KCNJ8

Summary

KCNJ8 (potassium inwardly rectifying channel subfamily J member 8, HGNC:6269) is a protein-coding gene on chromosome 12p12.1, encoding ATP-sensitive inward rectifier potassium channel 8 (Q15842). Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it.

Potassium channels are present in most mammalian cells, where they participate in a wide range of physiologic responses. The protein encoded by this gene is an integral membrane protein and inward-rectifier type potassium channel. The encoded protein, which has a greater tendency to allow potassium to flow into a cell rather than out of a cell, is controlled by G-proteins. Defects in this gene may be a cause of J-wave syndromes and sudden infant death syndrome (SIDS).

Source: NCBI Gene 3764 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hypertrichotic osteochondrodysplasia Cantu type (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 261 total — 1 likely-pathogenic
• Phenotypes (HPO): 50
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_004982

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6269
Approved symbol	KCNJ8
Name	potassium inwardly rectifying channel subfamily J member 8
Location	12p12.1
Locus type	gene with protein product
Status	Approved
Aliases	Kir6.1
Ensembl gene	ENSG00000121361
Ensembl biotype	protein_coding
OMIM	600935
Entrez	3764

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 14 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000240662, ENST00000537950, ENST00000657855, ENST00000665145, ENST00000667884, ENST00000859812, ENST00000859813, ENST00000859814, ENST00000859815, ENST00000859816, ENST00000859817, ENST00000859818, ENST00000951731, ENST00000951732, ENST00000951733

RefSeq mRNA: 1 — MANE Select: NM_004982 NM_004982

CCDS: CCDS8692

Canonical transcript exons

ENST00000240662 — 3 exons

Exon	Start	End
ENSE00000822273	21764955	21766623
ENSE00000822274	21773243	21773686
ENSE00000994924	21774546	21774706

Expression profiles

Bgee: expression breadth ubiquitous, 233 present calls, max score 96.23.

FANTOM5 (CAGE): breadth broad, TPM avg 2.6890 / max 119.6222, expressed in 760 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
130041	1.3132	425
130044	0.6108	381
130043	0.4295	255
130042	0.1858	96
130046	0.0782	42
130040	0.0528	29
130045	0.0187	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
heart right ventricle	UBERON:0002080	96.23	gold quality
left ventricle myocardium	UBERON:0006566	95.43	gold quality
cardiac ventricle	UBERON:0002082	95.08	gold quality
heart left ventricle	UBERON:0002084	95.06	gold quality
apex of heart	UBERON:0002098	94.30	gold quality
body of pancreas	UBERON:0001150	92.68	gold quality
heart	UBERON:0000948	92.48	gold quality
right lobe of liver	UBERON:0001114	91.30	gold quality
right atrium auricular region	UBERON:0006631	90.86	gold quality
myocardium	UBERON:0002349	90.85	gold quality
cardiac atrium	UBERON:0002081	90.52	gold quality
liver	UBERON:0002107	90.52	gold quality
mucosa of stomach	UBERON:0001199	89.97	gold quality
pericardium	UBERON:0002407	89.97	gold quality
pancreas	UBERON:0001264	89.70	gold quality
omental fat pad	UBERON:0010414	89.32	gold quality
peritoneum	UBERON:0002358	89.25	gold quality
adipose tissue of abdominal region	UBERON:0007808	88.80	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	88.44	gold quality
lower esophagus muscularis layer	UBERON:0035833	87.91	gold quality
lower esophagus	UBERON:0013473	87.85	gold quality
subcutaneous adipose tissue	UBERON:0002190	87.82	gold quality
visceral pleura	UBERON:0002401	87.69	gold quality
parietal pleura	UBERON:0002400	87.64	gold quality
pleura	UBERON:0000977	87.46	gold quality
popliteal artery	UBERON:0002250	87.38	gold quality
tibial artery	UBERON:0007610	87.36	gold quality
right lung	UBERON:0002167	87.20	gold quality
smooth muscle tissue	UBERON:0001135	87.11	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	87.05	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-MTAB-8142	yes	40.08
E-ANND-3	yes	15.53
E-MTAB-5061	yes	14.57
E-GEOD-81608	yes	7.55
E-GEOD-83139	yes	3.75

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FOXO1, FOXO3, HIF1A

miRNA regulators (miRDB)

56 targeting KCNJ8, 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-3163	100.00	77.23	8605
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-512-3P	99.97	67.35	1049
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-302A-3P	99.89	71.23	1777
HSA-MIR-302B-3P	99.89	71.23	1777
HSA-MIR-302C-3P	99.89	71.20	1778
HSA-MIR-302D-3P	99.89	71.25	1777
HSA-MIR-106B-5P	99.88	74.72	2795
HSA-MIR-20A-5P	99.88	74.76	2769
HSA-MIR-20B-5P	99.88	74.01	2621
HSA-MIR-519D-3P	99.88	73.97	2607
HSA-MIR-93-5P	99.88	73.98	2606
HSA-MIR-526B-3P	99.88	74.06	2587
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-373-3P	99.84	70.68	1668
HSA-MIR-520E-3P	99.84	70.55	1698
HSA-MIR-1323	99.83	69.89	2471
HSA-MIR-372-3P	99.83	70.58	1691
HSA-MIR-520A-3P	99.83	70.59	1687
HSA-MIR-520B-3P	99.83	70.56	1699
HSA-MIR-520C-3P	99.83	70.56	1699
HSA-MIR-520D-3P	99.83	70.78	1676
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-548O-3P	99.74	69.30	2228

Literature-anchored findings (GeneRIF, showing 30)

• Assembly limits the pharmacological complexity of ATP-sensitive potassium channels (PMID:11825905)
• cGMP/PKG-dependent processes participate in activating the ATP-regulated K(+) channel (PMID:12217870)
• down-regulation of this channel may facilitate myometrial function during late pregnancy (PMID:12356945)
• In corporal smooth muscle is composed of Kir6.1-Kir6.2 construct expressed with SUR2B.K(ATP) channel in corporal smooth muscle cells is composed of heteromultimers of Kir6.1 and Kir6.2 with the ratio of 3 : 1 or 4 : 0 and SUR2B. (PMID:12934053)
• Kir6.1/KCNJ8 hasa a role in the pathogenesis of impaired coronary vasomotility that varies among various ethnic groups (PMID:12964027)
• The effect of nicotine on Kir6.1 channels is mediated by the production of superoxides. (PMID:15821440)
• Results describe a new function of the Kir6.1-SUR2A complex, namely the regulation of paracellular permeability through tight junctions. (PMID:16820413)
• Results indicate that abnormality in the primary structure of Kir6.1 may not be involved in the genetic pathogenesis of coronary spastic angina. (PMID:16964409)
• caveolin-dependent internalization is involved in PKC-epsilon-mediated inhibition of vascular K(ATP) channels (Kir6.1 and SUR2B) by phorbol 12-myristate 13-acetate or angiotensin II (PMID:18663158)
• Kir6.1/SUR2B is the major functional K(ATP) channel complex in the pig MMA and MCA, and mRNA expression studies suggest that the human MMA shares this K(ATP) channel subunit profile (PMID:18996111)
• Analysis of two KCNJ11 neonatal diabetes mutations, V59G and V59A, and the analogous KCNJ8 I60G substitution: differences between the channel subtypes formed with SUR1. (PMID:19139106)
• sequence variants in KCNJ8 is unlikely to contribute to variation in postural change in systolic blood pressure (PMID:19952277)
• Lipopolysaccharides up-regulate Kir6.1/SUR2B channel expression and enhance vascular KATP channel activity via NF-kappaB-dependent signaling (PMID:19959479)
• These findings further implicate KCNJ8 as a novel J-wave syndrome susceptibility gene and a marked gain of function in the cardiac K(ATP) Kir6.1 channel secondary to KCNJ8-S422L as a novel pathogenic mechanism for J-wave syndromes. (PMID:20558321)
• Interaction with caveolin-1 causes a shift the channel’s sensitivity to its physiological regulator magnesium ADP (MgADP). (PMID:20624795)
• mammalian oocytes express K(ATP) channels. (PMID:20847183)
• Down-regulation of Kir6.1 and Kir6.2 expression in myometrium may contribute to the enhanced uterine contractility associated with the onset of labour. (PMID:21418633)
• The mutations localized to Kir6.1’s C-terminus, involved conserved residues and the pinacidil-activated K(ATP) current was decreased 45% to 68% for Kir6.1-E332del and 40% to 57% for V346I between -20 mV and 40 mV. (PMID:21836131)
• The researchers report evidence that the KCNJ8 gene increases susceptiblity to the brugada syndrome and early repolarization syndrome. (PMID:22056721)
• Data indicate that pharmacological KvLQT1 and KATP (Kir6.1) inhibition or silencing with siRNAs down-regulated alpha-ENaC expression. (PMID:22406554)
• Data suggest that Kir6.1 and M3 muscarinic receptor colocalize to detrusor caveolae; studies include tissue from both male and female subjects. (PMID:22410194)
• The KCNJ8-S422L variant was shown to be associated with both increased susceptibility to atrial fibrillation and early repolarization. (PMID:22562657)
• results suggest that acting on the 3’-UTR of Kir6.1 and the coding region of SUR2B, methylglyoxal causes instability of Kir6.1 and SUR2B mRNAs, disruption of vascular K(ATP) channels, and impairment of arterial function (PMID:22972803)
• KATP channels are up-regulated with increasing age in human myometrium (PMID:23369859)
• KCNJ8-S422L as pathogenic for J-wave syndromes failed to appropriately account for European population structure and the variant is likely benign, or (b) Ashkenazi Jews may be at significantly increased risk of J-wave syndromes (PMID:23632791)
• We identified a de novo missense mutation encoding Kir6.1[p.Cys176Ser] in the patient. Kir6.1[p.Cys176Ser] channels exhibited markedly higher activity than wild-type channels, as a result of reduced ATP sensitivity. (PMID:24700710)
• Three-dimensional facial morphology in Cantu syndrome. (PMID:32100467)
• A novel mutation in the KCNJ8 gene encoding the Kir6.1 subunit of an ATP-sensitive potassium channel in a Japanese patient with Cantu syndrome. (PMID:32215968)
• The expression of ATP-sensitive potassium channels in human umbilical arteries with severe pre-eclampsia. (PMID:33846486)
• Vascular KATP channel structural dynamics reveal regulatory mechanism by Mg-nucleotides. (PMID:34711681)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio	kcnj8	ENSDARG00000045589
mus_musculus	Kcnj8	ENSMUSG00000030247
rattus_norvegicus	Kcnj8	ENSRNOG00000013463
drosophila_melanogaster	Irk3	FBGN0032706
drosophila_melanogaster	Irk2	FBGN0039081
drosophila_melanogaster	Irk1	FBGN0265042
caenorhabditis_elegans		WBGENE00002149
caenorhabditis_elegans		WBGENE00002150
caenorhabditis_elegans		WBGENE00002151

Paralogs (15): KCNJ13 (ENSG00000115474), KCNJ5 (ENSG00000120457), KCNJ2 (ENSG00000123700), KCNJ1 (ENSG00000151704), KCNJ16 (ENSG00000153822), KCNJ6 (ENSG00000157542), KCNJ15 (ENSG00000157551), KCNJ9 (ENSG00000162728), KCNJ3 (ENSG00000162989), KCNJ4 (ENSG00000168135), KCNJ10 (ENSG00000177807), KCNJ14 (ENSG00000182324), KCNJ12 (ENSG00000184185), KCNJ11 (ENSG00000187486), KCNJ18 (ENSG00000260458)

Protein

Protein identifiers

ATP-sensitive inward rectifier potassium channel 8 — Q15842 (reviewed: Q15842)

Alternative names: Inward rectifier K(+) channel Kir6.1, Potassium channel, inwardly rectifying subfamily J member 8, uKATP-1

All UniProt accessions (2): Q15842, F5GY12

UniProt curated annotations — full annotation on UniProt →

Function. Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it. Their voltage dependence is regulated by the concentration of extracellular potassium; as external potassium is raised, the voltage range of the channel opening shifts to more positive voltages. The inward rectification is mainly due to the blockage of outward current by internal magnesium. This channel is activated by internal ATP and can be blocked by external barium. Can form a sulfonylurea-sensitive but ATP-insensitive potassium channel with ABCC9.

Subunit / interactions. Interacts with ABCC9.

Subcellular location. Membrane.

Tissue specificity. Predominantly detected in fetal and adult heart.

Disease relevance. Defects in KCNJ8 may be associated with susceptibility to J-wave syndromes, a group of heart disorders characterized by early repolarization events as indicated by abnormal J-wave manifestation on electrocardiogram (ECG). The J point denotes the junction of the QRS complex and the ST segment on the ECG, marking the end of depolarization and the beginning of repolarization. An abnormal J wave is a deflection with a dome or hump morphology immediately following the QRS complex of the surface ECG. Examples of J-wave disorders are arrhythmias associated with an early repolarization pattern in the inferior or mid to lateral precordial leads, Brugada syndrome, some cases of idiopathic ventricular fibrillation (VF) with an early repolarization pattern in the inferior, inferolateral or global leads, as well as arrhythmias associated with hypothermia. Sudden infant death syndrome (SIDS) [MIM:272120] SIDS is the sudden death of an infant younger than 1 year that remains unexplained after a thorough case investigation, including performance of a complete autopsy, examination of the death scene, and review of clinical history. Pathophysiologic mechanisms for SIDS may include respiratory dysfunction, cardiac dysrhythmias, cardiorespiratory instability, and inborn errors of metabolism, but definitive pathogenic mechanisms precipitating an infant sudden death remain elusive. Disease susceptibility is associated with variants affecting the gene represented in this entry. Hypertrichotic osteochondrodysplasia (HTOCD) [MIM:239850] A rare disorder characterized by congenital hypertrichosis, neonatal macrosomia, a distinct osteochondrodysplasia, and cardiomegaly. The hypertrichosis leads to thick scalp hair, which extends onto the forehead, and a general increase in body hair. In addition, macrocephaly and coarse facial features, including a broad nasal bridge, epicanthal folds, a wide mouth, and full lips, can be suggestive of a storage disorder. About half of affected individuals are macrosomic and edematous at birth, whereas in childhood they usually have a muscular appearance with little subcutaneous fat. Thickened calvarium, narrow thorax, wide ribs, flattened or ovoid vertebral bodies, coxa valga, osteopenia, enlarged medullary canals, and metaphyseal widening of long bones have been reported. Cardiac manifestations such as patent ductus arteriosus, ventricular hypertrophy, pulmonary hypertension, and pericardial effusions are present in approximately 80% of cases. Motor development is usually delayed due to hypotonia. Most patients have a mild speech delay, and a small percentage have learning difficulties or intellectual disability. The disease may be caused by variants affecting distinct genetic loci, including the gene represented in this entry.

Similarity. Belongs to the inward rectifier-type potassium channel (TC 1.A.2.1) family. KCNJ8 subfamily.

RefSeq proteins (1): NP_004973* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003278	K_chnl_inward-rec_Kir6.1	Family
IPR013518	K_chnl_inward-rec_Kir_cyto	Homologous_superfamily
IPR014756	Ig_E-set	Homologous_superfamily
IPR016449	K_chnl_inward-rec_Kir	Family
IPR040445	Kir_TM	Domain
IPR041647	IRK_C	Domain

Pfam: PF01007, PF17655

Catalyzed reactions (Rhea), 1 shown:

• K(+)(in) = K(+)(out) (RHEA:29463)

UniProt features (21 total): sequence variant 6, topological domain 4, transmembrane region 2, intramembrane region 2, chain 1, short sequence motif 1, compositionally biased region 1, site 1, modified residue 1, mutagenesis site 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q15842-F1	84.00	0.60

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 (1): 170 (role in the control of polyamine-mediated channel gating and in the blocking by intracellular magnesium)

Post-translational modifications (1): 6

Mutagenesis-validated functional residues (1):

Position	Phenotype
65	no effect on channel activity.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-1296025	ATP sensitive Potassium channels
R-HSA-112316	Neuronal System
R-HSA-1296065	Inwardly rectifying K+ channels
R-HSA-1296071	Potassium Channels

MSigDB gene sets: 500 (showing top): GOBP_CARDIAC_CHAMBER_DEVELOPMENT, GOBP_POTASSIUM_ION_TRANSPORT, GOBP_NEUROMUSCULAR_JUNCTION_DEVELOPMENT, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_GLUTAMATE_SECRETION, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_CARDIAC_SEPTUM_DEVELOPMENT, GOBP_REGULATION_OF_BLOOD_PRESSURE, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_CELL_POLARITY, GOBP_CORONARY_VASCULATURE_DEVELOPMENT, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_INFLAMMATORY_RESPONSE, GOBP_SYNAPSE_ASSEMBLY, GOBP_RESPONSE_TO_PEPTIDE, REACTOME_POTASSIUM_CHANNELS

GO Biological Process (59): response to hypoxia (GO:0001666), microglial cell activation (GO:0001774), kidney development (GO:0001822), regulation of heart rate (GO:0002027), adaptive immune response (GO:0002250), response to ischemia (GO:0002931), heart morphogenesis (GO:0003007), ventricular cardiac muscle tissue development (GO:0003229), potassium ion transport (GO:0006813), apoptotic process (GO:0006915), regulation of blood pressure (GO:0008217), determination of adult lifespan (GO:0008340), protein secretion (GO:0009306), response to xenobiotic stimulus (GO:0009410), gene expression (GO:0010467), fatty acid transport (GO:0015908), transmission of nerve impulse (GO:0019226), establishment of cell polarity (GO:0030010), response to lipopolysaccharide (GO:0032496), response to insulin (GO:0032868), response to ATP (GO:0033198), response to cytokine (GO:0034097), regulation of monoatomic ion transmembrane transport (GO:0034765), response to endoplasmic reticulum stress (GO:0034976), p38MAPK cascade (GO:0038066), vasodilation (GO:0042311), response to exogenous dsRNA (GO:0043330), NLRP3 inflammasome complex assembly (GO:0044546), fat cell differentiation (GO:0045444), fibroblast proliferation (GO:0048144), neuromuscular process (GO:0050905), synaptic assembly at neuromuscular junction (GO:0051124), defense response to virus (GO:0051607), atrioventricular node cell differentiation (GO:0060922), coronary vasculature development (GO:0060976), glutamate secretion, neurotransmission (GO:0061535), CAMKK-AMPK signaling cascade (GO:0061762), calcium ion transmembrane transport (GO:0070588), potassium ion transmembrane transport (GO:0071805), obsolete inorganic cation transmembrane transport (GO:0098662)

GO Molecular Function (8): inward rectifier potassium channel activity (GO:0005242), ATP binding (GO:0005524), ATP-activated inward rectifier potassium channel activity (GO:0015272), sulfonylurea receptor binding (GO:0017098), ATPase-coupled monoatomic cation transmembrane transporter activity (GO:0019829), voltage-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential (GO:0099508), voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization (GO:1902282), protein binding (GO:0005515)

GO Cellular Component (12): plasma membrane (GO:0005886), voltage-gated potassium channel complex (GO:0008076), inward rectifying potassium channel (GO:0008282), myofibril (GO:0030016), potassium ion-transporting ATPase complex (GO:0031004), sarcolemma (GO:0042383), presynaptic active zone membrane (GO:0048787), glutamatergic synapse (GO:0098978), membrane (GO:0016020), protein-containing complex (GO:0032991), monoatomic ion channel complex (GO:0034702), presynapse (GO:0098793)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Inwardly rectifying K+ channels	1
Potassium Channels	1
Neuronal System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
response to stress	2
regulation of biological quality	2
presynaptic membrane	2
potassium channel complex	2
plasma membrane protein complex	2
synapse	2
cellular anatomical structure	2
response to decreased oxygen levels	1
leukocyte activation involved in inflammatory response	1
macrophage activation	1
glial cell activation	1
animal organ development	1
renal system development	1
regulation of heart contraction	1
immune response	1
heart development	1
animal organ morphogenesis	1
cardiac muscle tissue development	1
metal ion transport	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
blood circulation	1
multicellular organismal process	1
protein transport	1
secretion by cell	1
establishment of protein localization to extracellular region	1
protein localization to extracellular region	1
response to chemical	1
macromolecule biosynthetic process	1
lipid transport	1
monocarboxylic acid transport	1
action potential	1
cell communication	1
chemical synaptic transmission	1
nervous system process	1
establishment or maintenance of cell polarity	1
response to molecule of bacterial origin	1
response to lipid	1
response to oxygen-containing compound	1

Protein interactions and networks

STRING

1192 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KCNJ8	ABCC8	Q09428	998
KCNJ8	ABCC9	O60706	992
KCNJ8	KCNJ11	Q14654	982
KCNJ8	KCNE3	Q9Y6H6	735
KCNJ8	KCND3	Q9UK17	730
KCNJ8	KCNE5	Q9UJ90	726
KCNJ8	SCN3B	Q9NY72	723
KCNJ8	SCN1B	Q07699	720
KCNJ8	CACNA2D1	P54289	715
KCNJ8	KCNA5	P22460	707
KCNJ8	RANGRF	Q9HD47	694
KCNJ8	GPD1L	Q8N335	686
KCNJ8	CACNB2	Q08289	679
KCNJ8	SCN5A	Q14524	667
KCNJ8	CACNA1C	Q13936	665

IntAct

62 interactions, top by confidence:

A	B	Type	Score
P2RX4	FAM20B	psi-mi:“MI:0914”(association)	0.640
EMD	KCNJ8	psi-mi:“MI:0915”(physical association)	0.560
KCNJ8	TMEM54	psi-mi:“MI:0915”(physical association)	0.560
KCNJ8	TMEM140	psi-mi:“MI:0915”(physical association)	0.560
GPR21	TMEM120B	psi-mi:“MI:0914”(association)	0.530
PLXDC2	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
MCOLN3	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
CD1B	TOR1B	psi-mi:“MI:0914”(association)	0.530
CD1E	SUSD5	psi-mi:“MI:0914”(association)	0.530
TCTN2	TPST2	psi-mi:“MI:0914”(association)	0.530
ADAM33	LRP5	psi-mi:“MI:0914”(association)	0.530
TMED6	SMPD2	psi-mi:“MI:0914”(association)	0.530
SLC30A2	ESYT2	psi-mi:“MI:0914”(association)	0.530
TCTN3	GPAA1	psi-mi:“MI:0914”(association)	0.480
TMED6	UPK3BL1	psi-mi:“MI:0914”(association)	0.350
CDH5	ARVCF	psi-mi:“MI:0914”(association)	0.350
P2RX4	ORC4	psi-mi:“MI:0914”(association)	0.350
NAALADL2	IGSF3	psi-mi:“MI:0914”(association)	0.350
HLA-DQA1	HLA-A	psi-mi:“MI:0914”(association)	0.350
TTMP	TMEM223	psi-mi:“MI:0914”(association)	0.350
TTYH1	TMEM223	psi-mi:“MI:0914”(association)	0.350
HLA-DQA1	TMEM223	psi-mi:“MI:0914”(association)	0.350
HCST	TMEM120B	psi-mi:“MI:0914”(association)	0.350
LRRC55	TMEM120B	psi-mi:“MI:0914”(association)	0.350
CDH5	NBAS	psi-mi:“MI:0914”(association)	0.350
TCTN2	TMEM131L	psi-mi:“MI:0914”(association)	0.350
IGHD	POTEF	psi-mi:“MI:0914”(association)	0.350

BioGRID (81): KCNJ8 (Affinity Capture-MS), KCNJ8 (Affinity Capture-MS), KCNJ8 (Affinity Capture-MS), KCNJ8 (Affinity Capture-MS), KCNJ8 (Affinity Capture-MS), KCNJ8 (Affinity Capture-MS), KCNJ8 (Affinity Capture-MS), KCNJ8 (Affinity Capture-MS), KCNJ8 (Affinity Capture-MS), KCNJ8 (Affinity Capture-MS), KCNJ8 (Affinity Capture-MS), KCNJ8 (Affinity Capture-MS), KCNJ8 (Affinity Capture-MS), KCNJ8 (Affinity Capture-MS), KCNJ8 (Affinity Capture-MS)

ESM2 similar proteins: B7U540, E1BNE9, F1MYR9, F1NHE9, O02670, O02822, O18839, O19182, O70617, P35561, P48050, P48051, P48542, P48543, P48544, P48545, P48548, P48549, P48550, P49656, P49658, P52185, P52186, P52187, P52188, P52189, P52190, P52191, P52192, P63250, P63251, P63252, P63253, P70673, P97794, Q14500, Q14654, Q15842, Q4TZY1, Q5NVJ6

Diamond homologs: B7U540, E1BN00, E1BNE9, F1MYR9, F1NHE9, O02670, O02822, O18839, O19182, O60928, O70339, O70596, O70617, O88335, O88932, P35560, P35561, P48048, P48050, P48051, P48542, P48543, P48544, P48545, P48548, P48549, P48550, P49655, P49656, P49658, P52185, P52186, P52187, P52188, P52189, P52190, P52191, P52192, P63250, P63251

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
phenformin	“down-regulates activity”	KCNJ8	“chemical inhibition”
KCNJ8	“down-regulates activity”	NLRP3	binding
KCNJ8	“form complex”	“KATP channel”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 77 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
SLC-mediated transmembrane transport	7	8.1×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
transmembrane transport	6	15.1×	3e-04
adaptive immune response	6	7.5×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	135
Likely benign	104
Benign	9

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
1708157	NM_004982.4(KCNJ8):c.712G>A (p.Gly238Arg)	Likely pathogenic

SpliceAI

477 predictions. Top by Δscore:

Variant	Effect	Δscore
12:21773237:TCTTA:T	donor_loss	1.0000
12:21773238:CTTA:C	donor_loss	1.0000
12:21773239:TTA:T	donor_loss	1.0000
12:21773240:TA:T	donor_loss	1.0000
12:21773241:ACCT:A	donor_loss	1.0000
12:21774540:ACTT:A	donor_loss	1.0000
12:21774542:TTA:T	donor_loss	1.0000
12:21774544:A:AC	donor_gain	1.0000
12:21774545:C:CA	donor_gain	1.0000
12:21774545:CA:C	donor_gain	1.0000
12:21774545:CAG:C	donor_gain	1.0000
12:21774545:CAGA:C	donor_gain	1.0000
12:21773242:CCTGA:C	donor_gain	0.9900
12:21773455:T:TA	donor_gain	0.9900
12:21774543:TACAG:T	donor_gain	0.9900
12:21774544:ACAGA:A	donor_gain	0.9900
12:21774545:CAGAC:C	donor_gain	0.9900
12:21774578:T:TA	donor_gain	0.9900
12:21773787:A:C	acceptor_gain	0.9800
12:21774548:A:AC	donor_gain	0.9800
12:21774549:C:CC	donor_gain	0.9800
12:21774793:C:CA	donor_gain	0.9800
12:21766624:C:CA	acceptor_loss	0.9700
12:21766625:T:G	acceptor_loss	0.9700
12:21773271:CCAA:C	donor_gain	0.9700
12:21773686:CCTG:C	acceptor_loss	0.9700
12:21773687:CTGCA:C	acceptor_loss	0.9700
12:21773688:T:A	acceptor_loss	0.9700
12:21769796:A:AC	donor_gain	0.9600
12:21769797:C:CC	donor_gain	0.9600

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000277319 (12:21766814 C>G), RS1000417676 (12:21773023 C>T), RS1000553224 (12:21767426 C>G,T), RS1001049525 (12:21767311 C>A,G,T), RS1001753692 (12:21766359 A>T), RS1001866118 (12:21775125 G>T), RS1001978813 (12:21773660 C>T), RS1002088446 (12:21774878 G>A), RS1002223710 (12:21766927 T>C), RS1002248524 (12:21767428 C>G), RS1002550703 (12:21771058 A>G), RS1002615176 (12:21769928 T>G), RS1002646432 (12:21770187 A>G), RS1003472107 (12:21768688 G>T), RS1003493924 (12:21765000 G>T)

Disease associations

OMIM: gene MIM:600935 | disease phenotypes: MIM:601144, MIM:239850

GenCC curated gene-disease

Disease	Classification	Inheritance
hypertrichotic osteochondrodysplasia Cantu type	Strong	Autosomal dominant
Brugada syndrome	Limited	Unknown
Brugada syndrome 1	Disputed Evidence	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Brugada syndrome	Disputed	AD

Mondo (8): Brugada syndrome (MONDO:0015263), hypertrophic cardiomyopathy (MONDO:0005045), hypertrichotic osteochondrodysplasia Cantu type (MONDO:0009406), cardiac rhythm disease (MONDO:0007263), syndromic disease (MONDO:0002254), long QT syndrome (MONDO:0002442), cardiac arrest (MONDO:0000745), Brugada syndrome 1 (MONDO:0011001)

Orphanet (3): Brugada syndrome (Orphanet:130), Rare hypertrophic cardiomyopathy (Orphanet:217569), Cantú syndrome (Orphanet:1517)

HPO phenotypes

50 total (30 of 50 shown, HPO-id order):

HPO	Term
HP:0000154	Wide mouth
HP:0000256	Macrocephaly
HP:0000280	Coarse facial features
HP:0000286	Epicanthus
HP:0000294	Low anterior hairline
HP:0000336	Prominent supraorbital ridges
HP:0000343	Long philtrum
HP:0000431	Wide nasal bridge
HP:0000463	Anteverted nares
HP:0000470	Short neck
HP:0000527	Long eyelashes
HP:0000574	Thick eyebrow
HP:0000774	Narrow chest
HP:0000885	Broad ribs
HP:0000926	Platyspondyly
HP:0000939	Osteoporosis
HP:0000944	Abnormal metaphysis morphology
HP:0001256	Mild intellectual disability
HP:0001279	Syncope
HP:0001537	Umbilical hernia
HP:0001639	Hypertrophic cardiomyopathy
HP:0001640	Cardiomegaly
HP:0001643	Patent ductus arteriosus
HP:0001649	Tachycardia
HP:0001654	Abnormal heart valve morphology
HP:0001663	Ventricular fibrillation
HP:0001695	Cardiac arrest
HP:0001869	Deep plantar creases
HP:0002162	Low posterior hairline
HP:0002230	Generalized hirsutism

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST008362_44	Birth weight	2.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004344	birth weight

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D053840	Brugada Syndrome	C14.280.067.322; C14.280.123.250; C16.320.100
D002312	Cardiomyopathy, Hypertrophic	C14.280.238.100; C14.280.484.048.750.070.160
D006323	Heart Arrest	C14.280.383
D008133	Long QT Syndrome	C14.280.067.565; C14.280.123.625; C16.131.240.400.715; C23.550.073.547
D013577	Syndrome	C23.550.288.500
C535572	Cantu syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2095152 (PROTEIN COMPLEX GROUP), CHEMBL4770 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 135 (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
CHEMBL49035	CROMAKALIM	2	135

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: vgic — Inwardly rectifying potassium channels (K_IR)

ChEMBL bioactivities

298 potent at pChembl≥5 of 326 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.27	EC50	0.537	nM	CHEMBL321455
8.30	EC50	5.012	nM	CHEMBL3138573
8.30	EC50	5.012	nM	CHEMBL2111694
8.20	EC50	6.31	nM	CHEMBL323159
8.06	EC50	8.71	nM	CHEMBL3392139
8.05	EC50	8.913	nM	CHEMBL50760
7.95	EC50	11.22	nM	CHEMBL2111694
7.90	EC50	12.59	nM	CHEMBL3138553
7.89	EC50	12.88	nM	CHEMBL108723
7.85	EC50	14.13	nM	CHEMBL108251
7.70	IC50	20	nM	CROMAKALIM
7.66	EC50	21.88	nM	CHEMBL11458
7.66	EC50	21.88	nM	CHEMBL3138587
7.65	EC50	22.39	nM	CHEMBL107888
7.64	EC50	22.91	nM	CHEMBL3138607
7.63	EC50	23.44	nM	CHEMBL110399
7.59	EC50	25.7	nM	CHEMBL3138549
7.59	EC50	25.7	nM	CHEMBL2112487
7.57	EC50	26.92	nM	CHEMBL320983
7.56	EC50	27.54	nM	CHEMBL108586
7.55	EC50	28.18	nM	CHEMBL3138545
7.52	EC50	30	nM	CHEMBL36665
7.52	EC50	30	nM	CHEMBL34523
7.51	EC50	30.9	nM	CHEMBL3138586
7.50	EC50	31.62	nM	CHEMBL321210
7.49	EC50	32.36	nM	CHEMBL320518
7.48	EC50	33.11	nM	CHEMBL3138586
7.46	EC50	35	nM	CHEMBL37534
7.46	EC50	34.67	nM	(-)-CROMAKALIM
7.45	EC50	35.48	nM	CHEMBL108440
7.42	EC50	38.02	nM	CHEMBL3138561
7.40	EC50	40	nM	CHEMBL35356
7.36	EC50	43.65	nM	CHEMBL3138553
7.36	IC50	44	nM	CHEMBL143181
7.35	EC50	44.67	nM	CHEMBL11458
7.31	EC50	48.98	nM	CHEMBL49153
7.28	EC50	52.48	nM	CHEMBL3138560
7.28	EC50	52.48	nM	CHEMBL300958
7.27	EC50	53.7	nM	CHEMBL3138606
7.27	EC50	53.7	nM	CHEMBL3138579
7.26	EC50	54.95	nM	CHEMBL3138596
7.20	EC50	63.1	nM	CHEMBL109412
7.20	EC50	63.1	nM	CHEMBL110399
7.19	EC50	64.57	nM	CHEMBL110511
7.17	EC50	67.61	nM	CHEMBL323787
7.17	EC50	67.61	nM	CHEMBL3138573
7.16	EC50	69.18	nM	CHEMBL3138553
7.14	EC50	72.44	nM	CHEMBL3392140
7.10	EC50	79.43	nM	CHEMBL326901
7.09	EC50	81.28	nM	CHEMBL47170

PubChem BioAssay actives

297 with measured affinity, of 566 total; 50 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
9-(3-bromo-4-fluorophenyl)-5,13-dithia-2-azatricyclo[8.4.0.03,8]tetradeca-1(10),3(8)-diene-7,11-dione	93975: Evaluated for K-ATP activity in terms of membrane potential change, through guinea pig bladder assay	ec50	0.0005	uM
(8R)-8-(3-bromo-4-fluorophenyl)-6,6-dioxo-12-oxa-6lambda6-thia-2-azatricyclo[7.4.0.03,7]trideca-1(9),3(7)-dien-10-one	93975: Evaluated for K-ATP activity in terms of membrane potential change, through guinea pig bladder assay	ec50	0.0050	uM
(8S)-8-(3-bromo-4-fluorophenyl)-5,12-dioxa-2-azatricyclo[7.4.0.03,7]trideca-1(9),3(7)-diene-6,10-dione	93985: Evaluated for K-ATP activity as in vitro bladder relaxation in spontaneous Landrace pig detrusor strips (SLPD)	ec50	0.0050	uM
(9S)-9-(3-bromo-4-fluorophenyl)-3,4,5,6,7,9-hexahydrofuro[3,4-b]quinoline-1,8-dione	93975: Evaluated for K-ATP activity in terms of membrane potential change, through guinea pig bladder assay	ec50	0.0063	uM
8-(3-bromo-4-fluorophenyl)-10,10-dioxo-5-oxa-10lambda6-thia-2-azatricyclo[7.4.0.03,7]trideca-1(9),3(7)-dien-6-one	93975: Evaluated for K-ATP activity in terms of membrane potential change, through guinea pig bladder assay	ec50	0.0087	uM
N-[2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)naphthalen-1-yl]propanamide	159672: Potent effective concentration was evaluated for KATP channel opening activity in pig bladder strips	ec50	0.0089	uM
(9R)-9-(3-bromo-4-fluorophenyl)-1,1-dioxo-3,4,5,6,7,9-hexahydro-2H-thieno[3,2-b]quinolin-8-one	93984: Evaluated for K-ATP activity as in vitro bladder relaxation in spontaneous Landrace pig detrusor strips (SLPD)	ec50	0.0126	uM
8-(3-bromo-4-fluorophenyl)-5-methyl-12-oxa-2,5-diazatricyclo[7.4.0.03,7]trideca-1(9),3(7)-diene-6,10-dione	93975: Evaluated for K-ATP activity in terms of membrane potential change, through guinea pig bladder assay	ec50	0.0129	uM
8-(3-bromo-4-fluorophenyl)-5,11-dioxa-2-azatricyclo[7.4.0.03,7]trideca-1(9),3(7)-diene-6,10-dione	93975: Evaluated for K-ATP activity in terms of membrane potential change, through guinea pig bladder assay	ec50	0.0141	uM
3-hydroxy-2,2-dimethyl-4-(2-oxopyrrolidin-1-yl)-3,4-dihydrochromene-6-carbonitrile	78296: Contraction and relaxation of guinea pig portal vein with KCl and glibenclamide respectively	ic50	0.0200	uM
(9S)-9-(3-iodo-4-methylphenyl)-1,1-dioxo-3,4,5,6,7,9-hexahydro-2H-thieno[3,2-b]quinolin-8-one	93974: Evaluated for K-ATP activity in terms of change in membrane potential through guinea pig bladder assay	ec50	0.0219	uM
1-cyano-2-(2-methylbutan-2-yl)-3-pyridin-3-ylguanidine	93984: Evaluated for K-ATP activity as in vitro bladder relaxation in spontaneous Landrace pig detrusor strips (SLPD)	ec50	0.0219	uM
(8S)-8-(3-bromo-4-fluorophenyl)-5-oxa-2-azatricyclo[7.3.0.03,7]dodeca-1(9),3(7)-diene-6,10-dione	93975: Evaluated for K-ATP activity in terms of membrane potential change, through guinea pig bladder assay	ec50	0.0224	uM
(9S)-9-(3-bromo-4-fluorophenyl)-1,1-dioxo-3,4,5,6,7,9-hexahydro-2H-thieno[3,2-b]quinolin-8-one	93984: Evaluated for K-ATP activity as in vitro bladder relaxation in spontaneous Landrace pig detrusor strips (SLPD)	ec50	0.0229	uM
8-(3-bromo-4-fluorophenyl)-5,11-dioxa-2-azatricyclo[7.3.0.03,7]dodeca-1(9),3(7)-diene-6,10-dione	93985: Evaluated for K-ATP activity as in vitro bladder relaxation in spontaneous Landrace pig detrusor strips (SLPD)	ec50	0.0234	uM
(8R)-8-(3-bromo-4-fluorophenyl)-5,12-dioxa-2-azatricyclo[7.4.0.03,7]trideca-1(9),3(7)-diene-6,10-dione	93975: Evaluated for K-ATP activity in terms of membrane potential change, through guinea pig bladder assay	ec50	0.0257	uM
(9S)-9-(3-bromo-4-chlorophenyl)-1,1-dioxo-3,4,5,6,7,9-hexahydro-2H-thieno[3,2-b]quinolin-8-one	93974: Evaluated for K-ATP activity in terms of change in membrane potential through guinea pig bladder assay	ec50	0.0257	uM
9-(3-bromo-4-fluorophenyl)-5,13-dioxa-2-azatricyclo[8.4.0.03,8]tetradeca-1(10),3(8)-diene-7,11-dione	93975: Evaluated for K-ATP activity in terms of membrane potential change, through guinea pig bladder assay	ec50	0.0269	uM
7-(3-bromo-4-fluorophenyl)-5-methyl-1,1-dioxo-2,3,4,7-tetrahydrothieno[3,2-b]pyridine-6-carbonitrile	93974: Evaluated for K-ATP activity in terms of change in membrane potential through guinea pig bladder assay	ec50	0.0275	uM
(9S)-9-(4-fluoro-3-iodophenyl)-1,1-dioxo-3,4,5,6,7,9-hexahydro-2H-thieno[3,2-b]quinolin-8-one	93974: Evaluated for K-ATP activity in terms of change in membrane potential through guinea pig bladder assay	ec50	0.0282	uM
9-(3-bromo-4-fluorophenyl)-5,6,7,9-tetrahydro-4H-pyrazolo[5,1-b]quinazolin-8-one	73908: Potassium channel opening activity determined in cultured guinea pig urinary bladder cells	ec50	0.0300	uM
9-(4-bromo-3-fluorophenyl)-5,6,7,9-tetrahydro-4H-pyrazolo[5,1-b]quinazolin-8-one	73908: Potassium channel opening activity determined in cultured guinea pig urinary bladder cells	ec50	0.0300	uM
(8R)-8-(3-bromo-4-fluorophenyl)-6,6-dioxo-6lambda6-thia-2-azatricyclo[7.3.0.03,7]dodeca-1(9),3(7)-dien-10-one	93977: Evaluated for K-ATP activity in terms of stable twitch response through field-stimulated landrace pig detrusor assay	ec50	0.0309	uM
8-(3-bromo-4-fluorophenyl)-12-oxa-2-azatricyclo[7.4.0.03,7]trideca-1(9),3(7)-diene-6,10-dione	93975: Evaluated for K-ATP activity in terms of membrane potential change, through guinea pig bladder assay	ec50	0.0316	uM
(9R)-9-(3-bromo-4-fluorophenyl)-3,4,5,6,7,9-hexahydrofuro[3,4-b]quinoline-1,8-dione	93985: Evaluated for K-ATP activity as in vitro bladder relaxation in spontaneous Landrace pig detrusor strips (SLPD)	ec50	0.0324	uM
(3R,4S)-3-hydroxy-2,2-dimethyl-4-(2-oxopyrrolidin-1-yl)-3,4-dihydrochromene-6-carbonitrile	93984: Evaluated for K-ATP activity as in vitro bladder relaxation in spontaneous Landrace pig detrusor strips (SLPD)	ec50	0.0347	uM
9-(3-bromo-4-fluorophenyl)-7,7-dimethyl-4,4a,5,6,8a,9-hexahydropyrazolo[5,1-b]quinazolin-8-one	73908: Potassium channel opening activity determined in cultured guinea pig urinary bladder cells	ec50	0.0350	uM
5-(3-bromo-4-fluorophenyl)-1,5,7,8,9,10-hexahydropyrano[3,4-b]quinoline-4,6-dione	93975: Evaluated for K-ATP activity in terms of membrane potential change, through guinea pig bladder assay	ec50	0.0355	uM
10-(3-bromo-4-fluorophenyl)-1,1-dioxo-2,3,4,5,6,7,8,10-octahydrothiopyrano[3,2-b]quinolin-9-one	93974: Evaluated for K-ATP activity in terms of change in membrane potential through guinea pig bladder assay	ec50	0.0380	uM
8-(3-bromo-4-fluorophenyl)-12-thia-2,6,7-triazatricyclo[7.4.0.03,7]trideca-3,5-dien-10-one	73908: Potassium channel opening activity determined in cultured guinea pig urinary bladder cells	ec50	0.0400	uM
N-[4-(benzenesulfonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide	78296: Contraction and relaxation of guinea pig portal vein with KCl and glibenclamide respectively	ic50	0.0440	uM
(E)-N-[2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)naphthalen-1-yl]but-2-enamide	159672: Potent effective concentration was evaluated for KATP channel opening activity in pig bladder strips	ec50	0.0490	uM
N-[2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)naphthalen-1-yl]-3-methylbenzamide	159672: Potent effective concentration was evaluated for KATP channel opening activity in pig bladder strips	ec50	0.0525	uM
(8R)-8-(3-bromo-4-fluorophenyl)-10,10-dioxo-10lambda6-thia-2-azatricyclo[7.4.0.03,7]trideca-1(9),3(7)-dien-6-one	93974: Evaluated for K-ATP activity in terms of change in membrane potential through guinea pig bladder assay	ec50	0.0525	uM
9-(3-bromo-4-fluorophenyl)-11,11-dioxo-5-oxa-11lambda6-thia-2-azatricyclo[8.4.0.03,8]tetradeca-1(10),3(8)-dien-7-one	93975: Evaluated for K-ATP activity in terms of membrane potential change, through guinea pig bladder assay	ec50	0.0537	uM
methyl 7-(3-bromo-4-fluorophenyl)-5-methyl-1,1-dioxo-2,3,4,7-tetrahydrothieno[3,2-b]pyridine-6-carboxylate	93974: Evaluated for K-ATP activity in terms of change in membrane potential through guinea pig bladder assay	ec50	0.0537	uM
(9S)-9-(3,4-dibromophenyl)-1,1-dioxo-3,4,5,6,7,9-hexahydro-2H-thieno[3,2-b]quinolin-8-one	93974: Evaluated for K-ATP activity in terms of change in membrane potential through guinea pig bladder assay	ec50	0.0549	uM
9-(3-bromo-4-fluorophenyl)-5-oxa-13-thia-2-azatricyclo[8.4.0.03,8]tetradeca-1(10),3(8)-diene-7,11-dione	93975: Evaluated for K-ATP activity in terms of membrane potential change, through guinea pig bladder assay	ec50	0.0631	uM
8-(3-bromo-4-fluorophenyl)-5-oxa-12-thia-2-azatricyclo[7.4.0.03,7]trideca-1(9),3(7)-diene-6,10-dione	93975: Evaluated for K-ATP activity in terms of membrane potential change, through guinea pig bladder assay	ec50	0.0646	uM
8-(3-bromo-4-fluorophenyl)-11-oxa-2-azatricyclo[7.4.0.03,7]trideca-1(9),3(7)-diene-6,10-dione	93975: Evaluated for K-ATP activity in terms of membrane potential change, through guinea pig bladder assay	ec50	0.0676	uM
8-(3-bromo-4-fluorophenyl)-10,10-dioxo-5-oxa-10lambda6-thia-2-azatricyclo[7.3.0.03,7]dodeca-1(9),3(7)-dien-6-one	93975: Evaluated for K-ATP activity in terms of membrane potential change, through guinea pig bladder assay	ec50	0.0724	uM
10-(3-bromo-4-fluorophenyl)-4,5,6,7,8,10-hexahydro-3H-pyrano[4,3-b]quinoline-1,9-dione	93975: Evaluated for K-ATP activity in terms of membrane potential change, through guinea pig bladder assay	ec50	0.0794	uM
N-[2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)naphthalen-1-yl]cyclobutanecarboxamide	159672: Potent effective concentration was evaluated for KATP channel opening activity in pig bladder strips	ec50	0.0813	uM
9-(3-bromo-4-fluorophenyl)-6,12-dioxa-2-azatricyclo[8.4.0.03,8]tetradeca-1(10),3(8)-diene-7,11-dione	93975: Evaluated for K-ATP activity in terms of membrane potential change, through guinea pig bladder assay	ec50	0.0813	uM
N-(4-benzoylphenyl)-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide	78296: Contraction and relaxation of guinea pig portal vein with KCl and glibenclamide respectively	ic50	0.0820	uM
(9S)-9-(3-bromo-4-fluorophenyl)-7,7-dimethyl-1,1-dioxo-2,3,4,5,6,9-hexahydrothieno[3,2-b]quinolin-8-one	93974: Evaluated for K-ATP activity in terms of change in membrane potential through guinea pig bladder assay	ec50	0.0832	uM
N-[2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)naphthalen-1-yl]acetamide	159672: Potent effective concentration was evaluated for KATP channel opening activity in pig bladder strips	ec50	0.0955	uM
4-[[2-[[(2R)-3,3-dimethylbutan-2-yl]amino]-3,4-dioxocyclobuten-1-yl]amino]-3-ethylbenzonitrile	93984: Evaluated for K-ATP activity as in vitro bladder relaxation in spontaneous Landrace pig detrusor strips (SLPD)	ec50	0.1023	uM
5-(3-bromo-4-fluorophenyl)-1,5,7,8,9,10-hexahydrothiopyrano[3,4-b]quinoline-4,6-dione	93975: Evaluated for K-ATP activity in terms of membrane potential change, through guinea pig bladder assay	ec50	0.1071	uM
(9R)-9-(3-bromo-4-fluorophenyl)-7,7-dimethyl-1,1-dioxo-2,3,4,5,6,9-hexahydrothieno[3,2-b]quinolin-8-one	93974: Evaluated for K-ATP activity in terms of change in membrane potential through guinea pig bladder assay	ec50	0.1071	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases methylation, affects cotreatment, increases expression, affects expression	8
Estradiol	increases expression, affects cotreatment, decreases expression	3
trichostatin A	increases expression	2
Decitabine	affects expression, increases expression	2
Air Pollutants	affects methylation, increases abundance, decreases expression	2
Cyclosporine	decreases expression	2
Aflatoxin B1	decreases expression, decreases methylation	2
Particulate Matter	affects methylation, increases abundance, decreases expression	2
pirinixic acid	affects binding, decreases expression, increases activity	1
bisphenol A	decreases expression	1
methylselenic acid	increases expression	1
sulforaphane	decreases expression	1
manganese chloride	increases abundance, decreases expression	1
beta-methylcholine	affects expression	1
CGP 52608	affects binding, increases reaction	1
deguelin	increases expression	1
2-palmitoylglycerol	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
pyrachlostrobin	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
(+)-JQ1 compound	decreases expression	1
Vorinostat	increases expression	1
Acetaminophen	decreases expression	1
Benzo(a)pyrene	increases methylation, affects methylation	1
Carbamazepine	affects expression	1
Cisplatin	affects expression	1
Doxorubicin	increases expression	1
Glyburide	decreases activity	1
Hydrogen Peroxide	affects expression	1
Lead	decreases expression	1

ChEMBL screening assays

43 unique, capped per target: 38 functional, 5 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4886523	Binding	KATP channel CEREP ligand profiling	Data for DCP probe A-485
CHEMBL678531	Functional	Potassium channel opening activity determined in cultured guinea pig urinary bladder cells	Structure-Activity studies for a novel series of tricyclic dihydropyrimidines as K(ATP) channel openers (KCOs). — Bioorg Med Chem Lett

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D7T3	Ubigene A-549 KCNJ8 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00702117	PHASE4	COMPLETED	Ajmaline Utilization in the Diagnosis and Treatment of Cardiac Arrhythmias
NCT00879060	PHASE4	COMPLETED	Clinical and Therapeutic Implications of Fibrosis in Hypertrophic Cardiomyopathy
NCT01721967	PHASE4	COMPLETED	Ranolazine for the Treatment of Chest Pain in HCM Patients
NCT02948998	PHASE4	UNKNOWN	Evaluating the Effect of Spironolactone on Hypertrophic Cardiomyopathy
NCT03249272	PHASE4	TERMINATED	Microvascular Dysfunction in Nonischemic Cardiomyopathy: Insights From CMR Assessment of Coronary Flow Reserve
NCT04133532	PHASE4	COMPLETED	Effect of Metoprolol in Post Alcohol Septal Ablation Patients With Hypertrophic Cardiomyopathy
NCT06401343	PHASE4	RECRUITING	Use of SGLT2i in noHCM With HFpEF
NCT07103655	PHASE4	NOT_YET_RECRUITING	The Therapeutic Value of Mavacamten in Hypertrophic Cardiomyopathy With Mid-to-Apical Left Ventricular Obstruction
NCT07600177	PHASE4	RECRUITING	Mavacamten to Aficamten Transition in Patients With Obstructive Hypertrophic Cardiomyopathy
NCT00701077	PHASE3	TERMINATED	DAPERB 3,4-DiAminoPyridine and Electrophysiological Response in Brugada Syndrome
NCT00927732	PHASE3	TERMINATED	Hydroquinidine Versus Placebo in Patients With Brugada Syndrome
NCT00317967	PHASE3	COMPLETED	Study to Determine if Atorvastatin Reduces Size and Stiffness of Muscle in the Left Ventricle of the Heart
NCT00698074	PHASE3	UNKNOWN	Diastolic Ventricular Interaction and the Effects of Biventricular Pacing in Hypertrophic Cardiomyopathy
NCT00821353	PHASE3	COMPLETED	Antiarrhythmic Therapy Versus Catheter Ablation for Atrial Fibrillation in Hypertrophic Cardiomyopathy
NCT02431221	PHASE3	WITHDRAWN	Efficacy, Safety, and Tolerability of Perhexiline in Subjects With Hypertrophic Cardiomyopathy and Heart Failure
NCT03470545	PHASE3	COMPLETED	Clinical Study to Evaluate Mavacamten (MYK-461) in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy
NCT05174416	PHASE3	COMPLETED	A Study to Evaluate the Efficacy and Safety of Mavacamten in Chinese Adults With Symptomatic Obstructive HCM
NCT05182658	PHASE3	ACTIVE_NOT_RECRUITING	Empagliflozin in Hypertrophic Cardiomyopathy
NCT05186818	PHASE3	COMPLETED	Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic oHCM
NCT05767346	PHASE3	COMPLETED	Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Metoprolol Succinate in Adults With Symptomatic oHCM
NCT06116968	PHASE3	COMPLETED	An Open-Label Study of Aficamten for Chinese Patients With Symptomatic oHCM
NCT06873828	PHASE3	NOT_YET_RECRUITING	Evaluation of the Efficacy and Safety of Wearable ECG (AT-Patch) in Patients With Hypertrophic Cardiomyopathy Requiring 48-Hour Holter MonitoringEvaluation of the Efficacy and Safety of Wearable ECG (AT-Patch) in Patients With Hypertrophic Cardiomyopathy Requiring 48-Hour Holter Monitoring
NCT07021976	PHASE3	RECRUITING	A Phase III Trial of HRS-1893 in Patients With Obstructive Hypertrophic Cardiomyopathy
NCT07023341	PHASE3	ACTIVE_NOT_RECRUITING	A Study to Learn More About How Well Aficamten Works in Japanese Participants With Symptomatic Obstructive Hypertrophic Cardiomyopathy
NCT07202897	PHASE3	NOT_YET_RECRUITING	LA-HCM Study : Rivaroxaban for Antithrombotic Prevention in Hypertrophic Cardiomyopathy Patients With Abnormal Left Atrial Strain.
NCT02933437	PHASE2	UNKNOWN	The Response To Ajmaline Provocation in Healthy Subjects
NCT07146880	PHASE2	NOT_YET_RECRUITING	Empagliflozin as a Potential Therapeutic Solution for Patients With Brugada Syndrome
NCT00001631	PHASE2	COMPLETED	Study of Blood Flow in Heart Muscle
NCT00001894	PHASE2	COMPLETED	A Comparison of Two Treatments: Pacemaker and Percutaneous Transluminal Septal Ablation for Hypertrophic Cardiomyopathy
NCT00001960	PHASE2	COMPLETED	Studying the Effectiveness of Pacemaker Therapy in Children Who Have Thickened Heart Muscle
NCT00011076	PHASE2	COMPLETED	Pirfenidone to Treat Hypertrophic Cardiomyopathy
NCT00035386	PHASE2	COMPLETED	Alcohol Septal Ablation in Obstructive Hypertrophic Cardiomyopathy: A Pilot Study
NCT00430833	PHASE2	UNKNOWN	CHANCE - Candesartan in Hypertrophic Cardiomyopathy
NCT00500552	PHASE2	COMPLETED	Perhexiline Therapy in Patients With Hypertrophic Cardiomyopathy
NCT01150461	PHASE2	COMPLETED	Effect of Losartan in Patients With Nonobstructive Hypertrophic Cardiomyopathy
NCT01230918	PHASE2	TERMINATED	Study to Develop a Non-invasive Marker for Monitoring Myocardial Fibrosis
NCT01447654	PHASE2	COMPLETED	Inhibition of the Renin Angiotensin System With Losartan in Patients With Hypertrophic Cardiomyopathy
NCT01696370	PHASE2	UNKNOWN	Trimetazidine Therapy in Hypertrophic Cardiomyopathy
NCT01912534	PHASE2	COMPLETED	Valsartan for Attenuating Disease Evolution In Early Sarcomeric HCM
NCT02590809	PHASE2	COMPLETED	Hypertrophic Cardiomyopathy Symptom Release by BX1514M