quality
right uterine tube	UBERON:0001302	96.42	gold quality
left adrenal gland cortex	UBERON:0035825	96.27	gold quality
ascending aorta	UBERON:0001496	96.25	gold quality
right coronary artery	UBERON:0001625	96.23	gold quality
ectocervix	UBERON:0012249	96.21	gold quality
right adrenal gland cortex	UBERON:0035827	96.20	gold quality
thoracic aorta	UBERON:0001515	96.18	gold quality
left ovary	UBERON:0002119	96.12	gold quality
apex of heart	UBERON:0002098	96.10	gold quality
left adrenal gland	UBERON:0001234	96.06	gold quality
right adrenal gland	UBERON:0001233	96.05	gold quality
left coronary artery	UBERON:0001626	96.05	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-GEOD-135922	yes	13.66
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): EGR1, GAST, HNF1A, MYC, SP1, TCF3

miRNA regulators (miRDB)

22 targeting SLC4A2, 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-5692A	100.00	74.40	6850
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-944	99.82	70.85	3042
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-4472	99.56	66.08	1478
HSA-MIR-7106-5P	99.53	67.47	3574
HSA-MIR-12123	99.52	71.79	2990
HSA-MIR-6722-3P	99.45	67.62	1919
HSA-MIR-4434	99.10	67.01	1984
HSA-MIR-5703	99.10	67.09	2053
HSA-MIR-423-5P	98.69	67.48	1522
HSA-MIR-3184-5P	98.56	67.13	1491
HSA-MIR-509-5P	97.21	67.90	1512
HSA-MIR-509-3-5P	97.21	67.74	1517
HSA-MIR-4418	97.04	67.16	1372

Literature-anchored findings (GeneRIF, showing 26)

• AE2 operates in parallel with NHE1 to regulate pH(i) during RVD of human cervical cancer cells. (PMID:11852051)
• Oxidative stress activates anion exchange protein 2 and AP-1 in airway epithelial cells. (PMID:12225956)
• findings suggest that HNF1 may have a major role in upregulating alternative transcription of the AE2 gene in the liver, and therefore it may contribute to the biliary secretion of bicarbonate in response to certain stimuli (PMID:14575719)
• The results indicated that overexpression of AE2 may be involved in the development of human HCC. (PMID:17058451)
• SLC4A2 colocalized with carbonic anhydrase IX in gastric mucosa. (PMID:17652430)
• AE2 might be associated with gastric carcinogenesis and the achlorhydria experienced by gastric cancer patients. (PMID:18438347)
• that AE2 may play an important role in the progression of hepatocellular carcinoma cells (PMID:19224338)
• The common genetic variation of SLC4A2 does not directly affect the risk of PBC or its clinical outcome. (PMID:19491853)
• AE2 mediated-apoptosis of endothelial cells induced by high glucose was Caspase-3-dependent. (PMID:20180022)
• CTLA4 and SLC4A2 genetic polymorphisms are differentially associated with primary biliary cirrhosis development and progression, as well as anti-gp210 or anti-centromere antibody production, in Japanese PBC patients (PMID:21594562)
• Dysfunctions related to AE2 might have a role in the pathogenesis of primary biliary cirrhosis. (PMID:21691115)
• miR-506 is up-regulated in primary biliary cirrhosis, binds the 3’UTR region of AE2 mRNA, and prevents protein translation, leading to diminished AE2 activity and impaired biliary secretory functions. (PMID:22383162)
• AE2 is a major pathway for basolateral Cl(-) loading during cAMP-stimulated secretion of Cl(-) and fluid by Calu-3 cells (PMID:22802585)
• A novel signal pathway involved in gastrin-stimulated AE2 expression mediated by EGR1 in gastric cancer cells. (PMID:23121767)
• regulatory proteins for Cl(-)/HCO3(-) exchanger 2 activity (PMID:26716707)
• down-regulation in primary biliary cholangitis sensitizes cholangiocytes to apoptotic insults by activating soluble adenylyl cyclase (PMID:26991014)
• ABA transport in human nucleated cells occurs via the anion exchanger AE2 (PMID:27015766)
• To match the stimulatory effect on acid uptake, cell-to-cell coupling in NHDF-Ad and CCD-112-CoN cells was strengthened with TGFbeta1.Importantly, the activities of stromal AE2 and connexin-43 do not place an energetic burden on cancer cells, allowing resources to be diverted for other activities (PMID:27543333)
• The regulation of a basolateral located, DIDS-sensitive, Cl(-)/HCO3(-) exchanger, anion exchanger 2 (AE2; SLC4A2) which is postulated to act as an acid loader, and therefore potential regulator of HCO3(-) secretion, in human airway epithelial cells. (PMID:28455748)
• Study found that AE2 was overexpressed in ovarian cancer samples, and up-regulated AE2 expression can activate the mTOR/p70S6K1 pathway, promoting ovarian cancer cell growth. (PMID:28743911)
• Intracellular Ca(2+)-Mediated AE2 Is Involved in the Vectorial Movement of HaCaT Keratinocyte. (PMID:33182643)
• Both IRBIT and long-IRBIT bind to and coordinately regulate Cl(-)/HCO3(-) exchanger AE2 activity through modulating the lysosomal degradation of AE2. (PMID:33727633)
• SLC4A2 anion exchanger promotes tumour cell malignancy via enhancing net acid efflux across golgi membranes. (PMID:34279699)
• Alterations in SLC4A2, SLC26A7 and SLC26A9 Drive Acid-Base Imbalance in Gastric Neuroendocrine Tumors and Uncover a Novel Mechanism for a Co-Occurring Polyautoimmune Scenario. (PMID:34944008)
• SLC4A2, another gene involved in acid-base balancing machinery of osteoclasts, causes osteopetrosis. (PMID:36343920)
• Acid-adapted cancer cells alkalinize their cytoplasm by degrading the acid-loading membrane transporter anion exchanger 2, SLC4A2. (PMID:37270778)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	slc4a2a	ENSDARG00000028173
danio_rerio	slc4a2b	ENSDARG00000052330
mus_musculus	Slc4a2	ENSMUSG00000028962
rattus_norvegicus	Slc4a2	ENSRNOG00000014347
drosophila_melanogaster	Ae2	FBGN0036043
drosophila_melanogaster	Ndae1	FBGN0259111
caenorhabditis_elegans	abts-1	WBGENE00009920
caenorhabditis_elegans		WBGENE00019844

Paralogs (9): SLC4A1 (ENSG00000004939), SLC4A7 (ENSG00000033867), SLC4A8 (ENSG00000050438), SLC4A4 (ENSG00000080493), SLC4A11 (ENSG00000088836), SLC4A9 (ENSG00000113073), SLC4A3 (ENSG00000114923), SLC4A10 (ENSG00000144290), SLC4A5 (ENSG00000188687)

Protein

Protein identifiers

Anion exchange protein 2 — P04920 (reviewed: P04920)

Alternative names: Non-erythroid band 3-like protein, Solute carrier family 4 member 2

All UniProt accessions (7): A0A7I2V5T6, C9J035, P04920, C9J459, C9J722, C9J9M9, C9JVC2

UniProt curated annotations — full annotation on UniProt →

Function. Sodium-independent anion exchanger which mediates the electroneutral exchange of chloride for bicarbonate ions across the cell membrane. Plays an important role in osteoclast differentiation and function. Regulates bone resorption and calpain-dependent actin cytoskeleton organization in osteoclasts via anion exchange-dependent control of pH. Essential for intracellular pH regulation in CD8(+) T-cells upon CD3 stimulation, modulating CD8(+) T-cell responses.

Subcellular location. Apical cell membrane. Basolateral cell membrane Apical cell membrane. Basolateral cell membrane.

Tissue specificity. Expressed in the liver, stomach, kidney, prostate, thyroid and rectum. Expressed in the liver and kidney. Expressed in the liver and kidney.

Disease relevance. Osteopetrosis, autosomal recessive 9 (OPTB9) [MIM:620366] A form of osteopetrosis, a rare genetic disease characterized by abnormally dense bone, due to defective resorption of immature bone. Osteopetrosis occurs in two forms: a severe autosomal recessive form occurring in utero, infancy, or childhood, and a benign autosomal dominant form occurring in adolescence or adulthood. Recessive osteopetrosis commonly manifests in early infancy with macrocephaly, feeding difficulties, evolving blindness and deafness, bone marrow failure, severe anemia, and hepatosplenomegaly. Deafness and blindness are generally thought to represent effects of pressure on nerves. OPTB9 is characterized by increased bone density and bone fragility, as well as renal failure. The disease may be caused by variants affecting the gene represented in this entry.

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

Isoforms (3)

UniProt ID	Names	Canonical?
P04920-1	A	yes
P04920-2	B1
P04920-3	B2

RefSeq proteins (4): NP_001186621, NP_001186622, NP_001186623, NP_003031* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001717	Anion_exchange	Family
IPR002978	Anion_exchange_2	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 (132 total): helix 40, strand 22, sequence conflict 15, modified residue 11, transmembrane region 10, compositionally biased region 8, turn 6, sequence variant 6, region of interest 4, topological domain 3, glycosylation site 3, splice variant 2, chain 1, lipid moiety-binding region 1

Structure

Experimental structures (PDB)

10 structures.

PDB	Method	Resolution (Å)
8GVC	ELECTRON MICROSCOPY	2.89
8GV9	ELECTRON MICROSCOPY	3.06
8GV8	ELECTRON MICROSCOPY	3.08
8GVF	ELECTRON MICROSCOPY	3.09
8GVE	ELECTRON MICROSCOPY	3.17
8JNI	ELECTRON MICROSCOPY	3.2
8GVA	ELECTRON MICROSCOPY	3.25
8JNJ	ELECTRON MICROSCOPY	3.3
8GVH	ELECTRON MICROSCOPY	3.32
8ZLE	ELECTRON MICROSCOPY	3.35

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P04920-F1	66.66	0.25

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 (12): 113, 132, 144, 170, 172, 173, 183, 243, 257, 274, 443, 1173

Glycosylation sites (3): 859, 868, 882

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-425381	Bicarbonate transporters
R-HSA-382551	Transport of small molecules
R-HSA-425393
R-HSA-425407	SLC-mediated transmembrane transport

MSigDB gene sets: 333 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, MORF_MTA1, TAKEDA_TARGETS_OF_NUP98_HOXA9_FUSION_6HR_DN, GOBP_REGULATION_OF_CELL_ACTIVATION, RNGTGGGC_UNKNOWN, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, WWTAAGGC_UNKNOWN, GOBP_REGULATION_OF_ALPHA_BETA_T_CELL_ACTIVATION, GOBP_NEGATIVE_REGULATION_OF_LEUKOCYTE_PROLIFERATION, SP3_Q3, GOBP_ALPHA_BETA_T_CELL_DIFFERENTIATION, ASTON_MAJOR_DEPRESSIVE_DISORDER_DN, MORF_CDK2, GOBP_NEGATIVE_REGULATION_OF_CELL_CELL_ADHESION

GO Biological Process (17): monoatomic anion transport (GO:0006820), spermatogenesis (GO:0007283), bicarbonate transport (GO:0015701), osteoclast differentiation (GO:0030316), regulation of actin cytoskeleton organization (GO:0032956), negative regulation of CD8-positive, alpha-beta T cell differentiation (GO:0043377), regulation of bone resorption (GO:0045124), digestive tract development (GO:0048565), regulation of intracellular pH (GO:0051453), transmembrane transport (GO:0055085), positive regulation of enamel mineralization (GO:0070175), amelogenesis (GO:0097186), negative regulation of CD8-positive, alpha-beta T cell proliferation (GO:2000565), monoatomic ion transport (GO:0006811), inorganic anion transport (GO:0015698), monoatomic anion transmembrane transport (GO:0098656), chloride transmembrane transport (GO:1902476)

GO Molecular Function (7): solute:inorganic anion antiporter activity (GO:0005452), monoatomic anion transmembrane transporter activity (GO:0008509), enzyme binding (GO:0019899), transmembrane transporter activity (GO:0022857), chloride:bicarbonate antiporter activity (GO:0140900), protein binding (GO:0005515), antiporter activity (GO:0015297)

GO Cellular Component (5): plasma membrane (GO:0005886), focal adhesion (GO:0005925), membrane (GO:0016020), basolateral plasma membrane (GO:0016323), apical plasma membrane (GO:0016324)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
SLC-mediated transport of inorganic anions	1
Transport of small molecules	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transport	4
negative regulation of CD8-positive, alpha-beta T cell activation	2
monoatomic anion transmembrane transport	2
plasma membrane region	2
monoatomic ion transport	1
developmental process involved in reproduction	1
male gamete generation	1
myeloid leukocyte differentiation	1
actin cytoskeleton organization	1
regulation of actin filament-based process	1
regulation of cytoskeleton organization	1
CD8-positive, alpha-beta T cell differentiation	1
regulation of CD8-positive, alpha-beta T cell differentiation	1
negative regulation of alpha-beta T cell differentiation	1
bone resorption	1
regulation of bone remodeling	1
tube development	1
digestive system development	1
regulation of pH	1
intracellular monoatomic cation homeostasis	1
regulation of biological quality	1
cellular process	1
enamel mineralization	1
positive regulation of tooth mineralization	1
regulation of enamel mineralization	1
odontogenesis of dentin-containing tooth	1
anatomical structure formation involved in morphogenesis	1
CD8-positive, alpha-beta T cell proliferation	1
negative regulation of alpha-beta T cell proliferation	1
regulation of CD8-positive, alpha-beta T cell proliferation	1
monoatomic anion transport	1
monoatomic ion transmembrane transport	1
chloride transport	1
antiporter activity	1
monoatomic ion transmembrane transporter activity	1
protein binding	1
transporter activity	1
transmembrane transport	1
solute:inorganic anion antiporter activity	1
chloride transmembrane transporter activity	1

Protein interactions and networks

STRING

1253 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SLC4A2	SLC12A2	P55011	909
SLC4A2	SLC12A1	Q13621	839
SLC4A2	SLC26A6	Q9BXS9	652
SLC4A2	CA12	O43570	632
SLC4A2	SLC9A1	P19634	629
SLC4A2	CFTR	P13569	626
SLC4A2	SLC26A7	Q8TE54	602
SLC4A2	SCT	P09683	591
SLC4A2	SLC12A5	Q9H2X9	588
SLC4A2	SLC26A3	P40879	562
SLC4A2	ERV3-1	Q14264	549
SLC4A2	ERVFRD-1	P60508	549
SLC4A2	SLC26A11	Q86WA9	548
SLC4A2	CA14	Q9ULX7	536
SLC4A2	AQP1	P29972	531

IntAct

110 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
RETREG3	PLSCR1	psi-mi:“MI:0914”(association)	0.640
GPR21	TMEM120B	psi-mi:“MI:0914”(association)	0.530
ADGRG5	KLRG2	psi-mi:“MI:0914”(association)	0.530
APLNR	METTL15	psi-mi:“MI:0914”(association)	0.530
LGALS1	PODXL	psi-mi:“MI:0914”(association)	0.530
LGALS3	PODXL	psi-mi:“MI:0914”(association)	0.530
CLGN	NPC1	psi-mi:“MI:0914”(association)	0.530
SLC30A2	RER1	psi-mi:“MI:0914”(association)	0.530
PTGIR	TMEM63A	psi-mi:“MI:0914”(association)	0.530
SLC39A4	TMEM120B	psi-mi:“MI:0914”(association)	0.530
CCR6	PODXL	psi-mi:“MI:0914”(association)	0.530
TMEM63A	AP3D1	psi-mi:“MI:0914”(association)	0.530
SIGMAR1	NPC1	psi-mi:“MI:0914”(association)	0.530
GPR17	IPO8	psi-mi:“MI:0914”(association)	0.530
SIDT2	AP3D1	psi-mi:“MI:0914”(association)	0.530
SRARP	SLC4A2	psi-mi:“MI:0915”(physical association)	0.500
SRARP	SLC4A2	psi-mi:“MI:0914”(association)	0.500
NRAS	ESYT2	psi-mi:“MI:2364”(proximity)	0.480
GAPDH	SLC4A2	psi-mi:“MI:0915”(physical association)	0.400
ATXN1	SLC4A2	psi-mi:“MI:0915”(physical association)	0.370
SLC4A2		psi-mi:“MI:0915”(physical association)	0.370
THOC2		psi-mi:“MI:0914”(association)	0.350
Myh10	LMO7	psi-mi:“MI:0914”(association)	0.350
Iqgap3	SRGAP3	psi-mi:“MI:0914”(association)	0.350
Ccn1	SRGAP3	psi-mi:“MI:0914”(association)	0.350
ELL2	TIA1	psi-mi:“MI:0914”(association)	0.350

BioGRID (217): SLC4A2 (Affinity Capture-RNA), SLC4A2 (Affinity Capture-RNA), SLC4A2 (Affinity Capture-MS), SLC4A2 (Affinity Capture-MS), SLC4A2 (Affinity Capture-MS), SLC4A2 (Affinity Capture-MS), SLC4A2 (Affinity Capture-MS), SLC4A2 (Affinity Capture-MS), SLC4A2 (Affinity Capture-MS), SLC4A2 (Affinity Capture-MS), SLC4A2 (Affinity Capture-MS), SLC4A2 (Affinity Capture-MS), SLC4A2 (Affinity Capture-MS), SLC4A2 (Affinity Capture-MS), SLC4A2 (Affinity Capture-MS)

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

2 interactions.

A	Effect	B	Mechanism
EGR1	“up-regulates quantity by expression”	SLC4A2	“transcriptional regulation”
GAST	“up-regulates quantity by expression”	SLC4A2	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 135 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
Disorders of transmembrane transporters	5	8.7×	3e-03
Class A/1 (Rhodopsin-like receptors)	8	7.4×	6e-04
GPCR ligand binding	9	7.2×	4e-04
Peptide ligand-binding receptors	6	5.6×	6e-03
G alpha (q) signalling events	7	5.0×	5e-03
Signaling by GPCR	10	5.0×	1e-03
GPCR downstream signalling	8	4.3×	5e-03
G alpha (i) signalling events	8	3.9×	7e-03

GO biological processes:

GO term	Partners	Fold	FDR
adenylate cyclase-activating G protein-coupled receptor signaling pathway	8	7.8×	3e-03
G protein-coupled receptor signaling pathway	15	4.7×	6e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	1
Uncertain significance	167
Likely benign	10
Benign	2

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
2500827	NM_003040.4(SLC4A2):c.556G>A (p.Ala186Thr)	Pathogenic
2500828	NM_003040.4(SLC4A2):c.1658T>C (p.Val553Ala)	Pathogenic
1344708	NM_003040.4(SLC4A2):c.2107G>A (p.Ala703Thr)	Likely pathogenic

SpliceAI

4096 predictions. Top by Δscore:

Variant	Effect	Δscore
7:151064200:A:AG	acceptor_gain	1.0000
7:151064201:G:GG	acceptor_gain	1.0000
7:151064201:GCCA:G	acceptor_gain	1.0000
7:151064307:G:GT	donor_gain	1.0000
7:151064327:G:T	donor_gain	1.0000
7:151064328:G:GT	donor_gain	1.0000
7:151064345:C:G	donor_gain	1.0000
7:151064351:G:T	donor_gain	1.0000
7:151064352:G:GT	donor_gain	1.0000
7:151064352:G:T	donor_gain	1.0000
7:151064355:G:GT	donor_gain	1.0000
7:151064358:GACTT:G	donor_gain	1.0000
7:151064362:T:TG	donor_gain	1.0000
7:151064366:G:GG	donor_gain	1.0000
7:151064684:G:GT	donor_gain	1.0000
7:151064965:GG:G	donor_gain	1.0000
7:151064966:GG:G	donor_gain	1.0000
7:151066757:GAAGA:G	donor_gain	1.0000
7:151066758:AAGA:A	donor_gain	1.0000
7:151066759:AGA:A	donor_gain	1.0000
7:151066760:GA:G	donor_gain	1.0000
7:151066760:GAG:G	donor_gain	1.0000
7:151066761:AG:A	donor_loss	1.0000
7:151066762:G:GG	donor_gain	1.0000
7:151066762:GTAA:G	donor_loss	1.0000
7:151066845:CCACA:C	acceptor_loss	1.0000
7:151066846:CACA:C	acceptor_loss	1.0000
7:151066847:ACAGG:A	acceptor_loss	1.0000
7:151066848:CA:C	acceptor_loss	1.0000
7:151066849:A:AG	acceptor_gain	1.0000

AlphaMissense

8025 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:151067877:T:C	F324L	1.000
7:151067878:T:C	F324S	1.000
7:151067878:T:G	F324C	1.000
7:151067879:T:A	F324L	1.000
7:151067879:T:G	F324L	1.000
7:151067885:G:C	E326D	1.000
7:151067885:G:T	E326D	1.000
7:151067887:T:C	L327P	1.000
7:151067896:T:C	L330S	1.000
7:151067925:T:A	W340R	1.000
7:151067925:T:C	W340R	1.000
7:151067926:G:C	W340S	1.000
7:151067927:G:C	W340C	1.000
7:151067927:G:T	W340C	1.000
7:151067933:G:C	E342D	1.000
7:151067933:G:T	E342D	1.000
7:151067937:G:C	A344P	1.000
7:151067938:C:A	A344D	1.000
7:151067940:C:A	R345S	1.000
7:151067941:G:C	R345P	1.000
7:151067943:T:A	W346R	1.000
7:151067943:T:C	W346R	1.000
7:151067944:G:C	W346S	1.000
7:151067945:G:C	W346C	1.000
7:151067945:G:T	W346C	1.000
7:151067947:T:A	I347N	1.000
7:151067947:T:C	I347T	1.000
7:151067947:T:G	I347S	1.000
7:151067949:A:G	K348E	1.000
7:151067951:A:C	K348N	1.000

dbSNP variants (sampled 300 via entrez): RS1000067453 (7:151065662 C>T), RS1000073954 (7:151075978 G>A), RS1000098107 (7:151065841 A>C), RS1000537231 (7:151060112 C>A), RS1000608841 (7:151069455 G>A), RS1000913138 (7:151069617 G>A,C), RS1001033761 (7:151065830 A>G), RS1001064694 (7:151057383 G>A), RS1001152459 (7:151069573 T>C), RS1001318709 (7:151065674 T>C), RS1001323510 (7:151057711 G>A,C,T), RS1001705040 (7:151069294 C>T), RS1002017660 (7:151068217 G>A,C), RS1002043628 (7:151068137 C>T), RS1002431647 (7:151073545 A>G)

Disease associations

OMIM: gene MIM:109280 | disease phenotypes: MIM:620366

GenCC curated gene-disease

Disease	Classification	Inheritance
hereditary spherocytosis type 4	Strong	Autosomal dominant
osteopetrosis, autosomal recessive 9	Moderate	Autosomal recessive

Mondo (3): distal renal tubular acidosis (MONDO:0015827), osteopetrosis, autosomal recessive 9 (MONDO:0957262), hereditary spherocytosis type 4 (MONDO:0012981)

Orphanet (1): Distal renal tubular acidosis (Orphanet:18)

HPO phenotypes

16 total (17 of 16 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000843	Hyperparathyroidism
HP:0001085	Papilledema
HP:0001903	Anemia
HP:0002153	Hyperkalemia
HP:0002737	Thick skull base
HP:0002756	Pathologic fracture
HP:0003155	Elevated circulating alkaline phosphatase concentration
HP:0003259	Elevated circulating creatinine concentration
HP:0003581	Adult onset
HP:0005652	Cortical sclerosis
HP:0007663	Reduced visual acuity
HP:0008897	Postnatal growth retardation
HP:0011001	Increased bone mineral density
HP:0011002	Osteopetrosis
HP:0012625	Stage 3 chronic kidney disease
HP:0008341	Distal renal tubular acidosis

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST003476_9	Eyebrow thickness	7.000000e-06
GCST006979_220	Heel bone mineral density	4.000000e-20
GCST90002390_232	Mean corpuscular hemoglobin	2.000000e-09

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0009270	heel bone mineral density
EFO:0004527	mean corpuscular hemoglobin

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C567208	Spherocytosis, Type 4 (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 — Anion exchangers

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases abundance, increases expression, affects cotreatment, decreases expression	2
Air Pollutants	affects expression, increases abundance, decreases expression	2
Arsenic	affects cotreatment, decreases expression, increases abundance, increases expression, affects methylation	2
Valproic Acid	increases expression	2
aristolochic acid I	increases expression	1
glycoursodeoxycholic acid	affects cotreatment, increases expression	1
taurine-ursodeoxycholate conjugate	affects cotreatment, increases expression	1
boric acid	increases expression	1
di-n-butylphosphoric acid	affects expression	1
ICG 001	decreases expression	1
abrine	increases expression	1
bisphenol S	increases expression, affects reaction, decreases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	1
Temozolomide	decreases expression	1
Arsenic Trioxide	increases expression, increases stability	1
Benzo(a)pyrene	increases methylation	1
Bicarbonates	affects cotreatment, affects transport	1
Caffeine	affects phosphorylation	1
Chlorides	affects cotreatment, affects transport	1
Cisplatin	increases expression	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Dexamethasone	affects binding, increases reaction, affects cotreatment, increases expression, increases activity	1
Diazinon	increases methylation	1
Doxorubicin	decreases expression	1
Folic Acid	decreases expression	1
Ivermectin	decreases expression	1
Lipopolysaccharides	affects expression, affects response to substance	1
Ozone	affects expression, increases abundance	1
Ribonucleotides	affects binding	1
Silicon Dioxide	decreases expression	1

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D4PQ	HCT116-SLC4A2-KO-c3	Cancer cell line	Male
CVCL_D4PR	HCT116-SLC4A2-KO-c5	Cancer cell line	Male
CVCL_TN90	HAP1 SLC4A2 (-) 1	Cancer cell line	Male
CVCL_TN91	HAP1 SLC4A2 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03644706	PHASE3	TERMINATED	Study Evaluating Subjects With Distal Renal Tubular Acidosis