KCNQ1

Summary

KCNQ1 (potassium voltage-gated channel subfamily Q member 1, HGNC:6294) is a protein-coding gene on chromosome 11p15.5-p15.4, encoding Potassium voltage-gated channel subfamily KQT member 1 (P51787). Pore-forming subunit of the voltage-gated potassium (Kv) channel involved in the regulation of cardiomyocyte excitability and important in normal development and functions of myocardium, inner ear, stomach and colon. It is haploinsufficient (ClinGen: sufficient evidence).

This gene encodes a voltage-gated potassium channel required for repolarization phase of the cardiac action potential. This protein can form heteromultimers with two other potassium channel proteins, KCNE1 and KCNE3. Mutations in this gene are associated with hereditary long QT syndrome 1 (also known as Romano-Ward syndrome), Jervell and Lange-Nielsen syndrome, and familial atrial fibrillation. This gene exhibits tissue-specific imprinting, with preferential expression from the maternal allele in some tissues, and biallelic expression in others. This gene is located in a region of chromosome 11 amongst other imprinted genes that are associated with Beckwith-Wiedemann syndrome (BWS), and itself has been shown to be disrupted by chromosomal rearrangements in patients with BWS. Alternatively spliced transcript variants have been found for this gene.

Source: NCBI Gene 3784 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Jervell and Lange-Nielsen syndrome (Definitive, ClinGen) — +8 more curated relationships
• GWAS associations: 327
• Clinical variants (ClinVar): 3,014 total — 269 pathogenic, 162 likely-pathogenic
• Phenotypes (HPO): 78
• Druggable target: yes — 15 molecules with ChEMBL bioactivity
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_000218

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6294
Approved symbol	KCNQ1
Name	potassium voltage-gated channel subfamily Q member 1
Location	11p15.5-p15.4
Locus type	gene with protein product
Status	Approved
Aliases	Kv7.1, KCNA8, KVLQT1, JLNS1, LQT1
Ensembl gene	ENSG00000053918
Ensembl biotype	protein_coding
OMIM	607542
Entrez	3784

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 7 protein_coding, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000155840, ENST00000335475, ENST00000345015, ENST00000380776, ENST00000496887, ENST00000526095, ENST00000646564, ENST00000713724, ENST00000713725, ENST00000910997

RefSeq mRNA: 6 — MANE Select: NM_000218 NM_000218, NM_001406836, NM_001406837, NM_001406838, NM_001406839, NM_181798

CCDS: CCDS7736

Canonical transcript exons

ENST00000155840 — 16 exons

Exon	Start	End
ENSE00001296137	2572013	2572109
ENSE00001297564	2570628	2570754
ENSE00001315757	2571325	2571403
ENSE00001871662	2572846	2572986
ENSE00002145989	2527928	2528018
ENSE00004011754	2661961	2662081
ENSE00004011755	2776986	2777032
ENSE00004011756	2588713	2588854
ENSE00004011758	2768844	2768919
ENSE00004011759	2775960	2776054
ENSE00004011760	2777976	2778037
ENSE00004011761	2587570	2587692
ENSE00004011762	2583435	2583545
ENSE00004020977	2585212	2585307
ENSE00004020990	2847767	2849105
ENSE00004021044	2445008	2445484

Expression profiles

Bgee: expression breadth ubiquitous, 132 present calls, max score 98.70.

FANTOM5 (CAGE): breadth broad, TPM avg 6.6092 / max 623.1083, expressed in 628 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
112701	5.4355	541
112700	1.0964	360
112708	0.0412	15
112702	0.0362	11

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left adrenal gland cortex	UBERON:0035825	98.70	gold quality
left adrenal gland	UBERON:0001234	98.42	gold quality
right adrenal gland cortex	UBERON:0035827	98.36	gold quality
right adrenal gland	UBERON:0001233	98.25	gold quality
adrenal gland	UBERON:0002369	95.95	gold quality
body of pancreas	UBERON:0001150	94.01	gold quality
duodenum	UBERON:0002114	93.99	gold quality
left lobe of thyroid gland	UBERON:0001120	93.57	gold quality
thyroid gland	UBERON:0002046	93.42	gold quality
right lobe of thyroid gland	UBERON:0001119	92.85	gold quality
body of stomach	UBERON:0001161	90.59	gold quality
apex of heart	UBERON:0002098	90.25	gold quality
monocyte	CL:0000576	89.78	gold quality
heart left ventricle	UBERON:0002084	89.74	gold quality
leukocyte	CL:0000738	89.45	gold quality
mucosa of transverse colon	UBERON:0004991	89.25	gold quality
right atrium auricular region	UBERON:0006631	89.25	gold quality
pancreas	UBERON:0001264	89.14	gold quality
metanephros cortex	UBERON:0010533	89.04	gold quality
adult mammalian kidney	UBERON:0000082	88.95	gold quality
stomach	UBERON:0000945	88.79	gold quality
blood	UBERON:0000178	88.75	gold quality
gall bladder	UBERON:0002110	87.40	gold quality
heart	UBERON:0000948	86.58	gold quality
fundus of stomach	UBERON:0001160	86.09	gold quality
granulocyte	CL:0000094	85.44	gold quality
small intestine	UBERON:0002108	84.16	gold quality
kidney	UBERON:0002113	83.92	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	83.87	gold quality
small intestine Peyer’s patch	UBERON:0003454	83.86	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.27

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): SP1, TP73

miRNA regulators (miRDB)

38 targeting KCNQ1, 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-4283	100.00	66.42	2097
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-3151-5P	99.86	63.83	1069
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-1200	99.71	70.42	1838
HSA-MIR-6134	99.63	65.68	1537
HSA-MIR-7159-3P	99.51	70.17	1920
HSA-MIR-4677-3P	99.49	67.91	1246
HSA-MIR-766-3P	99.47	65.24	1811
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-365A-3P	99.43	70.02	836
HSA-MIR-365B-3P	99.43	70.02	836
HSA-MIR-4667-3P	99.26	65.45	1608
HSA-MIR-6837-5P	99.25	65.47	1632
HSA-MIR-939-3P	98.97	65.07	2347
HSA-MIR-1304-5P	98.90	68.58	1054
HSA-MIR-6761-5P	98.71	68.03	1504
HSA-MIR-1227-5P	98.65	65.32	1549
HSA-MIR-6811-3P	98.62	66.54	944
HSA-MIR-615-5P	98.10	63.76	591
HSA-MIR-197-3P	98.09	69.23	1004
HSA-MIR-7113-5P	97.88	67.33	1735
HSA-MIR-1914-5P	97.83	66.21	807
HSA-MIR-4640-5P	97.42	66.33	1543
HSA-MIR-6799-3P	97.35	65.60	1302
HSA-MIR-3173-5P	97.35	65.82	1282
HSA-MIR-1225-3P	97.29	64.60	876
HSA-MIR-4726-5P	97.24	65.67	1299
HSA-MIR-4486	96.96	60.61	931

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• common polymorphisms of LQTS-associated genes might modify arrhythmia susceptibility in potential gene carriers. (PMID:11761407)
• regulation by PKA-dependent phosphorylation requires a macromolecular complex that includes PKA, PP1, and the targeting protein yotiao (PMID:11799244)
• Kcnq1 locus that regulates long range repression on the paternally derived p57Kip2 and Kcnq1 alleles in an imprinting domain that includes Igf2 and H19. This ICR appears to possess a unidirectional chromatin insulator function in somatic cells. (PMID:11877438)
• evidence that not only homozygous but also compound heterozygous mutations in KvLQT1 may cause Jervell and Lange-Nielsen syndrome in nonconsanguineous families (PMID:12051962)
• the analysed region of the KVLQT1 gene is not commonly involved in pathogenesis of the long QT syndrome (PMID:12080180)
• Four novel KCNQ1 missense mutations were identified in long QT syndrome in China. (PMID:12442276)
• External acidification acts on homomeric and heteromeric KCNQ1 channels via multiple mechanisms to affect gating and maximum conductance. (PMID:12482884)
• Kcnq1 analysis shows that methylation occurs as a consequence of silencing (PMID:12511562)
• the S140G mutation in KCNQ1 is likely to initiate and maintain atrial fibrillation by reducing action potential duration and effective refractory period in atrial myocytes (PMID:12522251)
• A cytoplasmic carboxy-terminal subunit interaction domain (sid) suffices to transfer assembly properties between KCNQ3 and KCNQ1. (PMID:12524525)
• Co-activation of hKvLQT1 improves CaCC-mediated Cl- secretion in native CF airway epithelia, and may have a therapeutic effect in the treatment of CF lung disease. (PMID:12612194)
• expressed strongly in heart, skeletal muscle, and kidney, less in placenta, lung, and liver, and weakly in brain and blood cells. Electrophysiological study showed that KCNE4 modulates the activation of the KCNQ1 channel. (PMID:12670483)
• missense mutations in KCNQ1 and SCN5A in a case of congenital Long QT Syndrome (PMID:12820704)
• Novel compound heterozygous nonsense mutations in C-terminus of KCNQ1 can cause Jervell and Lange-Nielsen syndrome (JLNS). (PMID:14510661)
• We characterize molecular determinants of R-L3 interaction with KCNQ1 channels, use computer modeling to propose a mechanism for drug-induced changes in channel gating, & determine its effect on several long-QT syndrome-associated mutant KCNQ1 channels (PMID:14576198)
• Two novel deletion mutations and one novel polymorphism of KCNQ1 gene were identified among 6 Chinese families with congenital long QT syndrome(LQTS). (PMID:14731347)
• Long-term follow-up of a LQT1 family with two KCNQ1amino acid alterations in cis (V254M-V417M); the V254M mutation introduced into Xenopus oocytes reduced the IKs current, while the effect of the V417M variant was negligible (PMID:14756674)
• ER quality control prevents minK-L51H/KvLQT1 complexes from trafficking to the plasma membrane, resulting in decreased I(Ks). (PMID:14761891)
• Beta-blockers are widely used to prevent the lethal cardiac events associated with the long QT syndrome (LQTS), especially in KCNQ1-related LQTS (LQT1) patients. (PMID:15028050)
• despite the high degree of homology of the pore region among the various K(+) channels, KCNQ1 channels display significant structural and functional uniqueness. (PMID:15226366)
• LQT1 patients with transmembrane mutations are at higher risk of congenital LQTS-related cardiac events and have greater sensitivity to sympathetic stimulation, as compared with patients with C-terminal mutations. (PMID:15234419)
• a P448R polymorphism in KCNQ1 may have a role in long QT syndrome in Chinese patients (PMID:15242738)
• The unmethylated Kcnq1 imprinting control region harbors bidirectional silencer activity and drives expression of an antisense RNA. (PMID:15340049)
• Expression of KCNQ1 and KCNE1 associated with early stages of spermatogenesis and with presence of undifferentiated healthy or neoplastic germ cells. KCNQ1/KCNE1 may be involved in K+ transport, probably during germ-cell development. (PMID:15389592)
• NF-Y transcription factor as a crucial regulator of antisense promoter-mediated bidirectional silencing and the parent of origin-specific epigenetic marks at the Kcnq1 imprinting control region (PMID:15459184)
• mutational analysis in a family with Romano-Ward syndrome (PMID:15511625)
• These findings indicate the importance of a putative pore helix-S5-S6 interaction for normal KCNQ1 channel deactivation and confirm its role in KCNQ1 inactivation. (PMID:15649981)
• A missense mutation G940A(G314S) in the KCNQ1 gene was identified, which was the ‘hot spot’ of long QT syndrome mutation. (PMID:15696484)
• Based upon previous studies and the present results, it is concluded that both hKCNE4 and mKCNE4 have a drastic inhibitory impact on both hKCNQ1 and mKCNQ1 currents. (PMID:15707997)
• A variant in intron 1 of the KCNQ1 gene (rs757092, +1.7 ms/allele) is associated with QT interval length. (PMID:15746444)
• hydrophobic or aromatic residues involved in S6 transmembrane domain and the base of the pore helix of KCNQ1 (PMID:15904893)
• The single heterozygous mutation in KCNQ1 may also cause Jervell-Lange-Nielsen syndrome. (PMID:15924777)
• can function as a repolarization reserve when IKr, the rapid delayed rectifier, is reduced by disease or drug and can prevent excessive action potential prolongation and development of arrhythmogenic early afterdepolarizations (PMID:16129795)
• This suggests that genetic determinants located in KCNQ1, KCNE1, KCNH2 and SCN5A influence QTc length in healthy individuals and may represent risk factors for arrhythmias or cardiac sudden death in patients with cardiovascular diseases. (PMID:16132053)
• KCNQ1-A341V single nucleotide polymorphism is associated with greater risk than that reported for large databases of long QT syndrome. (PMID:16246960)
• A variant in intron 1 of the KCNQ1 gene (rs757092, +1.7 ms/allele) is associated with QT interval length. (PMID:16253915)
• interaction of MiRP2-72 with KCNQ1-338; and MinK-59,58 with KCNQ1-339, 340 (PMID:16308347)
• Calmodulin binding to KCNQ1 is essential for correct channel folding and assembly and for conferring Ca(2+)-sensitive IKS-current stimulation, which prevents risk of ventricular arrhythmias. (PMID:16556865)
• Calmodulin is a constitutive component of KCNQ1 K+ channels, the most commonly mutated long-QT syndrome (LQTS) locus. (PMID:16556866)
• None of the SNPs of KCNQ1 were associated with atrial fibrillation phenotype. (PMID:16563243)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Kcnq1	ENSMUSG00000009545
rattus_norvegicus	Kcnq1	ENSRNOG00000020532

Paralogs (31): KCNG1 (ENSG00000026559), KCNQ2 (ENSG00000075043), KCND1 (ENSG00000102057), KCNA7 (ENSG00000104848), KCNA1 (ENSG00000111262), KCNC4 (ENSG00000116396), KCNQ4 (ENSG00000117013), KCNS1 (ENSG00000124134), KCNC1 (ENSG00000129159), KCNA5 (ENSG00000130037), KCNC3 (ENSG00000131398), KCNA10 (ENSG00000143105), KCNA6 (ENSG00000151079), KCNS2 (ENSG00000156486), KCNB1 (ENSG00000158445), KCNF1 (ENSG00000162975), KCNV1 (ENSG00000164794), KCNC2 (ENSG00000166006), KCNV2 (ENSG00000168263), KCNG4 (ENSG00000168418), KCNS3 (ENSG00000170745), KCNG3 (ENSG00000171126), KCND3 (ENSG00000171385), KCNA3 (ENSG00000177272), KCNA2 (ENSG00000177301), KCNG2 (ENSG00000178342), KCNA4 (ENSG00000182255), KCNB2 (ENSG00000182674), KCNQ3 (ENSG00000184156), KCND2 (ENSG00000184408), KCNQ5 (ENSG00000185760)

Protein

Protein identifiers

Potassium voltage-gated channel subfamily KQT member 1 — P51787 (reviewed: P51787)

Alternative names: IKs producing slow voltage-gated potassium channel subunit alpha KvLQT1, KQT-like 1, Voltage-gated potassium channel subunit Kv7.1

All UniProt accessions (6): A0A2R8YDV1, A0A2R8YEQ9, A0AAQ5BGS5, A0AAQ5BGV1, P51787, E9PPZ0

UniProt curated annotations — full annotation on UniProt →

Function. Pore-forming subunit of the voltage-gated potassium (Kv) channel involved in the regulation of cardiomyocyte excitability and important in normal development and functions of myocardium, inner ear, stomach and colon. Associates with KCNE beta subunits that modulates current kinetics. Induces a voltage-dependent current by rapidly activating and slowly deactivating potassium-selective outward current. Also promotes a delayed voltage activated potassium current showing outward rectification characteristic. During beta-adrenergic receptor stimulation, participates in cardiac repolarization by associating with KCNE1 to form the I(Ks) cardiac potassium current that increases the amplitude and slows down the activation kinetics of outward potassium current I(Ks). Muscarinic agonist oxotremorine-M strongly suppresses KCNQ1/KCNE1 current. When associated with KCNE3, forms the potassium channel that is important for cyclic AMP-stimulated intestinal secretion of chloride ions. This interaction with KCNE3 is reduced by 17beta-estradiol, resulting in the reduction of currents. During conditions of increased substrate load, maintains the driving force for proximal tubular and intestinal sodium ions absorption, gastric acid secretion, and cAMP-induced jejunal chloride ions secretion. Allows the provision of potassium ions to the luminal membrane of the secretory canaliculus in the resting state as well as during stimulated acid secretion. When associated with KCNE2, forms a heterooligomer complex leading to currents with an apparently instantaneous activation, a rapid deactivation process and a linear current-voltage relationship and decreases the amplitude of the outward current. When associated with KCNE4, inhibits voltage-gated potassium channel activity. When associated with KCNE5, this complex only conducts current upon strong and continued depolarization. Also forms a heterotetramer with KCNQ5; has a voltage-gated potassium channel activity. Binds with phosphatidylinositol 4,5-bisphosphate. KCNQ1-KCNE2 channel associates with Na(+)-coupled myo-inositol symporter in the apical membrane of choroid plexus epithelium and regulates the myo-inositol gradient between blood and cerebrospinal fluid with an impact on neuron excitability. Non-functional alone but modulatory when coexpressed with the full-length isoform 1.

Subunit / interactions. Tetramer. Heterotetramer with KCNE1; targets to the membrane raft. Interacts (via C-terminus) with calmodulin; forms a heterooctameric structure (with 4:4 KCNQ1:CALM stoichiometry); the interaction is calcium-independent, constitutive, participates in the proper assembly of a functional channel and also acts a calcium sensor. KCNQ1 channels interact more strongly with Ca(2+)-CALM than with apoCALM. Interacts with AKAP9; targets protein kinase A (PKA) catalytic and regulatory subunits and protein phosphatase 1 (PP1) to the KCNQ1-KCNE1 complex, allowing PKA-mediated phosphorylation and increase of delayed rectifier potassium channel activity. Interacts with KCNE2; forms a heterooligomer complex that targets to the membrane raft and leading to currents with an apparently instantaneous activation, a rapid deactivation process and a linear current-voltage relationship and decreases the amplitude of the outward current. Interacts with AP2M1; mediates estrogen-induced internalization via clathrin-coated vesicles. Interacts with NEDD4L; promotes internalization and decreases I(Ks) currents. Interacts with USP2; counteracts the NEDD4L-specific down-regulation of I(Ks) and restore plasma membrane localization. Heterotetramer with KCNQ5; has a voltage-gated potassium channel activity. Interacts with KCNE3; four KCNE3 molecules are bound to one KCNQ1 tetramer (4:4 KCNQ1:KCNE3 stoichiometry); alters membrane raft localization; affects KCNQ1 structure and gating properties. Interacts with KCNE4; impairs KCNQ1 localization in lipid rafts and inhibits voltage-gated potassium channel activity. Interacts with KCNE5; impairs KCNQ1 localization in lipid rafts and only conducts current upon strong and continued depolarization. Interacts with SLC5A3; forms coregulatory channel-transporter complexes that modulate Na(+)-coupled myo-inositol influx through the transporter.

Subcellular location. Cell membrane. Cytoplasmic vesicle membrane. Early endosome. Membrane raft. Endoplasmic reticulum. Basolateral cell membrane. Apical cell membrane.

Tissue specificity. Abundantly expressed in heart, pancreas, prostate, kidney, small intestine and peripheral blood leukocytes. Less abundant in placenta, lung, spleen, colon, thymus, testis and ovaries.

Post-translational modifications. Phosphorylation at Ser-27 by PKA; increases delayed rectifier potassium channel activity of the KCNQ1-KCNE1 complex through a macromolecular complex that includes PKA, PP1, and the targeting protein AKAP9. Ubiquitinated by NEDD4L; promotes internalization. The ubiquitinylated form is internalized through a clathrin-mediated endocytosis by interacting with AP2M1 and is recycled back to the cell membrane via RAB4A and RAB11A. Deubiquitinated by USP2; counteracts the NEDD4L-specific down-regulation of I(Ks) and restores the membrane localization.

Disease relevance. Long QT syndrome 1 (LQT1) [MIM:192500] A heart disorder characterized by a prolonged QT interval on the ECG and polymorphic ventricular arrhythmias. They cause syncope and sudden death in response to exercise or emotional stress, and can present with a sentinel event of sudden cardiac death in infancy. The disease is caused by variants affecting the gene represented in this entry. Jervell and Lange-Nielsen syndrome 1 (JLNS1) [MIM:220400] An autosomal recessive disorder characterized by congenital deafness, prolongation of the QT interval, syncopal attacks due to ventricular arrhythmias, and a high risk of sudden death. The disease is caused by variants affecting the gene represented in this entry. Atrial fibrillation, familial, 3 (ATFB3) [MIM:607554] An autosomal dominant form of atrial fibrillation, a common sustained cardiac rhythm disturbance. Atrial fibrillation is characterized by disorganized atrial electrical activity and ineffective atrial contraction promoting blood stasis in the atria and reduces ventricular filling. It can result in palpitations, syncope, thromboembolic stroke, and congestive heart failure. The disease is caused by variants affecting the gene represented in this entry. Short QT syndrome 2 (SQT2) [MIM:609621] An autosomal dominant form of short QT syndrome, a heart disorder characterized by idiopathic persistently and uniformly short QT interval on ECG in the absence of structural heart disease in affected individuals. It can cause syncope and sudden death. The disease is caused by variants affecting the gene represented in this entry. Type 2 diabetes mellitus (T2D) [MIM:125853] A multifactorial disorder of glucose homeostasis caused by a lack of sensitivity to insulin. Affected individuals usually have an obese body habitus and manifestations of a metabolic syndrome characterized by diabetes, insulin resistance, hypertension and hypertriglyceridemia. The disease results in long-term complications that affect the eyes, kidneys, nerves, and blood vessels. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Activity regulation. PIP2 molecule is essential to activate KCNQ channels by inducing the coupling of the voltage-sensing domain (VSD) and the pore-forming domain (PD). Upon channel activation, PIP2 disrupts the VSD-calmodulin/CALM interactions, causing the release of CALM from the VSD which triggers the opening of the gate. Calcium potentiates KCNQ1 channel current through calcium-bound CALM. Calcium-bound CALM competes with PIP2 to stabilize the channel open state.

Domain organisation. Each channel subunit contains six transmembrane segments (S1-S6) with S1-S4 forming one voltage sensing domain (VSD) and S5-S6 contributing to form one quarter of an interlocking pore-forming domain (PD). The segment S6 is involved in the inhibition of voltage-gated potassium channel activity by KCNE4. The CALM binding domains correspond to the first two membrane-proximal helical regions that interact with a single calmodulin/CALM molecule forming a clamp-like structure. Binding of CALM C-terminus to the first helix is calcium-independent and is essential for assembly of the structure. Binding of CALM N-terminus to the second helix is calcium-dependent and regulates electrophysiological activity of the channel. Residues Lys-526 and Lys-527 in the second helical region of the proximal C-terminus form a critical site where calcium-bound CALM N-lobe competes with PIP2 for the binding to KCNQ1 in order to stabilize the channel open state. The C-terminal assembly domain carries the major determinants of tetramerization and subunit assembly specificity. Its coiled-coil region is four-stranded.

Miscellaneous. Mutagenesis experiments were carried out by expressing in Xenopus oocytes or COS-7 cells KCNQ1 mutants either individually (homomultimers) or in combination with both wild-type KCNQ1 (mut/wt homomultimers) and minK (heteromultimers).

Similarity. Belongs to the potassium channel family. KQT (TC 1.A.1.15) subfamily. Kv7.1/KCNQ1 sub-subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
P51787-1	1	yes
P51787-2	2, TKvLQT1

RefSeq proteins (6): NP_000209, NP_001393765, NP_001393766, NP_001393767, NP_001393768, NP_861463 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003937	K_chnl_volt-dep_KCNQ	Family
IPR005821	Ion_trans_dom	Domain
IPR005827	K_chnl_volt-dep_KCQN1	Family
IPR013821	K_chnl_volt-dep_KCNQ_C	Domain
IPR027359	Volt_channel_dom_sf	Homologous_superfamily

Pfam: PF00520, PF03520

Catalyzed reactions (Rhea), 1 shown:

• K(+)(in) = K(+)(out) (RHEA:29463)

UniProt features (328 total): sequence variant 240, helix 23, mutagenesis site 17, region of interest 9, topological domain 8, sequence conflict 7, transmembrane region 6, strand 4, compositionally biased region 3, modified residue 3, splice variant 2, chain 1, intramembrane region 1, coiled-coil region 1, binding site 1, turn 1, glycosylation site 1

Structure

Experimental structures (PDB)

28 structures.

PDB	Method	Resolution (Å)
3HFE	X-RAY DIFFRACTION	1.7
3BJ4	X-RAY DIFFRACTION	2
7VVH	X-RAY DIFFRACTION	2.3
3HFC	X-RAY DIFFRACTION	2.45
7XNN	ELECTRON MICROSCOPY	2.5
9UJ4	ELECTRON MICROSCOPY	2.59
7XNK	ELECTRON MICROSCOPY	2.6
7VUO	X-RAY DIFFRACTION	2.68
9VEC	ELECTRON MICROSCOPY	2.7
4V0C	X-RAY DIFFRACTION	2.86
8SIK	ELECTRON MICROSCOPY	2.9
9U7F	ELECTRON MICROSCOPY	2.9
4UMO	X-RAY DIFFRACTION	3
6UZZ	ELECTRON MICROSCOPY	3.1
6V00	ELECTRON MICROSCOPY	3.1
7XNL	ELECTRON MICROSCOPY	3.1
7VVD	X-RAY DIFFRACTION	3.13
9UC8	ELECTRON MICROSCOPY	3.36
12DK	ELECTRON MICROSCOPY	3.47
7XNI	ELECTRON MICROSCOPY	3.5
9VEO	ELECTRON MICROSCOPY	3.7
9VEN	ELECTRON MICROSCOPY	3.8
6V01	ELECTRON MICROSCOPY	3.9
9VEI	ELECTRON MICROSCOPY	3.9
9WD8	ELECTRON MICROSCOPY	3.9
8SIM	ELECTRON MICROSCOPY	6.2
8SIN	ELECTRON MICROSCOPY	6.8
6MIE	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P51787-F1	68.83	0.36

Functional residue map

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

Ligand- & substrate-binding residues (1): 244

Post-translational modifications (3): 27, 407, 409

Glycosylation sites (1): 289

Mutagenesis-validated functional residues (17):

Position	Phenotype
27	no phosphorylation by pka. decreases delayed rectifier potassium channel activity.
231	strongly inhibits slc5a3 transporter activity.
324	has a voltage-gated potassium channel activity. inhibition of voltage-gated potassium channel activity by kcne4.
326	has a voltage-gated potassium channel activity. disrupts kcne4-mediated voltage-gated potassium channel activity inhibit
327	has a voltage-gated potassium channel activity. disrupts kcne4-mediated voltage-gated potassium channel activity inhibit
328	has a voltage-gated potassium channel activity. inhibition of voltage-gated potassium channel activity by kcne4.
338	inhibits voltage-gated potassium channel activity.
340	inhibits voltage-gated potassium channel activity.
375	reduced protein expression, probably due to misfolding and proteasomal degradation. no detectable electrophysiological a
516	reduced protein expression, probably due to misfolding and proteasomal degradation. significantly reduced electrophysiol
526	decreased interaction with pip2 and calmodulin/calm in the presence of calcium. insensitive to gating modulation by calc
527	decreased interaction with pip2 and calmodulin/calm in the presence of calcium. decreased interaction with pip2 and calm
589	no effect.
590	reduced cell surface expression and strongly reduced potassium current.
593	reduced cell surface expression and moderately reduced potassium current.
602	does not interact with akap9 and the targeting protein kinase a (pka) catalytic subunit and protein phosphatase 1 (pp1);
609	does not interact with akap9 and the kinase a (pka) catalytic subunit and protein phosphatase 1 (pp1); when associated w

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-1296072	Voltage gated Potassium channels
R-HSA-5576890	Phase 3 - rapid repolarisation
R-HSA-5576893	Phase 2 - plateau phase
R-HSA-112316	Neuronal System
R-HSA-1296071	Potassium Channels
R-HSA-397014	Muscle contraction
R-HSA-5576891	Cardiac conduction

MSigDB gene sets: 575 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_POTASSIUM_ION_TRANSPORT, GOBP_DIGESTION, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_NEGATIVE_REGULATION_OF_TRANSMEMBRANE_TRANSPORT, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_ACID_SECRETION, BENPORATH_ES_WITH_H3K27ME3, GOBP_BEHAVIOR, GOBP_MYELOID_CELL_HOMEOSTASIS, GOBP_REGULATION_OF_BLOOD_PRESSURE, GOBP_NEGATIVE_REGULATION_OF_TRANSPORTER_ACTIVITY, GOBP_CIRCULATORY_SYSTEM_PROCESS, REACTOME_VOLTAGE_GATED_POTASSIUM_CHANNELS, GOBP_SENSORY_PERCEPTION_OF_MECHANICAL_STIMULUS

GO Biological Process (64): action potential (GO:0001508), gastrin-induced gastric acid secretion (GO:0001698), glucose metabolic process (GO:0006006), heart development (GO:0007507), sensory perception of sound (GO:0007605), rhythmic behavior (GO:0007622), regulation of heart contraction (GO:0008016), regulation of blood pressure (GO:0008217), positive regulation of heart rate (GO:0010460), iodide transport (GO:0015705), erythrocyte differentiation (GO:0030218), intracellular chloride ion homeostasis (GO:0030644), response to insulin (GO:0032868), social behavior (GO:0035176), corticosterone secretion (GO:0035934), regulation of membrane potential (GO:0042391), inner ear morphogenesis (GO:0042472), inner ear development (GO:0048839), intestinal absorption (GO:0050892), detection of mechanical stimulus involved in sensory perception of sound (GO:0050910), potassium ion homeostasis (GO:0055075), cardiac muscle contraction (GO:0060048), auditory receptor cell development (GO:0060117), regulation of membrane repolarization (GO:0060306), regulation of ventricular cardiac muscle cell membrane repolarization (GO:0060307), regulation of atrial cardiac muscle cell membrane repolarization (GO:0060372), positive regulation of cardiac muscle contraction (GO:0060452), regulation of gastric acid secretion (GO:0060453), stomach development (GO:0062094), renal absorption (GO:0070293), renal sodium ion absorption (GO:0070294), cellular response to cAMP (GO:0071320), cellular response to xenobiotic stimulus (GO:0071466), potassium ion transmembrane transport (GO:0071805), cellular response to epinephrine stimulus (GO:0071872), adrenergic receptor signaling pathway (GO:0071875), cardiac muscle cell contraction (GO:0086003), ventricular cardiac muscle cell action potential (GO:0086005), membrane repolarization during action potential (GO:0086011), membrane repolarization during cardiac muscle cell action potential (GO:0086013)

GO Molecular Function (17): voltage-gated potassium channel activity (GO:0005249), delayed rectifier potassium channel activity (GO:0005251), calmodulin binding (GO:0005516), phosphatidylinositol-4,5-bisphosphate binding (GO:0005546), protein phosphatase 1 binding (GO:0008157), outward rectifier potassium channel activity (GO:0015271), ubiquitin protein ligase binding (GO:0031625), protein kinase A catalytic subunit binding (GO:0034236), protein kinase A regulatory subunit binding (GO:0034237), transmembrane transporter binding (GO:0044325), voltage-gated potassium channel activity involved in cardiac muscle cell action potential repolarization (GO:0086008), voltage-gated potassium channel activity involved in atrial cardiac muscle cell action potential repolarization (GO:0086089), scaffold protein binding (GO:0097110), voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization (GO:1902282), monoatomic ion channel activity (GO:0005216), potassium channel activity (GO:0005267), protein binding (GO:0005515)

GO Cellular Component (26): cytoplasm (GO:0005737), lysosome (GO:0005764), early endosome (GO:0005769), late endosome (GO:0005770), endoplasmic reticulum (GO:0005783), cytosol (GO:0005829), plasma membrane (GO:0005886), voltage-gated potassium channel complex (GO:0008076), membrane (GO:0016020), basolateral plasma membrane (GO:0016323), apical plasma membrane (GO:0016324), transport vesicle (GO:0030133), cytoplasmic vesicle membrane (GO:0030659), monoatomic ion channel complex (GO:0034702), neuron projection (GO:0043005), neuronal cell body (GO:0043025), membrane raft (GO:0045121), ciliary base (GO:0097546), lumenal side of membrane (GO:0098576), basolateral part of cell (GO:1990794), endosome (GO:0005768), endomembrane system (GO:0012505), cytoplasmic vesicle (GO:0031410), potassium channel complex (GO:0034705), apical part of cell (GO:0045177), basal part of cell (GO:0045178)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Cardiac conduction	2
Potassium Channels	1
Neuronal System	1
Muscle contraction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
voltage-gated potassium channel activity	3
protein binding	3
behavior	2
regulation of biological quality	2
protein kinase A binding	2
voltage-gated potassium channel activity involved in cardiac muscle cell action potential repolarization	2
endosome	2
cytoplasm	2
endomembrane system	2
plasma membrane region	2
cytoplasmic vesicle	2
regulation of membrane potential	1
gastric acid secretion	1
gastrin receptor activity	1
hexose metabolic process	1
animal organ development	1
circulatory system development	1
sensory perception of mechanical stimulus	1
heart contraction	1
regulation of blood circulation	1
blood circulation	1
regulation of heart rate	1
positive regulation of heart contraction	1
monoatomic anion transport	1
inorganic anion transport	1
myeloid cell differentiation	1
erythrocyte homeostasis	1
intracellular monoatomic anion homeostasis	1
chloride ion homeostasis	1
response to peptide hormone	1
biological process involved in intraspecies interaction between organisms	1
organic hydroxy compound transport	1
glucocorticoid secretion	1
monoatomic ion transmembrane transport	1
ear morphogenesis	1
embryonic morphogenesis	1
inner ear development	1
ear development	1
anatomical structure development	1

Protein interactions and networks

STRING

3188 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KCNQ1	KCNE1	P15382	999
KCNQ1	KCNE2	Q9Y6J6	999
KCNQ1	KCNE3	Q9Y6H6	996
KCNQ1	AKAP9	Q99996	993
KCNQ1	CALML3	P27482	985
KCNQ1	CALML5	Q9NZT1	985
KCNQ1	KCNH2	Q12809	984
KCNQ1	CALML6	Q8TD86	983
KCNQ1	CALML4	Q96GE6	983
KCNQ1	CALM1	P02593	975
KCNQ1	SCN5A	Q14524	973
KCNQ1	KCNJ2	P48049	922
KCNQ1	CDKN1C	P49918	918
KCNQ1	PHLDA2	Q53GA4	904
KCNQ1	SLC67A1	Q96BI1	867

IntAct

13 interactions, top by confidence:

A	B	Type	Score
KCNE1	KCNQ1	psi-mi:“MI:2364”(proximity)	0.580
KCNQ1	KCNE1	psi-mi:“MI:2364”(proximity)	0.580
KCNE1	KCNQ1	psi-mi:“MI:0915”(physical association)	0.580
KCNE1	KCNQ1	psi-mi:“MI:0407”(direct interaction)	0.580
Akap9	KCNQ1	psi-mi:“MI:0914”(association)	0.460
CALM1	KCNE1	psi-mi:“MI:0407”(direct interaction)	0.440
KCNQ1	AKAP9	psi-mi:“MI:0915”(physical association)	0.400
GRB2	KCNQ1	psi-mi:“MI:0915”(physical association)	0.400
HOMEZ	KCNQ1	psi-mi:“MI:0914”(association)	0.350
KCNQ1	AKAP9	psi-mi:“MI:0914”(association)	0.350
TRAF6	KCNQ1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (34): NEDD4L (Affinity Capture-Western), KCNQ1 (Affinity Capture-MS), KCNQ1 (Affinity Capture-Western), BACE1 (Affinity Capture-Western), AKAP9 (Affinity Capture-Western), KCNE1 (Affinity Capture-Western), AKAP9 (Affinity Capture-Western), KCNQ1 (Affinity Capture-MS), AKAP9 (Affinity Capture-Western), PRKAR2A (Affinity Capture-Western), PPP1CA (Affinity Capture-Western), PRKACA (Affinity Capture-Western), AKAP9 (Reconstituted Complex), PRKACA (Reconstituted Complex), PPP1CA (Reconstituted Complex)

ESM2 similar proteins: A0A1D5PXA5, A0A1S4GYH6, A1Z7G7, B3MFV7, B3N8M1, B4GD14, B4HS00, B4J780, B4KMZ1, B4LNA8, B4P3A0, G5EFJ9, O01635, O35607, O54852, O73925, P22815, P30432, P34410, P40145, P40146, P48994, P51787, P57789, P79701, P91682, P97414, P97490, Q09274, Q10025, Q13873, Q19187, Q21974, Q24738, Q292N4, Q86GV3, Q95TU8, Q96L42, Q9EPK8, Q9ER47

Diamond homologs: A4K2M4, A4K2N8, A4K2P6, A4K2Q6, A4K2R3, A4K2S2, A4K2T1, A4K2V2, A4K2W6, A4K2X4, A4K2Y2, A6H8H5, B2RQA1, G5EFC3, O15554, O18868, O35173, O35174, O43525, O43526, O70344, O73606, O73925, O88758, O88759, O88943, O88944, O89109, O97531, P08510, P0A333, P0A334, P10499, P15384, P15387, P16388, P16389, P16390, P17658, P17659

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
KCNQ1	“up-regulates quantity”	potassium(1+)	relocalization
CAMK2D	“down-regulates activity”	KCNQ1	phosphorylation
KCNE3	“up-regulates activity”	KCNQ1	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

3014 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	269
Likely pathogenic	162
Uncertain significance	799
Likely benign	928
Benign	387

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1018501	NM_000218.3(KCNQ1):c.1559T>C (p.Met520Thr)	Pathogenic
1066272	NM_000218.3(KCNQ1):c.1394-1G>C	Pathogenic
1068919	NM_000218.3(KCNQ1):c.1344dup (p.Glu449fs)	Pathogenic
1072801	NM_000218.3(KCNQ1):c.160_175del (p.Ile54fs)	Pathogenic
1074347	NM_000218.3(KCNQ1):c.359G>A (p.Trp120Ter)	Pathogenic
1074799	NC_000011.9:g.(?2797170)(2798282_?)del	Pathogenic
1074800	NC_000011.9:g.(?2591848)(2592643_?)del	Pathogenic
1074801	NC_000011.9:g.(?2604665)(2610084_?)del	Pathogenic
1074802	NC_000011.9:g.(?2606422)(2608942_?)del	Pathogenic
1075209	NM_000218.3(KCNQ1):c.385del (p.Val129fs)	Pathogenic
1076090	NM_000218.3(KCNQ1):c.1182del (p.Tyr395fs)	Pathogenic
1350731	NM_000218.3(KCNQ1):c.477+2T>C	Pathogenic
1384067	NM_000218.3(KCNQ1):c.921+1G>A	Pathogenic
1410886	NC_000011.9:g.(?2790054)(2799287_?)del	Pathogenic
1414164	NM_000218.3(KCNQ1):c.700C>T (p.Gln234Ter)	Pathogenic
1415094	NM_000218.3(KCNQ1):c.1733-2A>G	Pathogenic
1416082	NM_000218.3(KCNQ1):c.934_941dup (p.Tyr315fs)	Pathogenic
1426804	NM_000218.3(KCNQ1):c.1354del (p.Arg452fs)	Pathogenic
1437397	NM_000218.3(KCNQ1):c.770_773del (p.Ile257fs)	Pathogenic
1445000	NM_000218.3(KCNQ1):c.1210_1222del (p.Thr404fs)	Pathogenic
1454382	NM_000218.3(KCNQ1):c.361_370del (p.Lys121fs)	Pathogenic
1454509	NM_000218.3(KCNQ1):c.837dup (p.Val280fs)	Pathogenic
1454915	NM_000218.3(KCNQ1):c.1148dup (p.Ala384fs)	Pathogenic
1455898	NM_000218.3(KCNQ1):c.745_746dup (p.Leu250fs)	Pathogenic
1457098	NM_000218.3(KCNQ1):c.302T>A (p.Leu101Ter)	Pathogenic
1457216	NC_000011.9:g.(?2683171)(2683331_?)del	Pathogenic
1459721	NC_000011.9:g.(?2591848)(2683321_?)del	Pathogenic
1493047	NM_000218.3(KCNQ1):c.605-1G>A	Pathogenic
152834	GRCh38/hg38 11p15.5(chr11:2454516-2461603)x1	Pathogenic
1712921	NC_000011.10:g.2276821_2491742del	Pathogenic

SpliceAI

6437 predictions. Top by Δscore:

Variant	Effect	Δscore
11:2445480:GCCGT:G	donor_gain	1.0000
11:2527924:GCA:G	acceptor_loss	1.0000
11:2527926:A:AG	acceptor_gain	1.0000
11:2527927:G:GA	acceptor_gain	1.0000
11:2527927:GC:G	acceptor_gain	1.0000
11:2527927:GCTT:G	acceptor_gain	1.0000
11:2527927:GCTTC:G	acceptor_gain	1.0000
11:2528014:GGATG:G	donor_gain	1.0000
11:2528015:GATG:G	donor_gain	1.0000
11:2528015:GATGG:G	donor_gain	1.0000
11:2528016:ATGGT:A	donor_loss	1.0000
11:2528017:TGG:T	donor_loss	1.0000
11:2528018:GGTA:G	donor_loss	1.0000
11:2528019:G:GG	donor_gain	1.0000
11:2528019:GTAC:G	donor_loss	1.0000
11:2528020:T:TC	donor_loss	1.0000
11:2570622:CTGCA:C	acceptor_loss	1.0000
11:2570624:GCAGG:G	acceptor_loss	1.0000
11:2570626:A:AC	acceptor_loss	1.0000
11:2570626:A:AG	acceptor_gain	1.0000
11:2570626:AG:A	acceptor_gain	1.0000
11:2570627:G:GG	acceptor_gain	1.0000
11:2570627:GG:G	acceptor_gain	1.0000
11:2570627:GGA:G	acceptor_gain	1.0000
11:2570627:GGAGA:G	acceptor_gain	1.0000
11:2570699:G:GG	donor_gain	1.0000
11:2570755:G:GG	donor_gain	1.0000
11:2571400:TCAGG:T	donor_loss	1.0000
11:2571404:GTGC:G	donor_loss	1.0000
11:2571405:T:A	donor_loss	1.0000

AlphaMissense

4360 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:2570727:T:C	F193L	1.000
11:2570729:T:A	F193L	1.000
11:2570729:T:G	F193L	1.000
11:2572039:G:T	R237M	1.000
11:2572071:T:A	W248R	1.000
11:2572071:T:C	W248R	1.000
11:2572078:T:C	L250P	1.000
11:2572850:T:C	L262P	1.000
11:2572870:G:C	G269R	1.000
11:2572871:G:A	G269D	1.000
11:2572978:T:A	W305R	1.000
11:2572978:T:C	W305R	1.000
11:2572981:G:A	G306R	1.000
11:2572981:G:C	G306R	1.000
11:2583454:G:A	G314D	1.000
11:2583472:C:A	P320H	1.000
11:2583538:T:A	L342H	1.000
11:2583541:C:G	P343R	1.000
11:2585212:G:A	G345R	1.000
11:2585212:G:C	G345R	1.000
11:2585212:G:T	G345W	1.000
11:2585216:T:A	I346N	1.000
11:2585216:T:C	I346T	1.000
11:2585219:T:A	L347H	1.000
11:2585221:G:C	G348R	1.000
11:2585221:G:T	G348C	1.000
11:2585222:G:A	G348D	1.000
11:2585222:G:T	G348V	1.000
11:2585227:G:A	G350R	1.000
11:2585227:G:C	G350R	1.000

dbSNP variants (sampled 300 via entrez): RS1000004086 (11:2655468 G>A,C), RS1000004350 (11:2693158 T>C), RS1000008166 (11:2582602 C>T), RS1000012051 (11:2488423 A>G), RS1000019570 (11:2794545 C>T), RS1000029520 (11:2693958 G>C), RS1000042129 (11:2573518 C>T), RS1000043902 (11:2734436 G>C,T), RS1000052248 (11:2445861 T>C), RS1000052898 (11:2759546 G>A,T), RS1000072084 (11:2795604 G>A,T), RS1000077278 (11:2688050 T>C), RS1000078434 (11:2581719 G>A,T), RS1000081405 (11:2613860 G>A), RS1000086854 (11:2798185 C>G)

Disease associations

OMIM: gene MIM:607542 | disease phenotypes: MIM:192500, MIM:220400, MIM:130650, MIM:607554, MIM:609621, MIM:613688, MIM:609620, MIM:180860, MIM:601144, MIM:194200, MIM:128600, MIM:115080

GenCC curated gene-disease

Disease	Classification	Inheritance
Jervell and Lange-Nielsen syndrome	Definitive	Autosomal recessive
long QT syndrome 1	Definitive	Autosomal dominant
Jervell and Lange-Nielsen syndrome 1	Definitive	Autosomal recessive
atrial fibrillation, familial, 3	Strong	Autosomal dominant
short QT syndrome type 2	Strong	Autosomal dominant
familial atrial fibrillation	Supportive	Autosomal dominant
short QT syndrome	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (4)

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

Disease	Classification	Inheritance
Jervell and Lange-Nielsen syndrome	Definitive	AR
short QT syndrome	Strong	AD
hypertrophic cardiomyopathy	Disputed	AD
long QT syndrome	Definitive	AD

Mondo (27): long QT syndrome (MONDO:0002442), long QT syndrome 1 (MONDO:0100316), cardiac rhythm disease (MONDO:0007263), Jervell and Lange-Nielsen syndrome 1 (MONDO:0024540), Beckwith-Wiedemann syndrome (MONDO:0007534), atrial fibrillation, familial, 3 (MONDO:0011857), short QT syndrome type 2 (MONDO:0012313), familial long QT syndrome (MONDO:0019171), Jervell and Lange-Nielsen syndrome (MONDO:0002441), hearing loss disorder (MONDO:0005365), long QT syndrome 2 (MONDO:0013367), atrial fibrillation (MONDO:0004981), short QT syndrome (MONDO:0000453), Silver-Russell syndrome 1 (MONDO:0020796), hypertrophic cardiomyopathy (MONDO:0005045)

Orphanet (12): Romano-Ward syndrome (Orphanet:101016), Congenital long QT syndrome (Orphanet:768), Jervell and Lange-Nielsen syndrome (Orphanet:90647), Beckwith-Wiedemann syndrome (Orphanet:116), Congenital short QT syndrome (Orphanet:51083), Silver-Russell syndrome (Orphanet:813), Rare hypertrophic cardiomyopathy (Orphanet:217569), Brugada syndrome (Orphanet:130), Rare genetic deafness (Orphanet:96210), Rare cardiomyopathy (Orphanet:167848), Hereditary progressive cardiac conduction defect (Orphanet:871), NON RARE IN EUROPE: Wolff-Parkinson-White syndrome (Orphanet:907)

HPO phenotypes

78 total (30 of 78 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000076	Vesicoureteral reflux
HP:0000105	Enlarged kidney
HP:0000121	Nephrocalcinosis
HP:0000150	Gonadoblastoma
HP:0000158	Macroglossia
HP:0000239	Large fontanelles
HP:0000269	Prominent occiput
HP:0000280	Coarse facial features
HP:0000364	Hearing abnormality
HP:0000365	Hearing impairment
HP:0000520	Proptosis
HP:0000787	Nephrolithiasis
HP:0000803	Renal cortical cysts
HP:0001052	Nevus flammeus
HP:0001197	Abnormality of prenatal development or birth
HP:0001250	Seizure
HP:0001279	Syncope
HP:0001305	Dandy-Walker malformation
HP:0001528	Hemihypertrophy
HP:0001539	Omphalocele
HP:0001540	Diastasis recti
HP:0001548	Overgrowth
HP:0001638	Cardiomyopathy
HP:0001640	Cardiomegaly
HP:0001645	Sudden cardiac death
HP:0001657	Prolonged QT interval
HP:0001658	Myocardial infarction

GWAS associations

327 associations (top):

Study	Trait	p-value
GCST000189_16	Protein quantitative trait loci	1.000000e-06
GCST000219_1	Type 2 diabetes	2.000000e-42
GCST000221_1	Type 2 diabetes	1.000000e-16
GCST000363_10	QT interval	1.000000e-15
GCST000363_6	QT interval	3.000000e-17
GCST000364_4	QT interval	3.000000e-17
GCST000383_3	Type 2 diabetes	1.000000e-26
GCST000561_17	Electrocardiographic traits	8.000000e-11
GCST000601_2	Type 2 diabetes	1.000000e-09
GCST000693_1	Platelet aggregation	7.000000e-06
GCST000712_14	Type 2 diabetes	3.000000e-13
GCST000817_199	Height	2.000000e-13
GCST001070_3	Type 2 diabetes	4.000000e-06
GCST001173_1	Type 2 diabetes	2.000000e-17
GCST001666_10	Type 2 diabetes	1.000000e-07
GCST001746_20	QT interval	2.000000e-06
GCST002128_9	Type 2 diabetes	4.000000e-29
GCST002224_2	Type 2 diabetes	5.000000e-09
GCST002249_4	Blood pressure measurement (high sodium intervention)	4.000000e-07
GCST002249_6	Blood pressure measurement (high sodium intervention)	1.000000e-06
GCST002317_4	Type 2 diabetes	9.000000e-15
GCST002352_10	Type 2 diabetes	2.000000e-14
GCST002360_10	Plasma amyloid beta peptide concentrations (ABx-40)	9.000000e-06
GCST002461_1	Body mass index	9.000000e-13
GCST002500_67	QT interval	4.000000e-10
GCST002500_68	QT interval	2.000000e-28
GCST002500_69	QT interval	1.000000e-54
GCST002542_2	Electrocardiographic traits	3.000000e-07
GCST002560_10	Type 2 diabetes	1.000000e-10
GCST002560_16	Type 2 diabetes	5.000000e-13

EFO canonical traits (27, from GWAS)

EFO ID	Trait name
EFO:0004808	L lactate dehydrogenase measurement
EFO:0004682	QT interval
EFO:0005401	response to high sodium diet
EFO:0006340	mean arterial pressure
EFO:0006335	systolic blood pressure
EFO:0005659	plasma beta-amyloid 1-40 measurement
EFO:0004340	body mass index
EFO:0006832	disposition index measurement
EFO:0007789	BMI-adjusted waist circumference
EFO:0008002	physical activity measurement
EFO:0008378	mosquito bite reaction size measurement
EFO:0004541	HbA1c measurement
EFO:0004468	glucose measurement
EFO:0009104	hyperuricemia
EFO:0004761	uric acid measurement
EFO:0009924	Drugs used in diabetes use measurement
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0004344	birth weight
EFO:0005939	parental genotype effect measurement
EFO:0004531	urate measurement
EFO:0008398	T wave morphology measurement
EFO:0007783	mosaic loss of chromosome Y measurement
EFO:0004327	electrocardiography
EFO:0008039	BMI-adjusted hip circumference
EFO:0004980	appendicular lean mass
EFO:0007985	platelet crit
EFO:0004309	platelet count

MeSH disease descriptors (16)

Descriptor	Name	Tree numbers
D001281	Atrial Fibrillation	C14.280.067.198; C23.550.073.198
D001506	Beckwith-Wiedemann Syndrome	C16.131.077.133; C16.131.260.080; C16.320.180.080; C16.320.447.375
D053840	Brugada Syndrome	C14.280.067.322; C14.280.123.250; C16.320.100
D009202	Cardiomyopathies	C14.280.238
D002312	Cardiomyopathy, Hypertrophic	C14.280.238.100; C14.280.484.048.750.070.160
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341
D029593	Jervell-Lange Nielsen Syndrome	C14.280.067.565.440; C14.280.123.625.440; C16.131.240.400.715.440
D008133	Long QT Syndrome	C14.280.067.565; C14.280.123.625; C16.131.240.400.715; C23.550.073.547
D016171	Torsades de Pointes	C14.280.067.845.940.700; C14.280.123.875.940.700; C23.550.073.845.940.700
D014693	Ventricular Fibrillation	C14.280.067.922; C23.550.073.922
D014927	Wolff-Parkinson-White Syndrome	C14.280.067.780.977; C14.280.123.750.977; C16.131.240.400.980
C563817	Atrial Fibrillation, Familial, 3 (supp.)
C563614	Long Qt Syndrome 2 (supp.)
C566506	Short QT Syndrome 1 (supp.)
C566505	Short QT Syndrome 2 (supp.)
C580439	Short Qt Syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (5): CHEMBL1866 (SINGLE PROTEIN), CHEMBL2221347 (PROTEIN COMPLEX), CHEMBL2362996 (PROTEIN FAMILY), CHEMBL2363063 (PROTEIN FAMILY), CHEMBL3430890 (PROTEIN COMPLEX)

Molecules with ChEMBL bioactivity

15 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 296,531 (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
CHEMBL1111	AMBRISENTAN	4	7,009
CHEMBL1175	DULOXETINE	4	28,527
CHEMBL1189679	PALONOSETRON	4	9,399
CHEMBL1323	DARUNAVIR	4	15,382
CHEMBL1346	DARIFENACIN	4	8,259
CHEMBL1382	TOLTERODINE	4	13,460
CHEMBL1734	SOLIFENACIN	4	296
CHEMBL1908360	EVEROLIMUS	4	73,430
CHEMBL254316	RALTEGRAVIR	4	12,743
CHEMBL256907	MARAVIROC	4	5
CHEMBL270190	ALVIMOPAN	4	1,781
CHEMBL434394	NEBIVOLOL	4	9,645
CHEMBL535	SUNITINIB	4	79,020
CHEMBL584	NELFINAVIR	4	36,859
CHEMBL74355	VOLINANSERIN	3	716

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

PharmGKB clinical annotations

4 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs163184	Efficacy	3	sitagliptin	Diabetes Mellitus;Type 2
rs2237892	Efficacy	3	repaglinide	Diabetes Mellitus;Type 2
rs2237895	Efficacy	3	repaglinide	Diabetes Mellitus;Type 2
rs2237895	Toxicity	3	tacrolimus	Kidney Transplantation

PharmGKB variants

8 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs163182	KCNQ1		0.00	0
rs757092	KCNQ1		0.00	0
rs2237892	KCNQ1	3	1.50	1	repaglinide
rs2237895	KCNQ1	3	2.00	2	repaglinide;tacrolimus
rs2237897	KCNQ1		0.00	0
rs11022922	KCNQ1		0.00	0
rs163184	KCNQ1	3	2.50	1	sitagliptin
rs151290	KCNQ1		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: vgic — Voltage-gated potassium channels (K_v)

Most potent curated ligand interactions (13 total), top 13:

Ligand	Action	Affinity	Parameter
IKs124	Channel blocker	8.1	pIC50
L735821	Channel blocker	7.5	pIC50
JNJ303	Channel blocker	7.2	pIC50
HMR-1556	Antagonist	7.1	pIC50
ML277	Activation	6.6	pEC50
XE991	Inhibitor	6.1	pKd
R-L3	Activator	6.0	pEC50
ML252	Inhibitor	5.53	pIC50
azimilide	Channel blocker	5.3	pIC50
(3R,4S)-293B	Antagonist	5.0	pIC50
zinc pyrithione	Activator	5.0	pEC50
3S,4R-293B	Antagonist	4.52	pIC50
linopirdine	Inhibitor	4.4	pIC50

ChEMBL bioactivities

63 potent at pChembl≥5 of 101 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.82	Ki	0.15	nM	CHEMBL5722941
9.74	IC50	0.18	nM	CHEMBL5722941
8.05	IC50	9	nM	CHEMBL42205
7.30	IC50	50	nM	CHEMBL124454
6.92	IC50	120	nM	CHEMBL298475
6.70	IC50	200	nM	CHEMBL124308
6.62	IC50	240	nM	CHEMBL340910
6.60	IC50	250	nM	CHEMBL125307
6.58	EC50	260	nM	CHEMBL2070953
6.40	IC50	400	nM	CHEMBL127885
6.38	EC50	420	nM	CHEMBL2070970
6.36	IC50	440	nM	CHEMBL340236
6.22	EC50	600	nM	CHEMBL2070988
6.16	EC50	700	nM	CHEMBL2070954
6.16	IC50	700	nM	CHEMBL340025
6.14	EC50	730	nM	CHEMBL2070968
6.11	EC50	780	nM	CHEMBL2070962
6.10	IC50	790	nM	CHEMBL4065169
6.09	EC50	810	nM	CHEMBL2070961
6.06	EC50	880	nM	CHEMBL2070964
6.05	EC50	890	nM	CHEMBL2070952
6.05	IC50	900	nM	CHEMBL124810
6.00	EC50	1000	nM	CHEMBL2070958
5.99	EC50	1030	nM	CHEMBL2070967
5.97	Ki	1060	nM	VOLINANSERIN
5.96	IC50	1100	nM	CHEMBL338171
5.94	EC50	1160	nM	CHEMBL2070966
5.92	IC50	1200	nM	CHEMBL127435
5.89	IC50	1300	nM	CHEMBL2047511
5.88	EC50	1320	nM	CHEMBL2071004
5.87	EC50	1360	nM	CHEMBL2070978
5.86	EC50	1380	nM	CHEMBL2070832
5.85	EC50	1410	nM	CHEMBL2070969
5.83	EC50	1470	nM	CHEMBL2070830
5.79	EC50	1630	nM	CHEMBL2070965
5.77	EC50	1690	nM	CHEMBL1352968
5.77	EC50	1710	nM	CHEMBL2070959
5.75	EC50	1780	nM	CHEMBL2070960
5.72	IC50	1900	nM	CHEMBL2047506
5.70	IC50	2000	nM	CHEMBL42205
5.66	IC50	2200	nM	CHEMBL124812
5.59	EC50	2590	nM	CHEMBL2070955
5.58	IC50	2600	nM	CHEMBL4093377
5.58	IC50	2640	nM	CHEMBL4062193
5.54	IC50	2900	nM	CHEMBL2046674
5.54	EC50	2860	nM	CHEMBL2070985
5.54	IC50	2920	nM	CHEMBL2164048
5.51	IC50	3100	nM	CHEMBL125259
5.47	IC50	3400	nM	CHEMBL2046681
5.47	IC50	3400	nM	CHEMBL2046683

PubChem BioAssay actives

63 with measured affinity, of 389 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
3-[(1R,2aS,4S,5aS,8aS,10S,11aR,14aS,16S,17aS,19S,20aS,22S,23aS,25S,26aS,28S,29aS,31R,32aS,35aS,36R,38aS,39S,41aS,42S,44aS,45S,48R,50aS,51S,53aS,54S,56aS,57S,59aS,60S,63S,66S,69S,72S,75S,78S,87R,93S,96S,99S)-17a,20a,23a,53a,63-pentakis(4-aminobutyl)-31-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-5-carbamimidamido-2-[[(2S)-5-carbamimidamido-2-[[(2S)-1-[(2S)-5-oxopyrrolidine-2-carbonyl]pyrrolidine-2-carbonyl]amino]pentanoyl]amino]pentanoyl]amino]hexanoyl]amino]-4-methylpentanoyl]amino]-16,29a,72,78-tetrakis(2-amino-2-oxoethyl)-14a,26a-bis(3-amino-3-oxopropyl)-2a,38a,66-tribenzyl-28,50a,57-tris[(2S)-butan-2-yl]-4,5a,19,42,45,69-hexakis(3-carbamimidamidopropyl)-51,54-bis(2-carboxyethyl)-56a,99-bis(carboxymethyl)-36-[[(2S,3S)-1-(carboxymethylamino)-3-methyl-1-oxopentan-2-yl]carbamoyl]-39,60-bis[(1R)-1-hydroxyethyl]-75,93-bis(hydroxymethyl)-32a,35a,59a-tris[(4-hydroxyphenyl)methyl]-22-(1H-imidazol-4-ylmethyl)-96-(1H-indol-3-ylmethyl)-41a-methyl-25-(2-methylpropyl)-1a,3,4a,6,7a,9,10a,13a,15,16a,18,19a,21,22a,24,25a,27,28a,30,31a,34a,37a,38,40a,41,43a,44,47,49a,50,52a,53,55a,56,58a,59,61a,62,65,68,71,74,77,80,83,86,89,92,95,98-pentacontaoxo-33,34,63a,64a,67a,68a-hexathia-a,2,3a,5,6a,8,9a,12a,14,15a,17,18a,20,21a,23,24a,26,27a,29,30a,33a,36a,37,39a,40,42a,43,46,48a,49,51a,52,54a,55,57a,58,60a,61,64,67,70,73,76,79,82,85,88,91,94,97-pentacontazapentacyclo[85.74.4.448,111.010,14.0144,148]nonahexacontahectan-8a-yl]propanoic acid	2198828: Binding affinity to KV channel (unknown origin) assessed as inhibition constant	ki	0.0001	uM
2-(2-fluorophenyl)-2-(4-fluorophenyl)-2-phenylacetamide	74322: Selectivity for gardos channel; (Gardos channel vs 2000 nM for the cardiac IKs channel).)	ic50	0.0090	uM
N-[(3R,4S)-3-hydroxy-2,2-dimethyl-6-phenylmethoxy-3,4-dihydrochromen-4-yl]-N-methylethanesulfonamide	161293: Inhibition of human IKs-channel expressed in Xenopus oocytes	ic50	0.0500	uM
N-[(3R,4S)-3-hydroxy-2,2-dimethyl-6-(4,4,4-trifluorobutoxy)-3,4-dihydrochromen-4-yl]-N-methylmethanesulfonamide	161293: Inhibition of human IKs-channel expressed in Xenopus oocytes	ic50	0.1200	uM
N-(3-hydroxy-2,2-dimethyl-6-phenylmethoxy-3,4-dihydrochromen-4-yl)-N-methylmethanesulfonamide	161293: Inhibition of human IKs-channel expressed in Xenopus oocytes	ic50	0.2000	uM
N-[3-hydroxy-2,2-dimethyl-6-(4,4,4-trifluorobutoxy)-3,4-dihydrochromen-4-yl]-N-methylmethanesulfonamide	161293: Inhibition of human IKs-channel expressed in Xenopus oocytes	ic50	0.2400	uM
N-(6-butoxy-3-hydroxy-2,2-dimethyl-3,4-dihydrochromen-4-yl)-N-methylmethanesulfonamide	161293: Inhibition of human IKs-channel expressed in Xenopus oocytes	ic50	0.2500	uM
(2R)-N-[4-(4-methoxyphenyl)-1,3-thiazol-2-yl]-1-(4-methylphenyl)sulfonylpiperidine-2-carboxamide	678686: Activation of Kv7.1 channel expressed in CHO cells assessed as depolarization-induced thallium influx after 3 mins by patch clamp assay	ec50	0.2600	uM
N-[(3S,4R)-3-hydroxy-2,2-dimethyl-6-phenylmethoxy-3,4-dihydrochromen-4-yl]-N-methylethanesulfonamide	161293: Inhibition of human IKs-channel expressed in Xenopus oocytes	ic50	0.4000	uM
(2R)-1-(4-chlorophenyl)sulfonyl-N-[4-(4-methoxyphenyl)-1,3-thiazol-2-yl]piperidine-2-carboxamide	678686: Activation of Kv7.1 channel expressed in CHO cells assessed as depolarization-induced thallium influx after 3 mins by patch clamp assay	ec50	0.4200	uM
N-[(3S,4R)-3-hydroxy-2,2-dimethyl-6-(4,4,4-trifluorobutoxy)-3,4-dihydrochromen-4-yl]-N-methylmethanesulfonamide	161293: Inhibition of human IKs-channel expressed in Xenopus oocytes	ic50	0.4400	uM
N-[4-(4-methoxyphenyl)-1,3-thiazol-2-yl]-4-(4-methylphenyl)sulfonylthiomorpholine-3-carboxamide	678686: Activation of Kv7.1 channel expressed in CHO cells assessed as depolarization-induced thallium influx after 3 mins by patch clamp assay	ec50	0.6000	uM
N-[(3R,4S)-6-fluoro-3-hydroxy-2,2-dimethyl-3,4-dihydrochromen-4-yl]-N-methylethanesulfonamide	161293: Inhibition of human IKs-channel expressed in Xenopus oocytes	ic50	0.7000	uM
(2R)-N-[4-(4-methoxyphenyl)-1,3-thiazol-2-yl]-1-(4-propylphenyl)sulfonylpiperidine-2-carboxamide	678686: Activation of Kv7.1 channel expressed in CHO cells assessed as depolarization-induced thallium influx after 3 mins by patch clamp assay	ec50	0.7000	uM
(2R)-1-(2-chlorophenyl)sulfonyl-N-[4-(4-methoxyphenyl)-1,3-thiazol-2-yl]piperidine-2-carboxamide	678686: Activation of Kv7.1 channel expressed in CHO cells assessed as depolarization-induced thallium influx after 3 mins by patch clamp assay	ec50	0.7300	uM
(2R)-1-(1,3-benzodioxol-5-ylsulfonyl)-N-[4-(4-methoxyphenyl)-1,3-thiazol-2-yl]piperidine-2-carboxamide	678686: Activation of Kv7.1 channel expressed in CHO cells assessed as depolarization-induced thallium influx after 3 mins by patch clamp assay	ec50	0.7800	uM
N-[6-[(1S)-1-(4-fluorophenyl)-2,2-dipyridin-3-ylethyl]-2-pyridinyl]methanesulfonamide	1437178: Inhibition of human KCNQ1/KCNE1 expressed in HEK293 cells assessed as reduction in slowly activating delayed rectifier cardiac potassium current by patch clamp electrophysiology method	ic50	0.7900	uM
(2R)-1-(3-methoxyphenyl)sulfonyl-N-[4-(4-methoxyphenyl)-1,3-thiazol-2-yl]piperidine-2-carboxamide	678686: Activation of Kv7.1 channel expressed in CHO cells assessed as depolarization-induced thallium influx after 3 mins by patch clamp assay	ec50	0.8100	uM
(2R)-1-(3-cyanophenyl)sulfonyl-N-[4-(4-methoxyphenyl)-1,3-thiazol-2-yl]piperidine-2-carboxamide	678686: Activation of Kv7.1 channel expressed in CHO cells assessed as depolarization-induced thallium influx after 3 mins by patch clamp assay	ec50	0.8800	uM
(2R)-N-[4-(4-methoxyphenyl)-1,3-thiazol-2-yl]-1-(3-methylphenyl)sulfonylpiperidine-2-carboxamide	678686: Activation of Kv7.1 channel expressed in CHO cells assessed as depolarization-induced thallium influx after 3 mins by patch clamp assay	ec50	0.8900	uM
N-(3-hydroxy-2,2-dimethyl-6-propoxy-3,4-dihydrochromen-4-yl)-N-methylmethanesulfonamide	161293: Inhibition of human IKs-channel expressed in Xenopus oocytes	ic50	0.9000	uM
(2R)-N-[4-(4-methoxyphenyl)-1,3-thiazol-2-yl]-1-[3-(trifluoromethyl)phenyl]sulfonylpiperidine-2-carboxamide	678686: Activation of Kv7.1 channel expressed in CHO cells assessed as depolarization-induced thallium influx after 3 mins by patch clamp assay	ec50	1.0000	uM
(2R)-1-(4-fluorophenyl)sulfonyl-N-[4-(4-methoxyphenyl)-1,3-thiazol-2-yl]piperidine-2-carboxamide	678686: Activation of Kv7.1 channel expressed in CHO cells assessed as depolarization-induced thallium influx after 3 mins by patch clamp assay	ec50	1.0300	uM
(R)-(2,3-dimethoxyphenyl)-[1-[2-(4-fluorophenyl)ethyl]piperidin-4-yl]methanol	217617: Binding affinity at Voltage-gated potassium channel	ki	1.0600	uM
N-(6-chloro-3-hydroxy-2,2-dimethyl-3,4-dihydrochromen-4-yl)-N-methylmethanesulfonamide	161293: Inhibition of human IKs-channel expressed in Xenopus oocytes	ic50	1.1000	uM
(2R)-1-(3-fluorophenyl)sulfonyl-N-[4-(4-methoxyphenyl)-1,3-thiazol-2-yl]piperidine-2-carboxamide	678686: Activation of Kv7.1 channel expressed in CHO cells assessed as depolarization-induced thallium influx after 3 mins by patch clamp assay	ec50	1.1600	uM
N-(6-fluoro-3-hydroxy-2,2-dimethyl-3,4-dihydrochromen-4-yl)-N-methylethanesulfonamide	161293: Inhibition of human IKs-channel expressed in Xenopus oocytes	ic50	1.2000	uM
N-(6-chloro-3-pyridinyl)-3-fluoro-4-phenoxybenzamide	669436: Antagonist activity at KCNQ1/MINK expressed in CHO cells assessed as inhibition of KCl-induced 86Rb+ efflux incubated for 10 mins prior to KCl-induction by liquid scintillation counting	ic50	1.3000	uM
(2R)-N-[4-(1-benzofuran-5-yl)-1,3-thiazol-2-yl]-1-(4-methylphenyl)sulfonylpiperidine-2-carboxamide	678686: Activation of Kv7.1 channel expressed in CHO cells assessed as depolarization-induced thallium influx after 3 mins by patch clamp assay	ec50	1.3200	uM
(2R)-N-[4-(4-methoxyphenyl)-1,3-thiazol-2-yl]-1-pyridin-3-ylsulfonylpiperidine-2-carboxamide	678686: Activation of Kv7.1 channel expressed in CHO cells assessed as depolarization-induced thallium influx after 3 mins by patch clamp assay	ec50	1.3600	uM
(2R)-N-[4-(4-methoxyphenyl)-1,3-thiazol-2-yl]-1-(2-methylphenyl)sulfonylpiperidine-2-carboxamide	678686: Activation of Kv7.1 channel expressed in CHO cells assessed as depolarization-induced thallium influx after 3 mins by patch clamp assay	ec50	1.3800	uM
(2R)-1-(3-chlorophenyl)sulfonyl-N-[4-(4-methoxyphenyl)-1,3-thiazol-2-yl]piperidine-2-carboxamide	678686: Activation of Kv7.1 channel expressed in CHO cells assessed as depolarization-induced thallium influx after 3 mins by patch clamp assay	ec50	1.4100	uM
(2R)-1-(benzenesulfonyl)-N-[4-(4-methoxyphenyl)-1,3-thiazol-2-yl]piperidine-2-carboxamide	678686: Activation of Kv7.1 channel expressed in CHO cells assessed as depolarization-induced thallium influx after 3 mins by patch clamp assay	ec50	1.4700	uM
(2R)-1-(4-cyanophenyl)sulfonyl-N-[4-(4-methoxyphenyl)-1,3-thiazol-2-yl]piperidine-2-carboxamide	678686: Activation of Kv7.1 channel expressed in CHO cells assessed as depolarization-induced thallium influx after 3 mins by patch clamp assay	ec50	1.6300	uM
1-(benzenesulfonyl)-N-[4-(4-methoxyphenyl)-1,3-thiazol-2-yl]piperidine-2-carboxamide	678686: Activation of Kv7.1 channel expressed in CHO cells assessed as depolarization-induced thallium influx after 3 mins by patch clamp assay	ec50	1.6900	uM
(2R)-N-[4-(4-methoxyphenyl)-1,3-thiazol-2-yl]-1-[4-(trifluoromethyl)phenyl]sulfonylpiperidine-2-carboxamide	678686: Activation of Kv7.1 channel expressed in CHO cells assessed as depolarization-induced thallium influx after 3 mins by patch clamp assay	ec50	1.7100	uM
(2R)-1-(2-methoxyphenyl)sulfonyl-N-[4-(4-methoxyphenyl)-1,3-thiazol-2-yl]piperidine-2-carboxamide	678686: Activation of Kv7.1 channel expressed in CHO cells assessed as depolarization-induced thallium influx after 3 mins by patch clamp assay	ec50	1.7800	uM
N-(6-chloro-3-pyridinyl)-4-phenoxybenzamide	669436: Antagonist activity at KCNQ1/MINK expressed in CHO cells assessed as inhibition of KCl-induced 86Rb+ efflux incubated for 10 mins prior to KCl-induction by liquid scintillation counting	ic50	1.9000	uM
N-[(3S,4R)-6-fluoro-3-hydroxy-2,2-dimethyl-3,4-dihydrochromen-4-yl]-N-methylethanesulfonamide	161293: Inhibition of human IKs-channel expressed in Xenopus oocytes	ic50	2.2000	uM
(2R)-N-[4-(4-methoxyphenyl)-1,3-thiazol-2-yl]-1-(4-propan-2-ylphenyl)sulfonylpiperidine-2-carboxamide	678686: Activation of Kv7.1 channel expressed in CHO cells assessed as depolarization-induced thallium influx after 3 mins by patch clamp assay	ec50	2.5900	uM
N-(6-chloro-3-pyridinyl)-6-(trifluoromethyl)-1H-indazol-3-amine	1454474: Inhibition of KCNQ1 (unknown origin)	ic50	2.6000	uM
N-(3,4-difluorophenyl)-6-(trifluoromethoxy)-1H-pyrazolo[4,3-b]pyridin-3-amine	1454474: Inhibition of KCNQ1 (unknown origin)	ic50	2.6400	uM
N-[4-(4-methoxyphenyl)-1,3-thiazol-2-yl]-1-(4-methylphenyl)sulfonylpyrrolidine-2-carboxamide	678686: Activation of Kv7.1 channel expressed in CHO cells assessed as depolarization-induced thallium influx after 3 mins by patch clamp assay	ec50	2.8600	uM
N-(6-chloro-3-pyridinyl)-4-(trifluoromethyl)benzamide	669436: Antagonist activity at KCNQ1/MINK expressed in CHO cells assessed as inhibition of KCl-induced 86Rb+ efflux incubated for 10 mins prior to KCl-induction by liquid scintillation counting	ic50	2.9000	uM
(2S)-2-phenyl-N-(2-pyrrolidin-1-ylphenyl)butanamide	697780: Antagonist activity at KCNQ1 expressed in CHO cells incubated for 3 mins by automated patch clamp assay	ic50	2.9200	uM
N-(3-hydroxy-2,2-dimethyl-3,4-dihydrochromen-4-yl)-N-methylethanesulfonamide	161293: Inhibition of human IKs-channel expressed in Xenopus oocytes	ic50	3.1000	uM
N-(6-chloro-3-pyridinyl)-3-fluoro-4-(trifluoromethyl)benzamide	669436: Antagonist activity at KCNQ1/MINK expressed in CHO cells assessed as inhibition of KCl-induced 86Rb+ efflux incubated for 10 mins prior to KCl-induction by liquid scintillation counting	ic50	3.4000	uM
N-(6-chloro-3-pyridinyl)-4-fluoro-3-(trifluoromethyl)benzamide	669436: Antagonist activity at KCNQ1/MINK expressed in CHO cells assessed as inhibition of KCl-induced 86Rb+ efflux incubated for 10 mins prior to KCl-induction by liquid scintillation counting	ic50	3.4000	uM
N-[4-(4-methoxyphenyl)-1,3-thiazol-2-yl]-4-(4-methylphenyl)sulfonylmorpholine-3-carboxamide	678686: Activation of Kv7.1 channel expressed in CHO cells assessed as depolarization-induced thallium influx after 3 mins by patch clamp assay	ec50	4.3800	uM
(2R)-N-[4-(4-methoxyphenyl)-1,3-thiazol-2-yl]-1-[2-(trifluoromethyl)phenyl]sulfonylpiperidine-2-carboxamide	678686: Activation of Kv7.1 channel expressed in CHO cells assessed as depolarization-induced thallium influx after 3 mins by patch clamp assay	ec50	4.7400	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression, increases expression, increases methylation	4
Valproic Acid	increases expression, increases methylation, affects cotreatment	4
Air Pollutants	increases abundance, affects response to substance, affects methylation, affects expression	3
Doxorubicin	decreases expression	3
sodium arsenite	affects methylation, decreases expression	2
6-cyano-4-(N-ethylsulfonyl-N-methylamino)-3-hydroxy-2,2-dimethylchromane	decreases activity, affects binding	2
Arsenic	affects expression, affects methylation	2
Daunorubicin	decreases expression	2
Mitoxantrone	decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Aflatoxin B1	affects methylation, decreases expression, increases methylation	2
Acrylamide	decreases activity, increases expression, increases reaction	2
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, decreases methylation	1
arsenite	increases methylation	1
sulforaphane	decreases expression	1
butyraldehyde	decreases expression	1
barium chloride	affects binding, decreases activity	1
benzo(e)pyrene	affects methylation	1
aflatoxin B2	affects methylation	1
pentanal	increases expression	1
N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide	decreases reaction, increases activity, affects binding	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
7,8-benzoquinoline	increases activity	1
entinostat	increases expression	1
HMR 1556	affects binding, decreases activity	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression, increases expression	1
N-(1-(3-morpholin-4-ylphenyl)ethyl)-3-phenylacrylamide	increases reaction, decreases activity	1
abrine	increases expression	1

ChEMBL screening assays

179 unique, capped per target: 96 binding, 64 functional, 14 admet, 5 toxicity

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1693396	ADMET	Activation of KCNQ1 expressed in HEK293 cells by atomic absorption Rb’+ efflux assay	Design, synthesis and biological activity of pyrazolo[1,5-a]pyrimidin-7(4H)-ones as novel Kv7/KCNQ potassium channel activators. — Eur J Med Chem
CHEMBL2071936	Binding	Activation of Kv7.1 channel expressed in CHO cells assessed as depolarization-induced thallium influx after 3 mins by patch clamp assay	Identification of (R)-N-(4-(4-methoxyphenyl)thiazol-2-yl)-1-tosylpiperidine-2-carboxamide, ML277, as a novel, potent and selective K(v)7.1 (KCNQ1) potassium channel activator. — Bioorg Med Chem Lett
CHEMBL2169528	Functional	Antagonist activity at KCNQ1 expressed in CHO cells incubated for 3 mins by automated patch clamp assay	Discovery of a series of 2-phenyl-N-(2-(pyrrolidin-1-yl)phenyl)acetamides as novel molecular switches that modulate modes of K(v)7.2 (KCNQ2) channel pharmacology: identification of (S)-2-phenyl-N-(2-(pyrrolidin-1-yl)phenyl)butanamide (ML252) as a potent, brain penetrant K(v)7.2 channel inhibitor. — J Med Chem

Cellosaurus cell lines

81 cell lines: 68 induced pluripotent stem cell, 6 cancer cell line, 3 embryonic stem cell, 2 spontaneously immortalized cell line, 2 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A0MA	NCUFi001-A	Induced pluripotent stem cell	Male
CVCL_A7QT	LUMCi039-A	Induced pluripotent stem cell	Female
CVCL_A7RV	WAe009-A-62	Embryonic stem cell	Female
CVCL_A8PG	UTA.00102.LQT1	Induced pluripotent stem cell	Female
CVCL_A8PH	UTA.00118.LQT1	Induced pluripotent stem cell	Female
CVCL_A8WL	XACHi012-A	Induced pluripotent stem cell	Male
CVCL_A8WM	XACHi013-A	Induced pluripotent stem cell	Male
CVCL_A8WN	XACHi014-A	Induced pluripotent stem cell	Female
CVCL_A9AI	SCVIi014-A	Induced pluripotent stem cell	Male
CVCL_A9AJ	SCVIi015-A	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT06534671	PHASE4	COMPLETED	Diltiazem in Jervell and Lange-Nielsen Syndrome
NCT02513940	PHASE4	COMPLETED	Influence of Testosterone Administration on Drug-Induced QT Interval Prolongation and Torsades de Pointes
NCT03834883	PHASE4	COMPLETED	Reducing the Risk of Drug-Induced QT Interval Lengthening in Women
NCT04169100	PHASE4	UNKNOWN	Novel Form of Acquired Long QT Syndrome
NCT04675788	PHASE4	COMPLETED	Novel Approaches for Minimizing Drug-Induced QT Interval Lengthening
NCT00146822	PHASE4	COMPLETED	REFLEx Study (ENDOTAK RELIANCE G Evaluation of Handling and Electrical Performance
NCT00187239	PHASE4	COMPLETED	Reduce Ventricular Pacing in Dual Chamber Implantable Cardioverter Defibrillators Using AutoIntrinsic Conduction Search Study
NCT00247533	PHASE4	UNKNOWN	Cerebral Artery Stenosis, Coronary Artery Disease and Arrhythmia
NCT00282620	PHASE4	UNKNOWN	Magnesium to Reduce Implantable Cardioverter Defibrillator (ICD) Shocks and Improve Patient’s Quality of Life.
NCT00290056	PHASE4	UNKNOWN	Effect of Supplemental Intake of Omega-3 Polyunsaturated Fatty Acids on the Rate and Complexity of Spontaneously Occurring Ventricular and Supraventricular Arrhythmias in Patients With Implantable Cardioverter Defibrillator (ICD) - A Randomized Clinical Trial
NCT00313443	PHASE4	COMPLETED	Concentrations of Amiodarone in Fat Tissue During Chronic Treatment
NCT00457340	PHASE4	COMPLETED	Atorvastatin For The Reduction Of Ventricular Arrhythmias
NCT00507390	PHASE4	WITHDRAWN	Omega 3 Polyunsaturated Fatty Acid Supplements (PUFAs) and Microvolt T Wave Alternans (TWA) in Patients With Ventricular Arrhythmia
NCT00575523	PHASE4	COMPLETED	Atropine for Prevention of Dysrhythmias Caused by Percutaneous Ethanol Instillation for Hepatoma Therapy
NCT00579098	PHASE4	COMPLETED	The Use of Statins Following a Left Atrial Catheter Ablation Procedure to Prevent Atrial Fibrillation
NCT01613092	PHASE4	COMPLETED	Prevention of Arrhythmia Device Infection Trial (PADIT)
NCT01628666	PHASE4	COMPLETED	Prevention of Arrhythmia Device Infection Trial (PADIT)
NCT01717469	PHASE4	UNKNOWN	Safety and the Effects of Isolated Left Ventricular Pacing in Patients With Bradyarrhythmias
NCT01819064	PHASE4	COMPLETED	Heart Rate Response to Atropine Doses Less Than 0.1mg IV to Anesthetized Infants
NCT01834872	PHASE4	UNKNOWN	Safety and Feasibility of Arrhythmia Ablation Using the Amigo Remote Robotic System as Compared With Manual Ablation
NCT01841242	PHASE4	COMPLETED	Comparison of Alcoholic Chlorhexidine 2% Versus Alcoholic Povidone Iodine for Infections Prevention With Cardiac Resynchronization Therapy Device Implantation
NCT01991223	PHASE4	UNKNOWN	Dexmedetomidine for Catheter-related Bladder Discomfort
NCT02045173	PHASE4	COMPLETED	Automate Detection of Sleep Apnea by ApneascanTM
NCT02203630	PHASE4	TERMINATED	Phenylephrine Versus Norepinephrine for Septic Shock in Critically Ill Patients
NCT02565069	PHASE4	COMPLETED	Identification for the Treatment of Complex Arrhythmias
NCT03273634	PHASE4	COMPLETED	The Effect of Proton Pump Inhibition on Palpitations
NCT03289429	PHASE4	UNKNOWN	Antiarrhythmic and Cardioprotective Effects of Atorvastatin Versus Magnesium Sulfate in Cardiac Valve Replacement Surgery
NCT03895411	PHASE4	UNKNOWN	Efficacy and Safety of Sotalol in Children With Arrhythmia
NCT05486377	PHASE4	COMPLETED	Remimazolam vs Desflurane for General Anesthesia for Ablation of Arrhythmia
NCT06574555	PHASE4	COMPLETED	Norepinephrine ED90 Bolus After Spinal Anesthesia in Cesarean Section
NCT00000464	PHASE3	COMPLETED	Cardiac Arrest in Seattle: Conventional Versus Amiodarone Drug Evaluation (CASCADE)
NCT00000476	PHASE3	COMPLETED	Digitalis Investigation Group (DIG)
NCT00000480	PHASE3	COMPLETED	Multicenter Unsustained Tachycardia Trial (MUSTT)
NCT00000492	PHASE3	COMPLETED	Beta-Blocker Heart Attack Trial (BHAT)
NCT00000502	PHASE3	COMPLETED	Evaluation of SC-V Versus Conventional CPR
NCT00000517	PHASE3	COMPLETED	Boston Area Anticoagulation Trial for Atrial Fibrillation (BAATAF)
NCT00000518	PHASE3	COMPLETED	Electrophysiologic Study Versus Electrocardiographic Monitoring (ESVEM)
NCT00000531	PHASE3	COMPLETED	Antiarrhythmics Versus Implantable Defibrillators (AVID)
NCT00000540	PHASE3	COMPLETED	Coronary Artery Bypass Graft (CABG) Patch Trial
NCT00000556	PHASE3	COMPLETED	Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM)