SLC12A2

Summary

SLC12A2 (solute carrier family 12 member 2, HGNC:10911) is a protein-coding gene on chromosome 5q23.3, encoding Solute carrier family 12 member 2 (P55011). Cation-chloride cotransporter which mediates the electroneutral transport of chloride, potassium and/or sodium ions across the membrane.

The protein encoded by this gene mediates sodium and chloride transport and reabsorption. The encoded protein is a membrane protein and is important in maintaining proper ionic balance and cell volume. This protein is phosphorylated in response to DNA damage. Three transcript variants encoding two different isoforms have been found for this gene.

Source: NCBI Gene 6558 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Kilquist syndrome (Strong, GenCC) — +5 more curated relationships
• GWAS associations: 18
• Clinical variants (ClinVar): 594 total — 15 pathogenic, 14 likely-pathogenic
• Phenotypes (HPO): 44
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001046

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10911
Approved symbol	SLC12A2
Name	solute carrier family 12 member 2
Location	5q23.3
Locus type	gene with protein product
Status	Approved
Aliases	NKCC1, BSC2, BSC-2, PPP1R141, CCC1
Ensembl gene	ENSG00000064651
Ensembl biotype	protein_coding
OMIM	600840
Entrez	6558

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 6 protein_coding, 3 retained_intron, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000262461, ENST00000343225, ENST00000502849, ENST00000504416, ENST00000507791, ENST00000509205, ENST00000509616, ENST00000628403, ENST00000929370, ENST00000941318, ENST00000941319

RefSeq mRNA: 2 — MANE Select: NM_001046 NM_001046, NM_001256461

CCDS: CCDS4144, CCDS58965

Canonical transcript exons

ENST00000262461 — 27 exons

Exon	Start	End
ENSE00000365795	128149997	128150098
ENSE00000365798	128158053	128158164
ENSE00000761687	128152706	128152805
ENSE00000761698	128151241	128151396
ENSE00000761771	128114586	128114681
ENSE00000761772	128114212	128114287
ENSE00000761773	128112814	128112933
ENSE00000972307	128134165	128134275
ENSE00000972308	128135700	128135808
ENSE00000972309	128138597	128138724
ENSE00000972310	128138824	128138908
ENSE00001082730	128141830	128141981
ENSE00001082738	128177105	128177152
ENSE00001130362	128171667	128171746
ENSE00001131812	128184366	128184501
ENSE00001131839	128174541	128174666
ENSE00001238230	128148754	128148877
ENSE00001238239	128147622	128147729
ENSE00001388478	128184789	128184856
ENSE00001757452	128131067	128131206
ENSE00001820020	128186496	128189677
ENSE00001952007	128083766	128084710
ENSE00003464212	128180883	128180994
ENSE00003507288	128167761	128167867
ENSE00003570292	128161660	128161800
ENSE00003574333	128182855	128182941
ENSE00003615172	128178567	128178689

Expression profiles

Bgee: expression breadth ubiquitous, 277 present calls, max score 98.85.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 31.4535 / max 759.8381, expressed in 1783 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
58351	29.3985	1766
58350	2.0550	1155

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
palpebral conjunctiva	UBERON:0001812	98.85	gold quality
parotid gland	UBERON:0001831	98.53	gold quality
inferior vagus X ganglion	UBERON:0005363	98.32	gold quality
upper leg skin	UBERON:0004262	98.20	gold quality
mucosa of sigmoid colon	UBERON:0004993	98.19	gold quality
eye	UBERON:0000970	97.76	gold quality
subthalamic nucleus	UBERON:0001906	97.66	gold quality
substantia nigra pars reticulata	UBERON:0001966	97.51	gold quality
corpus callosum	UBERON:0002336	97.39	gold quality
colonic mucosa	UBERON:0000317	97.35	gold quality
oocyte	CL:0000023	97.05	gold quality
lateral globus pallidus	UBERON:0002476	96.98	gold quality
globus pallidus	UBERON:0001875	96.82	gold quality
medial globus pallidus	UBERON:0002477	96.67	gold quality
sperm	CL:0000019	96.64	gold quality
substantia nigra pars compacta	UBERON:0001965	96.54	gold quality
ileal mucosa	UBERON:0000331	96.51	gold quality
rectum	UBERON:0001052	96.24	gold quality
pylorus	UBERON:0001166	96.23	gold quality
superior vestibular nucleus	UBERON:0007227	96.16	gold quality
gall bladder	UBERON:0002110	95.80	gold quality
secondary oocyte	CL:0000655	95.61	gold quality
pons	UBERON:0000988	95.61	gold quality
ventral tegmental area	UBERON:0002691	95.08	gold quality
urethra	UBERON:0000057	95.06	gold quality
cardia of stomach	UBERON:0001162	94.85	gold quality
trachea	UBERON:0003126	94.80	gold quality
trigeminal ganglion	UBERON:0001675	94.60	gold quality
duodenum	UBERON:0002114	94.22	gold quality
pigmented layer of retina	UBERON:0001782	93.86	gold quality

Single-cell (SCXA)

Detected in 12 experiment(s), a significant marker in 10.

Experiment	Marker?	Max mean expression
E-ANND-2	yes	2752.75
E-GEOD-130473	yes	764.48
E-MTAB-8410	yes	345.80
E-GEOD-125970	yes	26.16
E-MTAB-10553	yes	22.36
E-HCAD-1	yes	11.15
E-GEOD-84465	yes	10.38
E-CURD-114	yes	10.26
E-MTAB-10137	yes	4.40
E-MTAB-6379	no	905.29
E-GEOD-124858	no	267.61
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): DNMT1, FOXA2

miRNA regulators (miRDB)

257 targeting SLC12A2, 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-340-5P	100.00	72.50	4437
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821

Literature-anchored findings (GeneRIF, showing 40)

• intracellular Cl(-) (Cl) regulates the activity of protein kinase C (PKC)-delta and thus the activation of Na-K-Cl cotransport (PMID:11943682)
• NKCC1 was found in human HuH-7 hepatoma cells. The data suggest a role of NKCC1 in stellate cell transformation, hepatic volume regulation, and long-term adaption to dehydrating conditions. (PMID:12054469)
• most CFTR-positive ADPKD cysts also express NKCC1 suggests that transepithelial Cl(-) secretion in ADPKD involves molecular mechanisms similar to secretory epithelia. (PMID:12355171)
• all of the CCCs examined (NKCC1, NKCC2, KCC1, KCC3, and KCC4) can promote NH4(+) translocation, presumably through binding of the ion at the K(+) site (PMID:12657561)
• data conclusively link PASK with the phosphorylation and activation of NKCC1 (PMID:12740379)
• the stimulation of either luminal or basolateral P2R increased NKCC1 activity, which was observed in the basolateral membrane, but not in the luminal membrane (PMID:14982922)
• the uncovered interacting domains are probably a major determinant of the NKCC1 conformational landscape (PMID:15280386)
• Data indicate that binding of hsp90 to the Na(+)-K(+)-Cl(-) cotransporter (NKCC1) may be required for sodium-potassium-chloride cotransport to occur at the cell surface. (PMID:15347682)
• role of the complex of serine/threonine protein kinases and a protein phosphatase is probably the maintenance of optimal phosphorylation of NKCC1 coincident with its physiological function in epithelial absorption and secretion (PMID:15899883)
• Taken together, the results of the present study indicate that the signal transduction protein, controlled by the Na+/K+/Cl- cotransporter, must be downstream of the PKC, and at/or upstream to MEK in the Ras/Raf/MEK/ERK cascade. (PMID:16222701)
• NKCC1 transporter facilitates seizures in the developing brain. (PMID:16227993)
• persistent NKCC1 activation by cAMP is constrained by a Ca(2+)-dependent cycle of co-transporter internalization, degradation and re-expression; this is a novel mechanism to limit intestinal fluid loss. (PMID:17478539)
• Ammonium was transported on NKCC1 in T84 cells nearly as well as potassium (PMID:18032481)
• Reveal a novel role for the EGFR in the chronic regulation of epithelial secretory capacity through upregulation of NKCC1 expression. (PMID:18400987)
• PKCdelta acts upstream of SPAK to increase activity of NKCC1 during hyperosmotic stress (PMID:18550547)
• membrane rafts render KCC2 inactive and NKCC1 active (PMID:19686239)
• NKCC1 mRNA is expressed predominately in small- and medium-diameter primary afferent neurons,21 and the NKCC1 population of sensory neurons includes a large proportion that express TrpV1 and thus are presumably capsaicin-sensitive nociceptorscu (PMID:19916249)
• decreased NKCC1 may contribute to the feature of the pathogenesis of salt-sensitive hypertension seen in African Americans. (PMID:20044742)
• NKCC1 modulates blood pressure through vascular and renal effects–REVIEW (PMID:20061948)
• phosphorylation-induced activation of NKCC1 by osmotic shrinkage does not involve AMP-activated protein kinase and is likely to be due to STE20/SPS1-related proline/alanine-rich kinase activation (PMID:20442269)
• The result points at secretion as the main mechanism of cyst filling, and NKCC1 as the key candidate of fluid transport. (PMID:20471979)
• PKC{delta} and PKC{epsilon}-regulated NKCC1 surface expression plays an important role in the regulation of chloride secretion (PMID:20732874)
• The coupling between salt and water transport in NKCC1 represents a novel aspect of cellular water homeostasis where cells can change their volume independently of the direction of an osmotic gradient across the membrane. (PMID:20819947)
• In schizophrenia, increased expression levels of OXSR1 and WNK3 may shift the balance of chloride transport by NKCC1 and KCC2 and alter the nature of gamma-aminobutyric acid neurotransmission in the prefrontal cortex. (PMID:20819979)
• The Wnk3 protein isoforms have a similar effect on SLC12 cotransporters. NKCC1/2 and NCC were inhibited, even in hypertonicity, while KCCs were activated, even in isotonic conditions. (PMID:21613606)
• NKCC1 plays an important and yet partial role in RVI in C-20/A4 chondrocytes. (PMID:21847667)
• NKCC1 activation occurred through time-dependent increases in protein-protein interaction between ERK1/2 and NKCC1, which were proportional to EGF concentration (PMID:22178882)
• predictions of homology models of NKCC1 and demonstrate important roles for TM3 residues in ion translocation and loop diuretic inhibition. (PMID:22437837)
• NKCC1 deficiency increases the size of focal adhesions. (PMID:22570591)
• A significant association is found between single nucleotide polymophisms in SLC12A2 and CTXN3 and schizophrenia in a Thai population. (PMID:22643131)
• Data show that intracellular association between WNK1 and oxidative stress-responsive 1 (OSR1) is required for stimulation of OSR1 and Na(+), K(+), Cl(-)-Cotransporter NKCC1 and NKCC2 activities by osmotic stress. (PMID:22989884)
• Capsaicin inhibits chloride secretion in part by causing NKCC1 internalization, but by a mechanism that appears to be independent of TRPV1. (PMID:23139219)
• The rs10089 single nucleotide polymorphism was associated with increased susceptibility to noise-induced hearing loss. (PMID:23224734)
• These findings suggest that NKCC1 and AQP1 participate in meningioma biology and invasion (PMID:23317544)
• The results indicate a role for COMMD1 in the regulation of NKCC1 membrane expression and ubiquitination. (PMID:23515529)
• Reduced KCC2/NKCC1 ratio in the cerebrospinal fluid of Rett Syndrome patients suggests a disturbed process of GABAergic neuronal maturation and open up a new therapeutic perspective. (PMID:23894354)
• Altered hippocampal area function and coupling in DISC1 and SLC12A2 minor allele carriers. (PMID:23921125)
• The hormone aldosterone was found to upregulate NKCC1 by increasing protein stability. (PMID:24173102)
• Functional expression of human NKCC1 from a synthetic cassette-based cDNA: introduction of extracellular epitope tags and removal of cysteines. (PMID:24339991)
• NKCC activation involves movement of TM12 relative to TM10, which is likely tied to movement of the large C terminus (PMID:24451383)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio	slc12a2l	ENSDARG00000113045
mus_musculus	Slc12a2	ENSMUSG00000024597
rattus_norvegicus	Slc12a2	ENSRNOG00000015971
drosophila_melanogaster	CG10413	FBGN0032689
drosophila_melanogaster	Ncc69	FBGN0036279
drosophila_melanogaster	kcc	FBGN0261794
caenorhabditis_elegans		WBGENE00012543
caenorhabditis_elegans		WBGENE00019205
caenorhabditis_elegans		WBGENE00020207

Paralogs (8): SLC12A3 (ENSG00000070915), SLC12A1 (ENSG00000074803), SLC12A7 (ENSG00000113504), SLC12A4 (ENSG00000124067), SLC12A5 (ENSG00000124140), SLC12A6 (ENSG00000140199), SLC12A9 (ENSG00000146828), SLC12A8 (ENSG00000221955)

Protein

Protein identifiers

Solute carrier family 12 member 2 — P55011 (reviewed: P55011)

Alternative names: Basolateral Na-K-Cl symporter, Bumetanide-sensitive sodium-(potassium)-chloride cotransporter 2, Na-K-2Cl cotransporter 1

All UniProt accessions (3): P55011, G3XAL9, Q53ZR1

UniProt curated annotations — full annotation on UniProt →

Function. Cation-chloride cotransporter which mediates the electroneutral transport of chloride, potassium and/or sodium ions across the membrane. Plays a vital role in the regulation of ionic balance and cell volume.

Subunit / interactions. Homodimer; adopts a domain-swap conformation at the scissor helices connecting the transmembrane domain and C-terminal domain.

Subcellular location. Basolateral cell membrane.

Tissue specificity. Expressed in many tissues.

Post-translational modifications. Phosphorylated at Thr-203, Thr-207 and Thr-212 by OXSR1/OSR1 and STK39/SPAK downstream of WNK kinases (WNK1, WNK2, WNK3 or WNK4), promoting its activity.

Disease relevance. Deafness, autosomal dominant, 78 (DFNA78) [MIM:619081] A form of non-syndromic deafness characterized by congenital, profound bilateral sensorineural hearing loss affecting all frequencies. Some patients may have mild motor delay early in life due to vestibular dysfunction. Sensorineural hearing loss results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. The disease is caused by variants affecting the gene represented in this entry. Delpire-McNeill syndrome (DELMNES) [MIM:619083] An autosomal dominant neurodevelopmental disorder characterized by global developmental delay, hypotonia with delayed or absent walking, bilateral sensorineural deafness, poor or absent speech, and mild to severe intellectual disability. Additional variable features may include spasticity or minor involvement of other organ systems, such as hip dislocation or ventricular septal defect. The disease is caused by variants affecting the gene represented in this entry. Kilquist syndrome (KILQS) [MIM:619080] An autosomal recessive, multisystem disorder characterized by severe global developmental delay, sensorineural hearing loss, poor overall growth, mild facial dysmorphism, gastrointestinal anomalies such as gastroesophageal reflux or midgut malrotation, and a striking lack of tear fluid, saliva, and sweat. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Activated following phosphorylation by OXSR1/OSR1 and STK39/SPAK downstream of WNK kinases (WNK1, WNK2, WNK3 or WNK4). Inhibited by bumetanide. Inhibited by furosemide.

Domain organisation. The RFXV motifs mediate binding with OXSR1/OSR1 and STK39/SPAK.

Similarity. Belongs to the SLC12A transporter family.

Isoforms (2)

UniProt ID	Names	Canonical?
P55011-1	1	yes
P55011-3	2

RefSeq proteins (2): NP_001037, NP_001243390 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002443	SLC12A1/SLC12A2	Family
IPR002444	NKCC1	Family
IPR004841	AA-permease/SLC12A_dom	Domain
IPR004842	SLC12A_fam	Family
IPR013612	AA_permease_N	Domain
IPR018491	SLC12_C	Domain

Pfam: PF00324, PF03522, PF08403

Catalyzed reactions (Rhea), 1 shown:

• K(+)(out) + 2 chloride(out) + Na(+)(out) = K(+)(in) + 2 chloride(in) + Na(+)(in) (RHEA:72395)

UniProt features (226 total): mutagenesis site 64, helix 41, strand 27, binding site 21, turn 13, modified residue 13, transmembrane region 12, topological domain 10, sequence variant 9, region of interest 5, compositionally biased region 3, short sequence motif 2, glycosylation site 2, disulfide bond 2, chain 1, splice variant 1

Structure

Experimental structures (PDB)

14 structures.

PDB	Method	Resolution (Å)
9C0H	ELECTRON MICROSCOPY	2.5
7ZGO	ELECTRON MICROSCOPY	2.55
9C0G	ELECTRON MICROSCOPY	2.6
9C0E	ELECTRON MICROSCOPY	2.7
7S1X	ELECTRON MICROSCOPY	2.9
7SMP	ELECTRON MICROSCOPY	3.28
7S1Z	ELECTRON MICROSCOPY	3.3
7N3N	ELECTRON MICROSCOPY	3.33
8STE	ELECTRON MICROSCOPY	3.34
6PZT	ELECTRON MICROSCOPY	3.46
7MXO	ELECTRON MICROSCOPY	3.47
7D10	ELECTRON MICROSCOPY	3.52
7S1Y	ELECTRON MICROSCOPY	3.6
7SFL	ELECTRON MICROSCOPY	3.87

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P55011-F1	74.23	0.40

Functional residue map

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

Ligand- & substrate-binding residues (21): 297; 298; 299; 300; 301; 302; 303; 372; 383; 496; 496; 497 …

Post-translational modifications (13): 1, 77, 79, 203, 207, 212, 217, 230, 242, 266, 940, 944, 994

Disulfide bonds (2): 563–568, 577–582

Glycosylation sites (2): 553, 562

Mutagenesis-validated functional residues (64):

Position	Phenotype
301	impairs transporter activity.
307	abolished cation-chloride cotransporter activity.
358	strongly reduced cation-chloride cotransporter activity.
383	impairs transporter activity.
389	strongly reduced cation-chloride cotransporter activity.
429	impairs transporter activity.
431	impairs transporter activity.
486	strongly reduced cation-chloride cotransporter activity.
487	impairs transporter activity.
487	does not affect cation-chloride cotransporter activity.
488	slighly reduced cation-chloride cotransporter activity.
489	slighly reduced cation-chloride cotransporter activity.
490	strongly reduced cation-chloride cotransporter activity.
491	reduced cation-chloride cotransporter activity.
492	reduced cation-chloride cotransporter activity.
492	active at elevated intracellular chloride concentrations that are inhibitory to wild-type. impairs transporter activity.
493	reduced cation-chloride cotransporter activity.
494	reduced cation-chloride cotransporter activity.
495	reduced cation-chloride cotransporter activity.
497	strongly reduced cation-chloride cotransporter activity.
498	strongly reduced cation-chloride cotransporter activity.
499	strongly reduced cation-chloride cotransporter activity.
500	strongly reduced cation-chloride cotransporter activity.
501	strongly reduced cation-chloride cotransporter activity.
502	strongly reduced cation-chloride cotransporter activity.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-426117	Cation-coupled Chloride cotransporters
R-HSA-382551	Transport of small molecules
R-HSA-425393
R-HSA-425407	SLC-mediated transmembrane transport

MSigDB gene sets: 586 (showing top): GOBP_POTASSIUM_ION_TRANSPORT, CREL_01, GOBP_REGULATION_OF_WOUND_HEALING, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_CELL_CHEMOTAXIS, GOBP_REGULATION_OF_ORGANIC_ACID_TRANSPORT, SWEET_KRAS_ONCOGENIC_SIGNATURE, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_RESPONSE_TO_PEPTIDE, GOBP_SODIUM_ION_TRANSMEMBRANE_TRANSPORT, GOZGIT_ESR1_TARGETS_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_RESPONSE_TO_POTASSIUM_ION, MCBRYAN_PUBERTAL_TGFB1_TARGETS_DN, GOBP_POTASSIUM_ION_HOMEOSTASIS

GO Biological Process (34): monoatomic ion transport (GO:0006811), intracellular sodium ion homeostasis (GO:0006883), cell volume homeostasis (GO:0006884), hyperosmotic response (GO:0006972), gamma-aminobutyric acid signaling pathway (GO:0007214), T cell chemotaxis (GO:0010818), intracellular potassium ion homeostasis (GO:0030007), transepithelial chloride transport (GO:0030321), intracellular chloride ion homeostasis (GO:0030644), maintenance of blood-brain barrier (GO:0035633), sodium ion transmembrane transport (GO:0035725), cellular response to potassium ion (GO:0035865), positive regulation of cell volume (GO:0045795), chloride ion homeostasis (GO:0055064), potassium ion homeostasis (GO:0055075), sodium ion homeostasis (GO:0055078), negative regulation of vascular wound healing (GO:0061044), transepithelial ammonium transport (GO:0070634), ammonium transmembrane transport (GO:0072488), inorganic anion import across plasma membrane (GO:0098658), inorganic cation import across plasma membrane (GO:0098659), sodium ion import across plasma membrane (GO:0098719), regulation of spontaneous synaptic transmission (GO:0150003), transport across blood-brain barrier (GO:0150104), chloride transmembrane transport (GO:1902476), positive regulation of aspartate secretion (GO:1904450), regulation of matrix metallopeptidase secretion (GO:1904464), potassium ion import across plasma membrane (GO:1990573), cellular response to chemokine (GO:1990869), potassium ion transport (GO:0006813), sodium ion transport (GO:0006814), chloride transport (GO:0006821), transmembrane transport (GO:0055085), potassium ion transmembrane transport (GO:0071805)

GO Molecular Function (11): sodium:potassium:chloride symporter activity (GO:0008511), ammonium channel activity (GO:0008519), potassium ion transmembrane transporter activity (GO:0015079), chloride:monoatomic cation symporter activity (GO:0015377), protein kinase binding (GO:0019901), metal ion transmembrane transporter activity (GO:0046873), protein-folding chaperone binding (GO:0051087), Hsp90 protein binding (GO:0051879), protein binding (GO:0005515), symporter activity (GO:0015293), transmembrane transporter activity (GO:0022857)

GO Cellular Component (16): plasma membrane (GO:0005886), basal plasma membrane (GO:0009925), membrane (GO:0016020), basolateral plasma membrane (GO:0016323), apical plasma membrane (GO:0016324), lateral plasma membrane (GO:0016328), cytoplasmic vesicle membrane (GO:0030659), cell projection membrane (GO:0031253), cell projection (GO:0042995), neuron projection (GO:0043005), neuronal cell body (GO:0043025), cell body (GO:0044297), cell body membrane (GO:0044298), extracellular exosome (GO:0070062), cell periphery (GO:0071944), extracellular vesicle (GO:1903561)

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
cellular anatomical structure	6
plasma membrane region	4
inorganic ion homeostasis	3
intracellular monoatomic cation homeostasis	2
transepithelial transport	2
monoatomic cation homeostasis	2
nitrogen compound transport	2
transmembrane transport	2
plasma membrane	2
plasma membrane bounded cell projection	2
cell body	2
transport	1
sodium ion homeostasis	1
regulation of cell size	1
cellular homeostasis	1
response to osmotic stress	1
cell-cell signaling	1
GABA receptor activity	1
lymphocyte chemotaxis	1
T cell migration	1
potassium ion homeostasis	1
chloride transport	1
intracellular monoatomic anion homeostasis	1
chloride ion homeostasis	1
tissue homeostasis	1
sodium ion transport	1
monoatomic cation transmembrane transport	1
response to potassium ion	1
cellular response to metal ion	1
cell volume homeostasis	1
monoatomic anion homeostasis	1
negative regulation of angiogenesis	1
vascular wound healing	1
regulation of vascular wound healing	1
negative regulation of wound healing	1
inorganic anion transport	1
inorganic ion import across plasma membrane	1
potassium:sodium symporter activity	1
sodium:chloride symporter activity	1
potassium:chloride symporter activity	1

Protein interactions and networks

STRING

2048 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SLC12A2	STK39	Q9UEW8	918
SLC12A2	SLC4A2	P04920	909
SLC12A2	WNK3	Q9BYP7	905
SLC12A2	WNK4	Q96J92	871
SLC12A2	WNK1	P54963	870
SLC12A2	OXSR1	O95747	844
SLC12A2	CFTR	P13569	804
SLC12A2	PSKH1	P11801	767
SLC12A2	MARVELD2	Q8N4S9	732
SLC12A2	SLC4A7	Q9Y6M7	678
SLC12A2	SLC4A4	Q9Y6R1	677
SLC12A2	SLC30A5	Q8TAD4	676
SLC12A2	WNK2	Q9Y3S1	670
SLC12A2	STK24	Q9Y6E0	664
SLC12A2	SLC9A1	P19634	637

IntAct

113 interactions, top by confidence:

A	B	Type	Score
CD9	ADAM10	psi-mi:“MI:0914”(association)	0.750
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
SLC12A2	CLGN	psi-mi:“MI:0914”(association)	0.640
PDGFRB	PIK3R2	psi-mi:“MI:0914”(association)	0.610
SLC12A2	EZR	psi-mi:“MI:0915”(physical association)	0.590
EZR	SLC12A2	psi-mi:“MI:0915”(physical association)	0.590
CANX	PGRMC1	psi-mi:“MI:0914”(association)	0.570
ILK	HAX1	psi-mi:“MI:0914”(association)	0.530
ARRDC4	WWP2	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
PTGIR	TMEM63A	psi-mi:“MI:0914”(association)	0.530
APLNR	SLC33A1	psi-mi:“MI:0914”(association)	0.530
SIDT2	AP3D1	psi-mi:“MI:0914”(association)	0.530
DLK1	SCAMP3	psi-mi:“MI:0914”(association)	0.530
LPAR1	TMEM223	psi-mi:“MI:0914”(association)	0.530
NRAS	ESYT2	psi-mi:“MI:2364”(proximity)	0.480
pipB2	SCD	psi-mi:“MI:0914”(association)	0.460
SLC12A2	SFPQ	psi-mi:“MI:0915”(physical association)	0.400
OXSR1	SLC12A2	psi-mi:“MI:0915”(physical association)	0.400
SLC12A2	OXSR1	psi-mi:“MI:0915”(physical association)	0.400
ESR1	ESYT2	psi-mi:“MI:0914”(association)	0.350
LRRK2		psi-mi:“MI:0914”(association)	0.350
PA	ESYT2	psi-mi:“MI:0914”(association)	0.350

BioGRID (300): SLC12A2 (Affinity Capture-MS), SLC12A2 (Affinity Capture-MS), SLC12A2 (Affinity Capture-MS), SLC12A2 (Affinity Capture-MS), SLC12A2 (Affinity Capture-MS), SLC12A2 (Affinity Capture-MS), SLC12A2 (Affinity Capture-MS), SLC12A2 (Affinity Capture-MS), SLC12A2 (Affinity Capture-MS), SLC12A2 (Affinity Capture-MS), SLC12A2 (Affinity Capture-MS), SLC12A2 (Affinity Capture-MS), GNG12 (Co-fractionation), SLC12A2 (Proximity Label-MS), SLC12A2 (Proximity Label-MS)

ESM2 similar proteins: A0A0G2KTI4, A0A0J9UR41, A2QHC2, A2QNG6, A2R0Z5, E9E1W3, E9EDR6, E9EE69, F1Q749, G2WY98, G2XEK6, G4MVT6, G4N1B2, H6C2T9, H6C4I7, I1S097, I1S0T9, O48538, P29070, P30583, P30588, P30601, P30602, P31596, P32481, P43004, P43006, P49283, P54267, P55011, P55012, P55013, P55014, P55015, P55016, P55017, P55018, P58421, P59158, Q12564

Diamond homologs: A0A0G2KTI4, A0AV02, A2BFP5, P38329, P55011, P55012, P55013, P55014, P55015, P55016, P55017, P55018, P55019, P59158, Q13621, Q25479, Q6A4L1, Q8CJI3, Q8VI23, Q9BXP2, O60146, Q2UVJ5, Q657W3, Q66HR0, Q99MR3, Q0VGW6, Q28677, Q63632, Q924N4, Q9JIS8, Q9UP95, Q6Z0E2

SIGNOR signaling

11 interactions.

A	Effect	B	Mechanism
OXSR1	up-regulates	SLC12A2	phosphorylation
SLC12A2	“up-regulates quantity”	chloride	relocalization
WNK1	“up-regulates activity”	SLC12A2	phosphorylation
WNK3	“up-regulates activity”	SLC12A2	phosphorylation
SLC12A2	“up-regulates quantity”	chloride	phosphorylation
STK39	“up-regulates activity”	SLC12A2	phosphorylation
AMPK	“down-regulates activity”	SLC12A2	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 128 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
Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants	5	29.8×	9e-05
Downstream signal transduction	5	21.9×	2e-04
DAP12 signaling	5	21.2×	2e-04
EPH-ephrin mediated repulsion of cells	6	15.2×	2e-04
Signaling by SCF-KIT	5	14.3×	7e-04
EPH-Ephrin signaling	7	13.3×	1e-04

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	15
Likely pathogenic	14
Uncertain significance	324
Likely benign	156
Benign	35

Top pathogenic / likely-pathogenic (29)

Variant ID	HGVS	Classification
2133915	NM_001046.3(SLC12A2):c.2371_2372insTAAATTAGGCCACT (p.Cys791delinsLeuAsnTer)	Pathogenic
2859777	NM_001046.3(SLC12A2):c.2935G>T (p.Glu979Ter)	Pathogenic
3033879	NM_001046.3(SLC12A2):c.1228C>T (p.Arg410Ter)	Pathogenic
3064190	NM_001046.3(SLC12A2):c.2617-2A>G	Pathogenic
617506	Single allele	Pathogenic
804310	NM_001046.3(SLC12A2):c.2935G>A (p.Glu979Lys)	Pathogenic
972899	NM_001046.3(SLC12A2):c.2962C>T (p.Pro988Ser)	Pathogenic
984662	NM_001046.3(SLC12A2):c.1431del (p.Phe477fs)	Pathogenic
984663	NM_001046.3(SLC12A2):c.2006-1G>A	Pathogenic
984668	NM_001046.3(SLC12A2):c.2938G>A (p.Glu980Lys)	Pathogenic
984669	NM_001046.3(SLC12A2):c.980C>T (p.Ala327Val)	Pathogenic
984670	NM_001046.3(SLC12A2):c.2675G>A (p.Trp892Ter)	Pathogenic
984671	NM_001046.3(SLC12A2):c.1127A>T (p.Asn376Ile)	Pathogenic
984672	NM_001046.3(SLC12A2):c.555dup (p.His186fs)	Pathogenic
984673	NC_000005.9:g.127441491_127471419delinsATGAAAAGCTTTACAGAAGTTGGAATTAAAAAAA	Pathogenic
1027650	NM_001046.3(SLC12A2):c.2016_2017insTAA (p.Val673Ter)	Likely pathogenic
1690481	NM_001046.3(SLC12A2):c.1059T>G (p.Tyr353Ter)	Likely pathogenic
1704394	NM_001046.3(SLC12A2):c.2476-1G>C	Likely pathogenic
2503954	NM_001046.3(SLC12A2):c.1279G>T (p.Gly427Ter)	Likely pathogenic
267304	NM_001046.3(SLC12A2):c.3076_3086del (p.Val1026fs)	Likely pathogenic
3064984	NM_001046.3(SLC12A2):c.959C>A (p.Ser320Ter)	Likely pathogenic
3601712	NM_001046.3(SLC12A2):c.1881+2T>C	Likely pathogenic
3601713	NM_001046.3(SLC12A2):c.2959C>T (p.Gln987Ter)	Likely pathogenic
3601714	NM_001046.3(SLC12A2):c.2977+1G>A	Likely pathogenic
3601715	NM_001046.3(SLC12A2):c.541G>T (p.Glu181Ter)	Likely pathogenic
3780607	NM_001046.3(SLC12A2):c.3147G>A (p.Trp1049Ter)	Likely pathogenic
3894582	NM_001046.3(SLC12A2):c.352dup (p.Ala118fs)	Likely pathogenic
3896581	NM_001046.3(SLC12A2):c.3100+2T>C	Likely pathogenic
4292146	NM_001046.3(SLC12A2):c.2160_2163dup (p.Leu722fs)	Likely pathogenic

SpliceAI

4039 predictions. Top by Δscore:

Variant	Effect	Δscore
5:128084708:AAGGT:A	donor_loss	1.0000
5:128084709:AGG:A	donor_loss	1.0000
5:128084711:GT:G	donor_loss	1.0000
5:128112807:T:G	acceptor_gain	1.0000
5:128112808:A:AG	acceptor_gain	1.0000
5:128112809:A:G	acceptor_gain	1.0000
5:128112812:A:AC	acceptor_loss	1.0000
5:128112812:A:AG	acceptor_gain	1.0000
5:128112812:AG:A	acceptor_gain	1.0000
5:128112813:G:GC	acceptor_gain	1.0000
5:128112813:GG:G	acceptor_gain	1.0000
5:128112813:GGA:G	acceptor_gain	1.0000
5:128112813:GGAA:G	acceptor_gain	1.0000
5:128112813:GGAAC:G	acceptor_gain	1.0000
5:128112889:GAAA:G	donor_gain	1.0000
5:128112890:A:T	donor_gain	1.0000
5:128112902:TCGTG:T	donor_gain	1.0000
5:128112906:G:GT	donor_gain	1.0000
5:128112924:GGGT:G	donor_gain	1.0000
5:128112925:G:GT	donor_gain	1.0000
5:128112930:ATTAG:A	donor_loss	1.0000
5:128112932:TAG:T	donor_loss	1.0000
5:128112934:GTAT:G	donor_gain	1.0000
5:128112935:T:G	donor_loss	1.0000
5:128113402:T:G	donor_gain	1.0000
5:128114579:C:CA	acceptor_gain	1.0000
5:128114581:TAAA:T	acceptor_loss	1.0000
5:128114582:A:AG	acceptor_gain	1.0000
5:128114582:AAAG:A	acceptor_gain	1.0000
5:128114583:A:G	acceptor_gain	1.0000

AlphaMissense

7907 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:128084619:C:A	P222H	1.000
5:128112916:T:A	W287R	1.000
5:128112916:T:C	W287R	1.000
5:128112925:G:C	G290R	1.000
5:128114220:T:G	C295W	1.000
5:128114229:C:A	N298K	1.000
5:128114229:C:G	N298K	1.000
5:128114236:G:C	G301R	1.000
5:128114236:G:T	G301C	1.000
5:128114255:G:C	R307T	1.000
5:128114634:C:A	T334K	1.000
5:128114634:C:T	T334I	1.000
5:128114636:G:A	G335R	1.000
5:128114636:G:C	G335R	1.000
5:128114637:G:A	G335E	1.000
5:128114643:C:A	S337Y	1.000
5:128114643:C:T	S337F	1.000
5:128114652:C:A	A340E	1.000
5:128114655:T:A	I341K	1.000
5:128114655:T:G	I341R	1.000
5:128114661:C:T	T343I	1.000
5:128114664:A:T	N344I	1.000
5:128114665:T:A	N344K	1.000
5:128114665:T:G	N344K	1.000
5:128114666:G:A	G345R	1.000
5:128114666:G:C	G345R	1.000
5:128114667:G:A	G345E	1.000
5:128114667:G:T	G345V	1.000
5:128114681:G:A	G350R	1.000
5:128114681:G:C	G350R	1.000

dbSNP variants (sampled 300 via entrez): RS1000010066 (5:128139045 A>T), RS1000032081 (5:128166693 T>C), RS1000076609 (5:128140355 A>T), RS1000083888 (5:128166462 GTGTGTGTGTGTGTGTGTGTT>G), RS1000087188 (5:128097861 G>C), RS1000088043 (5:128148161 A>G), RS1000165654 (5:128145162 T>G), RS1000171140 (5:128186287 A>G), RS1000190889 (5:128104023 C>A,G,T), RS1000280186 (5:128109647 A>G), RS1000300255 (5:128188636 C>G), RS1000301215 (5:128144853 C>T), RS1000341869 (5:128180125 A>G), RS1000378167 (5:128158399 G>T), RS1000380192 (5:128097171 G>T)

Disease associations

OMIM: gene MIM:600840 | disease phenotypes: MIM:619080, MIM:619081, MIM:619083

GenCC curated gene-disease

Disease	Classification	Inheritance
Kilquist syndrome	Strong	Autosomal recessive
hearing loss, autosomal dominant 78	Strong	Autosomal dominant
Delpire-McNeill syndrome	Strong	Autosomal dominant
syndromic intellectual disability	Supportive	Autosomal dominant
autosomal recessive non-syndromic intellectual disability	Supportive	Autosomal recessive
schizophrenia	No Known Disease Relationship	Unknown

Mondo (10): Kilquist syndrome (MONDO:0033664), hearing loss, autosomal dominant 78 (MONDO:0033665), Delpire-McNeill syndrome (MONDO:0033667), intellectual disability (MONDO:0001071), breast ductal adenocarcinoma (MONDO:0005590), autism spectrum disorder (MONDO:0005258), sensorineural hearing loss disorder (MONDO:0020678), schizophrenia (MONDO:0005090), syndromic intellectual disability (MONDO:0000508), autosomal recessive non-syndromic intellectual disability (MONDO:0019502)

Orphanet (4): SLC12A2-related autosomal recessive neonatal-developmental delay-intellectual disability-feeding difficulty-sensorineural deafness syndrome (Orphanet:633021), SLC12A2-related autosomal dominant infantile-developmental delay-intellectual disability-sensorineural deafness syndrome (Orphanet:633024), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658), NON RARE IN EUROPE: Autism (Orphanet:106)

HPO phenotypes

44 total (30 of 44 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000154	Wide mouth
HP:0000217	Xerostomia
HP:0000256	Macrocephaly
HP:0000303	Mandibular prognathia
HP:0000341	Narrow forehead
HP:0000369	Low-set ears
HP:0000402	Stenosis of the external auditory canal
HP:0000453	Choanal atresia
HP:0000522	Alacrima
HP:0000685	Hypoplasia of teeth
HP:0000729	Autistic behavior
HP:0000750	Delayed speech and language development
HP:0000768	Pectus carinatum
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001270	Motor delay
HP:0001274	Agenesis of corpus callosum
HP:0001276	Hypertonia
HP:0001290	Generalized hypotonia
HP:0001344	Absent speech
HP:0001347	Hyperreflexia
HP:0001629	Ventricular septal defect
HP:0002015	Dysphagia
HP:0002020	Gastroesophageal reflux
HP:0002539	Cortical dysplasia
HP:0002566	Intestinal malrotation
HP:0002575	Tracheoesophageal fistula
HP:0002673	Coxa valga

GWAS associations

18 associations (top):

Study	Trait	p-value
GCST000271_1	Brain imaging in schizophrenia (dorsolateral prefrontal cortex interaction)	9.000000e-08
GCST000908_3	Ileal carcinoids	2.000000e-06
GCST002647_125	Height	1.000000e-09
GCST003475_8	Beard thickness	1.000000e-06
GCST006804_12	Red cell distribution width	2.000000e-138
GCST007293_104	Body fat distribution (arm fat ratio)	2.000000e-06
GCST007293_144	Body fat distribution (arm fat ratio)	6.000000e-18
GCST007293_47	Body fat distribution (arm fat ratio)	2.000000e-38
GCST007294_113	Body fat distribution (trunk fat ratio)	7.000000e-06
GCST007295_23	Body fat distribution (leg fat ratio)	1.000000e-22
GCST007295_62	Body fat distribution (leg fat ratio)	7.000000e-16
GCST008552_1	Statin-induced myopathy	5.000000e-06
GCST008839_383	Height	3.000000e-10
GCST010174_10	Pelvic organ prolapse	1.000000e-06
GCST010241_138	Apolipoprotein A1 levels	4.000000e-22
GCST010242_319	HDL cholesterol levels	8.000000e-14
GCST012227_183	Hip circumference adjusted for BMI	4.000000e-08
GCST90002387_308	Immature fraction of reticulocytes	4.000000e-27

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0009188	Red cell distribution width
EFO:0004341	body fat distribution
EFO:0004614	apolipoprotein A 1 measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0008039	BMI-adjusted hip circumference

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D018270	Carcinoma, Ductal, Breast	C04.557.470.200.025.232.500; C04.557.470.615.132.500; C04.588.180.390; C17.800.090.500.390
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL1615383 (SINGLE PROTEIN), CHEMBL3885641 (PROTEIN COMPLEX)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 22,087 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1072	BUMETANIDE	4	22,087

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: transporter — SLC12 family of cation-coupled chloride transporters

Most potent curated ligand interactions (3 total), top 3:

Ligand	Action	Affinity	Parameter
piretanide	Inhibition	5.62	pIC50
bumetanide	Inhibition	5.6	pIC50
furosemide	Inhibition	5.13	pIC50

ChEMBL bioactivities

19 potent at pChembl≥5 of 26 total, top 19 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.62	IC50	240	nM	CHEMBL4100485
6.52	IC50	300	nM	CHEMBL1448067
6.25	IC50	560	nM	CHEMBL1491962
6.19	IC50	640	nM	CHEMBL1334636
5.92	IC50	1200	nM	CHEMBL1332312
5.89	IC50	1300	nM	CHEMBL1492301
5.82	IC50	1500	nM	CHEMBL1373514
5.81	IC50	1540	nM	BUMETANIDE
5.80	IC50	1600	nM	CHEMBL1360609
5.66	IC50	2200	nM	CHEMBL1489121
5.60	IC50	2500	nM	CHEMBL1561213
5.55	Kd	2843	nM	CHEMBL5653589
5.55	ED50	2843	nM	CHEMBL5653589
5.54	IC50	2900	nM	CHEMBL1344797
5.29	IC50	5100	nM	CHEMBL1414895
5.22	IC50	6000	nM	CHEMBL1414260
5.11	IC50	7700	nM	CHEMBL1331068
5.10	IC50	7900	nM	CHEMBL1331422
5.04	IC50	9100	nM	CHEMBL1449947

PubChem BioAssay actives

3 with measured affinity, of 78 total; 3 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
[2-[(4-chlorophenyl)methoxy]phenyl]-[5-[2-(methylamino)-1,3-thiazol-4-yl]-2,3-dihydroindol-1-yl]methanone	1928689: Inhibition of NKCC1 in human HT-29 cells assessed as inhibition of rubidium uptake incubated for 20 min by atomic absorption spectroscopy	ic50	0.2400	uM
Bumetanide	1928689: Inhibition of NKCC1 in human HT-29 cells assessed as inhibition of rubidium uptake incubated for 20 min by atomic absorption spectroscopy	ic50	1.5400	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149400: Binding affinity to human SLC12A2 incubated for 45 mins by Kinobead based pull down assay	kd	2.8425	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, decreases methylation, affects cotreatment, increases expression	5
Acetaminophen	affects cotreatment, affects expression, increases expression	4
Estradiol	affects cotreatment, increases expression, decreases expression	3
sodium arsenite	decreases expression, increases abundance, increases expression	2
Nickel	decreases expression	2
Quercetin	decreases expression, increases activity	2
Cyclosporine	decreases expression, affects cotreatment	2
Aflatoxin B1	decreases methylation, increases expression	2
Genistein	decreases expression	2
FR900359	decreases phosphorylation	1
daidzein	decreases expression	1
triphenyl phosphate	affects expression	1
beta-lapachone	decreases expression	1
piretanide	decreases reaction, increases uptake, decreases activity	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cobaltous chloride	decreases expression	1
azosemide	decreases reaction, increases uptake, decreases activity	1
butyraldehyde	decreases expression	1
nickel chloride	increases expression	1
nonylphenol	decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, decreases expression	1
fasudil	increases expression	1
glycitein	decreases expression	1
CGP 52608	affects binding, increases reaction	1
Y 27632	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	1
nutlin 3	affects cotreatment, increases secretion	1
abrine	decreases expression	1
dorsomorphin	increases expression, affects cotreatment	1
jinfukang	decreases expression	1

ChEMBL screening assays

13 unique, capped per target: 9 binding, 4 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2049731	Functional	Antagonist activity at NKKC1 expressed in human HEK293 cells assessed as [86Rb] uptake up to 100 uM after 30 mins by scintillation counting	Further optimization of the K-Cl cotransporter KCC2 antagonist ML077: development of a highly selective and more potent in vitro probe. — Bioorg Med Chem Lett
CHEMBL3998798	Binding	Inhibition of NKCC1 in human primary bronchial epithelial cells assessed as effect on short-circuit current at 10 uM after 10 mins by voltage clamp method	Nanomolar-Potency Aminophenyl-1,3,5-triazine Activators of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Chloride Channel for Prosecretory Therapy of Dry Eye Diseases. — J Med Chem

Cellosaurus cell lines

7 cell lines: 5 cancer cell line, 2 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D4DF	HEK-SLC12A2-KO-c10	Transformed cell line	Female
CVCL_D4DG	HEK-SLC12A2-KO-c5	Transformed cell line	Female
CVCL_D4V8	LS180-SLC12A2-KO-c11	Cancer cell line	Female
CVCL_D4V9	LS180-SLC12A2-KO-c9	Cancer cell line	Female
CVCL_TL47	HAP1 SLC12A2 (-) 4	Cancer cell line	Male
CVCL_TL48	HAP1 SLC12A2 (-) 5	Cancer cell line	Male
CVCL_TL49	HAP1 SLC12A2 (-) 6	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00000374	PHASE4	COMPLETED	Treatment for First-Episode Schizophrenia
NCT00001656	PHASE4	COMPLETED	Comparison of Clozapine vs Olanzapine in Childhood-Onset Psychotic Disorders
NCT00007774	PHASE4	COMPLETED	To Determine if Olanzapine is More Cost Effective Than Haloperidol for the Treatment of Schizophrenia
NCT00014001	PHASE4	COMPLETED	CATIE- Schizophrenia Trial
NCT00018668	PHASE4	COMPLETED	Antipsychotic Response in Schizophrenia
NCT00034801	PHASE4	COMPLETED	Olanzapine Versus Active Comparator in the Treatment of Depression in Patients With Schizophrenia
NCT00034905	PHASE4	COMPLETED	A Comparison of Seroquel vs. Risperidone in Schizophrenia
NCT00036088	PHASE4	COMPLETED	Olanzapine Versus An Active Comparator in the Treatment of Schizophrenia
NCT00044187	PHASE4	COMPLETED	The Assessment of a Weight-Gain Agent for the Treatment of Olanzapine-Associated Anti-Obesity Agent in Patients With Schizophrenia, Schizophreniform Disorder, Schizoaffective Disorder, and Bipolar I Disorder
NCT00044655	PHASE4	COMPLETED	Switching Medication to Treat Schizophrenia
NCT00048828	PHASE4	COMPLETED	Treating Drug-Resistant Childhood Schizophrenia
NCT00053703	PHASE4	COMPLETED	Treatment of Early Onset Schizophrenia Spectrum Disorders (TEOSS)
NCT00056498	PHASE4	COMPLETED	Risperidone Treatment in Schizophrenia Patients Who Are Currently Taking Clozapine
NCT00061802	PHASE4	COMPLETED	Efficacy and Safety of Two Atypical Antipsychotics vs. Placebo in Patients With an Acute Exacerbation of Either Schizophrenia or Schizoaffective Disorder
NCT00080327	PHASE4	COMPLETED	Study of Three Doses of Aripiprazole in Patients With Acute Schizophrenia
NCT00088049	PHASE4	COMPLETED	Study of Olanzapine vs. Aripiprazole in the Treatment of Schizophrenia
NCT00090012	PHASE4	COMPLETED	Comparison of Continuing Olanzapine to Switching to Quetiapine in Overweight or Obese Patients With Schizophrenia and Schizoaffective Disorder
NCT00100776	PHASE4	COMPLETED	Efficacy of High Dose Olanzapine for the Treatment of Schizophrenia and Schizoaffective Disorder
NCT00103571	PHASE4	COMPLETED	Olanzapine Versus Aripiprazole in the Treatment of Acutely Ill Patients With Schizophrenia
NCT00108368	PHASE4	COMPLETED	The Effects of Risperidone and Olanzapine on Thinking
NCT00114595	PHASE4	COMPLETED	Ethyl-Eicosapentaenoic Acid and Tardive Dyskinesia
NCT00130923	PHASE4	COMPLETED	Risperidone Long-acting Versus Oral Risperidone in Patients With Schizophrenia and Alcohol Use Disorder
NCT00137020	PHASE4	COMPLETED	Clinical Effect Of Cross Titration Of Antipsychotics With Ziprasidone In Schizophrenia Or Schizoaffective Disorder
NCT00140166	PHASE4	COMPLETED	Treatment of Acute Schizophrenia With Vitamin Therapy
NCT00145847	PHASE4	COMPLETED	Naltrexone Treatment of Alcohol Abuse in Schizophrenia
NCT00148564	PHASE4	COMPLETED	Energy Homeostasis Under Treatment With Atypical Antipsychotics
NCT00156715	PHASE4	COMPLETED	Efficacy of Quetiapine in the Treatment of Patients With Schizophrenia and a Comorbid Substance Use Disorder
NCT00158223	PHASE4	COMPLETED	Effectiveness of Pimozide in Augmenting the Effects of Clozapine in the Treatment of Schizophrenia
NCT00159081	PHASE4	COMPLETED	One Year Drug Treatment in First-Episode Schizophrenia
NCT00159120	PHASE4	COMPLETED	Maintenance Treatment vs. Stepwise Drug Discontinuation in First-Episode Schizophrenia
NCT00159133	PHASE4	COMPLETED	Prodrome-Based Early Intervention With Antipsychotics vs. Benzodiazepines in First-Episode Schizophrenia
NCT00159757	PHASE4	TERMINATED	12 Week Open, Non-Comparative Switch Study Of Oral Ziprazidone In Previously Treated Schizophrenic Patients
NCT00167817	PHASE4	COMPLETED	Effect of Switch to Aripiprazole on Health and Smoking Parameters in Patients With Schizophrenia: A Pilot Study
NCT00169026	PHASE4	TERMINATED	Alcoholism and Schizophrenia: Effects of Clozapine
NCT00169039	PHASE4	TERMINATED	Clozapine Versus Chlorpromazine for Treatment-Unresponsive Schizophrenia
NCT00169065	PHASE4	COMPLETED	Effectiveness of Clozapine Versus Olanzapine for Treatment-resistant Schizophrenia
NCT00169091	PHASE4	TERMINATED	Clozapine Versus Haloperidol for Treating the First Episode of Schizophrenia
NCT00176423	PHASE4	COMPLETED	Efficacy Study of Galantamine for Cognitive Impairments in Schizophrenia
NCT00176436	PHASE4	COMPLETED	Atomoxetine for Treatment of Weight Gain in Olanzapine or Clozapine Patients
NCT00177008	PHASE4	COMPLETED	Aripiprazole for the Treatment of Schizophrenia With Co-Morbid Social Anxiety