SLC12A4

Summary

SLC12A4 (solute carrier family 12 member 4, HGNC:10913) is a protein-coding gene on chromosome 16q22.1, encoding Solute carrier family 12 member 4 (Q9UP95). Mediates electroneutral potassium-chloride cotransport when activated by cell swelling.

This gene encodes a member of the SLC12A transporter family. The encoded protein mediates the coupled movement of potassium and chloride ions across the plasma membrane. This gene is expressed ubiquitously. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene.

Source: NCBI Gene 6560 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 217 total
• MANE Select transcript: NM_005072

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10913
Approved symbol	SLC12A4
Name	solute carrier family 12 member 4
Location	16q22.1
Locus type	gene with protein product
Status	Approved
Aliases	KCC1
Ensembl gene	ENSG00000124067
Ensembl biotype	protein_coding
OMIM	604119
Entrez	6560

Gene structure

Transcript identifiers

Ensembl transcripts: 34 — 20 protein_coding, 8 retained_intron, 5 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000316341, ENST00000537830, ENST00000541864, ENST00000570616, ENST00000570802, ENST00000571299, ENST00000572010, ENST00000572037, ENST00000572476, ENST00000572766, ENST00000573023, ENST00000573702, ENST00000574665, ENST00000575857, ENST00000576377, ENST00000576462, ENST00000576513, ENST00000576616, ENST00000705485, ENST00000858394, ENST00000858395, ENST00000858396, ENST00000858397, ENST00000858398, ENST00000858399, ENST00000937903, ENST00000937904, ENST00000937905, ENST00000964379, ENST00000964380, ENST00000964381, ENST00000964382, ENST00000964383, ENST00000964384

RefSeq mRNA: 5 — MANE Select: NM_005072 NM_001145961, NM_001145962, NM_001145963, NM_001145964, NM_005072

CCDS: CCDS10855, CCDS54030, CCDS54031

Canonical transcript exons

ENST00000316341 — 24 exons

Exon	Start	End
ENSE00002288382	67943474	67944931
ENSE00003466255	67949800	67949918
ENSE00003474358	67950654	67950711
ENSE00003479463	67947331	67947435
ENSE00003488475	67946937	67947105
ENSE00003499270	67951823	67952037
ENSE00003522862	67950319	67950493
ENSE00003531613	67952184	67952425
ENSE00003535679	67946438	67946633
ENSE00003550003	67954643	67954773
ENSE00003553943	67947669	67947788
ENSE00003557554	67945951	67946082
ENSE00003561361	67950962	67951060
ENSE00003581844	67968439	67968637
ENSE00003594862	67951140	67951304
ENSE00003595195	67945087	67945220
ENSE00003608859	67946171	67946340
ENSE00003611999	67948061	67948159
ENSE00003630935	67945369	67945553
ENSE00003633580	67957742	67957796
ENSE00003652756	67963465	67963559
ENSE00003662177	67957898	67958044
ENSE00003670475	67961575	67961706
ENSE00003683828	67945764	67945871

Expression profiles

Bgee: expression breadth ubiquitous, 219 present calls, max score 96.88.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 10.6029 / max 107.2030, expressed in 1721 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
157838	8.6602	1702
157836	1.5738	784
157837	0.2885	145
157835	0.0573	13
207921	0.0231	9

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	96.88	gold quality
ascending aorta	UBERON:0001496	96.64	gold quality
thoracic aorta	UBERON:0001515	96.59	gold quality
stromal cell of endometrium	CL:0002255	96.48	gold quality
lower esophagus muscularis layer	UBERON:0035833	96.07	gold quality
lower esophagus	UBERON:0013473	96.03	gold quality
body of uterus	UBERON:0009853	95.95	gold quality
descending thoracic aorta	UBERON:0002345	95.94	gold quality
right coronary artery	UBERON:0001625	95.92	gold quality
aorta	UBERON:0000947	95.91	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	95.78	gold quality
left lobe of thyroid gland	UBERON:0001120	95.74	gold quality
left coronary artery	UBERON:0001626	95.65	gold quality
tibial nerve	UBERON:0001323	95.64	gold quality
popliteal artery	UBERON:0002250	95.61	gold quality
tibial artery	UBERON:0007610	95.61	gold quality
upper lobe of left lung	UBERON:0008952	95.51	gold quality
mucosa of stomach	UBERON:0001199	95.39	gold quality
sural nerve	UBERON:0015488	95.39	gold quality
right lung	UBERON:0002167	95.35	gold quality
right lobe of thyroid gland	UBERON:0001119	95.34	gold quality
endocervix	UBERON:0000458	95.26	gold quality
right atrium auricular region	UBERON:0006631	95.12	gold quality
heart left ventricle	UBERON:0002084	94.69	gold quality
coronary artery	UBERON:0001621	94.66	gold quality
right adrenal gland cortex	UBERON:0035827	94.66	gold quality
left uterine tube	UBERON:0001303	94.60	gold quality
thyroid gland	UBERON:0002046	94.53	gold quality
muscle layer of sigmoid colon	UBERON:0035805	94.41	gold quality
right adrenal gland	UBERON:0001233	94.39	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

55 targeting SLC12A4, 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-4673	100.00	66.64	1490
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-7978	99.86	66.90	856
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-3913-3P	99.74	66.53	938
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-378G	99.71	64.90	1106
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-6132	99.60	65.83	1554
HSA-MIR-6836-5P	99.60	65.62	1538
HSA-MIR-762	99.58	66.61	1994
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-4472	99.56	66.08	1478
HSA-MIR-7106-5P	99.53	67.47	3574
HSA-MIR-136-5P	99.50	67.26	1153
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-4505	99.27	67.81	2678
HSA-MIR-7974	99.24	65.48	1137
HSA-MIR-5787	99.22	67.86	2628
HSA-MIR-5001-5P	99.05	66.76	1972
HSA-MIR-939-3P	98.97	65.07	2347
HSA-MIR-3190-5P	98.87	64.89	1345

Literature-anchored findings (GeneRIF, showing 12)

• human osteoblasts express functional K-Cl cotransporters in their cell membrane that seem to be able to induce the indirect activation of volume-sensitive Cl- channels by KCl through an increase in intracellular ions, water influx and cell swelling. (PMID:12637262)
• loss-of-function KCC mutant cervical cancer cells exhibit inhibited cell growth accompanied by decreased activity of cell cycle gene products (PMID:12902337)
• the KCC1 gene promoter lacks a TATA box and is composed of an initiator element (InR) and a downstream promoter element (DPE) (PMID:14976052)
• Hb polymerisation and sickling could be dissociated from the abnormal response of KCC to deoxygenation observed in HbS-containing red cells. (PMID:15039017)
• KCC activation by IGF-1 plays an important role in IGF-1 signaling to promote growth and spread of gynecological cancers. (PMID:15262997)
• IGF-II (insulin-like growth factors-2) can enhance KCC1 (KC1 co-transport-1) gene expression in cervical cancer cells through signal transduction pathways (PMID:19317253)
• 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)
• Insulin-like growth factors I can induce the upregulation of KCC1 gene, and KCC1 gene participates in the invasion ability of HEC-1B cells through the ERK signaling pathway. (PMID:21666489)
• KCC3 is the dominant isoform in erythrocytes, with variable expression of KCC1 and KCC4 that could result in modulation of KCC activity (PMID:21733850)
• data indicate that Zn(2+) acting via ZnR/GPR39 has a direct role in controlling Cl(-) absorption via upregulation of basolateral KCC1 in the colon. Moreover, colonocytic ZnR/GPR39 and KCC1 reduce water loss during diarrhea and may therefore serve as effective drug targets. (PMID:28093242)
• The main goal of the review is to discuss the molecular features and tissue-specific functions of KCC1 from the hematological perspective for the greater part. As will be seen, the characterization of KCC1 has led the way to important findings and promising therapeutic avenues. [review] (PMID:31296230)
• Structure of the human cation-chloride cotransport KCC1 in an outward-open state. (PMID:35759661)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio	slc12a4	ENSDARG00000014378
mus_musculus	Slc12a4	ENSMUSG00000017765
rattus_norvegicus	Slc12a4	ENSRNOG00000019651
drosophila_melanogaster	CG10413	FBGN0032689
drosophila_melanogaster	Ncc69	FBGN0036279
drosophila_melanogaster	kcc	FBGN0261794
caenorhabditis_elegans		WBGENE00012543
caenorhabditis_elegans		WBGENE00019205
caenorhabditis_elegans		WBGENE00020207

Paralogs (8): SLC12A2 (ENSG00000064651), SLC12A3 (ENSG00000070915), SLC12A1 (ENSG00000074803), SLC12A7 (ENSG00000113504), SLC12A5 (ENSG00000124140), SLC12A6 (ENSG00000140199), SLC12A9 (ENSG00000146828), SLC12A8 (ENSG00000221955)

Protein

Protein identifiers

Solute carrier family 12 member 4 — Q9UP95 (reviewed: Q9UP95)

Alternative names: Electroneutral potassium-chloride cotransporter 1, Erythroid K-Cl cotransporter 1

All UniProt accessions (7): A0A994J5J8, Q9UP95, I3L1N8, I3L4N6, J3QKM4, J3QRE2, J3QSF2

UniProt curated annotations — full annotation on UniProt →

Function. Mediates electroneutral potassium-chloride cotransport when activated by cell swelling. May contribute to cell volume homeostasis in single cells. May be involved in the regulation of basolateral Cl(-) exit in NaCl absorbing epithelia. No transporter activity.

Subunit / interactions. Homodimer; adopts a domain-swap conformation at the scissor helices connecting the transmembrane domain and C-terminal domain. Heterodimer with other K-Cl cotransporters.

Subcellular location. Cell membrane.

Tissue specificity. Ubiquitous. Levels are much higher in erythrocytes from patients with Hb SC and Hb SS compared to normal AA erythrocytes. This may contribute to red blood cell dehydration and to the manifestation of sickle cell disease by increasing the intracellular concentration of HbS. Not detected in circulating reticulocytes.

Post-translational modifications. Phosphorylated, phosphorylation may regulate transporter activity.

Activity regulation. Inhibited by WNK3.

Similarity. Belongs to the SLC12A transporter family. K/Cl co-transporter subfamily.

Isoforms (7)

UniProt ID	Names	Canonical?
Q9UP95-1	1	yes
Q9UP95-2	2
Q9UP95-3	3
Q9UP95-4	4
Q9UP95-5	5
Q9UP95-6	6
Q9UP95-7	7

RefSeq proteins (5): NP_001139433, NP_001139434, NP_001139435, NP_001139436, NP_005063* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000076	KCL_cotranspt	Family
IPR000622	KCC1	Family
IPR004841	AA-permease/SLC12A_dom	Domain
IPR004842	SLC12A_fam	Family
IPR018491	SLC12_C	Domain

Pfam: PF00324, PF03522

Catalyzed reactions (Rhea), 1 shown:

• K(+)(in) + chloride(in) = K(+)(out) + chloride(out) (RHEA:72427)

UniProt features (160 total): helix 41, strand 22, binding site 18, transmembrane region 12, topological domain 10, turn 10, modified residue 10, splice variant 10, mutagenesis site 10, sequence conflict 8, glycosylation site 5, disulfide bond 2, chain 1, region of interest 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
6KKR	ELECTRON MICROSCOPY	2.9
6KKT	ELECTRON MICROSCOPY	2.9
7AIP	ELECTRON MICROSCOPY	3.12
7TTH	ELECTRON MICROSCOPY	3.25
6KKU	ELECTRON MICROSCOPY	3.5
7TTI	ELECTRON MICROSCOPY	3.5
7AIR	ELECTRON MICROSCOPY	3.66
7AIQ	ELECTRON MICROSCOPY	3.72

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UP95-F1	81.37	0.52

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 (18): 131; 132; 216; 429; 432; 433; 434; 435; 589; 589; 697; 699 …

Post-translational modifications (10): 24, 47, 51, 81, 88, 734, 916, 967, 983, 1050

Disulfide bonds (2): 308–323, 343–353

Glycosylation sites (5): 245, 312, 331, 347, 361

Mutagenesis-validated functional residues (10):

Position	Phenotype
135	decrease in cl(-) efflux and reduced sensitivity to kcc inhibitor vu0463271.
136	decrease in cl(-) efflux.
139	decrease in cl(-) efflux.
140	decrease in cl(-) efflux.
215	decrease in cl(-) efflux and reduced sensitivity to kcc inhibitor vu0463271.
222	decrease in cl(-) efflux and reduced sensitivity to kcc inhibitor vu0463271.
223	decrease in cl(-) efflux and reduced sensitivity to kcc inhibitor vu0463271.
574	decrease in cl(-) efflux.
575	decrease in cl(-) efflux.
581	reduced sensitivity to kcc inhibitor vu0463271.

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: 230 (showing top): MORF_RAGE, GOBP_POTASSIUM_ION_TRANSPORT, CAR_TNFRSF25, chr16q22, GOCC_VACUOLAR_MEMBRANE, ENK_UV_RESPONSE_KERATINOCYTE_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, GOBP_POTASSIUM_ION_HOMEOSTASIS, GOBP_INORGANIC_ANION_TRANSPORT, AP2_Q3, RIZKI_TUMOR_INVASIVENESS_3D_DN, GGGTGGRR_PAX4_03, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_CELL_CELL_SIGNALING

GO Biological Process (10): monoatomic ion transport (GO:0006811), cell volume homeostasis (GO:0006884), chemical synaptic transmission (GO:0007268), chloride ion homeostasis (GO:0055064), potassium ion homeostasis (GO:0055075), potassium ion transmembrane transport (GO:0071805), chloride transmembrane transport (GO:1902476), potassium ion import across plasma membrane (GO:1990573), potassium ion transport (GO:0006813), transmembrane transport (GO:0055085)

GO Molecular Function (8): ATP binding (GO:0005524), potassium:chloride symporter activity (GO:0015379), protein serine/threonine kinase binding (GO:0120283), protein binding (GO:0005515), symporter activity (GO:0015293), chloride:monoatomic cation symporter activity (GO:0015377), protein kinase binding (GO:0019901), transmembrane transporter activity (GO:0022857)

GO Cellular Component (4): lysosomal membrane (GO:0005765), plasma membrane (GO:0005886), membrane (GO:0016020), synapse (GO:0045202)

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	2
inorganic ion homeostasis	2
regulation of cell size	1
cellular homeostasis	1
anterograde trans-synaptic signaling	1
monoatomic anion homeostasis	1
monoatomic cation homeostasis	1
potassium ion transport	1
monoatomic cation transmembrane transport	1
chloride transport	1
monoatomic anion transmembrane transport	1
potassium ion transmembrane transport	1
inorganic cation import across plasma membrane	1
metal ion transport	1
cellular process	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
potassium ion transmembrane transporter activity	1
chloride:monoatomic cation symporter activity	1
protein kinase binding	1
binding	1
secondary active transmembrane transporter activity	1
chloride transmembrane transporter activity	1
monoatomic anion:monoatomic cation symporter activity	1
kinase binding	1
transporter activity	1
transmembrane transport	1
lysosome	1
lytic vacuole membrane	1
membrane	1
cell periphery	1
cellular anatomical structure	1
cell junction	1

Protein interactions and networks

STRING

1190 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SLC12A4	WNK3	Q9BYP7	858
SLC12A4	PSKH1	P11801	806
SLC12A4	WNK1	P54963	789
SLC12A4	WNK4	Q96J92	780
SLC12A4	STK39	Q9UEW8	657
SLC12A4	PSMB10	P40306	654
SLC12A4	OXSR1	O95747	626
SLC12A4	WNK2	Q9Y3S1	592
SLC12A4	LCAT	P04180	577
SLC12A4	GABRA1	P14867	523
SLC12A4	SLC4A5	Q9BY07	493
SLC12A4	FGD3	Q5JSP0	470
SLC12A4	CACNA1E	Q15878	463
SLC12A4	SLC33A1	O00400	455
SLC12A4	SLC4A8	Q2Y0W8	444

IntAct

116 interactions, top by confidence:

A	B	Type	Score
TP53	MDM2	psi-mi:“MI:0914”(association)	1.000
ENTREP1	WWP2	psi-mi:“MI:0914”(association)	0.850
SLC12A4	AP3M1	psi-mi:“MI:0915”(physical association)	0.670
KRTAP12-2	SLC12A4	psi-mi:“MI:0915”(physical association)	0.560
TMEM102	SLC12A4	psi-mi:“MI:0915”(physical association)	0.560
MB21D2	SLC12A4	psi-mi:“MI:0915”(physical association)	0.560
CYSRT1	SLC12A4	psi-mi:“MI:0915”(physical association)	0.560
CNFN	SLC12A4	psi-mi:“MI:0915”(physical association)	0.560
ZNF655	SLC12A4	psi-mi:“MI:0915”(physical association)	0.560
KRTAP19-2	SLC12A4	psi-mi:“MI:0915”(physical association)	0.560
GPR21	TMEM120B	psi-mi:“MI:0914”(association)	0.530
SLC31A1	C2orf72	psi-mi:“MI:0914”(association)	0.530
LGALS3	PODXL	psi-mi:“MI:0914”(association)	0.530
SLC12A4	CLGN	psi-mi:“MI:0914”(association)	0.530
LYPD6	PLXNB2	psi-mi:“MI:0914”(association)	0.530
CHRND	TPST2	psi-mi:“MI:0914”(association)	0.530
NRN1	SLC1A1	psi-mi:“MI:0914”(association)	0.530
RAB6B	RAB6A	psi-mi:“MI:0914”(association)	0.530
SLC12A4	JAGN1	psi-mi:“MI:0914”(association)	0.530
PIP	TBKBP1	psi-mi:“MI:0914”(association)	0.530
RAB6B	SBF1	psi-mi:“MI:0914”(association)	0.530
SLC12A4	LGALS3	psi-mi:“MI:0914”(association)	0.530
pipB2	SCD	psi-mi:“MI:0914”(association)	0.460
SLC12A4	ATF7IP	psi-mi:“MI:0915”(physical association)	0.370
E5	ESYT2	psi-mi:“MI:0914”(association)	0.350
	SNAP23	psi-mi:“MI:0914”(association)	0.350

BioGRID (253): SLC12A4 (Affinity Capture-MS), SLC12A4 (Affinity Capture-MS), SLC12A4 (Affinity Capture-MS), SLC12A4 (Affinity Capture-MS), SLC12A4 (Affinity Capture-MS), SLC12A4 (Affinity Capture-MS), SLC12A4 (Affinity Capture-MS), SLC12A4 (Co-fractionation), SLC12A4 (Proximity Label-MS), SLC12A4 (Proximity Label-MS), SLC12A4 (Proximity Label-MS), SLC12A4 (Affinity Capture-MS), SLC12A4 (Affinity Capture-MS), SLC12A4 (Affinity Capture-MS), SLC12A4 (Affinity Capture-MS)

ESM2 similar proteins: A0A078H868, A0AAS4, A0JP80, A6X919, D4AD75, O70536, O77760, O77761, P23913, P35610, P53439, P56079, Q14739, Q20696, Q20735, Q28677, Q2PZI1, Q4JM44, Q4R763, Q5R7H4, Q5RK27, Q60457, Q61263, Q63632, Q63633, Q657W3, Q6AX73, Q6Z0E2, Q7T3T4, Q7TSX5, Q86VZ5, Q8IWX5, Q8NHU3, Q8VCQ6, Q91V14, Q924N4, Q965Q4, Q9D4B1, Q9FJB4, Q9H2X9

Diamond homologs: Q09573, Q28677, Q2UVJ5, Q5RK27, Q63632, Q63633, Q6Z0E2, Q7YRU6, Q91V14, Q924N4, Q9H2X9, Q9JIS8, Q9UHW9, Q9UP95, Q9WVL3, Q9Y666, A2BFP5, O60146, P38329, P55011, P55012, P55013, Q0VGW6, Q66HR0, Q99MR3, Q9BXP2, Q657W3, A0AV02, Q8VI23, Q6A4L1, Q8CJI3

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
WNK3	“down-regulates activity”	SLC12A4	phosphorylation
SLC12A4	“down-regulates quantity”	chloride	relocalization

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 129 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.

GO biological processes:

GO term	Partners	Fold	FDR
monoatomic ion transport	7	10.1×	5e-03
chemical synaptic transmission	9	6.4×	5e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	169
Likely benign	10
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

4912 predictions. Top by Δscore:

Variant	Effect	Δscore
16:67945362:CACT:C	donor_loss	1.0000
16:67945363:AC:A	donor_loss	1.0000
16:67945365:TCAC:T	donor_loss	1.0000
16:67945366:C:CC	donor_loss	1.0000
16:67945367:A:AC	donor_gain	1.0000
16:67945367:ACGG:A	donor_gain	1.0000
16:67945368:C:CT	donor_gain	1.0000
16:67945368:CG:C	donor_gain	1.0000
16:67945368:CGG:C	donor_gain	1.0000
16:67945368:CGGC:C	donor_gain	1.0000
16:67945368:CGGCT:C	donor_gain	1.0000
16:67945436:A:AC	donor_gain	1.0000
16:67945437:C:CC	donor_gain	1.0000
16:67945549:TGGGC:T	acceptor_gain	1.0000
16:67945554:C:CC	acceptor_gain	1.0000
16:67945555:T:G	acceptor_loss	1.0000
16:67945762:A:AC	donor_gain	1.0000
16:67945763:C:CC	donor_gain	1.0000
16:67945763:CTT:C	donor_gain	1.0000
16:67945765:T:TA	donor_gain	1.0000
16:67945772:C:CA	donor_gain	1.0000
16:67945796:T:C	donor_gain	1.0000
16:67945950:CCAT:C	donor_gain	1.0000
16:67946078:CAGAC:C	acceptor_gain	1.0000
16:67946080:GACCT:G	acceptor_loss	1.0000
16:67946083:C:CA	acceptor_loss	1.0000
16:67946083:C:CC	acceptor_gain	1.0000
16:67946089:C:CT	acceptor_gain	1.0000
16:67946090:A:T	acceptor_gain	1.0000
16:67946166:TCTA:T	donor_loss	1.0000

AlphaMissense

7088 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:67944910:A:G	L1063P	1.000
16:67944921:G:C	F1059L	1.000
16:67944921:G:T	F1059L	1.000
16:67944922:A:G	F1059S	1.000
16:67944923:A:G	F1059L	1.000
16:67945127:G:C	N1042K	1.000
16:67945127:G:T	N1042K	1.000
16:67945140:A:G	L1038P	1.000
16:67945155:G:A	S1033F	1.000
16:67945175:A:C	N1026K	1.000
16:67945175:A:T	N1026K	1.000
16:67945176:T:A	N1026I	1.000
16:67945179:A:G	L1025P	1.000
16:67945188:G:T	A1022D	1.000
16:67945189:C:G	A1022P	1.000
16:67945196:C:A	M1019I	1.000
16:67945196:C:G	M1019I	1.000
16:67945196:C:T	M1019I	1.000
16:67945197:A:G	M1019T	1.000
16:67945831:A:G	L927P	1.000
16:67946079:A:G	W871R	1.000
16:67946079:A:T	W871R	1.000
16:67946230:A:G	W850R	1.000
16:67946230:A:T	W850R	1.000
16:67946233:A:G	W849R	1.000
16:67946233:A:T	W849R	1.000
16:67946478:C:A	W799C	1.000
16:67946478:C:G	W799C	1.000
16:67946480:A:G	W799R	1.000
16:67946480:A:T	W799R	1.000

dbSNP variants (sampled 300 via entrez): RS1000163789 (16:67965712 A>T), RS1000217069 (16:67957150 C>T), RS1000369222 (16:67959517 G>A), RS1000469300 (16:67964143 G>A), RS1000509098 (16:67947774 A>G), RS1000585961 (16:67955462 C>T), RS1000677552 (16:67958401 A>C,T), RS1000956569 (16:67955679 G>A), RS1001016305 (16:67961865 G>C), RS1001530278 (16:67968705 G>A,C,T), RS1001552121 (16:67959962 C>G), RS1001566471 (16:67962824 G>A), RS1001580962 (16:67945274 TC>T), RS1001626358 (16:67954121 C>T), RS1001658085 (16:67966790 G>T)

Disease associations

OMIM: gene MIM:604119 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST002539_84	Schizophrenia	2.000000e-08
GCST006803_42	Schizophrenia	4.000000e-08
GCST010002_113	Refractive error	2.000000e-14

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 — SLC12 family of cation-coupled chloride transporters

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression, affects cotreatment, decreases expression, increases abundance	3
Resveratrol	affects cotreatment, increases expression	2
Arsenic	affects cotreatment, decreases expression, increases abundance	2
Benzo(a)pyrene	affects methylation, increases expression, increases methylation	2
Quercetin	increases expression, increases phosphorylation	2
6,7-dimethoxy-2-(pyrrolidin-1-yl)-N-(5-(pyrrolidin-1-yl)pentyl)quinazolin-4-amine	increases expression	1
FR900359	affects phosphorylation	1
bisphenol F	increases expression	1
triphenyl phosphate	affects expression	1
manganese chloride	decreases expression, increases abundance, affects cotreatment	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
di-n-butylphosphoric acid	affects expression	1
K 7174	increases expression	1
bisphenol B	increases expression	1
abrine	increases expression	1
Decitabine	increases expression	1
Leflunomide	increases expression	1
Air Pollutants	affects expression, increases abundance	1
Caffeine	decreases phosphorylation	1
Coumestrol	increases expression, affects cotreatment	1
Doxorubicin	increases expression	1
Estradiol	increases expression	1
Lead	affects expression	1
Manganese	affects cotreatment, decreases expression, increases abundance	1
Ozone	affects expression, increases abundance	1
Phthalic Acids	increases methylation	1
Ribonucleotides	affects binding	1
Rotenone	increases expression	1
Smoke	decreases expression	1
Thiram	increases expression	1

Cellosaurus cell lines

5 cell lines: 5 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D4HL	HCT116-SLC12A4-KO-c12	Cancer cell line	Male
CVCL_D4HM	HCT116-SLC12A4-KO-c6	Cancer cell line	Male
CVCL_E0NH	Ubigene HeLa SLC12A4 KO	Cancer cell line	Female
CVCL_TL50	HAP1 SLC12A4 (-) 1	Cancer cell line	Male
CVCL_TL51	HAP1 SLC12A4 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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