SLC12A5

Summary

SLC12A5 (solute carrier family 12 member 5, HGNC:13818) is a protein-coding gene on chromosome 20q13.12, encoding Solute carrier family 12 member 5 (Q9H2X9). Mediates electroneutral potassium-chloride cotransport in mature neurons and is required for neuronal Cl(-) homeostasis.

K-Cl cotransporters are proteins that lower intracellular chloride concentrations below the electrochemical equilibrium potential. The protein encoded by this gene is an integral membrane K-Cl cotransporter that can function in either a net efflux or influx pathway, depending on the chemical concentration gradients of potassium and chloride. The encoded protein can act as a homomultimer, or as a heteromultimer with other K-Cl cotransporters, to maintain chloride homeostasis in neurons. Alternative splicing results in two transcript variants encoding different isoforms.

Source: NCBI Gene 57468 — RefSeq curated summary.

At a glance

• Gene–disease (curated): developmental and epileptic encephalopathy, 34 (Strong, GenCC) — +4 more curated relationships
• GWAS associations: 9
• Clinical variants (ClinVar): 1,002 total — 32 pathogenic, 14 likely-pathogenic
• Phenotypes (HPO): 44
• Druggable target: yes
• MANE Select transcript: NM_020708

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13818
Approved symbol	SLC12A5
Name	solute carrier family 12 member 5
Location	20q13.12
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1176, KCC2, hKCC2
Ensembl gene	ENSG00000124140
Ensembl biotype	protein_coding
OMIM	606726
Entrez	57468

Gene structure

Transcript identifiers

Ensembl transcripts: 24 — 10 protein_coding, 8 retained_intron, 4 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay

ENST00000243964, ENST00000372315, ENST00000413737, ENST00000428198, ENST00000454036, ENST00000539566, ENST00000608594, ENST00000608944, ENST00000616202, ENST00000616933, ENST00000622711, ENST00000625683, ENST00000626144, ENST00000626695, ENST00000626701, ENST00000626937, ENST00000627290, ENST00000628272, ENST00000628413, ENST00000629054, ENST00000636324, ENST00000637437, ENST00000637831, ENST00000637863

RefSeq mRNA: 2 — MANE Select: NM_020708 NM_001134771, NM_020708

CCDS: CCDS13391, CCDS46610

Canonical transcript exons

ENST00000243964 — 26 exons

Exon	Start	End
ENSE00000000089	46029215	46029396
ENSE00000845129	46034948	46035042
ENSE00000845130	46035404	46035535
ENSE00000845134	46040373	46040614
ENSE00000845135	46041329	46041540
ENSE00000845136	46043153	46043323
ENSE00000845137	46043633	46043731
ENSE00000845144	46049622	46049790
ENSE00000845145	46051675	46051870
ENSE00000845146	46052957	46053126
ENSE00000845148	46054916	46055023
ENSE00000845149	46056150	46056272
ENSE00000845150	46056365	46056564
ENSE00000845152	46057170	46057303
ENSE00001648996	46037255	46037385
ENSE00001657609	46056897	46056911
ENSE00001723356	46044966	46045140
ENSE00001734833	46036741	46036795
ENSE00001739067	46035777	46035923
ENSE00001755564	46043876	46043933
ENSE00001789592	46053578	46053709
ENSE00001955822	46057514	46060150
ENSE00003549524	46046338	46046436
ENSE00003554925	46047454	46047573
ENSE00003581589	46045878	46045996
ENSE00003660611	46047981	46048085

Expression profiles

Bgee: expression breadth ubiquitous, 205 present calls, max score 99.11.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 26.1682 / max 448.9391, expressed in 1514 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
185040	15.2827	1472
185045	6.4159	103
185041	2.1423	730
185044	2.0958	103
185043	0.1718	76
185042	0.0596	45

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	99.11	gold quality
cerebellar hemisphere	UBERON:0002245	99.09	gold quality
cerebellar cortex	UBERON:0002129	99.00	gold quality
cerebellum	UBERON:0002037	98.90	gold quality
lateral nuclear group of thalamus	UBERON:0002736	98.66	gold quality
Brodmann (1909) area 23	UBERON:0013554	98.49	gold quality
Brodmann (1909) area 10	UBERON:0013541	98.39	gold quality
primary visual cortex	UBERON:0002436	98.36	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	98.20	gold quality
Brodmann (1909) area 9	UBERON:0013540	98.13	gold quality
frontal pole	UBERON:0002795	98.04	gold quality
orbitofrontal cortex	UBERON:0004167	98.04	gold quality
superior frontal gyrus	UBERON:0002661	98.01	gold quality
paraflocculus	UBERON:0005351	98.00	gold quality
nucleus accumbens	UBERON:0001882	97.89	gold quality
middle temporal gyrus	UBERON:0002771	97.85	gold quality
right frontal lobe	UBERON:0002810	97.74	gold quality
CA1 field of hippocampus	UBERON:0003881	97.74	gold quality
prefrontal cortex	UBERON:0000451	97.60	gold quality
postcentral gyrus	UBERON:0002581	97.57	gold quality
occipital lobe	UBERON:0002021	97.47	gold quality
frontal cortex	UBERON:0001870	97.43	gold quality
caudate nucleus	UBERON:0001873	97.21	gold quality
putamen	UBERON:0001874	97.21	gold quality
parietal lobe	UBERON:0001872	97.13	gold quality
cingulate cortex	UBERON:0003027	96.96	gold quality
anterior cingulate cortex	UBERON:0009835	96.90	gold quality
lateral globus pallidus	UBERON:0002476	96.71	gold quality
neocortex	UBERON:0001950	96.69	gold quality
cerebral cortex	UBERON:0000956	96.67	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-GEOD-137537	yes	13.36
E-GEOD-84465	yes	6.60
E-ANND-3	yes	4.65

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ARX, CXXC1, EBF3, EGR1, EGR4

miRNA regulators (miRDB)

157 targeting SLC12A5, 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-4262	100.00	73.26	3931
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-4650-5P	99.98	64.69	999
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504

Literature-anchored findings (GeneRIF, showing 40)

• chromosome 20 mapping (PMID:11701957)
• Expression of hKCC2 cRNA in Xenopus laevis oocytes results in significant Cl(-)-dependent (86)Rb(+) uptake under isotonic conditions (PMID:12106695)
• 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 the intracellular ions, water influx and cell swelling. (PMID:12637262)
• GABAergic transmission is influenced by the neuronal expression chloride-extruding K(+)-Cl(-) cotransporter KCC2–REVIEW (PMID:15528236)
• KCC2 expression is not only necessary but is also sufficient for ending the depolarizing period of GABA in developing cortical neurons (PMID:15932617)
• constitutive K(+)-Cl(-) cotransport mediated by KCC2 is completely independent of serine-threonine phosphatase activity (PMID:16291749)
• decrease in the spontaneous activity transients was associated with a developmental up-regulation of the neuronal chloride extruder K+-Cl- cotransporter 2 (PMID:16324114)
• PKC-dependent phosphorylation of KCC2 may play a central role in modulating both the functional expression of this critical transporter in the brain and the strength of synaptic inhibition (PMID:17693402)
• The novel KCC2a isoform differs from the only previously known KCC2 isoform (now termed KCC2b) by 40 unique N-terminal amino acid residues, including a putative Ste20-related proline alanine-rich kinase-binding site. (PMID:17715129)
• the two isoforms can be coimmunoprecipitated from the neonatal brain, suggesting the presence of endogenous KCC2a-KCC2b heteromers. (PMID:19307176)
• membrane rafts render KCC2 inactive and NKCC1 active (PMID:19686239)
• analysis of differences in large extracellular loop between the K(+)-Cl(-) cotransporters KCC2 and KCC4 (PMID:20516068)
• levels of KCC2 mRNA and protein were significantly decreased in the neurons around large abnormal neurons in focal cortical dysplasia (PMID:21256718)
• 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)
• KCC2 is widely expressed in several human cancer cell lines and serves to increase cervical tumourigenesis via an ion transport-independent mechanism (PMID:21911617)
• Hyperpolarizing GABAergic transmission depends on KCC2 function and membrane potential. (PMID:22082832)
• Alternate transcripts from KCC2 may participate in the abnormal GABA signaling in the dorsolateral prefrontal cortex associated with schizophrenia (PMID:22496567)
• BPA can disrupt Kcc2 gene expression through epigenetic mechanisms (PMID:23440186)
• Disrupted KCC2 activity seems to be involved in neuropathic pain, epilepsy, motor spasticity, stress and schizophrenia. (PMID:23621303)
• 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)
• KCC2-R952H from patients with febrile seizures impairs neuronal Cl- extrusion and dendritic spine formation. (PMID:24668262)
• Functional characterization of mutant SLC12A5 revealed its potential oncogenic effect in colon cancer. (PMID:24699064)
• These data describe a novel KCC2 variant significantly associated with a human disease and suggest genetically encoded impairment of KCC2 functional regulation may be a risk factor for the development of human IGE. (PMID:24928908)
• SLC12A5 plays a pivotal oncogenic role in colorectal carcinogenesis; its overexpression is an independent prognostic factor of patients with CRC. (PMID:25947013)
• a novel signaling pathway that couples KCC2 to the cytoskeleton and regulates the formation of glutamatergic synapses. (PMID:26056138)
• these data provide insight into the mechanism regulating Cl(-) homeostasis in immature neurons, and suggest that WNK1-regulated changes in KCC2 phosphorylation contribute to the developmental excitatory-to-inhibitory GABA sequence. (PMID:26126716)
• A KCC2 mutation causes epilepsy of infancy with migrating focal seizures. Decreased KCC2 expression, reduced protein glycosylation and impaired Cl- extrusion contribute to loss of KCC2 activity, impairing synaptic inhibition and promoting excitability. (PMID:26333769)
• Study shows that the overall expression of potassium-chloride cotransporter-2 is increased in the hippocampi of temporal lobe epilepsy patients. (PMID:26427846)
• Study describes the developmental patterns of cation-chloride cotransporters in the human brain from the fetal stage to senescence. Expression of KCC2 and its functionally associated proteins begins in early fetal period. (PMID:26428952)
• the functional deficit of KCC2 may offer an explanation for the delayed onset of Rett symptoms. (PMID:26733678)
• The KCC2 exerts specific functions for the maturation of glycinergic synapses in cultured spinal cord neurons. (PMID:26780567)
• These data clearly demonstrated that partially disrupted neuronal Cl(-) extrusion, mediated by two types of differentially impaired KCC2 mutant in an individual, causes epilepsy of infancy with migrating focal seizures. (PMID:27436767)
• Our network model suggested the loss of KCC2 in a critical number of pyramidal cells increased external potassium and intracellular chloride concentrations leading to seizure-like field potential oscillations. These oscillations included transient discharges leading to ictal-like field events with frequency spectra as in vitro Restoration of KCC2 function suppressed seizure activity and thus may present a useful therapeut (PMID:27852771)
• The authors show that APP can physically interact with KCC2, a neuron-specific K(+)-Cl(-) cotransporter that is essential for Cl(-) homeostasis and fast GABAergic inhibition. (PMID:28054918)
• SLC12A5 promoted the migration and invasion of BUC by enhancing MMP-7 expression. (PMID:28333147)
• the long-time considered “neuron-specific” KCC2 co-transporter is expressed in pancreatic islet beta-cells where it modulates Ca(2+)-dependent insulin secretion. (PMID:28496181)
• S31D, T34A, S932A/D, T999A, or T1008A/D of KCC2 abrogated staurosporine mediated stimulation, and S31A, T34D, or S932D abolished NEM-mediated stimulation. (PMID:30201606)
• Pathogenic potential of human SLC12A5 variants causing KCC2 dysfunction. (PMID:30576625)
• Sequence Variation Associated with SLC12A5 Gene Expression Is Linked to Brain Structure and Function in Healthy Adults. (PMID:30668668)
• Study significantly lower NKCC1 DNA methylation and significantly higher KCC2 DNA methylation levels in patients with juvenile myoclonic epilepsy (JME) compared with the healthy controls. This implies that NKCC1 expression can be higher and KCC2 expression can be reduced in affected people. (PMID:30759289)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
mus_musculus	Slc12a5	ENSMUSG00000017740
rattus_norvegicus	Slc12a5	ENSRNOG00000018111
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), SLC12A4 (ENSG00000124067), SLC12A6 (ENSG00000140199), SLC12A9 (ENSG00000146828), SLC12A8 (ENSG00000221955)

Protein

Protein identifiers

Solute carrier family 12 member 5 — Q9H2X9 (reviewed: Q9H2X9)

Alternative names: Electroneutral potassium-chloride cotransporter 2, K-Cl cotransporter 2, Neuronal K-Cl cotransporter

All UniProt accessions (11): A0A0D9SF89, A0A0D9SGA5, A0A0D9SGD0, A0A0D9SGF9, A0A1B0GVB1, B7Z3T3, Q9H2X9, M4PM71, M4PNB5, M4PNC0, V9GYL3

UniProt curated annotations — full annotation on UniProt →

Function. Mediates electroneutral potassium-chloride cotransport in mature neurons and is required for neuronal Cl(-) homeostasis. As major extruder of intracellular chloride, it establishes the low neuronal Cl(-) levels required for chloride influx after binding of GABA-A and glycine to their receptors, with subsequent hyperpolarization and neuronal inhibition. Involved in the regulation of dendritic spine formation and maturation.

Subunit / interactions. Homodimer; adopts a domain-swap conformation at the scissor helices connecting the transmembrane domain and C-terminal domain. Heterodimer with K-Cl cotransporters SLC12A6 and SLC12A7. Interacts with AP2A1.

Subcellular location. Cell membrane. Cell projection. Dendrite.

Tissue specificity. Brain specific. Detected in neuronal cells.

Post-translational modifications. Phosphorylated at Thr-929 and Thr-1030 by OXSR1/OSR1 and STK39/SPAK downstream of WNK kinases (WNK1, WNK2, WNK3 or WNK4), inhibiting the potassium-chloride cotransport activity.

Disease relevance. Developmental and epileptic encephalopathy 34 (DEE34) [MIM:616645] A form of epileptic encephalopathy, a heterogeneous group of severe early-onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. DEE34 is characterized by onset of refractory migrating focal seizures in infancy. Affected children show developmental regression and are severely impaired globally. The disease is caused by variants affecting the gene represented in this entry. Epilepsy, idiopathic generalized 14 (EIG14) [MIM:616685] An autosomal dominant form of idiopathic generalized epilepsy, a disorder characterized by recurring generalized seizures in the absence of detectable brain lesions and/or metabolic abnormalities. Generalized seizures arise diffusely and simultaneously from both hemispheres of the brain. Seizure types include juvenile myoclonic seizures, absence seizures, and generalized tonic-clonic seizures. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Activity regulation. Inhibited following phosphorylation by OXSR1/OSR1 and STK39/SPAK: phosphorylation takes place downstream of WNK kinases (WNK1, WNK2, WNK3 or WNK4) in response to hyperosmotic stress and subsequent cell shrinkage.

Miscellaneous. Inhibited by furosemide and bumetanide.

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

Isoforms (2)

UniProt ID	Names	Canonical?
Q9H2X9-1	1, KCC2a	yes
Q9H2X9-2	2, KCC2b

RefSeq proteins (2): NP_001128243, NP_065759* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000076	KCL_cotranspt	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 (170 total): helix 46, strand 31, turn 19, transmembrane region 12, topological domain 10, mutagenesis site 10, sequence variant 9, compositionally biased region 7, binding site 7, modified residue 6, region of interest 4, glycosylation site 4, disulfide bond 2, chain 1, sequence conflict 1, splice variant 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
6M23	ELECTRON MICROSCOPY	3.2
7D8Z	ELECTRON MICROSCOPY	3.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H2X9-F1	78.58	0.44

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 (7): 113; 184; 410; 414; 415; 446; 569

Post-translational modifications (6): 57, 929, 1030, 1045, 1048, 1049

Disulfide bonds (2): 310–325, 345–354

Glycosylation sites (4): 314, 333, 351, 362

Mutagenesis-validated functional residues (10):

Position	Phenotype
91	2-fold increase in k(+) influx.
92	2-fold increase in k(+) influx.
93	2-fold increase in k(+) influx.
94	3-fold increase in k(+) influx.
96	3-fold increase in k(+) influx.
101	2-fold increase in k(+) influx.
102	3-fold increase in k(+) influx; when associated with a-105.
105	3-fold increase in k(+) influx; when associated with a-102.
929	decreased phosphorylation by wnk kinases, leading to increased potassium-chloride cotransport activity; when associated
1030	decreased phosphorylation by wnk kinases, leading to increased potassium-chloride cotransport activity; when associated

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: 360 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_DN, GOBP_POTASSIUM_ION_TRANSPORT, GOBP_DENDRITE_DEVELOPMENT, RNGTGGGC_UNKNOWN, GOBP_COGNITION, GOBP_BEHAVIOR, TGCGCANK_UNKNOWN, GOBP_SYNAPSE_ASSEMBLY, GCANCTGNY_MYOD_Q6, SP3_Q3, GOBP_DENDRITIC_SPINE_DEVELOPMENT, GOBP_GROWTH, GOBP_POTASSIUM_ION_HOMEOSTASIS, GOBP_INORGANIC_ANION_TRANSPORT, GOBP_NEUROGENESIS

GO Biological Process (23): monoatomic ion transport (GO:0006811), cell volume homeostasis (GO:0006884), hypotonic response (GO:0006971), chemical synaptic transmission (GO:0007268), learning (GO:0007612), response to xenobiotic stimulus (GO:0009410), intracellular chloride ion homeostasis (GO:0030644), multicellular organism growth (GO:0035264), thermosensory behavior (GO:0040040), intracellular pH reduction (GO:0051452), chloride ion homeostasis (GO:0055064), potassium ion homeostasis (GO:0055075), dendritic spine development (GO:0060996), postsynaptic neurotransmitter receptor diffusion trapping (GO:0098970), regulation of postsynapse assembly (GO:0150052), chloride transmembrane transport (GO:1902476), potassium ion import across plasma membrane (GO:1990573), potassium ion transport (GO:0006813), chloride transport (GO:0006821), developmental process (GO:0032502), transmembrane transport (GO:0055085), potassium ion transmembrane transport (GO:0071805), ammonium transmembrane transport (GO:0072488)

GO Molecular Function (8): ammonium channel activity (GO:0008519), chloride transmembrane transporter activity (GO:0015108), potassium:chloride symporter activity (GO:0015379), protein kinase binding (GO:0019901), metal ion binding (GO:0046872), symporter activity (GO:0015293), chloride:monoatomic cation symporter activity (GO:0015377), transmembrane transporter activity (GO:0022857)

GO Cellular Component (11): plasma membrane (GO:0005886), membrane (GO:0016020), dendrite membrane (GO:0032590), neuron projection (GO:0043005), neuronal cell body (GO:0043025), perikaryon (GO:0043204), cell periphery (GO:0071944), glutamatergic synapse (GO:0098978), postsynaptic specialization membrane (GO:0099634), dendrite (GO:0030425), cell projection (GO:0042995)

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	4
inorganic ion homeostasis	2
postsynaptic membrane	2
transport	1
regulation of cell size	1
cellular homeostasis	1
response to osmotic stress	1
anterograde trans-synaptic signaling	1
learning or memory	1
response to chemical	1
intracellular monoatomic anion homeostasis	1
chloride ion homeostasis	1
multicellular organismal process	1
developmental growth	1
behavior	1
response to temperature stimulus	1
regulation of intracellular pH	1
monoatomic anion homeostasis	1
monoatomic cation homeostasis	1
dendrite development	1
anatomical structure development	1
receptor localization to synapse	1
regulation of postsynaptic membrane neurotransmitter receptor levels	1
neurotransmitter receptor diffusion trapping	1
postsynaptic specialization membrane	1
regulation of synapse assembly	1
postsynapse assembly	1
regulation of postsynapse organization	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
monoatomic anion transport	1
inorganic anion transport	1
biological_process	1
channel activity	1
ammonium transmembrane transport	1
monoatomic anion transmembrane transporter activity	1
chloride transmembrane transport	1

Protein interactions and networks

STRING

2240 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SLC12A5	WNK3	Q9BYP7	884
SLC12A5	WNK1	P54963	820
SLC12A5	NETO2	Q8NC67	808
SLC12A5	BDNF	P23560	794
SLC12A5	GABRA1	P14867	792
SLC12A5	WNK4	Q96J92	778
SLC12A5	STK39	Q9UEW8	736
SLC12A5	NTRK2	Q16620	660
SLC12A5	GRIN2A	Q12879	658
SLC12A5	WNK2	Q9Y3S1	640
SLC12A5	OXSR1	O95747	626
SLC12A5	SLC32A1	Q9H598	620
SLC12A5	GAD1	Q99259	620
SLC12A5	PVALB	P20472	612
SLC12A5	GAD2	Q05329	612

IntAct

12 interactions, top by confidence:

A	B	Type	Score
NUFIP1	PDE2A	psi-mi:“MI:0914”(association)	0.530
SLC12A4	LGALS3	psi-mi:“MI:0914”(association)	0.530
SLC12A5	YTHDC1	psi-mi:“MI:0915”(physical association)	0.400
SLC12A5	CCR4	psi-mi:“MI:0915”(physical association)	0.370
SLC12A5	F2RL1	psi-mi:“MI:0915”(physical association)	0.370
P		psi-mi:“MI:0914”(association)	0.350
ITM2B	ILVBL	psi-mi:“MI:0914”(association)	0.350
GPM6A	KIF2A	psi-mi:“MI:0914”(association)	0.350
DGUOK	BIN1	psi-mi:“MI:0914”(association)	0.350
CLGN	TMEM131L	psi-mi:“MI:0914”(association)	0.350
SLC12A5	KIF2A	psi-mi:“MI:0914”(association)	0.350

BioGRID (35): SLC12A5 (Affinity Capture-MS), SLC12A5 (Affinity Capture-MS), SLC12A5 (Affinity Capture-MS), SLC12A5 (Affinity Capture-MS), SLC12A5 (Proximity Label-MS), SLC12A5 (Two-hybrid), SLC12A5 (Two-hybrid), SLC12A5 (Affinity Capture-MS), SLC12A5 (Affinity Capture-MS), SLC12A5 (Affinity Capture-MS), SLC12A5 (Affinity Capture-MS), BAG5 (Affinity Capture-MS), CDC37 (Affinity Capture-MS), CUX1 (Affinity Capture-MS), CXADR (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, Q0VGW6, Q657W3, A0AV02, Q8VI23, Q9BXP2, Q66HR0, P38329

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
SLC12A5	“down-regulates activity”	chloride	relocalization
WNK1	“down-regulates activity”	SLC12A5	phosphorylation
WNK3	“down-regulates activity”	SLC12A5	phosphorylation
SLC12A5	“down-regulates quantity”	chloride	relocalization

Disease & clinical

Clinical variants and AI predictions

ClinVar

1002 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	32
Likely pathogenic	14
Uncertain significance	359
Likely benign	514
Benign	46

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1070214	NM_020708.5(SLC12A5):c.531_532insT (p.Gly178fs)	Pathogenic
1071231	NM_020708.5(SLC12A5):c.1492dup (p.Ala498fs)	Pathogenic
1073166	NM_020708.5(SLC12A5):c.2490G>A (p.Trp830Ter)	Pathogenic
1076121	NM_020708.5(SLC12A5):c.1845G>A (p.Trp615Ter)	Pathogenic
1362846	NM_020708.5(SLC12A5):c.2519del (p.Leu840fs)	Pathogenic
1364059	NM_020708.5(SLC12A5):c.2301_2302del (p.His768fs)	Pathogenic
1400790	NM_020708.5(SLC12A5):c.1888A>T (p.Lys630Ter)	Pathogenic
1404857	NM_020708.5(SLC12A5):c.2894_2898del (p.Glu965fs)	Pathogenic
1706538	NM_020708.5(SLC12A5):c.2017C>T (p.Gln673Ter)	Pathogenic
2042998	NM_020708.5(SLC12A5):c.962del (p.Phe321fs)	Pathogenic
2053420	NM_020708.5(SLC12A5):c.1287del (p.Lys429fs)	Pathogenic
2054215	NM_020708.5(SLC12A5):c.3159_3180del (p.Ala1053_Val1054insTer)	Pathogenic
2067002	NM_020708.5(SLC12A5):c.2708_2709del (p.Thr902_Tyr903insTer)	Pathogenic
2099159	NM_020708.5(SLC12A5):c.966C>A (p.Cys322Ter)	Pathogenic
2123969	NM_020708.5(SLC12A5):c.1936C>T (p.Arg646Ter)	Pathogenic
217906	NM_020708.5(SLC12A5):c.863T>A (p.Leu288His)	Pathogenic
2746599	NM_020708.5(SLC12A5):c.1787G>A (p.Trp596Ter)	Pathogenic
2825133	NM_020708.5(SLC12A5):c.2297del (p.Leu766fs)	Pathogenic
3640285	NM_020708.5(SLC12A5):c.2009G>A (p.Trp670Ter)	Pathogenic
3652634	NM_020708.5(SLC12A5):c.2161C>T (p.Gln721Ter)	Pathogenic
3663788	NM_020708.5(SLC12A5):c.542del (p.Gly181fs)	Pathogenic
4712630	NM_020708.5(SLC12A5):c.3050del (p.Lys1017fs)	Pathogenic
4725593	NM_020708.5(SLC12A5):c.687del (p.Asn229fs)	Pathogenic
475662	NM_020708.5(SLC12A5):c.980dup (p.Asn328fs)	Pathogenic
542316	NM_020708.5(SLC12A5):c.710_711del (p.Val237fs)	Pathogenic
659657	NM_020708.5(SLC12A5):c.115G>T (p.Glu39Ter)	Pathogenic
833121	NC_000020.11:g.(?46021746)(46057625_?)del	Pathogenic
833486	NC_000020.11:g.(?46045858)(46046456_?)del	Pathogenic
848475	NM_020708.5(SLC12A5):c.2250dup (p.Arg751fs)	Pathogenic
856637	NM_020708.5(SLC12A5):c.266del (p.Lys89fs)	Pathogenic

SpliceAI

3907 predictions. Top by Δscore:

Variant	Effect	Δscore
20:46029393:CCGGG:C	donor_loss	1.0000
20:46029395:GG:G	donor_gain	1.0000
20:46029396:GG:G	donor_gain	1.0000
20:46029396:GGT:G	donor_loss	1.0000
20:46029397:G:A	donor_loss	1.0000
20:46029397:G:GG	donor_gain	1.0000
20:46029398:T:G	donor_loss	1.0000
20:46035038:TTGAG:T	donor_loss	1.0000
20:46035039:TGAGG:T	donor_loss	1.0000
20:46035040:GAGGT:G	donor_loss	1.0000
20:46035041:AG:A	donor_loss	1.0000
20:46035042:GGT:G	donor_loss	1.0000
20:46035044:T:A	donor_loss	1.0000
20:46035531:TGCAG:T	donor_loss	1.0000
20:46035534:AGGT:A	donor_loss	1.0000
20:46035535:GGTG:G	donor_loss	1.0000
20:46035536:GTG:G	donor_loss	1.0000
20:46035537:T:G	donor_loss	1.0000
20:46035771:TGGCA:T	acceptor_loss	1.0000
20:46035772:GGCAG:G	acceptor_loss	1.0000
20:46035773:GCAGG:G	acceptor_loss	1.0000
20:46035774:CAG:C	acceptor_loss	1.0000
20:46035775:A:AG	acceptor_gain	1.0000
20:46035776:G:GG	acceptor_gain	1.0000
20:46035919:CCTGT:C	donor_gain	1.0000
20:46035920:CTGT:C	donor_gain	1.0000
20:46035921:TGTGT:T	donor_loss	1.0000
20:46035922:GT:G	donor_gain	1.0000
20:46035924:G:A	donor_loss	1.0000
20:46035924:G:GG	donor_gain	1.0000

AlphaMissense

7336 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:46035037:T:C	F71L	1.000
20:46035039:T:A	F71L	1.000
20:46035039:T:G	F71L	1.000
20:46035801:G:C	G125R	1.000
20:46035801:G:T	G125C	1.000
20:46035802:G:A	G125D	1.000
20:46035807:T:G	Y127D	1.000
20:46035814:C:A	P129Q	1.000
20:46035814:C:G	P129R	1.000
20:46035817:G:A	C130Y	1.000
20:46035818:C:G	C130W	1.000
20:46035820:T:C	L131P	1.000
20:46035824:G:C	Q132H	1.000
20:46035824:G:T	Q132H	1.000
20:46035827:C:A	N133K	1.000
20:46035827:C:G	N133K	1.000
20:46035834:G:C	G136R	1.000
20:46035834:G:T	G136C	1.000
20:46035835:G:A	G136D	1.000
20:46035835:G:T	G136V	1.000
20:46035846:T:A	F140I	1.000
20:46035846:T:C	F140L	1.000
20:46035848:C:A	F140L	1.000
20:46035848:C:G	F140L	1.000
20:46035861:T:A	W145R	1.000
20:46035861:T:C	W145R	1.000
20:46035917:C:G	C163W	1.000
20:46036748:T:C	L168P	1.000
20:46036753:G:C	A170P	1.000
20:46036760:C:A	S172Y	1.000

dbSNP variants (sampled 300 via entrez): RS1000077817 (20:46058675 A>T), RS1000152518 (20:46058455 G>A,C), RS1000215395 (20:46037953 A>G), RS1000226778 (20:46041084 A>T), RS1000273432 (20:46044526 AGG>A), RS1000296700 (20:46050386 A>G), RS1000390031 (20:46044219 G>A), RS1000460510 (20:46050067 G>T), RS1000470648 (20:46029111 C>T), RS1000508031 (20:46039836 A>G), RS1000632403 (20:46048939 A>G), RS1000684212 (20:46033886 G>A), RS1000736401 (20:46033665 C>A,G,T), RS1000748439 (20:46048637 G>A), RS1000860359 (20:46055455 G>T)

Disease associations

OMIM: gene MIM:606726 | disease phenotypes: MIM:616645, MIM:616685

GenCC curated gene-disease

Disease	Classification	Inheritance
developmental and epileptic encephalopathy, 34	Strong	Autosomal recessive
epilepsy of infancy with migrating focal seizures	Strong	Autosomal recessive
malignant migrating partial seizures of infancy	Supportive	Autosomal dominant
epilepsy, idiopathic generalized, susceptibility to, 14	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
genetic developmental and epileptic encephalopathy	Limited	AR

Mondo (8): developmental and epileptic encephalopathy, 34 (MONDO:0014718), epilepsy, idiopathic generalized, susceptibility to, 14 (MONDO:0014734), movement disorder (MONDO:0005395), developmental and epileptic encephalopathy (MONDO:0100620), intellectual disability (MONDO:0001071), microcephaly (MONDO:0001149), malignant migrating partial seizures of infancy (MONDO:0017385), (MONDO:0100025)

Orphanet (2): Epilepsy of infancy with migrating focal seizures (Orphanet:293181), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

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

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000505	Visual impairment
HP:0000826	Precocious puberty
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001273	Abnormal corpus callosum morphology
HP:0001276	Hypertonia
HP:0001508	Failure to thrive
HP:0002059	Cerebral atrophy
HP:0002069	Bilateral tonic-clonic seizure
HP:0002121	Generalized non-motor (absence) seizure
HP:0002123	Generalized myoclonic seizure
HP:0002133	Status epilepticus
HP:0002188	Delayed CNS myelination
HP:0002373	Febrile seizure (within the age range of 3 months to 6 years)
HP:0002376	Developmental regression
HP:0002384	Focal impaired awareness seizure
HP:0002521	Hypsarrhythmia
HP:0002540	Inability to walk
HP:0002650	Scoliosis
HP:0003593	Infantile onset
HP:0003621	Juvenile onset
HP:0003781	Excessive salivation
HP:0003829	Typified by incomplete penetrance
HP:0004302	Functional motor deficit
HP:0005484	Secondary microcephaly

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST004131_122	Inflammatory bowel disease	2.000000e-06
GCST004132_43	Crohn’s disease	2.000000e-07
GCST005554_4	Systemic sclerosis	1.000000e-07
GCST007325_173	General risk tolerance (MTAG)	1.000000e-08
GCST007576_286	Chronotype	4.000000e-09
GCST010173_37	Triglyceride levels	4.000000e-66
GCST011528_7	Response to antidepressants (symptom improvement)	2.000000e-06
GCST90002405_450	Reticulocyte count	2.000000e-09
GCST90013406_186	Liver enzyme levels (alkaline phosphatase)	2.000000e-13

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0008579	risk-taking behaviour
EFO:0008328	chronotype measurement
EFO:0004530	triglyceride measurement
EFO:0007006	depressive symptom measurement
EFO:0007986	reticulocyte count
EFO:0004533	alkaline phosphatase measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
D009069	Movement Disorders	C10.228.662

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL1615384 (SINGLE PROTEIN), CHEMBL3885641 (PROTEIN COMPLEX)

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 (1 total), top 1:

Ligand	Action	Affinity	Parameter
VU0240551	Inhibition	6.25	pIC50

Binding affinities (BindingDB)

436 measured of 442 human assays (450 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
3-(butylamino)-4-phenoxy-5-sulfamoylbenzoic acid	EC50	0.0469 nM
6-amino-3-methyl-5-[1-oxo-2-[[5-(phenylmethyl)-1,3,4-oxadiazol-2-yl]thio]ethyl]-1-propylpyrimidine-2,4-dione	EC50	0.11 nM
2-(4-Isobutoxy-phenyl)-5-(4-methoxy-phenyl)-[1,3,4]oxadiazole	EC50	1.27 nM
MLS000547345	EC50	10.6 nM
(4E)-4-[(2,4-difluoroanilino)methylene]-5-ethoxy-2-phenyl-2-pyrazolin-3-one	EC50	32.3 nM
5-(4-ethoxyanilino)-3H-1,3,4-thiadiazole-2-thione	EC50	46.5 nM
3-[(2-fluorophenyl)methylsulfanyl]-N-[(E)-3-phenylprop-2-enyl]-1,2,4-triazol-4-amine	EC50	56.7 nM
1-Benzo[1,3]dioxol-5-yl-3-(4-chloro-benzoyl)-thiourea	EC50	74.1 nM
1-(1-benzofuran-2-yl)-2-[[5-(3,4-dimethylanilino)-1,3,4-thiadiazol-2-yl]sulfanyl]ethanone	EC50	85.3 nM
6,8-Diphenyl-3,4a,7a,8-tetrahydro-pyrrolo[3’,4’:5,6]thiopyrano[2,3-d]thiazole-2,5,7-trione	EC50	102 nM
7-[[5-(4-ethylanilino)-1,3,4-thiadiazol-2-yl]sulfanylmethyl]-[1,3]thiazolo[3,2-a]pyrimidin-5-one	EC50	113 nM
MLS000688132	EC50	124 nM
MLS000558851	EC50	128 nM
2-[[(E)-1-oxo-3-phenylprop-2-enyl]amino]-4-phenyl-3-thiophenecarboxylic acid	EC50	134 nM
1-(2-Methyl-2,3-dihydro-indol-1-yl)-2-(5-phenylaminomethyl-[1,3,4]oxadiazol-2-ylsulfanyl)-ethanone	EC50	137 nM
2-(2,4-diketo-1,3-diazaspiro[4.4]nonan-3-yl)-N-[4-(4-fluorophenyl)thiazol-2-yl]acetamide	EC50	156 nM
2-[6-(4-fluorophenyl)pyridazin-3-yl]sulfanyl-N-(5-methyl-1,2-oxazol-3-yl)acetamide	EC50	171 nM
MLS000858987	EC50	174 nM
4-methoxy-N-[4-(4-nitrophenyl)piperazin-1-yl]carbothioyl-benzamide	EC50	178 nM
1-[2-Methyl-5-(5-methyl-benzooxazol-2-yl)-phenyl]-3-(thiophene-2-carbonyl)-thiourea	EC50	200 nM
N-(4-methyl-1,3-thiazol-2-yl)-2-(6-phenylpyridazin-3-yl)sulfanyl-ethanamide	EC50	249 nM
5-(1-naphthalenylmethyl)-3H-1,3,4-oxadiazole-2-thione	EC50	269 nM
MLS000674627	EC50	270 nM
3-(2-chlorophenyl)-5-methyl-N-(p-cumenylthiocarbamoyl)isoxazole-4-carboxamide	EC50	271 nM
(E)-3-(4-chlorophenyl)-2-[[5-(4-methoxyphenyl)-1,3,4-oxadiazol-2-yl]sulfanyl]prop-2-enoic acid	EC50	287 nM
1-[(Z)-[2-oxidanylidene-1-(phenylmethyl)indol-3-ylidene]amino]thiourea	EC50	295 nM
6-(4-ethoxyphenyl)-8-[(E)-2-phenylethenyl]-3,4a,7a,8-tetrahydropyrrolo[2,3]thiopyrano[4,5-b][1,3]thiazole-2,5,7-trione	IC50	300 nM
2-[(4-fluorobenzyl)thio]-N-[2-(2-fluorophenoxy)ethyl]benzamide	EC50	313 nM
(4-benzylpiperazin-1-yl)-(4-nitro-5-propan-2-yl-1,2-oxazol-3-yl)methanone	EC50	340 nM
(2-methyl-2,3-dihydroindol-1-yl)-(3-nitro-4-pyrrolidin-1-yl-phenyl)methanone	EC50	361 nM
1-[(5-bromanyl-2-oxidanylidene-indol-3-yl)amino]-3-(2-methoxyphenyl)thiourea	EC50	363 nM
2-chloranyl-5-[methyl-(phenylmethyl)sulfamoyl]-N-(2-pyridin-2-ylethyl)benzamide	EC50	373 nM
1-(4-azepan-1-yl-3-nitrobenzoyl)indoline	EC50	373 nM
MLS000558849	EC50	380 nM
1-(4-methoxybenzyl)-1H-benzimidazole-2-thiol	EC50	385 nM
3-(4-fluorobenzyl)-2-methyl-1-(2-thienylsulfonyl)isothiourea	EC50	498 nM
1-(2-fluorophenyl)-4-(4-nitrophenyl)-1,3-dihydro-2H-imidazole-2-thione	EC50	507 nM
MLS000047204	EC50	610 nM
3-[2-(1-naphthalenylmethylthio)-1-benzimidazolyl]propanoic acid	EC50	619 nM
2-(2-methoxyphenyl)-5-[4-(phenylmethyl)-1-piperidinyl]-4-oxazolecarbonitrile	EC50	733 nM
MLS000763429	EC50	806 nM
1-(5-bromanylthiophen-2-yl)-2-[[5-[(2,4-dimethylphenyl)amino]-1,3,4-thiadiazol-2-yl]sulfanyl]ethanone	EC50	1020 nM
1-phenyl-2-(6-phenylpyridazin-3-yl)sulfanyl-ethanone	EC50	1060 nM
2-[(5-chloranylthiophen-2-yl)sulfonylamino]-N-(4-methylphenyl)benzamide	EC50	1070 nM
3-(4-aminophenyl)-7-(diethylamino)-4-methyl-1-benzopyran-2-one	EC50	1080 nM
MLS000393282	EC50	1100 nM
MLS000074514	EC50	1130 nM
(phenylmethyl) 2-[[(Z)-2-[(4-bromophenyl)carbonylamino]-3-phenyl-prop-2-enoyl]amino]ethanoate	EC50	1150 nM
(2,6-dimethoxy-4-morpholin-4-ylcarbothioyl-phenyl) 2-phenylethanoate	EC50	1160 nM
2-(7-keto-3-phenyl-triazolo[4,5-d]pyrimidin-6-yl)-N-phenethyl-acetamide	EC50	1170 nM

ChEMBL bioactivities

29 potent at pChembl≥5 of 36 total, top 28 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.21	IC50	61	nM	CHEMBL2048855
6.82	IC50	152	nM	CHEMBL2048853
6.75	IC50	177	nM	CHEMBL2048856
6.52	IC50	300	nM	CHEMBL1448067
6.42	IC50	385	nM	CHEMBL2048854
6.27	IC50	537	nM	CHEMBL2048846
6.25	IC50	568	nM	CHEMBL1491962
6.25	IC50	560	nM	CHEMBL1491962
6.24	IC50	570	nM	CHEMBL2048853
6.19	IC50	640	nM	CHEMBL2048858
6.19	IC50	640	nM	CHEMBL1334636
6.12	IC50	756	nM	CHEMBL2048854
5.98	IC50	1057	nM	CHEMBL2048857
5.92	IC50	1200	nM	CHEMBL1332312
5.89	IC50	1300	nM	CHEMBL1492301
5.82	IC50	1500	nM	CHEMBL1373514
5.80	IC50	1600	nM	CHEMBL1360609
5.72	IC50	1900	nM	CHEMBL2048853
5.66	IC50	2200	nM	CHEMBL1489121
5.60	IC50	2500	nM	CHEMBL1561213
5.54	IC50	2900	nM	CHEMBL2048848
5.54	IC50	2900	nM	CHEMBL1344797
5.29	IC50	5100	nM	CHEMBL1414895
5.22	IC50	6000	nM	CHEMBL1414260
5.16	IC50	6900	nM	CHEMBL2048847
5.11	IC50	7700	nM	CHEMBL1331068
5.10	IC50	7900	nM	CHEMBL1331422
5.04	IC50	9100	nM	CHEMBL1449947

PubChem BioAssay actives

14 with measured affinity, of 37 total; 11 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
N-cyclopropyl-N-(4-methyl-1,3-thiazol-2-yl)-2-(6-phenylpyridazin-3-yl)sulfanylacetamide	670901: Antagonist activity at KCC2 expressed in human HEK293 cells assessed as decrease in Tl-stimulated fluorescence increase after 8 mins by fluorescence analysis	ic50	0.0610	uM
N-cyclopropyl-N-(4-methyl-1,3-thiazol-2-yl)-2-(6-phenylpyridazin-3-yl)sulfanylpropanamide	670901: Antagonist activity at KCC2 expressed in human HEK293 cells assessed as decrease in Tl-stimulated fluorescence increase after 8 mins by fluorescence analysis	ic50	0.1520	uM
N-cyclobutyl-N-(4-methyl-1,3-thiazol-2-yl)-2-(6-phenylpyridazin-3-yl)sulfanylacetamide	670901: Antagonist activity at KCC2 expressed in human HEK293 cells assessed as decrease in Tl-stimulated fluorescence increase after 8 mins by fluorescence analysis	ic50	0.1770	uM
N-cyclopropyl-N-(4-methyl-1,3-thiazol-2-yl)-2-(6-phenylpyridazin-3-yl)sulfanylbutanamide	670901: Antagonist activity at KCC2 expressed in human HEK293 cells assessed as decrease in Tl-stimulated fluorescence increase after 8 mins by fluorescence analysis	ic50	0.3850	uM
N-methyl-N-(4-methyl-1,3-thiazol-2-yl)-2-(6-phenylpyridazin-3-yl)sulfanylacetamide	670901: Antagonist activity at KCC2 expressed in human HEK293 cells assessed as decrease in Tl-stimulated fluorescence increase after 8 mins by fluorescence analysis	ic50	0.5370	uM
N-(4-methyl-1,3-thiazol-2-yl)-2-(6-phenylpyridazin-3-yl)sulfanylacetamide	670901: Antagonist activity at KCC2 expressed in human HEK293 cells assessed as decrease in Tl-stimulated fluorescence increase after 8 mins by fluorescence analysis	ic50	0.5680	uM
6-amino-5-[2-[(5-benzyl-1,3,4-oxadiazol-2-yl)sulfanyl]acetyl]-3-methyl-1-propyl-1,3-diazinane-2,4-dione	670901: Antagonist activity at KCC2 expressed in human HEK293 cells assessed as decrease in Tl-stimulated fluorescence increase after 8 mins by fluorescence analysis	ic50	0.6400	uM
N-cyclopentyl-N-(4-methyl-1,3-thiazol-2-yl)-2-(6-phenylpyridazin-3-yl)sulfanylacetamide	670901: Antagonist activity at KCC2 expressed in human HEK293 cells assessed as decrease in Tl-stimulated fluorescence increase after 8 mins by fluorescence analysis	ic50	1.0570	uM
3-benzyl-6-[2-(4-chlorophenyl)-2-oxoethyl]triazolo[4,5-d]pyrimidin-7-one	670901: Antagonist activity at KCC2 expressed in human HEK293 cells assessed as decrease in Tl-stimulated fluorescence increase after 8 mins by fluorescence analysis	ic50	1.2000	uM
N-methyl-N-(4-methyl-1,3-thiazol-2-yl)-2-[(5-phenyl-2-pyridinyl)sulfanyl]acetamide	670901: Antagonist activity at KCC2 expressed in human HEK293 cells assessed as decrease in Tl-stimulated fluorescence increase after 8 mins by fluorescence analysis	ic50	2.9000	uM
N-(4-methyl-1,3-thiazol-2-yl)-2-[(5-phenyl-2-pyridinyl)sulfanyl]acetamide	670901: Antagonist activity at KCC2 expressed in human HEK293 cells assessed as decrease in Tl-stimulated fluorescence increase after 8 mins by fluorescence analysis	ic50	6.9000	uM

CTD chemical–gene interactions

22 total (human), top 22 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects binding, increases reaction, decreases expression	1
arsenite	increases methylation	1
sodium arsenite	affects methylation	1
cobaltous chloride	increases expression	1
butyraldehyde	decreases expression	1
((dihydroindenyl)oxy)alkanoic acid	decreases reaction, increases import	1
Resveratrol	affects cotreatment, decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Chlorpyrifos	affects expression, affects response to substance	1
Estradiol	affects cotreatment, increases expression	1
Ethylmaleimide	decreases reaction, increases import, increases activity	1
Furosemide	decreases reaction, increases import	1
Ivermectin	decreases expression	1
Lead	affects expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Silicon Dioxide	decreases expression	1
Thallium	decreases reaction, increases import	1
Gold Compounds	decreases methylation, increases expression	1
Uranium Compounds	increases expression	1
Staurosporine	increases import, increases activity, decreases reaction	1
Particulate Matter	decreases expression, increases abundance	1

ChEMBL screening assays

6 unique, capped per target: 4 functional, 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2049717	Functional	Antagonist activity at KCC2 expressed in human HEK293 cells assessed as decrease in Tl-stimulated fluorescence increase at 2 uM after 8 mins by fluorescence analysis	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
CHEMBL2049732	Binding	Ratio of IC50 for ML077 to compound IC50 for KCC2 expressed in human HEK293 cells assessed as decrease in Tl-stimulated fluorescence increase at 2 uM after 8 mins by fluorescence analysis	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

Cellosaurus cell lines

7 cell lines: 7 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D1YZ	Abcam A-549 SLC12A5 KO	Cancer cell line	Male
CVCL_D2D0	Abcam HCT 116 SLC12A5 KO	Cancer cell line	Male
CVCL_D2P4	Abcam THP-1 SLC12A5 KO	Cancer cell line	Male
CVCL_D4RN	HuH7-SLC12A5-KO-c3	Cancer cell line	Male
CVCL_D4RP	HuH7-SLC12A5-KO-c4	Cancer cell line	Male
CVCL_TL52	HAP1 SLC12A5 (-) 1	Cancer cell line	Male
CVCL_TL53	HAP1 SLC12A5 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01662414	PHASE4	COMPLETED	Effect of Undenatured Cysteine-Rich Whey Protein Isolate (HMS 90®) in Patients With Parkinson’s Disease
NCT04871464	PHASE4	UNKNOWN	Role and Mechanism of Probiotics in Improving Motor Symptoms in Mild to Moderate Parkinson’s Disease
NCT06710574	PHASE4	RECRUITING	Multimodal Image Technologies Investigate the Role and Mechanism of Probiotics in Improving RBD with Parkinson’s Disease
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT01838278	PHASE3	UNKNOWN	Effectiveness of Vojta Therapy in Motor Development of Preterm Children
NCT03347526	PHASE3	SUSPENDED	A Novel Approach to Infantile Spasms
NCT03421496	PHASE3	TERMINATED	A Study to Assess Cannabidiol Oral Solution With Vigabatrin as Initial Therapy in Participants With Infantile Spasms
NCT06719141	PHASE3	RECRUITING	A Study to Investigate LP352 in Children and Adults With Developmental and Epileptic Encephalopathies (DEE)
NCT06908226	PHASE3	ENROLLING_BY_INVITATION	A Study to Investigate LP352 in Children and Adults With Developmental and Epileptic Encephalopathy (DEE)
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT00001929	PHASE2	COMPLETED	Treatment of Parkinson’s Disease With Eliprodil
NCT00331669	PHASE2	UNKNOWN	Efficacy and Safety of Deep Brain Stimulation (DBS) of the Pallidal (GPi) in Patients With Tardive Dystonia
NCT00406029	PHASE2	COMPLETED	Dyskinesia in Parkinson’s Disease (Study P04501)
NCT00537017	PHASE2	COMPLETED	Follow Up Safety Study of SCH 420814 in Subjects With Parkinson’s Disease (P05175)
NCT00693472	PHASE2	TERMINATED	Study of Preladenant for the Treatment of Neuroleptic Induced Akathisia (Study P05145)
NCT01385592	PHASE2	COMPLETED	Evaluation of the Efficacy and Safety of AFQ056 in Parkinson’s Patients With L-dopa Induced Dyskinesias
NCT01491529	PHASE2	COMPLETED	Evaluation of the Efficacy and Safety of Modified Release AFQ056 in Parkinson’s Patients With L-dopa Induced Dyskinesias
NCT01491932	PHASE2	COMPLETED	Open-label, Long-term Safety Extension Study of AFQ056 in Parkinson’s Patients With L-dopa Induced Dyskinesias
NCT02500628	PHASE2	COMPLETED	Heart Rate Variability in Response to Metformin Challenge
NCT04536987	PHASE2	COMPLETED	Robot Therapy for Rehabilitation of Hand Movement After Stroke
NCT04912115	PHASE2	SUSPENDED	Randomized, Double-Blind, Active Placebo-Controlled Study of Ketamine to Treat Levodopa-Induced Dyskinesia
NCT05636852	PHASE2	TERMINATED	Altropane Dose for Imaging Patients With Suspected Parkinson’s Disease
NCT04289467	PHASE2	RECRUITING	Treatment of Refractory Infantile Spasms With Fenfluramine
NCT05626634	PHASE2	COMPLETED	Open-label, Long-term Safety Study of LP352 in Subjects With Developmental and Epileptic Encephalopathy
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT00001663	PHASE1	COMPLETED	Treatment of Cortical Myoclonus With Repetitive Transcranial Magnetic Stimulation
NCT02589340	PHASE1	TERMINATED	Buspirone, in Combination With Amantadine, for the Treatment of Levodopa-induced Dyskinesia
NCT03065192	PHASE1	COMPLETED	Safety and Efficacy Study of VY-AADC01 for Advanced Parkinson’s Disease
NCT07232147	PHASE1	NOT_YET_RECRUITING	Clinical Research on Stem Cell Therapy for Parkinson’s Disease
NCT04727970	PHASE1	COMPLETED	Tricaprilin Infantile Spasms Pilot Study
NCT06700811	PHASE1	RECRUITING	Ketogenic Diet for Prevention of Epileptic Spasms in Infantile Onset Genetic Epilepsies
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism