KCNK9

Summary

KCNK9 (potassium two pore domain channel subfamily K member 9, HGNC:6283) is a protein-coding gene on chromosome 8q24.3, encoding Potassium channel subfamily K member 9 (Q9NPC2). K(+) channel that conducts voltage-dependent outward rectifying currents upon membrane depolarization.

This gene encodes a protein that contains multiple transmembrane regions and two pore-forming P domains and functions as a pH-dependent potassium channel. Amplification and overexpression of this gene have been observed in several types of human carcinomas. This gene is imprinted in the brain, with preferential expression from the maternal allele. A mutation in this gene was associated with Birk-Barel dysmorphism syndrome. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 51305 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Birk-Barel syndrome (Strong, GenCC)
• GWAS associations: 11
• Clinical variants (ClinVar): 86 total — 3 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 45
• Druggable target: yes — 4 molecules with ChEMBL bioactivity
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001282534

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6283
Approved symbol	KCNK9
Name	potassium two pore domain channel subfamily K member 9
Location	8q24.3
Locus type	gene with protein product
Status	Approved
Aliases	K2p9.1, TASK3, TASK-3
Ensembl gene	ENSG00000169427
Ensembl biotype	protein_coding
OMIM	605874
Entrez	51305

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 5 protein_coding, 4 protein_coding_CDS_not_defined, 3 nonsense_mediated_decay

ENST00000303015, ENST00000519923, ENST00000520439, ENST00000522317, ENST00000523477, ENST00000523653, ENST00000647605, ENST00000648164, ENST00000648481, ENST00000649473, ENST00000649696, ENST00000650269

RefSeq mRNA: 1 — MANE Select: NM_001282534 NM_001282534

CCDS: CCDS6377

Canonical transcript exons

ENST00000520439 — 2 exons

Exon	Start	End
ENSE00001157745	139702710	139703123
ENSE00003836170	139617121	139619099

Expression profiles

Bgee: expression breadth ubiquitous, 137 present calls, max score 96.25.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.6290 / max 155.6492, expressed in 136 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
95309	0.1750	64
95301	0.1196	33
95310	0.0786	29
95311	0.0613	17
95308	0.0545	22
205372	0.0342	11
95307	0.0321	14
95303	0.0318	7
95300	0.0307	10
205373	0.0113	1

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cerebellar hemisphere	UBERON:0002245	96.25	gold quality
right hemisphere of cerebellum	UBERON:0014890	96.14	gold quality
cerebellar cortex	UBERON:0002129	96.10	gold quality
cerebellum	UBERON:0002037	95.29	gold quality
cortical plate	UBERON:0005343	86.60	gold quality
cerebellar vermis	UBERON:0004720	83.15	gold quality
left ventricle myocardium	UBERON:0006566	81.27	gold quality
cardiac muscle of right atrium	UBERON:0003379	81.19	gold quality
right frontal lobe	UBERON:0002810	81.03	gold quality
secondary oocyte	CL:0000655	79.32	gold quality
kidney epithelium	UBERON:0004819	79.14	gold quality
Brodmann (1909) area 9	UBERON:0013540	78.87	gold quality
prefrontal cortex	UBERON:0000451	78.86	gold quality
primary visual cortex	UBERON:0002436	77.99	gold quality
Brodmann (1909) area 23	UBERON:0013554	77.73	silver quality
dorsolateral prefrontal cortex	UBERON:0009834	77.18	gold quality
frontal cortex	UBERON:0001870	77.17	gold quality
neocortex	UBERON:0001950	76.69	gold quality
hypothalamus	UBERON:0001898	75.82	gold quality
middle temporal gyrus	UBERON:0002771	75.76	silver quality
tibialis anterior	UBERON:0001385	75.29	silver quality
anterior cingulate cortex	UBERON:0009835	74.98	gold quality
cerebral cortex	UBERON:0000956	73.74	gold quality
occipital lobe	UBERON:0002021	70.66	gold quality
superior frontal gyrus	UBERON:0002661	69.99	gold quality
brain	UBERON:0000955	69.49	gold quality
endothelial cell	CL:0000115	69.33	gold quality
pons	UBERON:0000988	68.13	gold quality
postcentral gyrus	UBERON:0002581	66.48	silver quality
forebrain	UBERON:0001890	66.47	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	2.77

Regulation

Is transcription factor: no

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• TASK-1 and TASK-3 differed insofar as a large portion of the C terminus was necessary for the full effects of halothane and TRH on TASK-3 but not on TASK-1 (PMID:11886861)
• Overexpression of KCNK9 in cell lines promotes tumor formation and confers resistance to both hypoxia and serum deprivation. (PMID:12676587)
• results establish a direct link between the potassium channel activity of TASK3 and its oncogenic functions and imply that blockers for this potassium channel may have therapeutic potential for the treatment of cancers (PMID:12782791)
• TASK3 is expressed in pia mater, astrocytes, Purkinje and granule cells (PMID:15197476)
• TASK-3 channels underlie a major component of cerebellar granule neurons leak current which is sensitive to block by zinc (PMID:15284350)
• Overexpression rather than mutation of the KCNK9 gene may contribute to the development of colorectal cancers. (PMID:15601307)
• The expression pattern of TASK-3 in Melanoma cells is determined. (PMID:17013562)
• (Glutamic acid-aspartic acid-glutamic acid) in human TASK-3 is a major determinant of the rate of endoplasmic reticulum export and is required for efficient surface expression of the channel. (PMID:17547699)
• KCNK9 gene is imprinted in human and mouse, exhibiting preferential expression from the maternal allele in brain. (PMID:17704508)
• TASK-3 channels are present in the mitochondria in both malignantly transformed and healthy cells, suggesting that they might have roles in ensuring mitochondrial functions. (PMID:18094996)
• TASK3 channels may possibly represent a novel molecular target for the treatment of human glioblastoma (PMID:18217213)
• K(2)P channels as novel potassium conductance on T lymphocytes critically influencing T cell effector function and identify a possible molecular target for immunomodulation in T cell-mediated autoimmune disorders (PMID:18375952)
• the TASK3 M1P1 loop lies close to the pore, regulating TASK3 channel activity (PMID:18417474)
• a mutation in the genomically imprinted potassium channel KCNK9 may have a role in the maternally inherited Birk Barel mental retardation dysmorphism syndrome (PMID:18678320)
• Thus, regulated expression of TASK channels might contribute to a molecular switch between death and survival of neurons in autoimmune CNS inflammation. (PMID:18824070)
• Both TASK-3 and TREK-1 are functionally operational in the adrenocortical H295R cell line, modulate membrane potential and aldosterone secretion. (PMID:18854423)
• TASK-3 responds to voltage in a way that reveals gating at its inner, cytoplasmic mouth through movements of membrane helices M2 and M4. (PMID:19703964)
• TASK-1 and 3 are determinant of aldosterone secretion and adrenocortical zonation. (PMID:20049674)
• Western analysis confirms expression of TASK1 and TASK3 in medulloblastoma cells. (PMID:20931182)
• cAMP-dependent protein kinase is responsible for the phosphorylation of the terminal serine in both K(2P)3.1 and K(2P)9.1 (PMID:21357689)
• TASK-3 channels are functionally present in the mitochondria of the melanoma cells, and their function is essential for the survival of these cells. (PMID:21512417)
• Depletion of the endogenous phosphatidylinositol-4,5-bisphosphate pool in living cells consistently finds no change in currents mediated by TASK-1 and TASK-3. (PMID:21540350)
• TASK-3 immunoreactivity was detected in both astrocytes and microglia of temporal lobe epilepsy patients. (PMID:21710317)
• an increase in TASK-3 expression levels reduces cell migration/invasion in breast cancer cells (PMID:21910834)
• Results of an exploratory study suggest that blood pressure and aldosterone production may be affected by variations in KCNK9. The findings could have relevance to risk for hypertension. (PMID:22893713)
• Overexpression of TASK-3 expression is associated with ovarian cancer. (PMID:23564779)
• K2P3.1 and K2P9.1 undergo rapid dynamin-dependent endocytosis (PMID:23807092)
• We observed co-localization of the TASK-3 protein and a mitochondrial marker in the mitochondria of HaCaT cells. (PMID:24126847)
• TNFalpha activation and TASK3 channel activity can promote cellular apoptosis. (PMID:24307172)
• By both a gain-of-function additional mutation of TASK3 channels. (PMID:24342771)
• For KCNK9, two SNPs (i.e., rs3780039, rs11166921) were associated with the occurrence of preoperative breast pain. (PMID:24392765)
• Mutations of KCNK9 or epigenetic disturbances within the PEG13 imprinted cluster do not significantly contribute to the cause of the developmental disabilities tested in this study. (PMID:24980697)
• Two SNPs replicated: the paternal rs2471083-C allele (located near the imprinted KCNK9 gene) and the paternal rs3091869-T allele (located near the SLC2A10 gene) increased BMI equally (beta = 0.11 (SD), P<0.0027) (PMID:25078964)
• Interference with TASK-3 channel expression, therefore, induces caspase-dependent and -independent apoptosis of melanoma cells, most likely via causing mitochondrial depolarization. (PMID:25318378)
• Diacylglycerol mediates regulation of TASK1 and TASK3 potassium channels by GNAQ. (PMID:25420509)
• During conductance simulation experiments, both TASK-3 and TREK-1 channels were able to repolarise the membrane once AP threshold was reached (PMID:25482670)
• The findings of this study suggest that variations in KCNK9 genes are associated with both mild and severe persistent breast pain after breast cancer surgery. (PMID:25599232)
• TASK-1 and TASK-3 may form heterodimers in human atrial cardiomyocytes. (PMID:25655935)
• Our results provide evidence for new loci influencing abdominal visceral (BBS9, ADCY8, KCNK9) and subcutaneous (MLLT10/DNAJC1/EBLN1) fat, and confirmed a locus (THNSL2) previously reported to be associated with abdominal fat in women. (PMID:26480920)
• KCNK9 imprinting syndrome is a rare cause of intellectual disability, congenital hypotonia, palatal abnormalities, and occasional seizures. (PMID:27151206)

Cross-species orthologs

16 orthologs

Organism	Symbol	Gene ID
danio_rerio	kcnk9	ENSDARG00000104563
mus_musculus	Kcnk9	ENSMUSG00000036760
rattus_norvegicus	Kcnk9	ENSRNOG00000009265
drosophila_melanogaster	Ork1	FBGN0017561
drosophila_melanogaster	Task7	FBGN0037690
drosophila_melanogaster	Task6	FBGN0038165
drosophila_melanogaster	CG10864	FBGN0038621
drosophila_melanogaster	CG42340	FBGN0259242
caenorhabditis_elegans		WBGENE00006661
caenorhabditis_elegans		WBGENE00006674
caenorhabditis_elegans		WBGENE00006675
caenorhabditis_elegans		WBGENE00006679
caenorhabditis_elegans		WBGENE00006685
caenorhabditis_elegans		WBGENE00006686
caenorhabditis_elegans		WBGENE00006695
caenorhabditis_elegans		WBGENE00006696

Paralogs (14): KCNK2 (ENSG00000082482), KCNK16 (ENSG00000095981), KCNK6 (ENSG00000099337), KCNK10 (ENSG00000100433), KCNK15 (ENSG00000124249), KCNK17 (ENSG00000124780), KCNK1 (ENSG00000135750), KCNK13 (ENSG00000152315), KCNK5 (ENSG00000164626), KCNK3 (ENSG00000171303), KCNK7 (ENSG00000173338), KCNK4 (ENSG00000182450), KCNK12 (ENSG00000184261), KCNK18 (ENSG00000186795)

Protein

Protein identifiers

Potassium channel subfamily K member 9 — Q9NPC2 (reviewed: Q9NPC2)

Alternative names: Acid-sensitive potassium channel protein TASK-3, TWIK-related acid-sensitive K(+) channel 3, Two pore potassium channel KT3.2

All UniProt accessions (3): A0A3B3ITR0, A0A3B3IU12, Q9NPC2

UniProt curated annotations — full annotation on UniProt →

Function. K(+) channel that conducts voltage-dependent outward rectifying currents upon membrane depolarization. Voltage sensing is coupled to K(+) electrochemical gradient in an ‘ion flux gating’ mode where outward but not inward ion flow opens the gate. Changes ion selectivity and becomes permeable to Na(+) ions in response to extracellular acidification. Protonation of the pH sensor His-98 stabilizes C-type inactivation conformation likely converting the channel from outward K(+)-conducting, to inward Na(+)-conducting to nonconductive state. Homo- and heterodimerizes to form functional channels with distinct regulatory and gating properties. Allows K(+) currents with fast-gating kinetics important for the repolarization and hyperpolarization phases of action potentials. In granule neurons, hyperpolarizes the resting membrane potential to limit intrinsic neuronal excitability, but once the action potential threshold is reached, supports high-frequency action potential firing and increased neuronal excitability. Homomeric and/or heteromeric KCNK3:KCNK9 channels operate in cerebellar granule cells, whereas heteromeric KCNK1:KCNK9 enables currents in hippocampal dentate gyrus granule neurons. Dispensable for central chemosensory respiration i.e. breathing controlled by brainstem CO2/pH, it rather conducts pH-sensitive currents and controls the firing rate of serotonergic raphe neurons involved in potentiation of the respiratory chemoreflex. In retinal ganglion cells, mediates outward currents that regulate action potentials in response to acidification of the synaptic cleft. Involved in transmission of image-forming and nonimage-forming visual information in the retina. In adrenal gland, contributes to the maintenance of a hyperpolarized resting membrane potential of aldosterone-producing cells at zona glomerulosa and limits aldosterone release as part of a regulatory mechanism that controls arterial blood pressure and electrolyte homeostasis.

Subunit / interactions. Homodimer. Heterodimer with KCNK1. Heterodimer with KCNK3.

Subcellular location. Cell membrane. Mitochondrion inner membrane. Cell projection. Dendrite.

Tissue specificity. Mainly found in the cerebellum. Also found in adrenal gland, kidney and lung.

Disease relevance. Birk-Barel syndrome (BIBARS) [MIM:612292] A syndrome characterized by intellectual disability, hypotonia, hyperactivity, and facial dysmorphism. BIBARS transmission pattern is consistent with autosomal dominant inheritance with paternal imprinting. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Inhibited by extracellular acidification adopting a nonconductive conformation at pH 6.0. Inhibited by phorbol 12-myristate 13-acetate (PMA).

Domain organisation. Each subunit contributes two pore-forming domains 1 and 2 which assemble to form a single pore with M2 and M4 transmembrane helices lining the central cavity and M1 and M3 facing the lipid bilayer. The transmembrane helices are bridged by the selectivity filters 1 and 2 carrying a signature sequence TxTTxG(Y/F)G(D/H) that coordinate the permeant ions. Up to four ions can simultaneously occupy the selectivity filter and at least two elementary charges must translocate across the filter to convert it into the open conformation. The X-gate is positioned at the distal ends of M4 transmembrane helices forming a two-turn-helical structure with the methyl group of Thr-248 closing the ion conduction pathway.

Miscellaneous. Overexpressed in a high proportion of breast cancers. May confer resistance to growth factor deprivation and hypoxia, thereby promoting tumor cell survival in poorly oxygenated areas of solid tumors.

Similarity. Belongs to the two pore domain potassium channel (TC 1.A.1.8) family.

RefSeq proteins (1): NP_001269463* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003092	2pore_dom_K_chnl_TASK	Family
IPR003280	2pore_dom_K_chnl	Family
IPR005407	KCNK9	Family
IPR013099	K_chnl_dom	Domain

Pfam: PF07885

Catalyzed reactions (Rhea), 2 shown:

• K(+)(in) = K(+)(out) (RHEA:29463)
• Na(+)(in) = Na(+)(out) (RHEA:34963)

UniProt features (50 total): binding site 14, helix 9, topological domain 7, transmembrane region 4, mutagenesis site 4, region of interest 3, intramembrane region 2, site 2, sequence variant 2, chain 1, glycosylation site 1, strand 1

Structure

Experimental structures (PDB)

22 structures.

PDB	Method	Resolution (Å)
3P1N	X-RAY DIFFRACTION	1.4
3P1S	X-RAY DIFFRACTION	1.65
3P1Q	X-RAY DIFFRACTION	1.7
3P1R	X-RAY DIFFRACTION	1.7
3UX0	X-RAY DIFFRACTION	1.75
3SMO	X-RAY DIFFRACTION	1.8
3SP5	X-RAY DIFFRACTION	1.8
3P1O	X-RAY DIFFRACTION	1.9
3SML	X-RAY DIFFRACTION	1.9
4FR3	X-RAY DIFFRACTION	1.9
3P1P	X-RAY DIFFRACTION	1.95
6GHP	X-RAY DIFFRACTION	1.95
3SPR	X-RAY DIFFRACTION	1.99
3SMM	X-RAY DIFFRACTION	2
3SMN	X-RAY DIFFRACTION	2
3SMK	X-RAY DIFFRACTION	2.1
9G9W	ELECTRON MICROSCOPY	2.48
8K1J	ELECTRON MICROSCOPY	3
9G9V	ELECTRON MICROSCOPY	3.32
8K1Z	ELECTRON MICROSCOPY	3.41
8K1V	ELECTRON MICROSCOPY	3.48
8K1Q	ELECTRON MICROSCOPY	3.68

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NPC2-F1	75.89	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.

Catalytic / active sites (2): 78 (forms a cation-pi interaction with protonated h-98, stabilizing the c-type inactivated state); 98 (ph sensor)

Ligand- & substrate-binding residues (14): 93; 93; 94; 94; 95; 95; 96; 199; 199; 200; 200; 201 …

Glycosylation sites (1): 53

Mutagenesis-validated functional residues (4):

Position	Phenotype
78	impairs channel inhibition by extracellular acidification.
93	abolishes voltage gating. conducts currents with linear i-v relationship characteristic of classical leak channels.
98	impairs channel inhibition by extracellular acidification. does not affect channel ion selectivity.
199	abolishes voltage gating. conducts currents with linear i-v relationship characteristic of classical leak channels.

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-1299316	TWIK-releated acid-sensitive K+ channel (TASK)
R-HSA-5576886	Phase 4 - resting membrane potential
R-HSA-112316	Neuronal System
R-HSA-1296071	Potassium Channels
R-HSA-1296346	Tandem pore domain potassium channels
R-HSA-397014	Muscle contraction
R-HSA-5576891	Cardiac conduction

MSigDB gene sets: 311 (showing top): GOBP_POTASSIUM_ION_TRANSPORT, REACTOME_TANDEM_PORE_DOMAIN_POTASSIUM_CHANNELS, REACTOME_POTASSIUM_CHANNELS, GOBP_SODIUM_ION_TRANSMEMBRANE_TRANSPORT, GOBP_REGULATION_OF_HORMONE_LEVELS, GOBP_HORMONE_TRANSPORT, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_CELL_CELL_SIGNALING, GOBP_ORGANIC_HYDROXY_COMPOUND_TRANSPORT, GOBP_NEGATIVE_REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS, GOBP_NEGATIVE_REGULATION_OF_TRANSPORT, GOBP_REGULATION_OF_ENDOCRINE_PROCESS, GOBP_SENSORY_PERCEPTION_OF_LIGHT_STIMULUS, GOBP_NEGATIVE_REGULATION_OF_SECRETION, SCHAEFFER_PROSTATE_DEVELOPMENT_48HR_DN

GO Biological Process (12): potassium ion transport (GO:0006813), visual perception (GO:0007601), regulation of resting membrane potential (GO:0060075), cellular response to acidic pH (GO:0071468), regulation of action potential firing rate (GO:0099605), potassium ion import across plasma membrane (GO:1990573), negative regulation of aldosterone secretion (GO:2000859), monoatomic ion transport (GO:0006811), sodium ion transport (GO:0006814), monoatomic ion transmembrane transport (GO:0034220), sodium ion transmembrane transport (GO:0035725), potassium ion transmembrane transport (GO:0071805)

GO Molecular Function (9): potassium channel activity (GO:0005267), sodium channel activity (GO:0005272), outward rectifier potassium channel activity (GO:0015271), potassium ion leak channel activity (GO:0022841), identical protein binding (GO:0042802), metal ion binding (GO:0046872), protein heterodimerization activity (GO:0046982), voltage-gated potassium channel activity (GO:0005249), protein binding (GO:0005515)

GO Cellular Component (7): mitochondrial inner membrane (GO:0005743), plasma membrane (GO:0005886), synaptic vesicle (GO:0008021), dendrite (GO:0030425), mitochondrion (GO:0005739), membrane (GO:0016020), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Tandem pore domain potassium channels	1
Cardiac conduction	1
Neuronal System	1
Potassium Channels	1
Muscle contraction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
metal ion transport	2
monoatomic cation transmembrane transport	2
monoatomic cation channel activity	2
potassium channel activity	2
cellular anatomical structure	2
sensory perception of light stimulus	1
regulation of membrane potential	1
response to acidic pH	1
cellular response to pH	1
regulation of action potential	1
potassium ion transmembrane transport	1
inorganic cation import across plasma membrane	1
aldosterone secretion	1
negative regulation of mineralocorticoid secretion	1
regulation of aldosterone secretion	1
transport	1
monoatomic ion transport	1
transmembrane transport	1
sodium ion transport	1
potassium ion transport	1
potassium ion transmembrane transporter activity	1
sodium ion transmembrane transporter activity	1
voltage-gated potassium channel activity	1
leak channel activity	1
protein binding	1
cation binding	1
protein dimerization activity	1
voltage-gated monoatomic cation channel activity	1
binding	1
organelle inner membrane	1
mitochondrial membrane	1
membrane	1
cell periphery	1
exocytic vesicle	1
presynapse	1
neuron projection	1
dendritic tree	1
cytoplasm	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1494 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KCNK9	KRT76	Q01546	880
KCNK9	KCNK3	O14649	862
KCNK9	TRPM8	Q7Z2W7	661
KCNK9	KCNS1	Q96KK3	656
KCNK9	REN	P00797	640
KCNK9	KCNA3	P22001	624
KCNK9	KCNK5	O95279	618
KCNK9	KCNK1	O00180	575
KCNK9	PRKACB	P22694	568
KCNK9	KCNK10	P57789	566
KCNK9	PRKACG	P22612	565
KCNK9	PRKACA	P17612	563
KCNK9	KCNJ5	P48544	563
KCNK9	TRAPPC9	Q96Q05	561
KCNK9	KCNMA1	Q12791	544

IntAct

0 interactions, top by confidence:

BioGRID (2): COPB1 (Affinity Capture-Western), YWHAB (Affinity Capture-Western)

ESM2 similar proteins: A5D7L5, D4ADX7, G5E845, O00180, O08581, O14649, O17185, O35111, O54912, O95069, O95279, O97531, P15384, P16390, P17659, P57789, P97438, Q08E40, Q0P5A0, Q10937, Q15043, Q38898, Q3LS21, Q504Y0, Q5FWH7, Q5RAB7, Q5RD07, Q5UE96, Q63ZI0, Q6A4L1, Q7TSH7, Q8BUW1, Q8K449, Q8R454, Q8R5I0, Q91WD2, Q920B6, Q94A76, Q9ES08, Q9FWX6

Diamond homologs: G3V8R8, G3V8V5, G5E845, O00180, O08581, O14649, O17185, O35111, O54912, O88454, O95069, O95279, P57789, P97438, Q0P5A0, Q23435, Q3LS21, Q3TBV4, Q5RD07, Q5UE96, Q5VSE6, Q63ZI0, Q6Q1P3, Q6VV64, Q7Z418, Q8BUW1, Q8R454, Q8R5I0, Q920B6, Q96T54, Q96T55, Q9ERS1, Q9ES08, Q9H427, Q9HB14, Q9HB15, Q9JIS4, Q9JL58, Q9NPC2, Q9NYG8

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
PRKACA	up-regulates	KCNK9	phosphorylation
PKC	“down-regulates activity”	KCNK9	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	4
Uncertain significance	53
Likely benign	12
Benign	6

Top pathogenic / likely-pathogenic (7)

Variant ID	HGVS	Classification
3342854	NM_001282534.2(KCNK9):c.391C>A (p.Arg131Ser)	Pathogenic
397636	NM_001282534.2(KCNK9):c.706G>C (p.Gly236Arg)	Pathogenic
4741	NM_001282534.2(KCNK9):c.706G>A (p.Gly236Arg)	Pathogenic
3256793	NM_001282534.2(KCNK9):c.477G>A (p.Met159Ile)	Likely pathogenic
372887	NM_001282534.2(KCNK9):c.392G>A (p.Arg131His)	Likely pathogenic
4293529	NM_001282534.2(KCNK9):c.716T>C (p.Leu239Pro)	Likely pathogenic
982629	NM_001282534.2(KCNK9):c.710C>A (p.Ala237Asp)	Likely pathogenic

SpliceAI

783 predictions. Top by Δscore:

Variant	Effect	Δscore
8:139702704:CCTTA:C	donor_loss	1.0000
8:139702705:CTTA:C	donor_loss	1.0000
8:139702706:TTACC:T	donor_loss	1.0000
8:139702707:TAC:T	donor_loss	1.0000
8:139618269:T:TA	donor_gain	0.9900
8:139619096:TAAC:T	acceptor_gain	0.9900
8:139619097:AAC:A	acceptor_gain	0.9900
8:139619097:AACCT:A	acceptor_loss	0.9900
8:139619098:ACCT:A	acceptor_loss	0.9900
8:139619100:C:CA	acceptor_loss	0.9900
8:139619100:C:CC	acceptor_gain	0.9900
8:139619101:T:A	acceptor_loss	0.9900
8:139702708:A:AC	donor_gain	0.9900
8:139702709:C:CC	donor_gain	0.9900
8:139702709:CCT:C	donor_gain	0.9900
8:139702709:CCTA:C	donor_gain	0.9900
8:139619095:ATAAC:A	acceptor_gain	0.9800
8:139619098:AC:A	acceptor_gain	0.9800
8:139619099:CC:C	acceptor_gain	0.9800
8:139619113:A:C	acceptor_gain	0.9700
8:139702708:AC:A	donor_gain	0.9600
8:139702709:CC:C	donor_gain	0.9600
8:139702709:CCTAT:C	donor_gain	0.9600
8:139625642:A:AC	donor_gain	0.9500
8:139637997:ATTC:A	donor_gain	0.9500
8:139661888:C:A	donor_gain	0.9500
8:139638022:CTG:C	donor_gain	0.9300
8:139691506:G:T	donor_gain	0.9300
8:139612672:CCC:C	acceptor_gain	0.9200
8:139612673:CCC:C	acceptor_gain	0.9200

AlphaMissense

2467 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:139618652:A:G	L244P	1.000
8:139618661:A:G	L241P	1.000
8:139618663:G:C	N240K	1.000
8:139618663:G:T	N240K	1.000
8:139618667:A:G	L239P	1.000
8:139618667:A:T	L239H	1.000
8:139618676:C:T	G236E	1.000
8:139618677:C:A	G236W	1.000
8:139618677:C:G	G236R	1.000
8:139618677:C:T	G236R	1.000
8:139618688:A:C	L232R	1.000
8:139618688:A:G	L232P	1.000
8:139618688:A:T	L232Q	1.000
8:139618691:C:A	G231V	1.000
8:139618691:C:T	G231E	1.000
8:139618692:C:A	G231W	1.000
8:139618692:C:G	G231R	1.000
8:139618692:C:T	G231R	1.000
8:139618697:A:G	L229P	1.000
8:139618711:G:C	S224R	1.000
8:139618711:G:T	S224R	1.000
8:139618713:T:G	S224R	1.000
8:139618760:A:G	L208P	1.000
8:139618763:G:T	A207D	1.000
8:139618772:T:A	D204V	1.000
8:139618772:T:C	D204G	1.000
8:139618772:T:G	D204A	1.000
8:139618773:C:G	D204H	1.000
8:139618775:C:A	G203V	1.000
8:139618775:C:G	G203A	1.000

dbSNP variants (sampled 300 via entrez): RS1000001468 (8:139604130 C>T), RS1000086603 (8:139644667 G>C,T), RS1000107500 (8:139637760 T>C), RS1000116241 (8:139623470 C>A,T), RS1000184035 (8:139656468 C>T), RS1000229058 (8:139637650 A>G), RS1000271430 (8:139666869 C>G,T), RS1000274112 (8:139617598 G>T), RS1000317981 (8:139677273 C>T), RS1000340060 (8:139661038 C>G,T), RS1000349116 (8:139676819 G>A,C), RS1000361165 (8:139627752 C>G,T), RS1000446982 (8:139612264 C>T), RS1000451052 (8:139646256 C>T), RS1000451461 (8:139704782 C>T)

Disease associations

OMIM: gene MIM:605874 | disease phenotypes: MIM:612292

GenCC curated gene-disease

Disease	Classification	Inheritance
Birk-Barel syndrome	Strong	Autosomal dominant

Mondo (2): Birk-Barel syndrome (MONDO:0012856), autism spectrum disorder (MONDO:0005258)

Orphanet (2): Birk-Barel syndrome (Orphanet:166108), NON RARE IN EUROPE: Autism (Orphanet:106)

HPO phenotypes

45 total (30 of 45 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000193	Bifid uvula
HP:0000194	Open mouth
HP:0000218	High palate
HP:0000268	Dolichocephaly
HP:0000276	Long face
HP:0000289	Broad philtrum
HP:0000308	Microretrognathia
HP:0000322	Short philtrum
HP:0000338	Hypomimic face
HP:0000341	Narrow forehead
HP:0000347	Micrognathia
HP:0000411	Protruding ear
HP:0000446	Narrow nasal bridge
HP:0000455	Broad nasal tip
HP:0000527	Long eyelashes
HP:0000752	Hyperactivity
HP:0000954	Single transverse palmar crease
HP:0000960	Sacral dimple
HP:0001249	Intellectual disability
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001284	Areflexia
HP:0001290	Generalized hypotonia
HP:0001308	Tongue fasciculations
HP:0001319	Neonatal hypotonia
HP:0001618	Dysphonia
HP:0002015	Dysphagia
HP:0002553	Highly arched eyebrow
HP:0002705	High, narrow palate

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST001122_2	Adiponectin levels	8.000000e-07
GCST002541_67	Menarche (age at onset)	4.000000e-12
GCST002653_2	Circulating phylloquinone levels	2.000000e-07
GCST002829_27	Urate levels in overweight individuals	3.000000e-06
GCST002829_6	Urate levels in overweight individuals	3.000000e-07
GCST003070_3	Cerebrospinal T-tau levels	4.000000e-07
GCST003079_4	Cerebrospinal fluid t-tau:AB1-42 ratio	4.000000e-06
GCST003171_4	Visceral adipose tissue	6.000000e-07
GCST006248_1	Response to lurasidone in schizophrenia	5.000000e-08
GCST006248_6	Response to lurasidone in schizophrenia	2.000000e-06
GCST007204_10	Low density lipoprotein cholesterol levels	5.000000e-06

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0004502	adiponectin measurement
EFO:0004703	age at menarche
EFO:0004618	vitamin K measurement
EFO:0004531	urate measurement
EFO:0004760	t-tau measurement
EFO:0007708	t-tau:beta-amyloid 1-42 ratio measurement
EFO:0004611	low density lipoprotein cholesterol measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C567357	Birk-Barel Mental Retardation Dysmorphism Syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2321614 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

4 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 43,189 (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
CHEMBL1534525	MIBEFRADIL DIHYDROCHLORIDE	4	677
CHEMBL998	LORATADINE	4	42,161
CHEMBL5095055	BAFREKALANT	2	38
CHEMBL64249	CLOROTEPINE	2	313

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: vgic — Two-pore domain potassium channels (K_2P)

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
A-769662	Inhibition	3.52	pIC50

Binding affinities (BindingDB)

48 measured of 48 human assays (48 total across all organisms); most potent 48 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
US10414765, Example 4	IC50	59.9 nM	US-10414765: Substituted perhydropyrrolo[3,4-c]pyrrole derivatives and the use of same
US10414765, Example 48	IC50	78 nM	US-10414765: Substituted perhydropyrrolo[3,4-c]pyrrole derivatives and the use of same
US10414765, Example 49	IC50	94 nM	US-10414765: Substituted perhydropyrrolo[3,4-c]pyrrole derivatives and the use of same
US10414765, Example 27	IC50	170 nM	US-10414765: Substituted perhydropyrrolo[3,4-c]pyrrole derivatives and the use of same
US10414765, Example 36	IC50	180 nM	US-10414765: Substituted perhydropyrrolo[3,4-c]pyrrole derivatives and the use of same
US10414765, Example 10	IC50	206 nM	US-10414765: Substituted perhydropyrrolo[3,4-c]pyrrole derivatives and the use of same
US10414765, Example 26	IC50	220 nM	US-10414765: Substituted perhydropyrrolo[3,4-c]pyrrole derivatives and the use of same
US10414765, Example 25	IC50	230 nM	US-10414765: Substituted perhydropyrrolo[3,4-c]pyrrole derivatives and the use of same
US10414765, Example 28	IC50	300 nM	US-10414765: Substituted perhydropyrrolo[3,4-c]pyrrole derivatives and the use of same
US10414765, Example 24	IC50	330 nM	US-10414765: Substituted perhydropyrrolo[3,4-c]pyrrole derivatives and the use of same
US10414765, Example 33	IC50	460 nM	US-10414765: Substituted perhydropyrrolo[3,4-c]pyrrole derivatives and the use of same
US10414765, Example 46	IC50	460 nM	US-10414765: Substituted perhydropyrrolo[3,4-c]pyrrole derivatives and the use of same
US10414765, Example 30	IC50	480 nM	US-10414765: Substituted perhydropyrrolo[3,4-c]pyrrole derivatives and the use of same
US10414765, Example 34	IC50	500 nM	US-10414765: Substituted perhydropyrrolo[3,4-c]pyrrole derivatives and the use of same
US10414765, Example 41	IC50	580 nM	US-10414765: Substituted perhydropyrrolo[3,4-c]pyrrole derivatives and the use of same
US10414765, Example 37	IC50	600 nM	US-10414765: Substituted perhydropyrrolo[3,4-c]pyrrole derivatives and the use of same
US10414765, Example 6	IC50	683 nM	US-10414765: Substituted perhydropyrrolo[3,4-c]pyrrole derivatives and the use of same
US10414765, Example 35	IC50	700 nM	US-10414765: Substituted perhydropyrrolo[3,4-c]pyrrole derivatives and the use of same
US10414765, Example 44	IC50	700 nM	US-10414765: Substituted perhydropyrrolo[3,4-c]pyrrole derivatives and the use of same
US10414765, Example 13	IC50	712 nM	US-10414765: Substituted perhydropyrrolo[3,4-c]pyrrole derivatives and the use of same
US10414765, Example 17	IC50	721 nM	US-10414765: Substituted perhydropyrrolo[3,4-c]pyrrole derivatives and the use of same
US10414765, Example 23	IC50	728 nM	US-10414765: Substituted perhydropyrrolo[3,4-c]pyrrole derivatives and the use of same
US10414765, Example 42	IC50	740 nM	US-10414765: Substituted perhydropyrrolo[3,4-c]pyrrole derivatives and the use of same
US10414765, Example 9	IC50	749 nM	US-10414765: Substituted perhydropyrrolo[3,4-c]pyrrole derivatives and the use of same
US10414765, Example 7	IC50	787 nM	US-10414765: Substituted perhydropyrrolo[3,4-c]pyrrole derivatives and the use of same
US10414765, Example 29	IC50	920 nM	US-10414765: Substituted perhydropyrrolo[3,4-c]pyrrole derivatives and the use of same
US10414765, Example 15	IC50	1000 nM	US-10414765: Substituted perhydropyrrolo[3,4-c]pyrrole derivatives and the use of same
US10414765, Example 47	IC50	1000 nM	US-10414765: Substituted perhydropyrrolo[3,4-c]pyrrole derivatives and the use of same
US10414765, Example 20	IC50	1020 nM	US-10414765: Substituted perhydropyrrolo[3,4-c]pyrrole derivatives and the use of same
US10414765, Example 14	IC50	1060 nM	US-10414765: Substituted perhydropyrrolo[3,4-c]pyrrole derivatives and the use of same
US10414765, Example 32	IC50	1100 nM	US-10414765: Substituted perhydropyrrolo[3,4-c]pyrrole derivatives and the use of same
US10414765, Example 50	IC50	1100 nM	US-10414765: Substituted perhydropyrrolo[3,4-c]pyrrole derivatives and the use of same
US10414765, Example 5	IC50	1130 nM	US-10414765: Substituted perhydropyrrolo[3,4-c]pyrrole derivatives and the use of same
US10414765, Example 12	IC50	1200 nM	US-10414765: Substituted perhydropyrrolo[3,4-c]pyrrole derivatives and the use of same
US10414765, Example 11	IC50	1210 nM	US-10414765: Substituted perhydropyrrolo[3,4-c]pyrrole derivatives and the use of same
US10414765, Example 19	IC50	1250 nM	US-10414765: Substituted perhydropyrrolo[3,4-c]pyrrole derivatives and the use of same
US10414765, Example 21	IC50	1250 nM	US-10414765: Substituted perhydropyrrolo[3,4-c]pyrrole derivatives and the use of same
US10414765, Example 8	IC50	1360 nM	US-10414765: Substituted perhydropyrrolo[3,4-c]pyrrole derivatives and the use of same
US10414765, Example 51	IC50	1400 nM	US-10414765: Substituted perhydropyrrolo[3,4-c]pyrrole derivatives and the use of same
US10414765, Example 22	IC50	1460 nM	US-10414765: Substituted perhydropyrrolo[3,4-c]pyrrole derivatives and the use of same
US10414765, Example 38	IC50	1500 nM	US-10414765: Substituted perhydropyrrolo[3,4-c]pyrrole derivatives and the use of same
US10414765, Example 18	IC50	1680 nM	US-10414765: Substituted perhydropyrrolo[3,4-c]pyrrole derivatives and the use of same
US10414765, Example 43	IC50	1700 nM	US-10414765: Substituted perhydropyrrolo[3,4-c]pyrrole derivatives and the use of same
US10414765, Example 2	IC50	1730 nM	US-10414765: Substituted perhydropyrrolo[3,4-c]pyrrole derivatives and the use of same
US10414765, Example 16	IC50	1940 nM	US-10414765: Substituted perhydropyrrolo[3,4-c]pyrrole derivatives and the use of same
US10414765, Example 45	IC50	2300 nM	US-10414765: Substituted perhydropyrrolo[3,4-c]pyrrole derivatives and the use of same
US10414765, Example 1	IC50	2410 nM	US-10414765: Substituted perhydropyrrolo[3,4-c]pyrrole derivatives and the use of same
US10414765, Example 3	IC50	2500 nM	US-10414765: Substituted perhydropyrrolo[3,4-c]pyrrole derivatives and the use of same

ChEMBL bioactivities

415 potent at pChembl≥5 of 428 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.98	IC50	1.04	nM	CHEMBL6016320
8.96	IC50	1.1	nM	CHEMBL5925518
8.85	IC50	1.4	nM	CHEMBL5797600
8.82	IC50	1.5	nM	CHEMBL5757092
8.80	IC50	1.6	nM	CHEMBL5971519
8.74	IC50	1.8	nM	BAFREKALANT
8.66	IC50	2.2	nM	CHEMBL5885911
8.64	IC50	2.3	nM	CHEMBL5979320
8.60	IC50	2.5	nM	CHEMBL5925518
8.55	IC50	2.8	nM	CHEMBL5886272
8.52	IC50	3	nM	CHEMBL5948731
8.52	IC50	3	nM	CHEMBL5856031
8.49	IC50	3.2	nM	CHEMBL6059181
8.40	IC50	4	nM	CHEMBL5856031
8.39	IC50	4.1	nM	CHEMBL5943128
8.38	IC50	4.2	nM	CHEMBL5900523
8.36	IC50	4.4	nM	CHEMBL6006852
8.35	IC50	4.5	nM	CHEMBL5885911
8.34	IC50	4.6	nM	CHEMBL5822130
8.34	IC50	4.6	nM	CHEMBL5912507
8.33	IC50	4.7	nM	CHEMBL5886272
8.31	IC50	4.9	nM	CHEMBL5913004
8.30	IC50	5	nM	CHEMBL5916187
8.30	IC50	5	nM	CHEMBL6000419
8.29	IC50	5.1	nM	CHEMBL5857240
8.28	IC50	5.2	nM	CHEMBL6050684
8.28	IC50	5.2	nM	CHEMBL5764156
8.26	IC50	5.5	nM	CHEMBL5886272
8.25	IC50	5.6	nM	CHEMBL5809941
8.21	IC50	6.2	nM	CHEMBL5781241
8.18	IC50	6.6	nM	CHEMBL6059181
8.16	IC50	6.9	nM	CHEMBL5945500
8.14	IC50	7.3	nM	CHEMBL5895677
8.08	IC50	8.4	nM	CHEMBL5767128
8.07	IC50	8.6	nM	CHEMBL5825216
8.06	IC50	8.7	nM	CHEMBL5866632
8.04	IC50	9.1	nM	CHEMBL5928540
8.04	IC50	9.2	nM	CHEMBL6019370
8.03	IC50	9.4	nM	CHEMBL5172358
8.00	IC50	10	nM	CHEMBL5932576
8.00	IC50	10	nM	CHEMBL5766027
7.96	IC50	11	nM	CHEMBL5955132
7.96	IC50	11	nM	CHEMBL5927144
7.96	IC50	11	nM	CHEMBL6000419
7.92	IC50	12	nM	CHEMBL5979769
7.92	IC50	12	nM	CHEMBL5748362
7.92	IC50	12	nM	CHEMBL5885911
7.89	IC50	13	nM	CHEMBL5936147
7.89	IC50	13	nM	CHEMBL6058093
7.89	IC50	13	nM	CHEMBL5936911

PubChem BioAssay actives

56 with measured affinity, of 111 total; 45 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
1-[1-[6-(4-phenylbenzoyl)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-4-yl]piperidin-4-yl]butan-1-one	1525575: Inhibition of human TASK3 expressed in HEK293 cells by Qpatch HT platform based assay	ic50	0.0350	uM
2-ethoxy-N-[3-[(3-methylbenzoyl)amino]phenyl]benzamide	1183454: Inhibition of TASK-3 (unknown origin) expressed in HEK293 cells by QPatch assay	ic50	0.0380	uM
N-[3-[(2-ethoxybenzoyl)amino]phenyl]-2-methoxybenzamide	1183446: Inhibition of TASK-3 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	0.0660	uM
N-[(2,4-difluorophenyl)methyl]-2-[2-[[[2-(4-methoxyphenyl)acetyl]amino]methyl]phenyl]benzamide	1525551: Inhibition of human TASK3 expressed in CHO cells by Inside-out macro-patches based electrophysiology assay	ic50	0.0700	uM
2-propan-2-yloxy-N-[3-[[2-(trifluoromethoxy)benzoyl]amino]phenyl]benzamide	1183446: Inhibition of TASK-3 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	0.1100	uM
3-methyl-N-[3-[(3-methylbenzoyl)amino]phenyl]benzamide	1183446: Inhibition of TASK-3 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	0.1500	uM
N-[3-[(2-ethoxybenzoyl)amino]phenyl]-2-(trifluoromethyl)benzamide	1183454: Inhibition of TASK-3 (unknown origin) expressed in HEK293 cells by QPatch assay	ic50	0.2500	uM
N-[3-[(3-methylbenzoyl)amino]phenyl]thiophene-2-carboxamide	1183446: Inhibition of TASK-3 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	0.3300	uM
2-methoxy-N-[3-[(3-methylbenzoyl)amino]phenyl]benzamide	1183446: Inhibition of TASK-3 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	0.3900	uM
2-methoxy-N-[3-[[2-(trifluoromethoxy)benzoyl]amino]phenyl]benzamide	1183446: Inhibition of TASK-3 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	0.4100	uM
4-[1-(2-bicyclo[2.2.1]heptanyl)ethyl]-3-(furan-2-yl)-1H-1,2,4-triazole-5-thione	1525568: Inhibition of human TASK3 expressed in HEK293 by whole cell voltage clamp assay	ic50	0.4130	uM
N-[3-[(3-chlorobenzoyl)amino]phenyl]-3-methylbenzamide	1183446: Inhibition of TASK-3 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	0.4800	uM
N-(3-benzamidophenyl)-3-methylbenzamide	1183446: Inhibition of TASK-3 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	0.5000	uM
N-[3-[(3-fluorobenzoyl)amino]phenyl]-3-methylbenzamide	1183446: Inhibition of TASK-3 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	0.6000	uM
2-methoxy-N-[3-[(2-methoxybenzoyl)amino]phenyl]benzamide	1183454: Inhibition of TASK-3 (unknown origin) expressed in HEK293 cells by QPatch assay	ic50	0.7100	uM
2-propan-2-yl-N-[3-[[2-(trifluoromethoxy)benzoyl]amino]phenyl]benzamide	1183446: Inhibition of TASK-3 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	0.7300	uM
N-[3-[(3-methylbenzoyl)amino]phenyl]-2-(trifluoromethoxy)benzamide	1183446: Inhibition of TASK-3 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	0.7500	uM
2-(butylsulfonylamino)-N-[1-(6-methoxy-3-pyridinyl)propyl]benzamide	1525554: Inhibition of human TASK3 expressed in Xenopus oocytes by whole cell voltage clamp assay	ic50	0.9500	uM
2-methyl-N-[3-[(3-methylbenzoyl)amino]phenyl]benzamide	1183446: Inhibition of TASK-3 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	0.9600	uM
N-(3-benzamidophenyl)thiophene-2-carboxamide	1183446: Inhibition of TASK-3 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	0.9700	uM
N-[3-[(2-methoxybenzoyl)amino]phenyl]-2-propan-2-ylbenzamide	1183446: Inhibition of TASK-3 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	1.0000	uM
2-chloro-N-[3-[(3-methylbenzoyl)amino]phenyl]benzamide	1183446: Inhibition of TASK-3 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	1.3400	uM
N-[3-[(3-methylbenzoyl)amino]phenyl]-2-(trifluoromethyl)benzamide	1183446: Inhibition of TASK-3 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	1.4000	uM
N-(3-benzamidophenyl)-2-methoxybenzamide	1183446: Inhibition of TASK-3 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	1.5000	uM
N-[3-[(3-methylbenzoyl)amino]phenyl]-2-propan-2-ylbenzamide	1183446: Inhibition of TASK-3 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	1.7000	uM
3-benzamido-N-(2-ethylphenyl)benzamide	1849491: Inhibition of human TASK-3 expressed in Xenopus laevis oocytes assessed as inhibition of channel current at +40mV holding potential by two-electrode voltage clamp assay	ic50	1.7500	uM
N-(3-benzamidophenyl)-4-methoxybenzamide	1183446: Inhibition of TASK-3 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	2.1000	uM
N-[3-[(2-methoxybenzoyl)amino]phenyl]-2-methylbenzamide	1183446: Inhibition of TASK-3 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	2.2000	uM
N-[3-[(3-methoxybenzoyl)amino]phenyl]-3-methylbenzamide	1183446: Inhibition of TASK-3 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	2.2000	uM
2,5-dimethoxy-N-[3-[(3-methylbenzoyl)amino]phenyl]benzamide	1183446: Inhibition of TASK-3 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	2.3000	uM
N-(3-benzamidophenyl)-3-chlorobenzamide	1183446: Inhibition of TASK-3 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	2.4000	uM
2-methoxy-N-[3-[(3-methylbenzoyl)amino]phenyl]pyridine-4-carboxamide	1183446: Inhibition of TASK-3 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	2.4300	uM
N-(3-benzamidophenyl)-2-(trifluoromethyl)benzamide	1183446: Inhibition of TASK-3 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	2.5000	uM
N-(3-benzamidophenyl)pyridine-2-carboxamide	1183446: Inhibition of TASK-3 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	2.5000	uM
N-[3-[(3-methylbenzoyl)amino]phenyl]-2-propan-2-yloxybenzamide	1183446: Inhibition of TASK-3 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	2.7000	uM
N-[3-[(3-methylbenzoyl)amino]phenyl]furan-2-carboxamide	1183446: Inhibition of TASK-3 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	2.7000	uM
N-(3-benzamidophenyl)-4-tert-butylbenzamide	1183446: Inhibition of TASK-3 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	3.2000	uM
3-methyl-N-[3-[[3-(trifluoromethyl)benzoyl]amino]phenyl]benzamide	1183454: Inhibition of TASK-3 (unknown origin) expressed in HEK293 cells by QPatch assay	ic50	3.9400	uM
N-(3-benzamidophenyl)-3-methoxybenzamide	1183446: Inhibition of TASK-3 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	4.3000	uM
N-[3-(cyclohexanecarbonylamino)phenyl]benzamide	1183446: Inhibition of TASK-3 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	5.4800	uM
N-(3-benzamidophenyl)thiophene-3-carboxamide	1183446: Inhibition of TASK-3 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	5.6000	uM
N-(3-benzamidophenyl)furan-2-carboxamide	1183446: Inhibition of TASK-3 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	5.9000	uM
N-(3-benzamidophenyl)-2-methylbenzamide	1183446: Inhibition of TASK-3 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	6.5000	uM
N-(3-benzamidophenyl)-2-chlorobenzamide	1183446: Inhibition of TASK-3 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	7.1000	uM
3-benzamido-N-(1,3-thiazol-2-yl)benzamide	1849491: Inhibition of human TASK-3 expressed in Xenopus laevis oocytes assessed as inhibition of channel current at +40mV holding potential by two-electrode voltage clamp assay	ic50	7.1700	uM

CTD chemical–gene interactions

20 total (human), top 20 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Potassium	decreases reaction, increases transport, increases reaction, affects binding	3
bisphenol A	affects cotreatment, decreases methylation	1
ethyl-p-hydroxybenzoate	increases expression	1
terbufos	increases methylation	1
butyraldehyde	increases expression	1
4-O-methyl-12-O-tetradecanoylphorbol 13-acetate	decreases reaction, increases transport	1
sanshool	increases transport, decreases activity, affects response to substance, affects binding, decreases reaction	1
NSC 689534	increases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Benzo(a)pyrene	increases methylation, affects methylation	1
Bupivacaine	increases transport, decreases reaction	1
Calcitriol	increases expression	1
Fonofos	increases methylation	1
Halothane	increases reaction, increases transport	1
Methotrexate	decreases expression	1
Methyl Methanesulfonate	increases expression	1
Parathion	increases methylation	1
Phthalic Acids	increases methylation	1
Tobacco Smoke Pollution	decreases methylation	1
Valproic Acid	increases expression	1

ChEMBL screening assays

33 unique, capped per target: 31 binding, 2 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2327430	Binding	Inhibition of TASK-3 (unknown origin)	Ion channels as therapeutic targets: a drug discovery perspective. — J Med Chem
CHEMBL3214982	Functional	PubChem BioAssay. SAR analysis for the identification of selective inhibitors of the two-pore domain potassium channel TASK1(KCNK3) -selectivity assay against TASK3(KCNK9): Automated Electrophysiology. (Class of assay: confirmatory)	PubChem BioAssay data set

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01333865	PHASE4	COMPLETED	A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders
NCT01337700	PHASE4	COMPLETED	Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism
NCT01695200	PHASE4	COMPLETED	Omega-3 Fatty Acids in Autism Spectrum Disorders
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02940574	PHASE4	COMPLETED	Neural and Behavioral Effects of Oxytocin in Autism Spectrum Disorders
NCT03333629	PHASE4	COMPLETED	Promoting Positive Outcomes for Individuals With ASD: Linking Early Detection, Treatment, and Long-term Outcomes
NCT03337646	PHASE4	COMPLETED	Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With ADHD and Autism
NCT03538431	PHASE4	COMPLETED	Improving Driving in Young People With Autism Spectrum Disorders
NCT03757585	PHASE4	COMPLETED	Natural Treatments for the Management of Emotional Dysregulation in Youth With Non-verbal Learning Disability (NVLD) and/or Autism Spectrum Disorders (ASD)
NCT04903353	PHASE4	COMPLETED	Pragmatic Trial Comparing Weight Gain in Children With Autism Taking Risperidone Versus Aripiprazole
NCT05063656	PHASE4	COMPLETED	Biomarker-Driven Pharmacological Treatment of Adolescents With Autism Spectrum Disorder With Gabapentin
NCT05146245	PHASE4	UNKNOWN	Safety and Pharmacokinetics of Antipsychotics in Children 2: Studying TDM in an RCT
NCT05916339	PHASE4	RECRUITING	AWARE: Management of ADHD in Autism Spectrum Disorder
NCT05954052	PHASE4	TERMINATED	A Study of Glutathione in Children With Autism Spectrum Disorder
NCT06853665	PHASE4	RECRUITING	The TEAM Study - Treatment Efficacy for Autism/Attention Using Mixed Amphetamine
NCT07054697	PHASE4	COMPLETED	Pilot-RCT With Individualized Homeopathic Treatment in the Children With Autism Spectrum Disorder
NCT07161804	PHASE4	COMPLETED	Pilot RCT Using Homeopathic Medicines in ASD
NCT07439042	PHASE4	NOT_YET_RECRUITING	Buspirone for Anxiety in Autistic Youth
NCT01302964	PHASE3	COMPLETED	Mirtazapine Treatment of Anxiety in Children and Adolescents With Pervasive Developmental Disorders
NCT01706523	PHASE3	TERMINATED	Open Label Extension Study of STX209 (Arbaclofen) in Autism Spectrum Disorders
NCT01825798	PHASE3	COMPLETED	Treatment of Overweight Induced by Antipsychotic Medication in Young People With Autism Spectrum Disorders (ASD)
NCT01972074	PHASE3	COMPLETED	Behavioral and Neural Response to Memantine in Adolescents With Autism Spectrum Disorder
NCT02985749	PHASE3	COMPLETED	A Study of Oxytocin for the Treatment of Social Impairment in Individuals With High Functioning Autism Spectrum Disorder
NCT03197922	PHASE3	COMPLETED	Treatment of Encopresis in Children With Autism Spectrum Disorders
NCT03504917	PHASE3	TERMINATED	A Study of Balovaptan in Adults With Autism Spectrum Disorder With a 2-Year Open-Label Extension
NCT03553875	PHASE3	TERMINATED	Memantine for the Treatment of Social Deficits in Youth With Disorders of Impaired Social Interactions
NCT03640156	PHASE3	COMPLETED	Modulating Socially Adaptive Mirror System Functioning in Autism by Oxytocin
NCT03715153	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children Aged From 2 to Less Than 7 Years Old With Autism Spectrum Disorder.
NCT03715166	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children and Adolescents Aged From 7 to Less Than 18 Years Old With Autism Spectrum Disorder
NCT04233502	PHASE3	WITHDRAWN	Efficacy and Safety of Slenyto for Insomnia in Children With ASD
NCT04578756	PHASE3	COMPLETED	Open-Label, Flexible-dose Study to Evaluate the Long-Term Safety and Tolerability of Cariprazine in the Treatment of Pediatric Participants With Schizophrenia, Bipolar I Disorder, or Autism Spectrum Disorder
NCT04623398	PHASE3	COMPLETED	Effect of Lithium in Patients With Autism Spectrum Disorder and Phelan-McDermid Syndrome (SHANK3 Haploinsufficiency)
NCT04725383	PHASE3	TERMINATED	Amitriptyline for Repetitive Behaviors in Autism Spectrum Disorders
NCT05212493	PHASE3	COMPLETED	The Effects of Medical Cannabis in Children With Autistic Spectrum Disorder
NCT05361707	PHASE3	UNKNOWN	Evaluating the Effects of Tasimelteon in Individuals With Autism Spectrum Disorder (ASD) and Sleep Disturbances
NCT05439616	PHASE3	COMPLETED	Study of Cariprazine Oral Capsules or Solution to Assess Adverse Events and Change in Irritability Due to Autism Spectrum Disorder (ASD) in Participants Aged 5-17 Years With ASD
NCT06229210	PHASE3	RECRUITING	Safety and Tolerability Trial of Lumateperone in Pediatric Patients With Schizophrenia, Bipolar Disorder or Autism Spectrum Disorder