KCNH2

Summary

KCNH2 (potassium voltage-gated channel subfamily H member 2, HGNC:6251) is a protein-coding gene on chromosome 7q36.1, encoding Voltage-gated inwardly rectifying potassium channel KCNH2 (Q12809). Pore-forming (alpha) subunit of voltage-gated inwardly rectifying potassium channel. It is haploinsufficient (ClinGen: sufficient evidence).

This gene encodes a component of a voltage-activated potassium channel found in cardiac muscle, nerve cells, and microglia. Four copies of this protein interact with one copy of the KCNE2 protein to form a functional potassium channel. Mutations in this gene can cause long QT syndrome type 2 (LQT2). Transcript variants encoding distinct isoforms have been identified.

Source: NCBI Gene 3757 — RefSeq curated summary.

At a glance

• Gene–disease (curated): long QT syndrome (Definitive, ClinGen) — +4 more curated relationships
• GWAS associations: 59 (top 1% of genes corpus-wide)
• Clinical variants (ClinVar): 3,920 total — 498 pathogenic, 195 likely-pathogenic (top 1% of genes corpus-wide)
• Regional missense constraint (gnomAD): 1 of 7 regions constrained (≈2% of expected missense variation)
• GTEx eGene: eQTL in 20 tissues, sQTL in 10 (q < 0.05)
• Phenotypes (HPO): 19
• Drug target: yes — 7 curated mechanism-of-action drugs; 706 molecules with ChEMBL bioactivity (top 1% of genes corpus-wide)
• Approved drugs (ChEMBL mechanism of action): 5 — Amiodarone Hydrochloride, Dofetilide, Ibutilide Fumarate, +2 more
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• Constraint (gnomAD): pLI 0.07 (LoF-tolerant), LOEUF 0.57 (moderately constrained)
• MANE Select transcript: NM_000238

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6251
Approved symbol	KCNH2
Name	potassium voltage-gated channel subfamily H member 2
Location	7q36.1
Locus type	gene with protein product
Status	Approved
Aliases	Kv11.1, HERG, erg1
Ensembl gene	ENSG00000055118
Ensembl biotype	protein_coding
OMIM	152427
Entrez	3757

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 9 protein_coding, 7 retained_intron, 1 nonsense_mediated_decay

MANE Select: ENST00000262186

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 3, TSL 2: 2

ENST00000262186, ENST00000330883, ENST00000461280, ENST00000473610, ENST00000532957, ENST00000683359, ENST00000684116, ENST00000684241, ENST00000713700, ENST00000713701, ENST00000713710, ENST00000945646, ENST00000945647, ENST00001037187, ENST00001112396, ENST00001112397, ENST00001134767

RefSeq mRNA: 8 — MANE Select: NM_000238 NM_000238, NM_001204798, NM_001406753, NM_001406755, NM_001406756, NM_001406757, NM_172056, NM_172057

CCDS: CCDS5910, CCDS5911

Canonical transcript exons

ENST00000262186 — 15 exons

Exon	Start	End
ENSE00000872388	150944961	150945514
ENSE00000872389	150948444	150948543
ENSE00000978099	150948856	150949049
ENSE00001141370	150946877	150947054
ENSE00001141375	150947328	150947514
ENSE00001141381	150947606	150947878
ENSE00002511912	150950168	150950420
ENSE00003469830	150959572	150959736
ENSE00003526373	150952425	150952853
ENSE00003531790	150958059	150958502
ENSE00003562537	150951448	150951835
ENSE00003570568	150950921	150951120
ENSE00003634780	150957291	150957502
ENSE00003726746	150974711	150974941
ENSE00004020818	150977838	150978321

Expression profiles

Bgee: expression breadth ubiquitous, 211 present calls, max score 95.99.

FANTOM5 (CAGE): breadth broad, TPM avg 9.7590 / max 345.2428, expressed in 550 samples.

Highest expression (Bgee): apex of heart, atrium auricular region, cardiac atrium, heart left ventricle, muscle layer of sigmoid colon.

Genetic regulation across tissues (GTEx eQTL / sQTL)

KCNH2 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 20 tissues and its splicing (sQTL) in 10 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 30 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Brain Cerebellum	eqtl	4.5e-25	-0.41	7:150978780:A:G
Artery Aorta	eqtl	1.3e-19	-0.54	7:150940932:T:C
Brain Cerebellar Hemisphere	eqtl	3.5e-16	-0.33	7:150978780:A:G
Nerve Tibial	eqtl	3.4e-13	-0.27	7:150970122:C:T
Artery Tibial	eqtl	1.5e-08	-0.22	7:150956248:T:C
Adrenal Gland	eqtl	3.4e-08	-0.34	7:150901391:T:C
Testis	sqtl	1.7e-07	+0.56	7:150940746:C:T
Colon Sigmoid	sqtl	1.5e-06	+0.53	7:150960121:G:A
Ovary	eqtl	4.7e-06	-1.15	7:150849357:C:T
Esophagus Muscularis	sqtl	2.3e-05	+0.46	7:150940746:C:T
Heart Atrial Appendage	sqtl	1.9e-04	-0.49	7:150951110:A:G
Thyroid	eqtl	4.9e-04	-0.57	7:151848003:G:T
Skin Not Sun Exposed Suprapubic	eqtl	9.6e-04	-0.76	7:150375140:A:G
Pituitary	eqtl	1.1e-03	-0.20	7:150969466:T:TGAA
Brain Cerebellar Hemisphere	sqtl	2.7e-03	+0.60	7:150940746:C:T
Cells Cultured fibroblasts	eqtl	3.6e-03	-0.24	7:150763803:G:T
Prostate	eqtl	4.1e-03	-0.13	7:150992309:A:T
Nerve Tibial	sqtl	1.1e-02	-1.53	7:151403741:C:T
Esophagus Gastroesophageal Junction	sqtl	1.3e-02	+0.50	7:150960007:G:A
Testis	eqtl	1.6e-02	+0.11	7:150917846:T:C

FANTOM5 promoters

7 alternative TSS:

Promoter ID	TPM avg	Samples expressed
86835	6.0367	229
86843	1.7547	439
86833	1.2722	149
86836	0.2575	61
86834	0.2110	59
86842	0.1892	95
86841	0.0377	14

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	95.99	gold quality
right atrium auricular region	UBERON:0006631	95.19	gold quality
cardiac atrium	UBERON:0002081	94.63	gold quality
heart left ventricle	UBERON:0002084	94.06	gold quality
muscle layer of sigmoid colon	UBERON:0035805	93.87	gold quality
right hemisphere of cerebellum	UBERON:0014890	93.70	gold quality
cardiac ventricle	UBERON:0002082	93.66	gold quality
pituitary gland	UBERON:0000007	93.06	gold quality
cerebellar hemisphere	UBERON:0002245	93.00	gold quality
cerebellar cortex	UBERON:0002129	92.89	gold quality
left ventricle myocardium	UBERON:0006566	92.70	gold quality
adenohypophysis	UBERON:0002196	92.24	gold quality
cerebellum	UBERON:0002037	91.93	gold quality
right testis	UBERON:0004534	91.09	gold quality
left testis	UBERON:0004533	90.98	gold quality
cardiac muscle of right atrium	UBERON:0003379	90.89	gold quality
endothelial cell	CL:0000115	89.20	silver quality
heart	UBERON:0000948	89.14	gold quality
myocardium	UBERON:0002349	89.01	gold quality
testis	UBERON:0000473	88.75	gold quality
lower esophagus muscularis layer	UBERON:0035833	88.69	gold quality
lower esophagus	UBERON:0013473	88.66	gold quality
trabecular bone tissue	UBERON:0002483	88.46	gold quality
cortical plate	UBERON:0005343	88.14	gold quality
sigmoid colon	UBERON:0001159	87.97	gold quality
body of uterus	UBERON:0009853	86.87	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	86.57	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	85.78	gold quality
bone marrow	UBERON:0002371	85.74	gold quality
left uterine tube	UBERON:0001303	85.46	gold quality
hypothalamus	UBERON:0001898	84.99	gold quality
right frontal lobe	UBERON:0002810	84.37	gold quality
nucleus accumbens	UBERON:0001882	84.11	gold quality
cauda epididymis	UBERON:0004360	84.06	gold quality
caudate nucleus	UBERON:0001873	83.99	gold quality
myometrium	UBERON:0001296	83.66	gold quality
islet of Langerhans	UBERON:0000006	83.46	gold quality
putamen	UBERON:0001874	83.45	gold quality
bone marrow cell	CL:0002092	83.20	gold quality
prefrontal cortex	UBERON:0000451	83.19	gold quality
heart right ventricle	UBERON:0002080	82.39	gold quality
cingulate cortex	UBERON:0003027	82.33	gold quality
fundus of stomach	UBERON:0001160	82.29	gold quality
anterior cingulate cortex	UBERON:0009835	82.27	gold quality
smooth muscle tissue	UBERON:0001135	82.05	gold quality
brain	UBERON:0000955	81.88	gold quality
central nervous system	UBERON:0001017	81.65	gold quality
colon	UBERON:0001155	81.34	gold quality
neocortex	UBERON:0001950	81.15	gold quality
forebrain	UBERON:0001890	81.13	gold quality
frontal cortex	UBERON:0001870	81.09	gold quality
Brodmann (1909) area 9	UBERON:0013540	80.98	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	80.86	gold quality
large intestine	UBERON:0000059	80.76	gold quality
gall bladder	UBERON:0002110	80.58	gold quality
transverse colon	UBERON:0001157	80.19	gold quality
telencephalon	UBERON:0001893	79.90	gold quality
saphenous vein	UBERON:0007318	79.82	gold quality
seminal vesicle	UBERON:0000998	79.76	gold quality
cerebral cortex	UBERON:0000956	79.73	gold quality
amygdala	UBERON:0001876	79.67	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	79.60	gold quality
mucosa of stomach	UBERON:0001199	79.58	gold quality
cerebellar vermis	UBERON:0004720	79.54	gold quality
prostate gland	UBERON:0002367	79.10	gold quality
pancreatic ductal cell	CL:0002079	78.96	silver quality
intestine	UBERON:0000160	78.93	gold quality
body of stomach	UBERON:0001161	78.87	gold quality
corpus epididymis	UBERON:0004359	78.70	gold quality
primary visual cortex	UBERON:0002436	78.46	gold quality
substantia nigra	UBERON:0002038	77.81	gold quality
pons	UBERON:0000988	77.68	gold quality
ganglionic eminence	UBERON:0004023	77.43	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	77.26	gold quality
Ammon’s horn	UBERON:0001954	77.10	gold quality
stomach	UBERON:0000945	77.06	gold quality
midbrain	UBERON:0001891	77.00	gold quality
Brodmann (1909) area 46	UBERON:0006483	76.79	gold quality
middle temporal gyrus	UBERON:0002771	76.73	silver quality
lower esophagus mucosa	UBERON:0035834	76.44	gold quality
temporal lobe	UBERON:0001871	76.13	gold quality
Brodmann (1909) area 23	UBERON:0013554	76.12	gold quality
small intestine Peyer’s patch	UBERON:0003454	76.07	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	75.89	gold quality
esophagus	UBERON:0001043	75.84	gold quality
Brodmann (1909) area 10	UBERON:0013541	75.67	gold quality
buccal mucosa cell	CL:0002336	75.61	silver quality
inferior olivary complex	UBERON:0002127	75.55	gold quality
caput epididymis	UBERON:0004358	75.33	gold quality
urinary bladder	UBERON:0001255	75.26	gold quality
small intestine	UBERON:0002108	75.13	gold quality
lateral nuclear group of thalamus	UBERON:0002736	74.65	gold quality
spinal cord	UBERON:0002240	74.60	gold quality
right ovary	UBERON:0002118	74.43	gold quality
occipital lobe	UBERON:0002021	73.89	gold quality
choroid plexus epithelium	UBERON:0003911	73.88	silver quality
vena cava	UBERON:0004087	72.27	gold quality
vermiform appendix	UBERON:0001154	71.99	gold quality
adult organism	UBERON:0007023	71.92	gold quality
pancreas	UBERON:0001264	71.80	gold quality

Single-cell (SCXA)

Detected in 14 experiment(s), a significant marker in 12.

Experiment	Marker?	Max mean expression
E-GEOD-130473	yes	817.91
E-CURD-98	yes	496.67
E-ANND-5	yes	481.11
E-MTAB-7407	yes	416.00
E-MTAB-10432	yes	292.50
E-CURD-112	yes	250.06
E-MTAB-9067	yes	185.08
E-HCAD-6	yes	53.24
E-CURD-122	yes	23.48
E-GEOD-137537	yes	18.78
E-ANND-3	yes	8.63
E-MTAB-9801	yes	4.48
E-MTAB-5061	no	3.10
E-HCAD-10	no	1.91

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 70 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM
Pituitary gland	tissue	41.5
Bone marrow	tissue	39.0
Cerebellum	tissue	34.6
Locus coeruleus	tissue	25.9
Superior colliculi	tissue	23.7
Thalamus	tissue	21.7
Pons	tissue	20.4
Midbrain	tissue	19.6
Parathyroid gland	tissue	16.6
Nucleus accumbens	tissue	16.5
Postcentral gyrus	tissue	14.9
Choroid plexus	tissue	13.8
Medulla oblongata	tissue	13.5
Hippocampus	tissue	13.5
Substantia nigra	tissue	13.4
Testis	tissue	13.2
Olfactory bulb	tissue	12.3
Cerebral cortex	tissue	12.1
Somatosensory cortex	tissue	12.1
Putamen	tissue	12.0
Frontal cortex	tissue	11.8
Caudate putamen	tissue	11.7
Ventral forebrain	tissue	11.6
Basal ganglia	tissue	11.5
Heart muscle	tissue	11.1
Prefrontal cortex	tissue	11.0
Motor cortex	tissue	10.6
Insular cortex	tissue	10.0
Temporal cortex	tissue	9.7
Hippocampal formation	tissue	9.5
Entorhinal cortex	tissue	9.5
Occipital cortex	tissue	9.5
Retrosplenial and cingulate cortex	tissue	9.4
Hypothalamus	tissue	9.2
Septum	tissue	9.1
Retrosplenial cortex	tissue	9.0
Spinal cord	tissue	8.0
Periaqueductal gray	tissue	7.4
Seminal vesicle	tissue	7.3
Smooth muscle	tissue	7.0
Amygdala	tissue	5.7
Retina	tissue	5.3
Endometrium 1	tissue	4.2
Prostate	tissue	3.5
Adrenal gland	tissue	3.4
Pancreas	tissue	3.2
Gallbladder	tissue	2.7
Fallopian tube	tissue	2.7
Vagina	tissue	2.4
Small intestine	tissue	2.4
Duodenum	tissue	2.4
Corpus callosum	tissue	2.3
Appendix	tissue	2.2
Colon	tissue	2.1
Urinary bladder	tissue	2.1
Stomach 1	tissue	1.8
Ovary	tissue	1.2
Esophagus	tissue	1.2
Placenta	tissue	1.2
Salivary gland	tissue	0.9

Brain sub-regions (HPA Brain Atlas): detected in 189; highest nTPM — Nucleus raphe magnus (50.2), Nuclei of the trapezoid body (49.9), Lateral lemniscal nuclei (43.8), Ventral periolivary nuclei (43.4), Motor facial nucleus (41.9).

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets:

Target	Regulation
NR4A1	Activation

Upstream regulators (CollecTRI, top): AR, HSPA1A, HSPA1B, NFKB, NKX3-1, RNF207, SP1

miRNA regulators (miRDB)

Targeting KCNH2 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

23 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-944	99.82	70.85	3042
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-12123	99.52	71.79	2990
HSA-MIR-5007-3P	99.51	68.14	1242
HSA-MIR-365A-3P	99.43	70.02	836
HSA-MIR-365B-3P	99.43	70.02	836
HSA-MIR-3199	99.17	65.19	696
HSA-MIR-4292	99.16	65.57	1767
HSA-MIR-6791-5P	99.16	65.92	1844
HSA-MIR-6814-5P	99.03	66.68	1273
HSA-MIR-6887-5P	98.56	68.49	1295
HSA-MIR-6795-5P	98.52	68.51	1277
HSA-MIR-4722-5P	98.46	66.34	1611
HSA-MIR-2278	97.30	66.19	1130
HSA-MIR-4749-3P	96.40	66.24	798
HSA-MIR-3918	96.13	64.65	1300

Functional genomics

gnomAD constraint: pLI 0.0668, LOEUF 0.568, missense Z 2.5 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000262186 splits into 7 regions with different missense tolerance; 1 is missense-constrained (≈2% of the expected missense variation). Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
7:150,945,368–150,948,527	457 / 416.1	1.10	no
7:150,948,528–150,951,065	159 / 282.5	0.56	no
7:150,951,066–150,951,453	5 / 30.1	0.17	yes (p 4.9e-06)
7:150,951,454–150,952,771	147 / 344.4	0.43	no
7:150,952,772–150,959,629	392 / 429.9	0.91	no
7:150,959,630–150,977,859	85 / 174.7	0.49	no
7:150,977,860–150,977,913	29 / 25.2	1.15	no
ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• the trafficking-deficient pore mutation HERG G601S was rescued by a series of HERG channel blockers that increased cell surface expression. Rescue by these pharmacological chaperones varied directly with their blocking potency. (PMID:11741928)
• Patients with mutations in the pore region of the HERG gene are at markedly increased risk for arrhythmia-related cardiac events compared with patients with nonpore mutations (PMID:11854117)
• Mapping the binding site of a human ether-a-go-go-related gene-specific peptide toxin (ErgTx) to the channel’s outer vestibule (PMID:11864985)
• a key function of the C-terminal 104 amino acids is to mask the RGR ER retention signal, which becomes exposed when mutations truncate the HERG C terminus. (PMID:12021266)
• The common K897T polymorphism of the HERG channel is associated with the maximal duration and transmural dispersion of ventricular repolarization in middle-aged females. (PMID:12142119)
• identification of the residues that are important for the binding specificity to the scorpion toxin BeKm-1 (PMID:12151390)
• positioning of S6 aromatic residues relative to the central cavity of the channel, not inactivation per se determines drug block of HERG or eag channels (PMID:12209010)
• the cytoplasmic C terminus of HERG participates in the tethering or possibly targeting of HERG-containing vesicles within the Golgi via its interaction with GM130 (PMID:12270925)
• determination of relation of a PAS domain mutation in HERG to a trafficking deficiency at body temperature, apart from effects on channel deactivation (PMID:12354768)
• Description of a HERG isoform found in human and rabbit colon that has a functional role in smooth muscle (PMID:12427763)
• cell cycle dependent expression of isoforms in tumor cells (PMID:12431979)
• Three KCNH2 mutations, L413P, E444D and L559H were identified in long QT syndrome in China. (PMID:12442276)
• We conclude that normal HERG function in HEK293 cells requires basal activity of PKB. Our data represent the first evidence that PKB phosphorylation regulates K(+) channels (PMID:12527373)
• Different proximal amino-terminal domain sequences contribute to set HERG gating characteristics and its regulation by TRH (PMID:12560090)
• sustains a cardiac-type action potential in neuroblastoma S cells (PMID:12593854)
• The strong effects of Cs+ on inactivation but not on activation highlight the importance of ion and channel interactions during the onset of inactivation in the HERG channel. (PMID:12626667)
• Transcripts for HERG1 were present in all adenomas and although transcripts for HERG2 and HERG3 were also detected, their expression level was more variable. (PMID:12634931)
• Voltage-dependent profile of human ether-a-go-go-related gene channel block is influenced by a single residue in the S6 transmembrane domain. (PMID:12695533)
• gene expression; KCNH2 channels play a fundamental role in the control of motility patterns in human jejunum through their ability to modulate the electrical behavior of smooth muscle cells (PMID:12736144)
• procainamide inhibits the HERG K(+) channel by a primarily ‘open’ or ‘activated’ channel state blocking mechanism and that avidity of drug-binding is decreased by extensive I(HERG) inactivation (PMID:12804575)
• defective trafficking as a common mechanism for abnormal channel function resulting from mutations of critical COOH-terminal residues, including the long QT syndrome mutant HERGN861I (PMID:12885765)
• the amphipathic helix in the S5P linker interacts with the pore region of the channel in a voltage-dependent manner (PMID:12902341)
• erythromycin and clarithromycin significantly inhibit the HERG potassium current at clinically relevant concentrations (PMID:14674677)
• In 2 of 3 families with hereditary short-QT syndrome and a high incidence of ventricular arrhythmias and sudden cardiac death,we identified 2 different missense mutations in the cardiac IKr channel HERG (KCNH2). (PMID:14676148)
• HERG C-terminus mutations may have a role in with long QT syndrome (PMID:14714110)
• herg1 gene and HERG1 protein were expressed in a high percentage of primary human colorectal cancers, with the highest incidence occurring in metastatic cancers (PMID:14744775)
• that the TNF-alpha/TNFR1 system impairs HERG/I(Kr) function mainly by stimulating reactive oxygen species, particularly superoxide anion, but not by altering HERG expression (PMID:14973143)
• Four single nucleotide polymorphisms were identified in sudden infant death syndrome: K897T, P967L, R1047L, and Q1068R. (PMID:14975928)
• The KCNH2 A561T mutant channel revealed a post-translational defect that resulted in absence of the voltage-dependent delayed rectifier potassium current. (PMID:15120823)
• WT channels K525 stabilizes the closed state, R531 stabilizes the open state and R534 participates in interactions that stabilize pre-open closed states. (PMID:15181157)
• HERG channels are selectively involved in proliferation of distinct uterine cancer cells. (PMID:15202000)
• The NMR structure of gamma-KTx1.1 & critical residues for its binding to hERG channel were studied, showing a novel interaction between scorpion gamma-KTx & hERG channel, in which the toxin acts as a turret blocker over the channel’s outer vestibule. (PMID:15211519)
• Physiological role for PIP2 regulation of the rapidly activating delayed rectifier K+ current during autonomic stimulation and localize a site of interaction to the COOH-terminal tail of the HERG K+ channel. (PMID:15231497)
• native ventricular IKr channels are heteromers containing two alpha subunit types, ERG1a and -1b (PMID:15304481)
• T1945+6C is a disease-causing mutation. It alters KCNH2 splicing and cosegregates with the LQT2 phenotype. (PMID:15364333)
• Here we describe the mechanism by which both drugs block human Eag1 (hEag1) channels. (PMID:15365094)
• currents are modulated by alpha(1A)-adrenoceptors via protein kinases A and C (PMID:15365637)
• analysis of HERG channel function by dynamic action potential clamp technique (PMID:15475579)
• 1047L in leads KCNH2 to a functional impairment of the KCNH2 channel, which may contribute to the higher incidence of Torsades de Pointes in 1047L carriers when challenged with a channel blocker. (PMID:15522280)
• results define regions on the S4 domain voltage sensor that contribute differentially to hERG activation and inactivation gating (PMID:15528201)

Cross-species orthologs

15 orthologs

Organism	Symbol	Gene ID
danio_rerio	kcnh2a	ENSDARG00000029881
danio_rerio		ENSDARG00000106473
mus_musculus	Kcnh2	ENSMUSG00000038319
rattus_norvegicus	Kcnh2	ENSRNOG00000009872
drosophila_melanogaster	sei	FBGN0003353
drosophila_melanogaster	Elk	FBGN0011589
drosophila_melanogaster	CG6026	FBGN0038676
drosophila_melanogaster	CngA	FBGN0261612
drosophila_melanogaster	Cngl	FBGN0263257
drosophila_melanogaster	CngB	FBGN0266346
caenorhabditis_elegans		WBGENE00000487
caenorhabditis_elegans	tax-2	WBGENE00006525
caenorhabditis_elegans		WBGENE00006526
caenorhabditis_elegans		WBGENE00006830
caenorhabditis_elegans		WBGENE00022295

Paralogs (17): CNGB1 (ENSG00000070729), KCNH4 (ENSG00000089558), HCN2 (ENSG00000099822), CNGA4 (ENSG00000132259), KCNH3 (ENSG00000135519), HCN4 (ENSG00000138622), KCNH5 (ENSG00000140015), KCNH1 (ENSG00000143473), HCN3 (ENSG00000143630), CNGA3 (ENSG00000144191), HCN1 (ENSG00000164588), CNGB3 (ENSG00000170289), KCNH6 (ENSG00000173826), CNGA2 (ENSG00000183862), KCNH8 (ENSG00000183960), KCNH7 (ENSG00000184611), CNGA1 (ENSG00000198515)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1341722) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 1 distinct phenotype terms.

Mouse phenotype (MP)	Records
decreased heart rate	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Oryctolagus cuniculus	Q8WNY2	97.4%	Diamond
Bos taurus	O18965	96.9%	Diamond
Canis lupus familiaris	Q9TSZ3	96.2%	Diamond
Sus scrofa	Q9TUI4	96.0%	Diamond
Cavia porcellus	O08703	95.2%	Diamond
Pseudomonas syringae pv. syringae B728a	Q4ZSY3	92.7%	Diamond
Pseudomonas savastanoi pv. phaseolicola 1448A	Q48IV1	92.1%	Diamond
Arabidopsis thaliana	Q8W420	74.4%	Diamond
Gallus gallus	Q9PT84	61.4%	Diamond
Erythrobacter litoralis HTCC2594	Q2NB98	53.1%	Diamond
Rhizobium johnstonii 3841	Q1M667	52.7%	Diamond
Halobacterium salinarum NRC-1	Q9HPU8	47.5%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
AOC1	protein-coding	26
ATG9B	protein-coding	285973
TMEM176B	protein-coding	28959
NOS3	protein-coding	4846
TMEM176A	protein-coding	55365
ABCB8	protein-coding	11194
ASIC3	protein-coding	9311

Protein

Protein identifiers

Voltage-gated inwardly rectifying potassium channel KCNH2 — Q12809 (reviewed: Q12809)

Alternative names: Eag homolog, Ether-a-go-go-related gene potassium channel 1, Potassium voltage-gated channel subfamily H member 2, Voltage-gated potassium channel subunit Kv11.1

All UniProt accessions (5): A0A090N7X5, A0A090N8Q0, A0AAQ5BGQ9, A0AAQ5BGR0, Q12809

UniProt curated annotations — full annotation on UniProt →

Function. Pore-forming (alpha) subunit of voltage-gated inwardly rectifying potassium channel. Channel properties are modulated by cAMP and subunit assembly. Characterized by unusual gating kinetics by producing relatively small outward currents during membrane depolarization and large inward currents during subsequent repolarization which reflect a rapid inactivation during depolarization and quick recovery from inactivation but slow deactivation (closing) during repolarization. Forms a stable complex with KCNE1 or KCNE2, and that this heteromultimerization regulates inward rectifier potassium channel activity. Has no inward rectifier potassium channel activity by itself, but modulates channel characteristics by forming heterotetramers with other isoforms which are retained intracellularly and undergo ubiquitin-dependent degradation. Has no inward rectifier potassium channel activity by itself, but modulates channel characteristics by forming heterotetramers with other isoforms which are retained intracellularly and undergo ubiquitin-dependent degradation.

Subunit / interactions. The potassium channel is probably composed of a homo- or heterotetrameric complex of pore-forming alpha subunits that can associate with modulating beta subunits. Interacts with DNAJB12 and DNAJB14; chaperones DNAJB12 and DNAJB14 promote tetramerization. Heteromultimer with KCNH6/ERG2 and KCNH7/ERG3. Interacts with ALG10B. Forms a stable complex with KCNE1 or KCNE2, and that this heteromultimerization regulates inward rectifier potassium channel activity. Interacts with CANX. The core-glycosylated, but not the fully glycosylated form interacts with RNF207. Interacts with NDFIP1 and NDFIP2; this interaction decreases the cell membrane expression by targeting KCNH2, through interaction with NEDD4L, for the degradation through the multivesicular bodies (MVBs)-lysosomal pathway.

Subcellular location. Cell membrane.

Tissue specificity. Highly expressed in heart and brain. Isoforms USO are frequently overexpressed in cancer cells.

Post-translational modifications. Phosphorylated on serine and threonine residues. Phosphorylation by PKA inhibits ion conduction.

Disease relevance. Long QT syndrome 2 (LQT2) [MIM:613688] 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. Deafness is often associated with long QT syndrome type 2. The disease is caused by variants affecting the gene represented in this entry. Short QT syndrome 1 (SQT1) [MIM:609620] A 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.

Domain organisation. The S4-S5 linker acts as a signal integrator where it both couples voltage-sensor domain (VSD) movement to pore opening and closure, as well as providing a binding site for other domains that regulate activation and/or deactivation of the channel.

Induction. Up-regulated by RNF207 (at protein level).

Miscellaneous. Twice more abundant than isoform 1 in heart. Primate-specific. Lacks a domain that is crucial for slow channel deactivation.

Similarity. Belongs to the potassium channel family. H (Eag) (TC 1.A.1.20) subfamily. Kv11.1/KCNH2 sub-subfamily.

Isoforms (6)

UniProt ID	Names	Canonical?
Q12809-1	A, KCNH2-1A	yes
Q12809-2	B, HERG1B
Q12809-4	4
Q12809-5	A-USO, HERG1USO
Q12809-6	B-USO, HERG1BUSO
Q12809-7	3.1, KCNH2-3.1

RefSeq proteins (7): NP_000229, NP_001393682, NP_001393684, NP_001393685, NP_001393686, NP_742053, NP_742054 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000014	PAS	Domain
IPR000595	cNMP-bd_dom	Domain
IPR000700	PAS-assoc_C	Domain
IPR001610	PAC	Repeat
IPR003938	K_chnl_volt-dep_EAG/ELK/ERG	Family
IPR003967	K_chnl_volt-dep_ERG	Family
IPR005821	Ion_trans_dom	Domain
IPR014710	PpnP-like_jellyroll	Homologous_superfamily
IPR018490	cNMP-bd_dom_sf	Homologous_superfamily
IPR035965	PAS-like_dom_sf	Homologous_superfamily
IPR050818	KCNH_animal-type	Family

Pfam: PF00027, PF00520, PF13426

Catalyzed reactions (Rhea)

• K(+)(in) = K(+)(out) (RHEA:29463)

UniProt features (382 total): sequence variant 269, helix 30, strand 19, mutagenesis site 14, modified residue 10, topological domain 8, splice variant 7, transmembrane region 6, region of interest 5, compositionally biased region 4, turn 3, domain 2, chain 1, intramembrane region 1, coiled-coil region 1, short sequence motif 1, glycosylation site 1

Structure

Experimental structures (PDB)

24 structures by resolution:

PDB	Title	Method	Resolution (Å)
6SYG	Crystal structure of the Cyclic Nucleotide-Binding Homology Domain of the human KCNH2 …	X-RAY DIFFRACTION	1.5
4HQA	Crystal structure of PAS domain from the human ERG (hERG) potassium channel	X-RAY DIFFRACTION	1.96
4HP9	Crystal structure of the N-terminal truncated PAS domain from the hERG potassium channel	X-RAY DIFFRACTION	2.12
1BYW	STRUCTURE OF THE N-TERMINAL DOMAIN OF THE HUMAN-ERG POTASSIUM CHANNEL	X-RAY DIFFRACTION	2.6
9CHQ	Cryo-EM structure of the human ether-a-go-go related K+ channel (hERG) in 3 mM K+	ELECTRON MICROSCOPY	3
8ZYQ	Cryo-EM Structure of pimozide-bound hERG Channel	ELECTRON MICROSCOPY	3.18
8ZYP	Cryo-EM Structure of E-4031-bound hERG Channel	ELECTRON MICROSCOPY	3.19
8ZYN	Cryo-EM Structure of inhibitor-free hERG Channel	ELECTRON MICROSCOPY	3.27
8ZYO	Cryo-EM Structure of astemizole-bound hERG Channel	ELECTRON MICROSCOPY	3.29
9CHP	Cryo-EM structure of the human ether-a-go-go related K+ channel (hERG) in 300 mM K+	ELECTRON MICROSCOPY	3.3
9CHS	Cryo-EM structure of the human ether-a-go-go related K+ channel (hERG) in 3 mM K+ without …	ELECTRON MICROSCOPY	3.4
8IO4	Herg1a-herg1b open state	ELECTRON MICROSCOPY	3.5
9CHR	Cryo-EM structure of the human ether-a-go-go related K+ channel (hERG) in 300 mM K+ …	ELECTRON MICROSCOPY	3.5
5VA1	Cryo-EM structure of the human ether-a-go-go related K+ channel	ELECTRON MICROSCOPY	3.7
5VA2	Cryo-EM structure of the human ether-a-go-go related K+ channel	ELECTRON MICROSCOPY	3.8
8IO5	Herg1a-herg1b closed state 2	ELECTRON MICROSCOPY	3.8
8IOB	Herg1a-herg1b closed state 1	ELECTRON MICROSCOPY	3.9
5VA3	Cryo-EM structure of the human ether-a-go-go related K+ channel	ELECTRON MICROSCOPY	4
1UJL	Solution Structure of the HERG K+ channel S5-P extracellular linker	SOLUTION NMR
2L0W	Solution NMR structure of the N-terminal PAS domain of HERG potassium channel	SOLUTION NMR
2L1M	Solution structure of the eag domain of the hERG (Kv11.1) K+ channel	SOLUTION NMR
2L4R	NMR solution structure of the N-terminal PAS domain of hERG	SOLUTION NMR
2LE7	Solution nmr structure of the S4S5 linker of herg potassium channel	SOLUTION NMR
2N7G	Structure of the cyclic nucleotide-binding homology domain of the hERG channel	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q12809-F1	63.94	0.29

Human Protein Atlas

Protein class: Transporters, Transporter channels and pores, Voltage-gated ion channels, Voltage-Gated Potassium Channels, Predicted membrane proteins, Plasma proteins, Disease related genes, FDA approved drug targets, Small molecule drugs, Human disease related genes

Protein evidence: Evidence at protein level

Functional residue map

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

Post-translational modifications (10)

Type	Positions
Phosphoserine	239, 243, 283, 284, 320, 351, 871, 874, 1137
Omega-n-methylarginine	1014

Glycosylation sites (1)

Type	Positions
N-linked (glcnac…) asparagine	598

Mutagenesis-validated functional residues (14)

Position	Phenotype
29	slows down deactivation.
43	slows down deactivation.
283	abolishes phosphorylation; when associated with a-890; a-895 and a-1137.
540	does not affect steady-state activation. significantly slow the activation rate at the most depolarised potentials. accelerates the …
543	increases the activation rate more rapidly at high voltages.
546	slows the activation rate.
548	perturbs steady-state activation. accelerates the activation rate at the most depolarised potentials. affects modestly the activation rate …
550	slows the activation rate at low voltage gradients. increases the activation rate more rapidly at high voltages.
598	no effect on cell surface expression, but changes inactivation kinetics; when associated with a-631.
629	abolishes cell surface expression; has no effect on n-glycosylation.
631	no effect on cell surface expression, but changes inactivation kinetics; when associated with q-598.
890	abolishes phosphorylation; when associated with a-283; a-895 and a-1137.
895	abolishes phosphorylation; when associated with a-283; a-890 and a-1137.
1137	abolishes phosphorylation; when associated with a-283; a-890 and a-895.

Function

Pathways and Gene Ontology

Reactome pathways

2 curated (TAS) of 6; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

6 pathways:

ID	Pathway	Evidence
R-HSA-5576890	Phase 3 - rapid repolarisation	curated
R-HSA-1296072	Voltage gated Potassium channels	curated
R-HSA-5576891	Cardiac conduction	—
R-HSA-397014	Muscle contraction	—
R-HSA-112316	Neuronal System	—
R-HSA-1296071	Potassium Channels	—

MSigDB gene sets: 375 (showing top): GOBP_POTASSIUM_ION_TRANSPORT, GGGACCA_MIR133A_MIR133B, RNGTGGGC_UNKNOWN, GOBP_MEMBRANE_DEPOLARIZATION, GOBP_NEGATIVE_REGULATION_OF_TRANSMEMBRANE_TRANSPORT, TAATAAT_MIR126, GOBP_CIRCULATORY_SYSTEM_PROCESS, REACTOME_VOLTAGE_GATED_POTASSIUM_CHANNELS, REACTOME_POTASSIUM_CHANNELS, PEREZ_TP63_TARGETS, GCANCTGNY_MYOD_Q6, GOBP_MEMBRANE_DEPOLARIZATION_DURING_ACTION_POTENTIAL, MODULE_64, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_DN, GOCC_CELL_SURFACE

GO Biological Process (27): regulation of heart rate by hormone (GO:0003064), potassium ion transport (GO:0006813), regulation of membrane potential (GO:0042391), positive regulation of DNA-templated transcription (GO:0045893), potassium ion homeostasis (GO:0055075), cardiac muscle contraction (GO:0060048), regulation of membrane repolarization (GO:0060306), regulation of ventricular cardiac muscle cell membrane repolarization (GO:0060307), cellular response to xenobiotic stimulus (GO:0071466), potassium ion transmembrane transport (GO:0071805), ventricular cardiac muscle cell action potential (GO:0086005), membrane repolarization (GO:0086009), membrane depolarization during action potential (GO:0086010), membrane repolarization during action potential (GO:0086011), membrane repolarization during cardiac muscle cell action potential (GO:0086013), regulation of heart rate by cardiac conduction (GO:0086091), potassium ion export across plasma membrane (GO:0097623), membrane repolarization during ventricular cardiac muscle cell action potential (GO:0098915), regulation of potassium ion transmembrane transport (GO:1901379), negative regulation of potassium ion transmembrane transport (GO:1901380), positive regulation of potassium ion transmembrane transport (GO:1901381), negative regulation of potassium ion export across plasma membrane (GO:1903765), potassium ion import across plasma membrane (GO:1990573), monoatomic ion transport (GO:0006811), monoatomic ion transmembrane transport (GO:0034220), transmembrane transport (GO:0055085), monoatomic cation transmembrane transport (GO:0098655)

GO Molecular Function (12): transcription cis-regulatory region binding (GO:0000976), inward rectifier potassium channel activity (GO:0005242), voltage-gated potassium channel activity (GO:0005249), delayed rectifier potassium channel activity (GO:0005251), ubiquitin protein ligase binding (GO:0031625), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), 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 (7): plasma membrane (GO:0005886), voltage-gated potassium channel complex (GO:0008076), cell surface (GO:0009986), perinuclear region of cytoplasm (GO:0048471), inward rectifier potassium channel complex (GO:1902937), membrane (GO:0016020), monoatomic ion channel complex (GO:0034702)

Reactome top-level categories

4 top-level categories:

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

GO top-level categories

showing 60 of 62 GO namespaces:

Category	Terms
potassium ion transmembrane transport	3
cellular anatomical structure	3
regulation of membrane potential	2
membrane repolarization	2
ventricular cardiac muscle cell membrane repolarization	2
action potential	2
voltage-gated potassium channel activity	2
protein binding	2
regulation of heart rate by chemical signal	1
metal ion transport	1
monoatomic ion transmembrane transport	1
regulation of biological quality	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
monoatomic cation homeostasis	1
inorganic ion homeostasis	1
striated muscle contraction	1
heart contraction	1
regulation of biological process	1
regulation of cardiac muscle cell membrane repolarization	1
response to xenobiotic stimulus	1
cellular response to chemical stimulus	1
potassium ion transport	1
monoatomic cation transmembrane transport	1
cardiac muscle cell action potential involved in contraction	1
membrane depolarization	1
cardiac muscle cell action potential	1
membrane repolarization during action potential	1
cardiac muscle cell membrane repolarization	1
regulation of heart rate	1
cardiac conduction	1
export across plasma membrane	1
ventricular cardiac muscle cell action potential	1
membrane repolarization during cardiac muscle cell action potential	1
regulation of potassium ion transport	1
regulation of monoatomic cation transmembrane transport	1
negative regulation of potassium ion transport	1
regulation of potassium ion transmembrane transport	1
negative regulation of cation transmembrane transport	1
transcription regulatory region nucleic acid binding	1
sequence-specific double-stranded DNA binding	1
ligand-gated monoatomic cation channel activity	1
potassium channel activity	1
voltage-gated monoatomic cation channel activity	1
ubiquitin-like protein ligase binding	1
identical protein binding	1
protein dimerization activity	1
voltage-gated potassium channel activity involved in cardiac muscle cell action potential repolarization	1
membrane repolarization during ventricular cardiac muscle cell action potential	1
monoatomic ion transmembrane transporter activity	1
channel activity	1
monoatomic cation channel activity	1
potassium ion transmembrane transporter activity	1
binding	1
membrane	1
cell periphery	1
potassium channel complex	1
plasma membrane protein complex	1
cytoplasm	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 36 of 46 annotations. The rest are phylogenetic / computational / electronic (IEA).

36 experimentally-supported GO terms:

GO term	NS	Evidence
cardiac muscle contraction	BP	mutant phenotype
cellular response to xenobiotic stimulus	BP	direct assay
membrane depolarization during action potential	BP	direct assay
membrane repolarization	BP	mutant phenotype
membrane repolarization during action potential	BP	direct assay
membrane repolarization during cardiac muscle cell action potential	BP	mutant phenotype
membrane repolarization during ventricular cardiac muscle cell action potential	BP	mutant phenotype
negative regulation of potassium ion export across plasma membrane	BP	direct assay
negative regulation of potassium ion transmembrane transport	BP	direct assay
positive regulation of DNA-templated transcription	BP	mutant phenotype
positive regulation of potassium ion transmembrane transport	BP	direct assay
potassium ion export across plasma membrane	BP	direct assay
potassium ion homeostasis	BP	direct assay
potassium ion import across plasma membrane	BP	direct assay
potassium ion transmembrane transport	BP	direct assay
potassium ion transport	BP	direct assay
regulation of heart rate by cardiac conduction	BP	mutant phenotype
regulation of membrane potential	BP	direct assay
regulation of membrane repolarization	BP	direct assay
regulation of potassium ion transmembrane transport	BP	direct assay
regulation of ventricular cardiac muscle cell membrane repolarization	BP	mutant phenotype
ventricular cardiac muscle cell action potential	BP	mutant phenotype
cell surface	CC	direct assay
inward rectifier potassium channel complex	CC	mutant phenotype
perinuclear region of cytoplasm	CC	mutant phenotype
plasma membrane	CC	direct assay
voltage-gated potassium channel complex	CC	direct assay
delayed rectifier potassium channel activity	MF	direct assay
identical protein binding	MF	physical interaction
inward rectifier potassium channel activity	MF	direct assay
protein homodimerization activity	MF	physical interaction
scaffold protein binding	MF	physical interaction
transcription cis-regulatory region binding	MF	direct assay
ubiquitin protein ligase binding	MF	physical interaction
voltage-gated potassium channel activity	MF	direct assay
voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization	MF	mutant phenotype

Protein interactions and networks

STRING

showing 15 of 1,580 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KCNH2	KCNE1	P15382	979
KCNH2	KCNE2	Q9Y6J6	978
KCNH2	KCNQ1	P51787	974
KCNH2	SCN5A	Q14524	971
KCNH2	KCNA3	P22001	940
KCNH2	KCNJ2	P48049	934
KCNH2	CACNA1C	Q13936	866
KCNH2	KCNE3	Q9Y6H6	848
KCNH2	A0A1W2PPA2	A0A1W2PPA2	816
KCNH2	SCN4B	Q8IWT1	805
KCNH2	CAV3	P56539	790
KCNH2	AKAP9	Q99996	784
KCNH2	KCND3	Q9UK17	771
KCNH2	KCNA5	P22460	759
KCNH2	KCNJ5	P48544	758

IntAct

Human interaction partners of KCNH2 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

6 partners by confidence:

Partner	Interaction type	MIscore	Records
CAV1	physical association	0.440	5
PASK	phosphorylation reaction	0.440	1
KLHDC10	association	0.350	1
ARHH	physical association	0.000	1
CDC73	physical association	0.000	1
NDUFS6	physical association	0.000	1

BioGRID (71 interactions; top human partners by supporting records): TRIOBP (Two-hybrid; 6 records), HSP90AA1 (Affinity Capture-Western; 5 records), FKBP8 (Affinity Capture-MS; 3 records), HSPA4 (Affinity Capture-Western; 3 records), KCND3 (Co-localization; 3 records), RNF207 (Affinity Capture-Western; 3 records), YWHAE (Reconstituted Complex; 3 records), CANX (Affinity Capture-Western; 2 records), CAV3 (Affinity Capture-Western; 2 records), HSPA8 (Affinity Capture-Western; 2 records), NEDD4L (Affinity Capture-Western; 2 records), RAB11A (Affinity Capture-Western; 2 records), STUB1 (Affinity Capture-Western; 2 records), ALG10B (Affinity Capture-Western), ANKRD13D (Affinity Capture-MS)

SIGNOR signaling

showing 11 of 15 signaling interactions:

A	Effect	B	Mechanism
cisapride	“down-regulates activity”	KCNH2	“chemical inhibition”
Terfenadine	“down-regulates activity”	KCNH2	“chemical inhibition”
NEDD4	“down-regulates quantity by destabilization”	KCNH2	ubiquitination
PRKD1	“down-regulates activity”	KCNH2	phosphorylation
KCNH2	“up-regulates activity”	ITGB1	binding
ITGB1	“up-regulates activity”	KCNH2	binding
NEDD4L	“down-regulates quantity by destabilization”	KCNH2	ubiquitination
MINK1	up-regulates	KCNH2	binding
PRKACA	up-regulates	KCNH2	phosphorylation
PTPN6	down-regulates	KCNH2	dephosphorylation
3-(dibutylamino)-1-[1,3-dichloro-6-(trifluoromethyl)-9-phenanthrenyl]-1-propanol	“down-regulates activity”	KCNH2	“chemical inhibition”

Protein complexes (CORUM) (4)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

4 complexes by size:

Complex	Subunits	Members
★ KCNH2-YWHAE complex	2	YWHAE, KCNH2
★ KCNE1-KCNH2 complex	2	KCNE1, KCNH2
★ KCNE2-KCNH2 complex	2	KCNH2, KCNE2
★ SIGMAR1-KCNH2 complex	2	KCNH2, SIGMAR1

Disease & clinical

Genetic variants

Variant evidence for KCNH2: 3,920 ClinVar records (693 pathogenic / likely pathogenic); 4 PharmGKB clinical annotations; 59 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

3,920 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	498
Likely pathogenic	195
Uncertain significance	1531
Likely benign	1054
Benign	57

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 693 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
67248	NM_000238.4(KCNH2):c.1714G>A (p.Gly572Ser)	Pathogenic	criteria provided, multiple submitters, no conflicts	13
29777	NM_000238.4(KCNH2):c.1841C>T (p.Ala614Val)	Pathogenic	criteria provided, multiple submitters, no conflicts	11
67225	NM_000238.4(KCNH2):c.1655T>C (p.Leu552Ser)	Pathogenic	criteria provided, multiple submitters, no conflicts	11
180383	NM_000238.4(KCNH2):c.2230C>T (p.Arg744Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	11
200672	NM_000238.4(KCNH2):c.2775dup (p.Pro926fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	10
200693	NM_000238.4(KCNH2):c.2959_2960del (p.Leu987fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	10
14432	NM_000238.4(KCNH2):c.2453C>T (p.Ser818Leu)	Pathogenic	criteria provided, multiple submitters, no conflicts	9
67315	NM_000238.4(KCNH2):c.1886A>G (p.Asn629Ser)	Pathogenic	criteria provided, multiple submitters, no conflicts	8
200518	NM_000238.4(KCNH2):c.3040C>T (p.Arg1014Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	8
220208	NM_000238.4(KCNH2):c.2587C>T (p.Arg863Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	8
14424	NM_000238.4(KCNH2):c.2464G>A (p.Val822Met)	Pathogenic	criteria provided, multiple submitters, no conflicts	7
67281	NM_000238.4(KCNH2):c.1810G>A (p.Gly604Ser)	Pathogenic	criteria provided, multiple submitters, no conflicts	7
67323	NM_000238.4(KCNH2):c.1898A>G (p.Asn633Ser)	Pathogenic	criteria provided, multiple submitters, no conflicts	7
200513	NM_000238.4(KCNH2):c.3002G>A (p.Trp1001Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	7
503669	NM_000238.4(KCNH2):c.453dup (p.Thr152fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	6

Per-variant reference — Sugi Variant

Explore KCNH2’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 34 predictions of 1,489):

Position(s)	Effect	Δscore	Sites
7:150946875–150946876	donor_loss	1.0000	3
7:150947326–150947327	donor_loss	1.0000	5
7:150948855	donor_loss	1.0000
7:150949050–150949051	acceptor_loss	1.0000	3
7:150949058–150949059	acceptor_gain	1.0000	2
7:150950919–150950920	donor_loss	1.0000	5
7:150951446–150951447	donor_loss	1.0000	5
7:150951834	acceptor_gain	1.0000
7:150951836–150951837	acceptor_loss	1.0000	4
7:150957289–150957290	donor_loss	1.0000	5

AlphaMissense

3,640 missense substitutions predicted likely pathogenic (of 7,508 scored), across 712 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M645	9	0.989	1.000
M60	9	0.970	0.998
M651	9	0.968	1.000
M677	9	0.963	0.999
M554	9	0.949	0.999
M713	9	0.939	0.998
D411	8	1.000	1.000
D466	8	1.000	1.000
D501	8	1.000	1.000
D460	8	0.999	1.000
F463	8	0.999	1.000
F656	8	0.999	1.000
N658	8	0.998	1.000
F720	8	0.998	1.000
D727	8	0.998	1.000
F508	8	0.997	1.000
F557	8	0.997	1.000
H562	8	0.997	1.000
H687	8	0.997	1.000
H703	8	0.997	0.999

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

1 prognostic cancer types:

Cancer	Prognostic	p-value
Lung Adenocarcinoma (TCGA)	favorable	0.000321

Disease associations

OMIM: gene MIM:152427 | disease phenotypes: MIM:613688, MIM:192500, MIM:609620, MIM:617047, MIM:616100, MIM:192600

GenCC curated gene-disease

4 curated gene-disease records:

Disease	Classification	Inheritance	Records
short QT syndrome type 1	Definitive	Autosomal dominant	3
long QT syndrome 2	Definitive	Autosomal dominant	3
Brugada syndrome	Moderate	Autosomal dominant	2
short QT syndrome	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity

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

3 validity classifications:

Disease	Classification	Inheritance
long QT syndrome	Definitive	AD
short QT syndrome	Definitive	AD
Brugada syndrome	Disputed	AD

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (6 panels, 5 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

6 panels:

Panel	Rating
Cardiac arrhythmias	green
Long QT syndrome	green
Short QT syndrome	green
Sudden unexplained death or survivors of a cardiac event	green
Unexplained death in infancy and sudden unexplained death in childhood	green
Fetal anomalies	amber

Mondo (12): long QT syndrome (MONDO:0002442), long QT syndrome 2 (MONDO:0013367), cardiac rhythm disease (MONDO:0007263), familial long QT syndrome (MONDO:0019171), obesity disorder (MONDO:0011122), short QT syndrome type 1 (MONDO:0012312), long QT syndrome 1 (MONDO:0100316), short QT syndrome (MONDO:0000453), hypertrophic cardiomyopathy 26 (MONDO:0014883), autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency (MONDO:0014493), familial hypertrophic cardiomyopathy (MONDO:0024573), Brugada syndrome (MONDO:0015263)

Orphanet (9): Romano-Ward syndrome (Orphanet:101016), Congenital long QT syndrome (Orphanet:768), Congenital short QT syndrome (Orphanet:51083), Obesity due to melanocortin 4 receptor deficiency (Orphanet:71529), Familial isolated restrictive cardiomyopathy (Orphanet:75249), Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsuffiency (Orphanet:436159), Rare familial disorder with hypertrophic cardiomyopathy (Orphanet:99739), NON RARE IN EUROPE: Non rare obesity (Orphanet:521399), NON RARE IN EUROPE: Familial isolated hypertrophic cardiomyopathy (Orphanet:155)

HPO phenotypes

19 phenotypes (HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0001279	Syncope
HP:0001645	Sudden cardiac death
HP:0001657	Prolonged QT interval
HP:0001662	Bradycardia
HP:0001663	Ventricular fibrillation
HP:0001664	Torsade de pointes
HP:0001678	Atrioventricular block
HP:0001695	Cardiac arrest
HP:0001962	Palpitations
HP:0003581	Adult onset
HP:0004308	Ventricular arrhythmia
HP:0004757	Paroxysmal atrial fibrillation
HP:0005110	Atrial fibrillation
HP:0005184	Prolonged QTc interval
HP:0011463	Childhood onset
HP:0012232	Shortened QT interval
HP:0025708	Early young adult onset
HP:0034303	Notched T wave

GWAS associations

showing 30 of 59 associations:

Study	Trait	p-value
GCST010919_12	QT interval	7e-51
GCST002500_37	QT interval	1e-49
GCST002500_38	QT interval	3e-33
GCST010346_42	TPE interval (resting)	4e-23
GCST010796_5302	Electrocardiogram morphology (amplitude at temporal datapoints)	3e-21
GCST010796_5363	Electrocardiogram morphology (amplitude at temporal datapoints)	6e-21
GCST010796_5362	Electrocardiogram morphology (amplitude at temporal datapoints)	7e-21
GCST010796_5366	Electrocardiogram morphology (amplitude at temporal datapoints)	8e-21
GCST010796_5361	Electrocardiogram morphology (amplitude at temporal datapoints)	2e-20
GCST010796_5365	Electrocardiogram morphology (amplitude at temporal datapoints)	3e-20
GCST010796_5364	Electrocardiogram morphology (amplitude at temporal datapoints)	4e-20
GCST010796_5360	Electrocardiogram morphology (amplitude at temporal datapoints)	9e-20
GCST010796_5359	Electrocardiogram morphology (amplitude at temporal datapoints)	1e-19
GCST010796_5367	Electrocardiogram morphology (amplitude at temporal datapoints)	2e-19
GCST010796_5358	Electrocardiogram morphology (amplitude at temporal datapoints)	3e-19
GCST010796_5357	Electrocardiogram morphology (amplitude at temporal datapoints)	2e-18
GCST007218_13	QT interval	5e-18
GCST010796_5370	Electrocardiogram morphology (amplitude at temporal datapoints)	1e-17
GCST010796_5368	Electrocardiogram morphology (amplitude at temporal datapoints)	2e-17
GCST010796_5369	Electrocardiogram morphology (amplitude at temporal datapoints)	3e-17
GCST010796_5356	Electrocardiogram morphology (amplitude at temporal datapoints)	4e-17
GCST010796_5371	Electrocardiogram morphology (amplitude at temporal datapoints)	5e-17
GCST000363_11	QT interval	5e-16
GCST010796_5355	Electrocardiogram morphology (amplitude at temporal datapoints)	6e-16
GCST000363_12	QT interval	8e-16
GCST000364_3	QT interval	2e-15
GCST010796_5354	Electrocardiogram morphology (amplitude at temporal datapoints)	2e-15
GCST010796_5372	Electrocardiogram morphology (amplitude at temporal datapoints)	2e-15
GCST007293_143	Body fat distribution (arm fat ratio)	3e-15
GCST010796_5373	Electrocardiogram morphology (amplitude at temporal datapoints)	3e-15

EFO canonical traits (from GWAS)

9 canonical traits:

EFO ID	Trait name
EFO:0004682	QT interval
EFO:0004327	electrocardiography
EFO:0009959	diverticular disease
EFO:0004341	body fat distribution
EFO:0008328	chronotype measurement
EFO:0004340	body mass index
EFO:0008398	T wave morphology measurement
EFO:0000195	metabolic syndrome
EFO:0004644	TPE interval measurement

MeSH disease descriptors

6 disease descriptors:

Descriptor	Name	Tree numbers
D053840	Brugada Syndrome	C14.280.067.322; C14.280.123.250; C16.320.100
D024741	Cardiomyopathy, Hypertrophic, Familial	C14.280.238.100.500; C14.280.484.048.750.070.160.500; C16.320.160
D008133	Long QT Syndrome	C14.280.067.565; C14.280.123.625; C16.131.240.400.715; C23.550.073.547
C563614	Long Qt Syndrome 2 *(supp.)*
C566506	Short QT Syndrome 1 *(supp.)*
C580439	Short Qt Syndrome *(supp.)*

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (3): CHEMBL2362996 (PROTEIN FAMILY), CHEMBL240 (SINGLE PROTEIN), CHEMBL4106188 (SELECTIVITY GROUP)

Drugs by curated mechanism of action (ChEMBL)

Drugs whose curated ChEMBL mechanism of action targets the KCNH2 protein itself — single-protein targets only (drugs acting on a protein family or complex that merely includes it are excluded). Includes antibodies and oligonucleotides that bioactivity screening does not capture.

7 curated-mechanism drugs:

Drug	Modality	Max phase
AMIODARONE HYDROCHLORIDE	Small molecule	4
DOFETILIDE	Small molecule	4
IBUTILIDE FUMARATE	Small molecule	4
SOTALOL HYDROCHLORIDE	Small molecule	4
VERNAKALANT HYDROCHLORIDE	Small molecule	4
AZD1305	Small molecule	2
AZD7009	Small molecule	2

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 407,078 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

showing 60 of 706 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL633	AMIODARONE	4	30,023
CHEMBL473	DOFETILIDE	4	7,527
CHEMBL533	IBUTILIDE	4	49
CHEMBL2107383	VERNAKALANT HYDROCHLORIDE	4	116
CHEMBL3301610	ABEMACICLIB	4	7,497
CHEMBL397420	ACENOCOUMAROL	4	6,968
CHEMBL1085	ACETOPHENAZINE	4	5,157
CHEMBL551466	ACLIDINIUM BROMIDE	4	248
CHEMBL752	ADENOSINE PHOSPHATE	4	166,120
CHEMBL1173655	AFATINIB	4	15,878
CHEMBL1483	ALBENDAZOLE	4	19,210
CHEMBL709	ALFUZOSIN	4	6,651
CHEMBL1505	ALMOTRIPTAN	4	7,500
CHEMBL1110	ALOSETRON	4	10,895
CHEMBL54349	ALPIDEM	4	1,703
CHEMBL1652	AMBENONIUM	4	1,748
CHEMBL1200732	AMCINONIDE	4	16,276
CHEMBL243712	AMISULPRIDE	4	10,675
CHEMBL629	AMITRIPTYLINE	4	53,007
CHEMBL1491	AMLODIPINE	4	39,830
CHEMBL682	AMODIAQUINE	4
CHEMBL489411	AMOROLFINE	4
CHEMBL1113	AMOXAPINE	4
CHEMBL43	AMSACRINE	4
CHEMBL1186610	ANISOTROPINE	4
CHEMBL1305	ANTAZOLINE	4
CHEMBL53	APOMORPHINE	4
CHEMBL1112	ARIPIPRAZOLE	4
CHEMBL4208229	ASCIMINIB	4
CHEMBL3187365	ASENAPINE	4
CHEMBL296419	ASTEMIZOLE	4
CHEMBL641	ATOMOXETINE	4
CHEMBL1360	ATRACURIUM	4
CHEMBL2103883	AVATROMBOPAG	4
CHEMBL946	AZATADINE	4
CHEMBL639	AZELASTINE	4
CHEMBL46740	BAZEDOXIFENE	4
CHEMBL376488	BEDAQUILINE	4
CHEMBL400599	BENFLUOREX	4
CHEMBL1200	BENOXINATE	4
CHEMBL297302	BENPERIDOL	4
CHEMBL3545985	BENZPHETAMINE	4
CHEMBL1201203	BENZTROPINE	4
CHEMBL12610	BENZYDAMINE	4
CHEMBL1008	BEPRIDIL	4
CHEMBL295124	BERBERINE	4
CHEMBL512351	BETRIXABAN	4
CHEMBL1023	BEXAROTENE	4
CHEMBL277535	BIFONAZOLE	4
CHEMBL1101	BIPERIDEN	4
CHEMBL290106	BITHIONOL	4
CHEMBL288441	BOSUTINIB	4
CHEMBL253376	BROMHEXINE	4
CHEMBL28218	BROMPERIDOL	4
CHEMBL811	BROMPHENIRAMINE	4
CHEMBL1201271	BUCLIZINE	4
CHEMBL188921	BUFLOMEDIL	4
CHEMBL1098	BUPIVACAINE	4
CHEMBL1200396	BUPIVACAINE HYDROCHLORIDE	4
CHEMBL511142	BUPRENORPHINE	4

PharmGKB: 1 entry (CPIC guideline: no)

PharmGKB clinical annotations

4 annotations by evidence level (1 strongest → 4):

Variant	Association	Level	Drugs	Phenotypes
rs104894021	Efficacy	3	disopyramide	short qt syndrome 1
rs104894021	Efficacy	3	quinidine	short qt syndrome 1
rs1137617	Efficacy	3	Calcium channel blockers;nitrendipine	Essential hypertension
rs12720441	Toxicity	3	amiodarone	Torsades de Pointes

PharmGKB variants

3 variants:

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1137617	KCNH2	3	2.25	1	Calcium channel blockers;nitrendipine
rs12720441	KCNH2	3	0.00	1	amiodarone
rs104894021	KCNH2	3	0.00	2	disopyramide;quinidine

PharmGKB variant annotations

Per-publication pharmacogenomic findings for this gene (significant associations).

14 published findings:

Variant	Drug(s)	Category	Finding	PMID
rs104894021	disopyramide	Efficacy	Allele C is associated with decreased inhibition of KCNH2 when exposed to disopyramide as compared to allele G.	PMID:16842817
rs104894021	disopyramide	Efficacy	Allele T is associated with decreased inhibition of KCNH2 when exposed to disopyramide as compared to allele G.	PMID:16842817
rs104894021	quinidine	Efficacy	Allele C is associated with decreased inhibition of KCNH2 when exposed to quinidine as compared to allele G.	PMID:16842817
rs104894021	quinidine	Efficacy	Allele T is associated with decreased inhibition of KCNH2 when exposed to quinidine as compared to allele G.	PMID:16842817
rs3807372	escitalopram	Toxicity	Genotype AA is associated with increased likelihood of Acquired Long QT Syndrome (aLQTS) when treated with escitalopram as compared to genotypes AG + GG.	PMID:38000475
rs1805123		Other	Allele T is associated with increased likelihood of Atrial Fibrillation.	PMID:18222980
rs3807375		Other	Genotypes CT + TT are associated with increased QT interval as compared to genotype CC.	PMID:17709632
rs1805123		Other	Genotypes GT + TT are associated with increased QT interval as compared to genotype GG.	PMID:17709632
rs3815459		Other	Allele T is associated with increased QT interval.	PMID:17534376
rs3815459		Other	Allele T is associated with increased QT interval as compared to genotype CC.	PMID:15746444
rs1805123		Other	Genotype GG is associated with decreased QT interval as compared to genotypes GT + TT.	PMID:15746444
rs1805123		Other	Allele G is associated with decreased QT interval as compared to genotype TT.	PMID:19019189
rs3807375		Other	Allele T is associated with increased QT interval as compared to allele C.	PMID:19019189
rs1137617	Calcium channel blockers, nitrendipine	Efficacy	Genotypes AA + AG are associated with increased reduction in blood pressure when treated with calcium channel blockers or nitrendipine in people with Essential hypertension as compared to genotype GG.	PMID:23613831

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 (28 total), top 25:

Ligand	Action	Affinity	Parameter
astemizole	Channel blocker	9.0	pIC50
ErgTx-1	Channel blocker	8.3	pKd
BeKm-1	Channel blocker	8.2	pKd
dofetilide	Inhibition	8.19	pKi
E4031	Channel blocker	8.1	pIC50
ibutilide	Channel blocker	8.0	pIC50
γ-KTx1.7	Channel blocker	7.9	pKd
APETx-1	Inhibition	7.5	pIC50
halofantrine	Inhibition	7.4	pIC50
cisapride	Channel blocker	7.4	pIC50
terfenadine	Channel blocker	7.3	pIC50
rottlerin	Activation	6.5	pEC50
ginsenoside Rg3	Activation	6.4	pEC50
ICA-105574	Activation	6.3	pEC50
PF-04885614	Inhibition	5.74	pIC50
nemiralisib	Inhibition	5.5	pIC50
LUF7244	Negative	5.41	pIC50
danuglipron	Inhibition	5.03	pIC50
NS1643	Activation	5.0	pEC50
VU0405601	Activation	5.0	pEC50
KB-130015	Activation	4.9	pEC50
zorifertinib	Inhibition	4.88	pIC50
AZD3778	Inhibition	4.8	pIC50
MK-7145	Inhibition	4.66	pIC50
DA-302168S	Inhibition	4.52	pIC50

Binding affinities (BindingDB)

4538 measured of 5688 human assays (6100 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
N-[3-[(3R)-5-amino-3,6,6-trimethyl-1,1-dioxo-2H-1,4-thiazin-3-yl]-4-fluorophenyl]-5-methoxypyrazine-2-carboxamide	IC50	0.0009 nM	US-9273042: 5-amino[1,4]thiazines as BACE 1 inhibitors
(4aR,6R,8aS)-8a-[2,4-difluoro-5-[(2,2,2-trifluoroethylamino)methyl]phenyl]-6-(fluoromethyl)-4a,5,6,8-tetrahydro-4H-pyrano[3,4-d][1,3]thiazin-2-amine	IC50	0.006 nM	US-9045498: Hexahydropyrano[3,4-d][1,3]thiazin-2-amine compounds
[O-methyl-11C]2-{4-[4-(7-methoxynaphthalen-1-yl)piperazin-1-yl]butyl}-4-methyl-2H-[1,2,4]triazine-3,5-dione	EC50	0.01 nM
2-[[2-ethyl-6-[4-[2-(3-hydroxyazetidin-1-yl)-2-oxoethyl]piperazin-1-yl]-8-methylimidazo[1,2-a]pyridin-3-yl]-methylamino]-4-(4-fluorophenyl)-1,3-thiazole-5-carbonitrile	IC50	0.01 nM	US-9670204: Compounds and pharmaceutical compositions thereof for the treatment of inflammatory disorders
N-[2-[(4aR,6S,8aR)-2-amino-6-methyl-4a,5,6,8-tetrahydro-4H-pyrano[3,4-d][1,3]thiazin-8a-yl]-1,3-thiazol-4-yl]-5-methoxypyridine-2-carboxamide	IC50	0.014 nM	US-9315520: 2-amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl-1,3-thiazol-4-yl amides
CHEMBL4088234	IC50	0.024 nM
6-Fluoro-3-(4-fluoro-piperidin-3-yl)-2-phenyl-1H-indole	KI	0.06 nM
N-(4-chloro-2-(5-chloropyridin-2-ylcarbamoyl)phenyl)-4-(N,N-dimethylcarbamimidoyl)-2-fluorobenzamide	KI	0.06 nM
CHEMBL3329814	KI	0.0794 nM
N-[(2S)-2-(diethylamino)propyl]-2-(5-thiophen-2-ylpyrazolo[1,5-a]pyrimidin-3-yl)pyridine-4-carboxamide	IC50	0.09 nM	US-10100058: Fused heterocyclic compounds as CaM kinase inhibitors
6-Fluoro-2-(4-fluoro-phenyl)-3-piperidin-3-yl-1H-indole	KI	0.09 nM
6-Fluoro-3-(4-fluoro-piperidin-3-yl)-1H-indole-2-carboxylic acid phenylamide	KI	0.09 nM
2-[((2R)-3-{[1,1-Dimethyl-2-(2-naphthalenyl)ethyl]amino}-2-hydroxypropyl)oxy]benzonitrile	IC50	0.1 nM
5-fluoro-1-(4-(3-(piperidin-1-yl)propoxy)phenyl)-2-(pyridin-2-yl)-1H-benzo[d]imidazole	KI	0.1 nM
CHEMBL3736358	KI	0.1 nM
6-Fluoro-3-(4-fluoro-piperidin-3-yl)-2-thiophen-3-yl-1H-indole	KI	0.11 nM
6-Fluoro-2-(4-fluoro-phenyl)-3-(4-fluoro-piperidin-3-yl)-1H-indole	KI	0.12 nM
5-{4-[4-(5-Cyano-1H-indol-3-yl)-butyl]-piperazin-1-yl}-benzofuran-2-carboxylic acid amide	EC50	0.12 nM
1-(6-(((S)-3-(4-fluorobenzyl) piperidin-1-yl)methyl)-3,5-dimethyl-2-oxo-1,3-oxazinan-5-yl)-3-(3-(1-methyl-1H-tetrazol-5-yl)phenyl)urea	IC50	0.12 nM
US8975415, 221	IC50	0.16 nM	US-9242973: Chromane compounds
CHEMBL3734774	KI	0.16 nM
(+/-)-(S)-1-{3-[4-(8-Methoxy-3-methyl-4,4-dioxo-3,4-dihydro-2H-4lambda*6*-benzo[1,4]oxathiin-2-yl)-phenoxy]-propyl}-3-methyl-piperidine	IC50	0.16 nM
CHEMBL3979322	IC50	0.18 nM
(E)-5-fluoro-2-(2-(5-(2-fluorophenylsulfonyl)pyridin-2-yl)vinyl)phenol	KI	0.19 nM
1-[(4R)-4-[3-(dimethylamino)propyl]-1-(2-fluoro-5-methylphenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-3-yl]ethan-1-one	IC50	0.2 nM
3-[3-[4-[dideuterio(methylamino)methyl]phenyl]isoxazol-5-yl]-5-(4-isopropylsulfonylphenyl)pyrazin-2-amine	IC50	0.2 nM
CHEMBL3233186	IC50	0.2 nM
CHEMBL3233188	IC50	0.2 nM
CHEMBL3394218	IC50	0.2 nM
CHEMBL3394226	IC50	0.2 nM
CHEMBL3394227	IC50	0.2 nM
N-(2-((dimethylamino)methyl)-4-(3-(piperidin-1-yl)propoxy)phenyl)quinazolin-4-amine	EC50	0.2 nM
CHEMBL4104464	EC50	0.2 nM
CHEMBL4078799	IC50	0.2 nM
(4-(3-(4H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)phenylsulfonyl)piperazin-1-yl)((1R,2R)-2-(4-(trifluoromethyl)phenyl)cyclopropyl)methanone	IC50	0.2 nM
(+/-)-(R)-1-{3-[4-(8-Methoxy-3-methyl-4,4-dioxo-3,4-dihydro-2H-4lambda*6*-benzo[1,4]oxathiin-2-yl)-phenoxy]-propyl}-2-methyl-pyrrolidine	IC50	0.21 nM
6-Fluoro-3-(4-fluoro-piperidin-3-yl)-2-naphthalen-2-yl-1H-indole	KI	0.23 nM
CHEMBL3577945	IC50	0.24 nM
CHEMBL3263286	IC50	0.25 nM
2-Cyclohexyl-6-fluoro-3-(4-fluoro-piperidin-3-yl)-1H-indole	KI	0.25 nM
N-(2-Benzoyl-phenyl)-4-[3-(3-piperidin-1-yl-propyl)-ureido]-benzenesulfonamide	KI	0.25 nM
3-(4-[(1-Cyclobutyl-4-piperidinyl)oxy]phenyl)-2,5-dimethyl-4(3H)-quinazolinone	IC50	0.27 nM
CHEMBL3354718	IC50	0.3 nM
CHEMBL3394216	IC50	0.3 nM
CHEMBL3394220	IC50	0.3 nM
CHEMBL3394221	IC50	0.3 nM
CHEMBL3394224	IC50	0.3 nM
CHEMBL3394225	IC50	0.3 nM
CHEMBL3394228	IC50	0.3 nM
CHEMBL3394211	IC50	0.3 nM

ChEMBL bioactivities

6100 potent at pChembl≥5 of 6100 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.68	IC50	0.021	nM	CHEMBL4595328
10.54	IC50	0.029	nM	CHEMBL327980
9.85	IC50	0.14	nM	CHEMBL5432371
9.85	IC50	0.14	nM	CHEMBL1257821
9.82	Ki	0.15	nM	CHEMBL5722941
9.74	IC50	0.18	nM	CHEMBL5722941
9.60	IC50	0.25	nM	CHEMBL1257820
9.59	IC50	0.26	nM	CHEMBL1257578
9.55	Ki	0.28	nM	CHEMBL3590463
9.42	IC50	0.38	nM	CHEMBL1257698
9.41	IC50	0.39	nM	CHEMBL3422978
9.41	Ki	0.39	nM	CHEMBL227134
9.40	Ki	0.4	nM	CHEMBL598270
9.39	IC50	0.41	nM	CHEMBL410832
9.37	IC50	0.43	nM	CHEMBL1257577
9.36	Kd	0.44	nM	CHEMBL3590463
9.32	IC50	0.48	nM	CHEMBL5858906
9.29	IC50	0.51	nM	CHEMBL5870278
9.29	IC50	0.51	nM	CHEMBL5794967
9.28	IC50	0.52	nM	CHEMBL6063759
9.28	IC50	0.52	nM	CHEMBL1257937
9.26	Ki	0.55	nM	CHEMBL1085090
9.25	Ki	0.56	nM	CHEMBL1085806
9.21	IC50	0.61	nM	CHEMBL1223951
9.21	IC50	0.62	nM	CHEMBL1257938
9.21	IC50	0.62	nM	CHEMBL1258280
9.19	IC50	0.65	nM	CHEMBL259732
9.19	IC50	0.65	nM	CHEMBL5956282
9.17	IC50	0.67	nM	CHEMBL1642479
9.16	IC50	0.69	nM	CHEMBL5944633
9.14	IC50	0.73	nM	CHEMBL3422952
9.14	Kd	0.73	nM	CHEMBL3590452
9.14	Ki	0.73	nM	CHEMBL1091775
9.14	IC50	0.72	nM	CHEMBL1258503
9.12	IC50	0.76	nM	CHEMBL2146867
9.09	IC50	0.81	nM	CHEMBL6009034
9.09	IC50	0.81	nM	CHEMBL1642487
9.06	IC50	0.87	nM	CHEMBL3422970
9.06	IC50	0.88	nM	CHEMBL5839811
9.05	IC50	0.89	nM	CHEMBL3422959
9.05	IC50	0.9	nM	ASTEMIZOLE
9.04	IC50	0.912	nM	ASTEMIZOLE
9.03	IC50	0.94	nM	CHEMBL4777139
9.02	IC50	0.95	nM	CHEMBL4171244
9.02	IC50	0.95	nM	CHEMBL1258725
9.00	IC50	1	nM	DESMETHEYLASTEMIZOLE
9.00	IC50	0.99	nM	CHEMBL3422977
9.00	IC50	1	nM	NAVACAPRANT
9.00	IC50	1	nM	CHEMBL5885156
8.96	IC50	1.1	nM	CHEMBL4457529

PubChem BioAssay actives

1982 with measured affinity, of 6100 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
N-[(4R,4aS,7S,7aR,12bS)-3-(cyclopropylmethyl)-4a,9-dihydroxy-1,2,4,5,6,7,7a,13-octahydro-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl]-1H-indole-7-carboxamide	1964636: Inhibition of human ERG expressed in CHO-K1 cells with holding potential of -80 mV by automated patch clamp assay	ic50	<0.0001	uM
2,6-diheptyl-1-methylpyridin-1-ium;trifluoromethanesulfonate	1234160: Displacement of [3H]dofetilide from human Kv11.1 expressed in HEK293 cell membranes by competitive radioligand displacement assay	ki	0.0003	uM
6-[[[1-[2-[7-(trifluoromethyl)-1,5-naphthyridin-4-yl]ethyl]-2-oxabicyclo[2.2.2]octan-4-yl]amino]methyl]-4H-pyrido[3,2-b][1,4]oxazin-3-one	1204043: Inhibition of MK499 binding to human ERG	ic50	0.0004	uM
6-[[[1-[2-[3-fluoro-7-(trifluoromethyl)-1,5-naphthyridin-4-yl]ethyl]-2-oxabicyclo[2.2.2]octan-4-yl]amino]methyl]-4H-pyrido[3,2-b][1,4]oxazin-3-one	1204043: Inhibition of MK499 binding to human ERG	ic50	0.0009	uM
2-methyl-8-[2-[4-[(3-oxo-4H-pyrido[3,2-b][1,4]oxazin-6-yl)methylamino]-2-oxabicyclo[2.2.2]octan-1-yl]ethyl]-1,5-naphthyridine-3-carbonitrile	1204043: Inhibition of MK499 binding to human ERG	ic50	0.0009	uM
methyl 2-hydroxy-3-[N-[4-[(2S)-2-[(4-methylpiperazin-1-yl)methyl]-5-oxopyrrolidin-1-yl]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylate	1504566: Inhibition of human ERG	ic50	0.0009	uM
6-[[[1-[2-[6-(trifluoromethyl)-1,5-naphthyridin-4-yl]ethyl]-2-oxabicyclo[2.2.2]octan-4-yl]amino]methyl]-4H-pyrido[3,2-b][1,4]oxazin-3-one	1204043: Inhibition of MK499 binding to human ERG	ic50	0.0010	uM
1-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine	1624462: Inhibition of human ERG expressed in HEK293 cells at 10 uM by Qpatch clamp assay	ic50	0.0010	uM
N-[1-(1,3-benzodioxol-5-ylmethyl)piperidin-4-yl]-6,7-dichloro-4-oxochromene-2-carboxamide	271871: Displacement of [3H]dofetilide from hERG	ic50	0.0014	uM
6-[[[1-[2-(6,7-dimethoxy-1,5-naphthyridin-4-yl)ethyl]-2-oxabicyclo[2.2.2]octan-4-yl]amino]methyl]-4H-pyrido[3,2-b][1,4]oxazin-3-one	1204043: Inhibition of MK499 binding to human ERG	ic50	0.0014	uM
methyl 2-hydroxy-3-[N-[4-[(2R)-2-[(4-methylpiperazin-1-yl)methyl]-5-oxopyrrolidin-1-yl]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylate	1504566: Inhibition of human ERG	ic50	0.0014	uM
2-methoxy-8-[2-[4-[(3-oxo-4H-pyrido[3,2-b][1,4]oxazin-6-yl)methylamino]-2-oxabicyclo[2.2.2]octan-1-yl]ethyl]-1,5-naphthyridine-3-carbonitrile	1204043: Inhibition of MK499 binding to human ERG	ic50	0.0016	uM
4-[(4-chlorophenyl)methoxy]-1-[4-(2-pyrrolidin-1-ylethoxy)phenyl]pyridin-2-one	551222: Displacement of [35S]N-[(4R)-10-[(2R)-6-cyano-1,2,3,4-tetrahydro-2-naphthyl]-3,4-dihydro-4-hydroxyspiro[2H-1-benzopyran-2,40-piperidin]-6-yl]methanesulfonamide from human ERG expressed in HEK293 cells	ic50	0.0017	uM
6-[[[1-[2-[3-fluoro-6-methoxy-7-(trifluoromethyl)-1,5-naphthyridin-4-yl]ethyl]-2-oxabicyclo[2.2.2]octan-4-yl]amino]methyl]-4H-pyrido[3,2-b][1,4]oxazin-3-one	1204043: Inhibition of MK499 binding to human ERG	ic50	0.0017	uM
3-methoxy-8-[2-[4-[(3-oxo-4H-pyrido[3,2-b][1,4]oxazin-6-yl)methylamino]-2-oxabicyclo[2.2.2]octan-1-yl]ethyl]-1,5-naphthyridine-2-carbonitrile	1204043: Inhibition of MK499 binding to human ERG	ic50	0.0020	uM
4-methyl-8-[2-[4-[(3-oxo-4H-pyrido[3,2-b][1,4]oxazin-6-yl)methylamino]-2-oxabicyclo[2.2.2]octan-1-yl]ethyl]-1,5-naphthyridine-2-carbonitrile	1204043: Inhibition of MK499 binding to human ERG	ic50	0.0021	uM
6-[[[1-[2-[6-(dimethylamino)-7-(trifluoromethyl)-1,5-naphthyridin-4-yl]ethyl]-2-oxabicyclo[2.2.2]octan-4-yl]amino]methyl]-4H-pyrido[3,2-b][1,4]oxazin-3-one	1204043: Inhibition of MK499 binding to human ERG	ic50	0.0023	uM
N-[1-(1,3-benzodioxol-5-ylmethyl)piperidin-4-yl]-7-bromo-4-oxochromene-2-carboxamide	271871: Displacement of [3H]dofetilide from hERG	ic50	0.0025	uM
6-[[[1-[2-(7-fluoro-6-methoxy-1,5-naphthyridin-4-yl)ethyl]-2-oxabicyclo[2.2.2]octan-4-yl]amino]methyl]-4H-pyrido[3,2-b][1,4]oxazin-3-one	1204043: Inhibition of MK499 binding to human ERG	ic50	0.0025	uM
methyl 2-hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylate	1504566: Inhibition of human ERG	ic50	0.0026	uM
2-(3-ethylpyrazol-1-yl)-1-[(2R)-2-(2-hydroxyethyl)-4-[2-(trifluoromethyl)-4-[2-(trifluoromethyl)pyrimidin-5-yl]-1,3-thiazol-5-yl]piperazin-1-yl]ethanone	1947871: Inhibition of human ERG stably expressed in CHO cells at -80 mV holding voltage by automated QPatch electrophysiological assay	ic50	0.0029	uM
6-[[[1-[2-(7-chloro-3-fluoro-1,5-naphthyridin-4-yl)ethyl]-2-oxabicyclo[2.2.2]octan-4-yl]amino]methyl]-4H-pyrido[3,2-b][1,4]oxazin-3-one	1204043: Inhibition of MK499 binding to human ERG	ic50	0.0033	uM
1-methyl-2,6-di(nonyl)pyridin-1-ium;trifluoromethanesulfonate	1234160: Displacement of [3H]dofetilide from human Kv11.1 expressed in HEK293 cell membranes by competitive radioligand displacement assay	ki	0.0034	uM
N-[1-(1,3-benzodioxol-5-ylmethyl)piperidin-4-yl]-7-chloro-4-oxochromene-2-carboxamide	271871: Displacement of [3H]dofetilide from hERG	ic50	0.0036	uM
N-[1-(1,3-benzodioxol-5-ylmethyl)piperidin-4-yl]-7-(difluoromethoxy)-4-oxochromene-2-carboxamide	271871: Displacement of [3H]dofetilide from hERG	ic50	0.0036	uM
N-[1-(1,3-benzodioxol-5-ylmethyl)piperidin-4-yl]-6-fluoro-4-oxochromene-2-carboxamide	271871: Displacement of [3H]dofetilide from hERG	ic50	0.0040	uM
6-[[[1-[2-(7-chloro-6-methoxy-1,5-naphthyridin-4-yl)ethyl]-2-oxabicyclo[2.2.2]octan-4-yl]amino]methyl]-4H-pyrido[3,2-b][1,4]oxazin-3-one	1204043: Inhibition of MK499 binding to human ERG	ic50	0.0042	uM
6-[[[1-[2-(2,6-dimethoxy-1,5-naphthyridin-4-yl)ethyl]-2-oxabicyclo[2.2.2]octan-4-yl]amino]methyl]-4H-pyrido[3,2-b][1,4]oxazin-3-one	1204043: Inhibition of MK499 binding to human ERG	ic50	0.0042	uM
2-(1-bromonaphthalen-2-yl)oxy-N-pyridin-3-ylacetamide	1264994: Binding affinity to Kv11.1 channel (unknown origin)	ki	0.0048	uM
6-[[[1-[2-(7-chloro-1,5-naphthyridin-4-yl)ethyl]-2-oxabicyclo[2.2.2]octan-4-yl]amino]methyl]-4H-pyrido[3,2-b][1,4]oxazin-3-one	1204043: Inhibition of MK499 binding to human ERG	ic50	0.0049	uM
N-[1-(1,3-benzodioxol-5-ylmethyl)piperidin-4-yl]-7-cyano-4-oxochromene-2-carboxamide	271871: Displacement of [3H]dofetilide from hERG	ic50	0.0050	uM
1-[(2R)-2-(2-hydroxyethyl)-4-[2-(trifluoromethyl)-4-[2-(trifluoromethyl)pyrimidin-5-yl]-1,3-thiazol-5-yl]piperazin-1-yl]-2-(3-methylpyrazol-1-yl)ethanone	1947871: Inhibition of human ERG stably expressed in CHO cells at -80 mV holding voltage by automated QPatch electrophysiological assay	ic50	0.0050	uM
6-[[[1-[2-(6-methoxy-8-methyl-1,5-naphthyridin-4-yl)ethyl]-2-oxabicyclo[2.2.2]octan-4-yl]amino]methyl]-4H-pyrido[3,2-b][1,4]oxazin-3-one	1204043: Inhibition of MK499 binding to human ERG	ic50	0.0052	uM
7-fluoro-N-[1-[(4-methoxyphenyl)methyl]piperidin-4-yl]-4-oxochromene-2-carboxamide	271871: Displacement of [3H]dofetilide from hERG	ic50	0.0054	uM
N-[1-[(2,2-difluoro-1,3-benzodioxol-5-yl)methyl]piperidin-4-yl]-7-fluoro-4-oxochromene-2-carboxamide	271871: Displacement of [3H]dofetilide from hERG	ic50	0.0056	uM
1-[(2R)-2-(2-hydroxyethyl)-4-[2-(trifluoromethyl)-4-[2-(trifluoromethyl)pyrimidin-5-yl]-1,3-thiazol-5-yl]piperazin-1-yl]-2-(3-propan-2-yl-1,2,4-triazol-1-yl)ethanone	1947871: Inhibition of human ERG stably expressed in CHO cells at -80 mV holding voltage by automated QPatch electrophysiological assay	ic50	0.0058	uM
1-[2-[4-[1-(4-fluorophenyl)indol-3-yl]piperidin-1-yl]ethyl]imidazolidine-2-thione	161283: Inhibition of K+ channel activity in CHO cells expressing HERG Kv11.1	ic50	0.0062	uM
N-[1-(1,3-benzodioxol-5-ylmethyl)piperidin-4-yl]-6,7-difluoro-4-oxochromene-2-carboxamide	271871: Displacement of [3H]dofetilide from hERG	ic50	0.0062	uM
(4-chlorophenyl)-[9-[(2-phenoxyphenyl)methyl]-3,9-diazaspiro[5.5]undecan-3-yl]methanone	317758: Displacement of [3H]dofetilide from human recombinant ERG potassium channel expressed in HEK293 cells by patch clamp method	ic50	0.0065	uM
6-[[[1-[2-(8-methyl-6-methylsulfonyl-1,5-naphthyridin-4-yl)ethyl]-2-oxabicyclo[2.2.2]octan-4-yl]amino]methyl]-4H-pyrido[3,2-b][1,4]oxazin-3-one	1204043: Inhibition of MK499 binding to human ERG	ic50	0.0067	uM
N-[1-(1,3-benzodioxol-5-ylmethyl)piperidin-4-yl]-4-oxochromene-2-carboxamide	271871: Displacement of [3H]dofetilide from hERG	ic50	0.0067	uM
1-[2-[4-[1-(4-fluorophenyl)indol-3-yl]piperidin-1-yl]ethyl]imidazolidin-2-one	576612: Inhibition of human ERG	ic50	0.0069	uM
1-[(2R)-2-methyl-4-[2-(trifluoromethyl)-4-[2-(trifluoromethyl)pyrimidin-5-yl]-1,3-thiazol-5-yl]piperazin-1-yl]-2-(3-propan-2-yl-1,2,4-triazol-1-yl)ethanone	1947871: Inhibition of human ERG stably expressed in CHO cells at -80 mV holding voltage by automated QPatch electrophysiological assay	ic50	0.0070	uM
(3S,4S)-8-[7-(2,3-dichlorophenyl)-5H-pyrrolo[2,3-b]pyrazin-3-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine	1614711: Inhibition of human ERG by Q-patch assay	ic50	0.0070	uM
2-(3-cyclopropyl-1,2,4-triazol-1-yl)-1-[(2R)-2-(2-hydroxyethyl)-4-[2-(trifluoromethyl)-4-[2-(trifluoromethyl)pyrimidin-5-yl]-1,3-thiazol-5-yl]piperazin-1-yl]ethanone	1947871: Inhibition of human ERG stably expressed in CHO cells at -80 mV holding voltage by automated QPatch electrophysiological assay	ic50	0.0073	uM
N-[1-(1,3-benzodioxol-5-ylmethyl)piperidin-4-yl]-7-ethyl-4-oxochromene-2-carboxamide	271871: Displacement of [3H]dofetilide from hERG	ic50	0.0074	uM
2-(3-tert-butyl-1,2,4-triazol-1-yl)-1-[(2R)-2-methyl-4-[2-(trifluoromethyl)-4-[2-(trifluoromethyl)pyrimidin-5-yl]-1,3-thiazol-5-yl]piperazin-1-yl]ethanone	1947871: Inhibition of human ERG stably expressed in CHO cells at -80 mV holding voltage by automated QPatch electrophysiological assay	ic50	0.0075	uM
ethyl 3-methoxy-8-[2-[4-[(3-oxo-4H-pyrido[3,2-b][1,4]oxazin-6-yl)methylamino]-2-oxabicyclo[2.2.2]octan-1-yl]ethyl]-1,5-naphthyridine-4-carboxylate	1204043: Inhibition of MK499 binding to human ERG	ic50	0.0079	uM
(3R)-3-[[4-[[(E)-3-(2,5-difluorophenyl)prop-2-enyl]amino]-2-oxabicyclo[2.2.2]octan-1-yl]methyl]-5-fluoro-3-hydroxy-1,7-diazatricyclo[6.3.1.04,12]dodeca-4(12),5,7,9-tetraen-11-one	1204682: Displacement of MK499 from human ERG	ic50	0.0080	uM
4-phenylmethoxy-1-[4-(2-pyrrolidin-1-ylethoxy)phenyl]pyridin-2-one	551222: Displacement of [35S]N-[(4R)-10-[(2R)-6-cyano-1,2,3,4-tetrahydro-2-naphthyl]-3,4-dihydro-4-hydroxyspiro[2H-1-benzopyran-2,40-piperidin]-6-yl]methanesulfonamide from human ERG expressed in HEK293 cells	ic50	0.0081	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Terfenadine	increases transport, decreases activity, affects binding, increases reaction, affects cotreatment (+1 more)	29
Astemizole	decreases reaction, increases degradation, decreases metabolic processing, increases transport, increases reaction (+3 more)	20
Cisapride	affects localization, affects binding, increases transport, decreases activity, decreases reaction	19
E 4031	decreases activity, increases reaction, increases transport, increases glycosylation, decreases reaction (+4 more)	17
Quinidine	decreases reaction, affects response to substance, increases reaction, affects activity, affects localization (+5 more)	16
dofetilide	affects binding, increases transport, increases reaction, affects reaction, affects cotreatment (+2 more)	15
Amiodarone	decreases reaction, increases transport, increases reaction, affects activity, affects binding (+1 more)	14
Potassium	increases reaction, decreases export, decreases expression, affects cotreatment, increases transport (+10 more)	11
Arsenic Trioxide	affects expression, increases activity, decreases activity, affects localization, decreases localization (+6 more)	9
Fluoxetine	affects localization, affects binding, decreases activity, decreases reaction, increases transport (+2 more)	6
Ketoconazole	affects cotreatment, increases reaction, decreases response to substance, affects activity, affects localization (+2 more)	6
Sotalol	decreases response to substance, decreases activity, decreases reaction, affects binding	6
Verapamil	decreases activity, decreases import, decreases reaction, increases transport	6
Loratadine	decreases activity, affects activity, affects binding, decreases reaction, increases transport (+1 more)	6
Haloperidol	decreases reaction, increases transport, decreases activity	5
Propafenone	decreases reaction, increases transport, affects activity, affects binding, decreases activity	5
Tamoxifen	decreases reaction, increases transport, decreases import, affects binding, decreases activity	5
nefazodone	affects activity, affects binding, decreases activity	4
Domperidone	affects response to substance, decreases reaction, increases transport, decreases activity	4
Doxorubicin	decreases expression, affects reaction, decreases response to substance	4
Erythromycin	affects reaction, decreases response to substance, affects binding, decreases activity	4
Imipramine	affects binding, decreases activity, decreases reaction, increases transport	4
Pimozide	increases transport, decreases activity, decreases reaction	4
Thallium	decreases reaction, increases transport, increases reaction, decreases activity, decreases import (+1 more)	4
Thioridazine	decreases reaction, increases transport, decreases activity	4
Bepridil	decreases activity, decreases reaction, increases transport, affects binding	4
sertindole	decreases reaction, increases transport, decreases activity	3
azimilide	decreases activity, decreases reaction, increases reaction	3
fexofenadine	decreases expression, increases degradation, decreases reaction, increases activity	3
Sunitinib	decreases activity	3

ChEMBL screening assays

4851 unique, capped per target: 3558 binding, 1071 toxicity, 169 functional, 53 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1787442	Binding	Inhibition of human recombinant Kv channel at 10 uM by radioligand binding assay	Structure-activity relationships of pyrrole based S-nitrosoglutathione reductase inhibitors: pyrrole regioisomers and propionic acid replacement. — *Bioorg Med Chem Lett*
CHEMBL5522525	Toxicity	Inhibition of human K+ channel by automated electrophysiology	Discovery of Clinical Candidate AZD5462, a Selective Oral Allosteric RXFP1 Agonist for Treatment of Heart Failure. — *J Med Chem*
CHEMBL1614368	ADMET	PUBCHEM_BIOASSAY: Dosage response for compounds that protect hERG from block by proarrhythmic agents using manual patch clamp. (Class of assay: confirmatory) [Related pubchem assays: 1680 (Summary assay for hERG assays.), 1511 (Primary HTS	PubChem BioAssay data set

Cellosaurus cell lines

49 cell lines: 34 induced pluripotent stem cell, 5 transformed cell line, 4 embryonic stem cell, 3 spontaneously immortalized cell line, 2 cancer cell line, 1 finite cell line

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

Cellosaurus	Name	Category	Sex
CVCL_1N94	GM25305	Induced pluripotent stem cell	Female
CVCL_9S61	UKKi009-A	Induced pluripotent stem cell	Female
CVCL_9S62	UKKi009-B	Induced pluripotent stem cell	Female
CVCL_A4JN	UMGi120-A.7	Induced pluripotent stem cell	Male
CVCL_A4JP	UMGi120-A.8	Induced pluripotent stem cell	Male
CVCL_A4JQ	UMGi120-A.15	Induced pluripotent stem cell	Male
CVCL_A7KP	SCVIi009-A	Induced pluripotent stem cell	Female
CVCL_A7KQ	SCVIi010-A	Induced pluripotent stem cell	Male
CVCL_A7KR	SCVIi011-A	Induced pluripotent stem cell	Female
CVCL_A9XX	WAe009-A-43	Embryonic stem cell	Female

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

showing 60 of 334 trials:

NCT	Phase	Status	Title
NCT00702117	Phase 4	COMPLETED	Ajmaline Utilization in the Diagnosis and Treatment of Cardiac Arrhythmias
NCT02513940	Phase 4	COMPLETED	Influence of Testosterone Administration on Drug-Induced QT Interval Prolongation and Torsades de Pointes
NCT03834883	Phase 4	COMPLETED	Reducing the Risk of Drug-Induced QT Interval Lengthening in Women
NCT04169100	Phase 4	UNKNOWN	Novel Form of Acquired Long QT Syndrome
NCT04675788	Phase 4	COMPLETED	Novel Approaches for Minimizing Drug-Induced QT Interval Lengthening
NCT00146822	Phase 4	COMPLETED	REFLEx Study (ENDOTAK RELIANCE G Evaluation of Handling and Electrical Performance
NCT00187239	Phase 4	COMPLETED	Reduce Ventricular Pacing in Dual Chamber Implantable Cardioverter Defibrillators Using AutoIntrinsic Conduction Search Study
NCT00247533	Phase 4	UNKNOWN	Cerebral Artery Stenosis, Coronary Artery Disease and Arrhythmia
NCT00282620	Phase 4	UNKNOWN	Magnesium to Reduce Implantable Cardioverter Defibrillator (ICD) Shocks and Improve Patient’s Quality of Life.
NCT00290056	Phase 4	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	Phase 4	COMPLETED	Concentrations of Amiodarone in Fat Tissue During Chronic Treatment
NCT00457340	Phase 4	COMPLETED	Atorvastatin For The Reduction Of Ventricular Arrhythmias
NCT00507390	Phase 4	WITHDRAWN	Omega 3 Polyunsaturated Fatty Acid Supplements (PUFAs) and Microvolt T Wave Alternans (TWA) in Patients With Ventricular Arrhythmia
NCT00575523	Phase 4	COMPLETED	Atropine for Prevention of Dysrhythmias Caused by Percutaneous Ethanol Instillation for Hepatoma Therapy
NCT00579098	Phase 4	COMPLETED	The Use of Statins Following a Left Atrial Catheter Ablation Procedure to Prevent Atrial Fibrillation
NCT01613092	Phase 4	COMPLETED	Prevention of Arrhythmia Device Infection Trial (PADIT)
NCT01628666	Phase 4	COMPLETED	Prevention of Arrhythmia Device Infection Trial (PADIT)
NCT01717469	Phase 4	UNKNOWN	Safety and the Effects of Isolated Left Ventricular Pacing in Patients With Bradyarrhythmias
NCT01819064	Phase 4	COMPLETED	Heart Rate Response to Atropine Doses Less Than 0.1mg IV to Anesthetized Infants
NCT01834872	Phase 4	UNKNOWN	Safety and Feasibility of Arrhythmia Ablation Using the Amigo Remote Robotic System as Compared With Manual Ablation
NCT01841242	Phase 4	COMPLETED	Comparison of Alcoholic Chlorhexidine 2% Versus Alcoholic Povidone Iodine for Infections Prevention With Cardiac Resynchronization Therapy Device Implantation
NCT01991223	Phase 4	UNKNOWN	Dexmedetomidine for Catheter-related Bladder Discomfort
NCT02045173	Phase 4	COMPLETED	Automate Detection of Sleep Apnea by ApneascanTM
NCT02203630	Phase 4	TERMINATED	Phenylephrine Versus Norepinephrine for Septic Shock in Critically Ill Patients
NCT03273634	Phase 4	COMPLETED	The Effect of Proton Pump Inhibition on Palpitations
NCT03289429	Phase 4	UNKNOWN	Antiarrhythmic and Cardioprotective Effects of Atorvastatin Versus Magnesium Sulfate in Cardiac Valve Replacement Surgery
NCT03895411	Phase 4	UNKNOWN	Efficacy and Safety of Sotalol in Children With Arrhythmia
NCT05486377	Phase 4	COMPLETED	Remimazolam vs Desflurane for General Anesthesia for Ablation of Arrhythmia
NCT06574555	Phase 4	COMPLETED	Norepinephrine ED90 Bolus After Spinal Anesthesia in Cesarean Section
NCT07617376	Phase 4	RECRUITING	Pre-discharge Influenza Vaccination in Patients Hospitalized for Acute Cardiac Conditions
NCT00701077	Phase 3	TERMINATED	DAPERB 3,4-DiAminoPyridine and Electrophysiological Response in Brugada Syndrome
NCT00927732	Phase 3	TERMINATED	Hydroquinidine Versus Placebo in Patients With Brugada Syndrome
NCT00000464	Phase 3	COMPLETED	Cardiac Arrest in Seattle: Conventional Versus Amiodarone Drug Evaluation (CASCADE)
NCT00000476	Phase 3	COMPLETED	Digitalis Investigation Group (DIG)
NCT00000480	Phase 3	COMPLETED	Multicenter Unsustained Tachycardia Trial (MUSTT)
NCT00000492	Phase 3	COMPLETED	Beta-Blocker Heart Attack Trial (BHAT)
NCT00000502	Phase 3	COMPLETED	Evaluation of SC-V Versus Conventional CPR
NCT00000517	Phase 3	COMPLETED	Boston Area Anticoagulation Trial for Atrial Fibrillation (BAATAF)
NCT00000518	Phase 3	COMPLETED	Electrophysiologic Study Versus Electrocardiographic Monitoring (ESVEM)
NCT00000531	Phase 3	COMPLETED	Antiarrhythmics Versus Implantable Defibrillators (AVID)
NCT00000540	Phase 3	COMPLETED	Coronary Artery Bypass Graft (CABG) Patch Trial
NCT00000556	Phase 3	COMPLETED	Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM)
NCT00000561	Phase 3	COMPLETED	Mode Selection Trial in Sinus Node Dysfunction (MOST)
NCT00000609	Phase 3	COMPLETED	Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT)
NCT00004559	Phase 3	COMPLETED	Fatty Acid Antiarrhythmia Trial (FAAT)
NCT00004560	Phase 3	COMPLETED	Public Access Defibrillation (PAD) Community Trial
NCT00035490	Phase 3	COMPLETED	Efficacy and Safety Evaluation of Azimilide Dihydrochloride in Patients With Implantable Cardioverter Defibrillators
NCT00098137	Phase 3	COMPLETED	Trial to Investigate the Efficacy of Olmesartan in Paroxysmal Atrial Fibrillation
NCT00110838	Phase 3	COMPLETED	SOFA: Study on Omega-3 Fatty Acids and Ventricular Arrhythmia
NCT00116428	Phase 3	COMPLETED	NAVISTAR® THERMOCOOL® Catheter for the Radiofrequency Ablation of Symptomatic Paroxysmal Atrial Fibrillation
NCT00624520	Phase 3	TERMINATED	Mental Stress Reduction in Defibrillator Patients
NCT00721149	Phase 3	TERMINATED	NAVISTAR® THERMOCOOL® Catheter for the Radiofrequency Ablation of Symptomatic Paroxysmal Atrial Fibrillation- Treatment Use Study
NCT00751738	Phase 3	COMPLETED	Long Term Safety of 125 mg Per Day of Oral Azimilide in Patients With Implantable Cardioverter Defibrillator (ICDs)
NCT01385202	Phase 3	COMPLETED	THERMOCOOL® SMARTTOUCH™ Catheter for the Treatment of Symptomatic Paroxysmal Atrial Fibrillation
NCT01951079	Phase 3	UNKNOWN	Intra Amniotic Injection of DIGOXIN for Feticide in Second Trimester Termination of Pregnancy
NCT03021343	Phase 3	COMPLETED	Effect of Colchicine on the Incidence of Atrial Fibrillation in Open Heart Surgery Patients
NCT02933437	Phase 2	UNKNOWN	The Response To Ajmaline Provocation in Healthy Subjects
NCT07146880	Phase 2	NOT_YET_RECRUITING	Empagliflozin as a Potential Therapeutic Solution for Patients With Brugada Syndrome
NCT01648205	Phase 2	COMPLETED	Long-term Efficacy Study of Sodium Channel Blocker in LQT3 Patients
NCT02412709	Phase 2	UNKNOWN	Long QT Syndrome Screening in Newborns

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for KCNH2 across ~30M SureChEMBL compounds — explore on Sugi Predict.