KCNH7

Summary

KCNH7 (potassium voltage-gated channel subfamily H member 7, HGNC:18863) is a protein-coding gene on chromosome 2q24.2, encoding Voltage-gated inwardly rectifying potassium channel KCNH7 (Q9NS40). Pore-forming (alpha) subunit of voltage-gated inwardly rectifying potassium channel.

Voltage-gated potassium (Kv) channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. This gene encodes a member of the potassium channel, voltage-gated, subfamily H. This member is a pore-forming (alpha) subunit. There are at least two alternatively spliced transcript variants derived from this gene and encoding distinct isoforms.

Source: NCBI Gene 90134 — RefSeq curated summary.

At a glance

• Gene–disease (curated): epilepsy (Limited, GenCC)
• GWAS associations: 14
• Clinical variants (ClinVar): 109 total
• Regional missense constraint (gnomAD): 2 of 8 regions constrained (≈9% of expected missense variation)
• GTEx eGene: eQTL in 4 tissues, sQTL in 0 (q < 0.05)
• Constraint (gnomAD): pLI 0.91 (loss-of-function intolerant), LOEUF 0.50 (moderately constrained)
• MANE Select transcript: NM_033272
• Notable: 109 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18863
Approved symbol	KCNH7
Name	potassium voltage-gated channel subfamily H member 7
Location	2q24.2
Locus type	gene with protein product
Status	Approved
Aliases	Kv11.3, HERG3, erg3
Ensembl gene	ENSG00000184611
Ensembl biotype	protein_coding
OMIM	608169
Entrez	90134

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 3 protein_coding, 1 protein_coding_CDS_not_defined

MANE Select: ENST00000332142

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

ENST00000332142, ENST00000328032, ENST00000477019, ENST00001138593

RefSeq mRNA: 2 — MANE Select: NM_033272 NM_033272, NM_173162

CCDS: CCDS2219, CCDS2220

Canonical transcript exons

ENST00000332142 — 16 exons

Exon	Start	End
ENSE00001297884	162394389	162394485
ENSE00001298151	162446018	162446443
ENSE00001299106	162379853	162380021
ENSE00001299408	162423336	162423535
ENSE00001305842	162836537	162836767
ENSE00001307236	162371407	162372095
ENSE00001316282	162384688	162384939
ENSE00001316605	162435198	162435597
ENSE00001317374	162400189	162400441
ENSE00001320476	162396740	162396945
ENSE00001322934	162838443	162838767
ENSE00001324813	162536925	162537080
ENSE00001325992	162512654	162512674
ENSE00001330536	162373470	162373662
ENSE00003524600	162504443	162504657
ENSE00003636659	162517730	162518158

Expression profiles

Bgee: expression breadth broad, 90 present calls, max score 88.23.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.8970 / max 88.8407, expressed in 171 samples.

Highest expression (Bgee): male germ line stem cell (sensu Vertebrata) in testis, pancreatic ductal cell, ventricular zone, ganglionic eminence, tibialis anterior.

Genetic regulation across tissues (GTEx eQTL / sQTL)

KCNH7 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 4 tissues and its splicing (sQTL) in 0 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

4 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Brain Cerebellum	eqtl	9.6e-29	-0.83	2:162976417:C:T
Brain Cerebellar Hemisphere	eqtl	9.6e-23	-0.69	2:162979505:T:C
Heart Atrial Appendage	eqtl	2.5e-03	+0.49	2:162851919:T:C
Artery Tibial	eqtl	7.2e-03	-0.24	2:162453904:C:T

FANTOM5 promoters

6 alternative TSS:

Promoter ID	TPM avg	Samples expressed
31568	0.3888	115
31567	0.2146	87
31566	0.1405	71
31570	0.1043	41
31569	0.0383	23
31563	0.0105	2

Top tissues by expression

showing 100 of 224 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	88.23	gold quality
pancreatic ductal cell	CL:0002079	78.82	gold quality
ventricular zone	UBERON:0003053	77.72	gold quality
ganglionic eminence	UBERON:0004023	76.87	gold quality
tibialis anterior	UBERON:0001385	74.00	gold quality
cortical plate	UBERON:0005343	70.78	gold quality
islet of Langerhans	UBERON:0000006	67.17	gold quality
prefrontal cortex	UBERON:0000451	64.61	gold quality
ileal mucosa	UBERON:0000331	63.92	gold quality
blood	UBERON:0000178	62.41	gold quality
corpus callosum	UBERON:0002336	61.45	gold quality
deltoid	UBERON:0001476	57.88	silver quality
epithelial cell of pancreas	CL:0000083	56.93	silver quality
frontal cortex	UBERON:0001870	55.73	gold quality
neocortex	UBERON:0001950	54.55	gold quality
cardiac muscle of right atrium	UBERON:0003379	54.34	gold quality
left ventricle myocardium	UBERON:0006566	54.23	gold quality
kidney epithelium	UBERON:0004819	53.93	gold quality
upper arm skin	UBERON:0004263	53.52	gold quality
left testis	UBERON:0004533	53.34	gold quality
Brodmann (1909) area 46	UBERON:0006483	53.29	silver quality
buccal mucosa cell	CL:0002336	53.20	silver quality
upper leg skin	UBERON:0004262	53.10	gold quality
testis	UBERON:0000473	52.68	gold quality
right testis	UBERON:0004534	52.46	gold quality
spleen	UBERON:0002106	51.79	gold quality
adrenal tissue	UBERON:0018303	51.71	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	50.74	gold quality
leukocyte	CL:0000738	50.39	silver quality
myocardium	UBERON:0002349	50.25	gold quality
skin of hip	UBERON:0001554	50.18	silver quality
cerebral cortex	UBERON:0000956	50.05	gold quality
monocyte	CL:0000576	49.85	silver quality
Brodmann (1909) area 9	UBERON:0013540	49.57	gold quality
primary visual cortex	UBERON:0002436	49.13	gold quality
right hemisphere of cerebellum	UBERON:0014890	49.13	gold quality
anterior cingulate cortex	UBERON:0009835	48.91	gold quality
cerebellar cortex	UBERON:0002129	48.30	gold quality
quadriceps femoris	UBERON:0001377	48.08	gold quality
cerebellar hemisphere	UBERON:0002245	48.03	gold quality
cerebellum	UBERON:0002037	47.91	gold quality
right frontal lobe	UBERON:0002810	47.87	gold quality
bone marrow cell	CL:0002092	47.85	gold quality
vermiform appendix	UBERON:0001154	47.44	gold quality
granulocyte	CL:0000094	47.26	silver quality
superior frontal gyrus	UBERON:0002661	47.08	gold quality
nasal cavity epithelium	UBERON:0005384	47.03	gold quality
pancreas	UBERON:0001264	47.02	gold quality
liver	UBERON:0002107	46.96	gold quality
occipital lobe	UBERON:0002021	46.79	gold quality
popliteal artery	UBERON:0002250	46.59	gold quality
tibial artery	UBERON:0007610	46.59	gold quality
calcaneal tendon	UBERON:0003701	46.41	silver quality
caecum	UBERON:0001153	45.71	gold quality
vastus lateralis	UBERON:0001379	45.62	gold quality
brain	UBERON:0000955	45.60	gold quality
forebrain	UBERON:0001890	45.28	gold quality
right lung	UBERON:0002167	44.73	gold quality
sural nerve	UBERON:0015488	43.89	gold quality
bone marrow	UBERON:0002371	43.72	gold quality
amygdala	UBERON:0001876	43.57	gold quality
layer of synovial tissue	UBERON:0007616	43.55	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	43.37	gold quality
stomach	UBERON:0000945	43.33	gold quality
temporal lobe	UBERON:0001871	43.23	gold quality
duodenum	UBERON:0002114	43.13	silver quality
right lobe of liver	UBERON:0001114	42.70	silver quality
secondary oocyte	CL:0000655	42.57	gold quality
body of stomach	UBERON:0001161	42.55	gold quality
placenta	UBERON:0001987	42.39	silver quality
medial globus pallidus	UBERON:0002477	42.38	gold quality
cardiac atrium	UBERON:0002081	42.23	silver quality
left coronary artery	UBERON:0001626	42.10	gold quality
coronary artery	UBERON:0001621	41.86	gold quality
globus pallidus	UBERON:0001875	41.71	gold quality
colonic epithelium	UBERON:0000397	41.47	gold quality
right atrium auricular region	UBERON:0006631	41.47	silver quality
middle temporal gyrus	UBERON:0002771	41.38	gold quality
superficial temporal artery	UBERON:0001614	41.33	gold quality
hypothalamus	UBERON:0001898	41.28	gold quality
aorta	UBERON:0000947	41.15	gold quality
palpebral conjunctiva	UBERON:0001812	41.10	gold quality
mucosa of paranasal sinus	UBERON:0005030	40.98	gold quality
cartilage tissue	UBERON:0002418	40.77	gold quality
amniotic fluid	UBERON:0000173	40.69	gold quality
right coronary artery	UBERON:0001625	40.67	silver quality
jejunal mucosa	UBERON:0000399	40.59	gold quality
biceps brachii	UBERON:0001507	40.57	gold quality
epithelium of nasopharynx	UBERON:0001951	40.45	gold quality
gingival epithelium	UBERON:0001949	40.43	gold quality
adenohypophysis	UBERON:0002196	40.38	silver quality
multicellular organism	UBERON:0000468	40.35	gold quality
material anatomical entity	UBERON:0000465	40.34	gold quality
anatomical system	UBERON:0000467	40.33	gold quality
germinal epithelium of ovary	UBERON:0001304	40.33	gold quality
medulla oblongata	UBERON:0001896	40.33	gold quality
esophagus squamous epithelium	UBERON:0006920	40.29	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	40.27	gold quality
epithelium of mammary gland	UBERON:0003244	40.25	gold quality
jejunum	UBERON:0002115	40.18	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	59.77
E-ANND-3	yes	4.20

HPA expression

RNA tissue specificity: Tissue enhanced

45 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM
Cerebral cortex	tissue	85.1
Somatosensory cortex	tissue	85.1
Occipital cortex	tissue	69.0
Temporal cortex	tissue	61.3
Motor cortex	tissue	60.9
Retrosplenial and cingulate cortex	tissue	60.5
Prefrontal cortex	tissue	56.2
Hippocampal formation	tissue	55.9
Entorhinal cortex	tissue	55.9
Olfactory bulb	tissue	53.9
Retrosplenial cortex	tissue	45.6
Insular cortex	tissue	45.5
Postcentral gyrus	tissue	33.6
Amygdala	tissue	21.6
Frontal cortex	tissue	18.5
Superior colliculi	tissue	12.4
Ventral forebrain	tissue	11.9
Basal ganglia	tissue	11.5
Midbrain	tissue	11.5
Putamen	tissue	10.2
Pons	tissue	10.0
Thalamus	tissue	9.6
Hypothalamus	tissue	9.3
Medulla oblongata	tissue	9.1
Septum	tissue	8.7
Nucleus accumbens	tissue	7.2
Locus coeruleus	tissue	6.4
Periaqueductal gray	tissue	5.9
Substantia nigra	tissue	5.7
Corpus callosum	tissue	5.6
Caudate putamen	tissue	4.2
Spinal cord	tissue	3.6
Hippocampus	tissue	3.5
Cerebellum	tissue	2.5
Retina	tissue	1.4
Choroid plexus	tissue	1.0
Stomach 1	tissue	0.5
Liver	tissue	0.5
Testis	tissue	0.3
Seminal vesicle	tissue	0.2
Pituitary gland	tissue	0.1
Pancreas	tissue	0.1
Adrenal gland	tissue	0.1
Bone marrow	tissue	0.1
Appendix	tissue	0.1

Brain sub-regions (HPA Brain Atlas): detected in 189; highest nTPM — Subiculum (29.0), Posterior insular cortex (25.5), Dorsal hippocampus (24.7), Parieto-insular cortex (23.9), Temporal pole (23.8).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

Targeting KCNH7 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 83 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-552-5P	99.93	68.56	1583
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-605-3P	99.88	69.22	1833
HSA-MIR-4496	99.88	68.89	2236
HSA-MIR-3121-3P	99.82	71.96	3630

Functional genomics

gnomAD constraint: pLI 0.905, LOEUF 0.498, missense Z 3.84 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000332142 splits into 8 regions with different missense tolerance; 2 are missense-constrained (≈9% 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
2:162,371,832–162,396,817	406 / 410.5	0.99	no
2:162,396,818–162,423,393	101 / 176.3	0.57	no
2:162,423,394–162,435,308	24 / 105.8	0.23	yes (p 1.8e-15)
2:162,435,309–162,435,426	36 / 46.8	0.77	no
2:162,435,427–162,435,481	2 / 21.9	0.09	yes (p 2.1e-05)
2:162,435,482–162,446,381	109 / 196.8	0.55	no
2:162,446,382–162,836,565	362 / 372.2	0.97	no
2:162,836,566–162,838,518	57 / 116.2	0.49	no

Literature-anchored findings (GeneRIF, showing 9)

• 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)
• The recombinant wild-type ERG3 protein produced in HEK cells generates two prominent bands. When the entire CNBD of ERG3 protein was deleted, only an EndoH-sensitive band was generated, indicating that this band constitutes the immature species. (PMID:15961404)
• IFIH1 interferon induced helicase, GCA grancalcin or the potassium channel KCNH7 - are potential candidates implicated in the pathogenesis of multiple sclerosis. (PMID:18285833)
• IFIH1-GCA-KCNH7 locus is not associated with genetic susceptibility to multiple sclerosis in French patients (PMID:19156166)
• KCNH7 c.1181G>A had the highest enrichment among individuals with bipolar spectrum disorder (x2 5 7.3) and the strongest family-based association with bipolar 1 (P 5 0.021), bipolar spectrum (P 5 0.031) and any major affective disorder (P 5 0.016). (PMID:24986916)
• we have discovered that, the Kv11.3 (hERG3) a plasma-membrane potassium channel plays a critical role in the regulation of autophagy in a melanoma cell model (PMID:26942884)
• Low ERG3 expression is associated with epilepsy. (PMID:30016551)
• Discovery of a heme-binding domain in a neuronal voltage-gated potassium channel. (PMID:32723862)
• Potassium Ion Channel Protein (KCNH) Levels in Patients with Fibromyalgia Syndrome. (PMID:35818223)

Cross-species orthologs

14 orthologs

Organism	Symbol	Gene ID
danio_rerio	kcnh7a	ENSDARG00000062687
mus_musculus	Kcnh7	ENSMUSG00000059742
rattus_norvegicus	Kcnh7	ENSRNOG00000007528
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): KCNH2 (ENSG00000055118), 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), CNGA1 (ENSG00000198515)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:2159566) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 1 distinct phenotype terms.

Mouse phenotype (MP)	Records
decreased vertical activity	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
Listeria innocua Clip11262	Q92DM1	93.7%	Diamond
Pseudomonas syringae pv. syringae B728a	Q4ZSY3	92.7%	Diamond
Pseudomonas syringae pv. tomato str. DC3000	Q881J7	92.7%	Diamond
Pseudomonas savastanoi pv. phaseolicola 1448A	Q48IV1	92.1%	Diamond
Haemophilus influenzae Rd KW20	P29281	82.2%	Diamond
Gallus gallus	Q9PT84	61.4%	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
KCNH7-AS1	ncRNA	101929570
GCA	protein-coding	25801
IFIH1	protein-coding	64135
FAP	protein-coding	2191
GCG	protein-coding	2641
FIGN	protein-coding	55137

Protein

Protein identifiers

Voltage-gated inwardly rectifying potassium channel KCNH7 — Q9NS40 (reviewed: Q9NS40)

Alternative names: Ether-a-go-go-related gene potassium channel 3, Potassium voltage-gated channel subfamily H member 7, Voltage-gated potassium channel subunit Kv11.3

All UniProt accessions (1): Q9NS40

UniProt curated annotations — full annotation on UniProt →

Function. Pore-forming (alpha) subunit of voltage-gated inwardly rectifying potassium channel. Exhibits faster activation and deactivation kinetics and slow inactivation at membrane potentials positive to 240 mV, resulting in the weakest inward rectification.

Subunit / interactions. The potassium channel is probably composed of a homo- or heterotetrameric complex of pore-forming alpha subunits that can associate only within their subfamily.

Subcellular location. Cell membrane.

Tissue specificity. Expressed in prolactin-secreting adenomas.

Activity regulation. Heme inhibits voltage-gated inwardly rectifying potassium channel activity.

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.

Similarity. Belongs to the potassium channel family. H (Eag) (TC 1.A.1.20) subfamily. Kv11.3/KCNH7 sub-subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9NS40-1	1	yes
Q9NS40-2	2

RefSeq proteins (2): NP_150375, NP_775185 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000014	PAS	Domain
IPR000595	cNMP-bd_dom	Domain
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 (48 total): topological domain 8, transmembrane region 6, modified residue 5, helix 5, strand 5, sequence conflict 4, region of interest 3, splice variant 3, domain 2, chain 1, intramembrane region 1, coiled-coil region 1, short sequence motif 1, compositionally biased region 1, glycosylation site 1, sequence variant 1

Structure

Experimental structures (PDB)

1 structures by resolution:

PDB	Title	Method	Resolution (Å)
6Y7Q	Crystal Structure of the N-terminal PAS domain from the hERG3 Potassium Channel	X-RAY DIFFRACTION	1.39

Predicted structure (AlphaFold)

No AlphaFold model available for Q9NS40 — AlphaFold DB does not currently provide models for proteins above ~3000 aa.

Human Protein Atlas

Protein class: Voltage-gated ion channels, Voltage-Gated Potassium Channels, Predicted membrane proteins, FDA approved drug targets, Small molecule drugs

Protein evidence: Evidence at protein level

Antibody reliability (HPA): IH uncertain

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 (5)

Type	Positions
Phosphoserine	174, 238, 319, 896, 899

Glycosylation sites (1)

Type	Positions
N-linked (glcnac…) asparagine	600

Function

Pathways and Gene Ontology

Reactome pathways

0 curated (TAS) of 3; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

3 pathways:

ID	Pathway	Evidence
R-HSA-112316	Neuronal System	—
R-HSA-1296071	Potassium Channels	—
R-HSA-1296072	Voltage gated Potassium channels	—

MSigDB gene sets: 119 (showing top): GOBP_POTASSIUM_ION_TRANSPORT, BENPORATH_ES_WITH_H3K27ME3, REACTOME_VOLTAGE_GATED_POTASSIUM_CHANNELS, REACTOME_POTASSIUM_CHANNELS, AREB6_01, TGACCTY_ERR1_Q2, CACCAGC_MIR138, GGGTGGRR_PAX4_03, GOBP_MONOATOMIC_CATION_TRANSPORT, CEBP_Q2, GARGALOVIC_RESPONSE_TO_OXIDIZED_PHOSPHOLIPIDS_BLUE_DN, chr2q24, CDPCR3HD_01, GOBP_TRANSMEMBRANE_TRANSPORT, TGGAAA_NFAT_Q4_01

GO Biological Process (6): potassium ion transport (GO:0006813), regulation of membrane potential (GO:0042391), potassium ion transmembrane transport (GO:0071805), monoatomic ion transport (GO:0006811), monoatomic ion transmembrane transport (GO:0034220), transmembrane transport (GO:0055085)

GO Molecular Function (5): inward rectifier potassium channel activity (GO:0005242), heme binding (GO:0020037), monoatomic ion channel activity (GO:0005216), voltage-gated potassium channel activity (GO:0005249), potassium channel activity (GO:0005267)

GO Cellular Component (3): plasma membrane (GO:0005886), monoatomic ion channel complex (GO:0034702), membrane (GO:0016020)

Reactome top-level categories

2 top-level categories:

Category	Pathways
Potassium Channels	1
Neuronal System	1

GO top-level categories

22 GO namespaces:

Category	Terms
transport	2
metal ion transport	1
monoatomic ion transmembrane transport	1
regulation of biological quality	1
potassium ion transport	1
monoatomic cation transmembrane transport	1
monoatomic ion transport	1
transmembrane transport	1
cellular process	1
voltage-gated potassium channel activity	1
ligand-gated monoatomic cation channel activity	1
tetrapyrrole binding	1
monoatomic ion transmembrane transporter activity	1
channel activity	1
potassium channel activity	1
voltage-gated monoatomic cation channel activity	1
monoatomic cation channel activity	1
potassium ion transmembrane transporter activity	1
membrane	1
cell periphery	1
transmembrane transporter complex	1
cellular anatomical structure	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 3 of 14 annotations. The rest are phylogenetic / computational / electronic (IEA).

3 experimentally-supported GO terms:

GO term	NS	Evidence
potassium ion transport	BP	direct assay
heme binding	MF	direct assay
inward rectifier potassium channel activity	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 672 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KCNH7	GCA	P28676	876
KCNH7	IFIH1	Q9BYX4	646
KCNH7	PRL	P01236	603
KCNH7	KCNJ3	P48549	591
KCNH7	KCNQ2	O43526	581
KCNH7	KCNQ5	Q9NR82	571
KCNH7	IGSF21	Q96ID5	499
KCNH7	ARFGEF3	Q5TH69	469
KCNH7	LRMDA	Q9H2I8	469
KCNH7	KCND2	Q9NZV8	469
KCNH7	GALNTL6	Q49A17	464
KCNH7	SEMA5A	Q13591	454
KCNH7	SLC4A10	Q6U841	443
KCNH7	CLVS1	Q8IUQ0	441
KCNH7	KCNV1	Q6PIU1	439

IntAct

Human interaction partners of KCNH7 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

2 partners by confidence:

Partner	Interaction type	MIscore	Records
GRB2	physical association	0.400	1
LRSAM1	physical association	0.400	1

BioGRID (9 interactions; top human partners by supporting records): CUL4A (Affinity Capture-MS), KCNH2 (Affinity Capture-MS), KRAS (Synthetic Lethality), LRSAM1 (Affinity Capture-MS), NEK4 (Affinity Capture-MS), PARP11 (Proximity Label-MS), PARP12 (Proximity Label-MS), PARP2 (Proximity Label-MS)

Disease & clinical

Genetic variants

Variant evidence for KCNH7: 109 ClinVar records (0 pathogenic / likely pathogenic); 14 GWAS associations.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	90
Likely benign	10
Benign	5

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 32 predictions of 2,426):

Position(s)	Effect	Δscore	Sites
2:162373663–162373664	acceptor_loss	1.0000	6
2:162379851–162379852	donor_loss	1.0000	5
2:162380022–162380023	acceptor_loss	1.0000	5
2:162394387–162394388	donor_loss	1.0000	5
2:162394486–162394487	acceptor_loss	1.0000	5
2:162394488	acceptor_gain	1.0000
2:162394491	acceptor_gain	1.0000
2:162394494	acceptor_gain	1.0000
2:162394501	acceptor_gain	1.0000	2
2:162394507	acceptor_gain	1.0000

AlphaMissense

3,750 missense substitutions predicted likely pathogenic (of 7,901 scored), across 722 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
M648	9	0.992	1.000
M60	9	0.975	0.999
M654	9	0.963	1.000
M556	9	0.925	0.999
M680	9	0.907	0.995
M716	9	0.897	0.994
D459	8	1.000	1.000
D465	8	1.000	1.000
D500	8	1.000	1.000
D411	8	0.999	1.000
F462	8	0.999	1.000
F559	8	0.998	1.000
F659	8	0.998	1.000
D455	8	0.997	0.999
H564	8	0.997	1.000
F630	8	0.997	1.000
N661	8	0.997	1.000
F431	8	0.996	1.000
F507	8	0.996	0.999
D508	8	0.996	0.999

HPA cancer prognostics

RNA cancer specificity: Not detected

Disease associations

OMIM: gene MIM:608169 | disease phenotypes:

GenCC curated gene-disease

1 curated gene-disease records:

Disease	Classification	Inheritance	Records
epilepsy	Limited	Autosomal dominant

Mondo (1): epilepsy (MONDO:0005027)

GWAS associations

14 associations:

Study	Trait	p-value
GCST005527_5	Psoriasis	3e-18
GCST009875_10	Type 1 diabetes	3e-14
GCST003268_23	Psoriasis vulgaris	5e-13
GCST002740_18	Inflammatory skin disease	4e-11
GCST006269_134	General cognitive ability	1e-9
GCST010569_1	Polycystic ovary syndrome (metabolic subtype)	1e-8
GCST002861_1	Breast cancer (survival)	2e-8
GCST005527_37	Psoriasis	3e-8
GCST001414_3	Phospholipid levels (plasma)	4e-8
GCST005196_221	Coronary artery disease	1e-7
GCST003098_7	Diabetic kidney disease	1e-6
GCST003264_1265	Post bronchodilator FEV1/FVC ratio	4e-6
GCST008154_18	Trunk fat mass	4e-6
GCST008157_25	Body fat mass	5e-6

EFO canonical traits (from GWAS)

4 canonical traits:

EFO ID	Trait name
EFO:0000714	survival time
EFO:0004713	FEV/FVC ratio
EFO:1001494	psoriasis vulgaris
EFO:0004337	intelligence

MeSH disease descriptors

1 disease descriptors:

Descriptor	Name	Tree numbers
D004827	Epilepsy	C10.228.140.490

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2362996 (PROTEIN FAMILY)

PharmGKB: 1 entry (CPIC guideline: no)

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 (3 total), top 3:

Ligand	Action	Affinity	Parameter
ErgTx-1	Pore blocker	8.4	pKd
BeKm-1	Pore blocker	7.9	pKd
E4031	Channel blocker	6.7	pKd

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 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

PubChem BioAssay actives

2 with measured affinity, of 34 total; 1 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

CTD chemical–gene interactions

19 total (human), top 19 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression, increases methylation, increases mutagenesis	3
Valproic Acid	increases expression, affects cotreatment	3
methyleugenol	decreases expression	1
testosterone undecanoate	increases expression, affects cotreatment	1
sodium arsenite	increases expression	1
perfluorooctane sulfonic acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
bisphenol S	decreases methylation	1
(+)-JQ1 compound	decreases expression	1
Acetaminophen	decreases expression	1
Doxorubicin	decreases expression	1
N-Nitrosopyrrolidine	decreases expression	1
Phenylmercuric Acetate	affects cotreatment, increases expression	1
Silicon Dioxide	increases expression	1
Triclosan	decreases expression	1
Levonorgestrel	affects cotreatment, increases expression	1
Uranium Compounds	decreases expression	1
Okadaic Acid	decreases expression	1

ChEMBL screening assays

21 unique, capped per target: 20 binding, 1 toxicity

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*

Clinical trials (associated diseases)

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

showing 60 of 300 trials:

NCT	Phase	Status	Title
NCT00004637	Phase 4	COMPLETED	Double-Blind, Placebo-Controlled Trial of Vitamin E as Add-on Therapy for Children With Epilepsy
NCT00043914	Phase 4	COMPLETED	Measurement Of Serum Levels Of Two Antiepileptic Drugs During Conversion In Patients With Epilepsy
NCT00132223	Phase 4	UNKNOWN	Effects on the Diagnostic Accuracy of Magnetic Imaging Angiographies of the Supra-Aortic Vessels by Three Different Magnetic Resonance Contrast Agents in Patients
NCT00133081	Phase 4	UNKNOWN	Study to Improve the Treatment of Epilepsy (SITE)
NCT00137709	Phase 4	UNKNOWN	Hormone Profiles in Adults With Newly Diagnosed Epilepsy
NCT00154076	Phase 4	COMPLETED	A Multicenter Comparative Trial of Zonisamide and Topiramate as Initial Monotherapy in Untreated Epilepsies
NCT00165828	Phase 4	TERMINATED	Efficacy and Safety of an add-on Treatment With Zonisamide in Adults With Focal Epileptic Seizures With or Without Secondary Generalization
NCT00181116	Phase 4	COMPLETED	Levetiracetam for Benign Rolandic Epilepsy
NCT00207935	Phase 4	COMPLETED	Use of Sustained Release Antiepileptic Medication (Depakote® ER) for Pediatric Epilepsy in a Mental Retardation/Developmental Disorder Population
NCT00215592	Phase 4	COMPLETED	Open Label, Zonegran (Zonisamide) In Partial Onset Seizures
NCT00266604	Phase 4	COMPLETED	A Study to Evaluate the Dosing, Effectiveness and Safety of Topiramate for the Treatment of Epilepsy
NCT00288639	Phase 4	COMPLETED	Lyrica (Pregabalin) Administered as an Add-on Therapy for Partial Seizures (LEADER).
NCT00312676	Phase 4	UNKNOWN	Compare Tolerability of an Overnight Switch to Gradual Switch Between Two Different Forms of Depakote
NCT00323947	Phase 4	COMPLETED	Methylphenidate for Treating Attention Deficit Hyperactivity Disorder in Children With Both ADHD and Epilepsy
NCT00385411	Phase 4	COMPLETED	Study of Valproate in Young Patients Suffering From Epilepsy
NCT00522418	Phase 4	TERMINATED	Study Comparing Best Medical Practice With or Without VNS Therapy in Pharmacoresistant Partial Epilepsy Patients
NCT00537940	Phase 4	COMPLETED	Comparative Study Of Pregabalin And Gabapentin As Adjunctive Therapy In Subjects With Partial Seizures
NCT00552526	Phase 4	UNKNOWN	Ketogenic Diet vs.Antiepileptic Drug Treatment in Drug Resistant Epilepsy
NCT00564915	Phase 4	COMPLETED	RCT of the Efficacy of the Ketogenic Diet in the Treatment of Epilepsy
NCT00571155	Phase 4	COMPLETED	Trial of Levetiracetam in Patients With Primary Brain Tumors and Symptomatic Seizures Who Undergo Surgery
NCT00572195	Phase 4	COMPLETED	RNS® System LTT Study
NCT00610532	Phase 4	TERMINATED	Evaluating the Transporter Protein Inhibitor Probenecid In Patients With Epilepsy
NCT00630357	Phase 4	COMPLETED	Trial to Evaluate the Safety and Efficacy of Keppra After Conversion to Mono-therapy in Subjects With Partial Epilepsy
NCT00630630	Phase 4	COMPLETED	Study on Safety and Efficacy of Levetiracetam in the Adjunctive Treatment of Female Subjects With C1 Catamenial Epilepsy
NCT00630968	Phase 4	COMPLETED	S.K.A.T.E.: Safety of Keppra as Adjunctive Therapy in Epilepsy
NCT00631150	Phase 4	COMPLETED	A Phase IV-Pharmacovigilance Study of Keppra Greece - S.K.A.T.E.: Safety of Keppra as Adjunctive Therapy in Epilepsy
NCT00659958	Phase 4	COMPLETED	ZAGAL Study: Evaluating Effectiveness and Tolerability of Zonisamide as Adjunctive Therapy in Patients With Partial Onset Seizures Treated With Two Antiepileptic Drugs
NCT00713622	Phase 4	COMPLETED	Comparing The Effect On Cognition Of Adjunctive Therapy With Zonisamide Versus Sodium Valproate
NCT00807989	Phase 4	COMPLETED	The Efficacy and Safety of Low Dose Combination of LTG and VPA Compared to CBZ Monotherapy
NCT00832884	Phase 4	COMPLETED	The Safety of Intravenous Lacosamide
NCT00869622	Phase 4	COMPLETED	Antiepileptic Drugs and Osteoporotic Prevention Trial
NCT00896987	Phase 4	COMPLETED	Lamotrigine Cognitive Function Study in Adult Untreated Epilepsies
NCT00952081	Phase 4	COMPLETED	A Pilot Study to Evaluate Efficacy and Safety of Clevidipine in Neurosurgical Patients
NCT01118455	Phase 4	TERMINATED	Trial to Assess Vagus Nerve Stimulation Therapy vs. Anti-Epileptic Drug (AED) Treatment in Children With Refractory Seizures
NCT01127165	Phase 4	COMPLETED	Low and High Dose Zonisamide in Children as Monotherapy
NCT01127256	Phase 4	COMPLETED	Comparative Study of Zonisamide and Carbamazepine as an Initial Monotherapy: Efficacy and Safety Evaluation
NCT01140867	Phase 4	COMPLETED	Open-label, Multi-center Trial of Zonisamide as Adjunctive Therapy in Patients With Uncontrolled Partial Epilepsy
NCT01175954	Phase 4	COMPLETED	Cognitive and Behavioral Effects of Lacosamide
NCT01229735	Phase 4	COMPLETED	Levetiracetam Versus Topiramate as Adjunctive Therapy to Evaluate Efficacy and Safety in Subjects With Refractory Partial Onset Seizures
NCT01244724	Phase 4	TERMINATED	Lexapro for Major Depression in Patients With Epilepsy
NCT01309074	Phase 4	WITHDRAWN	Does Pregabalin Improve Symptoms of Anxiety in Patients With Epilepsy? A Comparison With Sertraline
NCT01318408	Phase 4	COMPLETED	Levetiracetam: The Anti-Convulsant of Choice for Elderly Patients With Dementia
NCT01498822	Phase 4	COMPLETED	Levetiracetam Versus Oxcarbazepine as Monotherapy to Evaluate Efficacy and Safety in Subjects With Newly or Recently Diagnosed Partial Epilepsy
NCT01546688	Phase 4	TERMINATED	A Study to Evaluate the Safety and Tolerability and Explore the Efficacy of Zonisamide as add-on Therapy in Elderly Patients With Refractory Partial Seizures
NCT01607346	Phase 4	TERMINATED	An Open Label Study to Evaluate the Effects of Ezogabine/Retigabine Added to Existing Anti-epileptic Drug(s) on Urinary Voiding Function in Subjects With Partial Onset Seizures
NCT01627860	Phase 4	COMPLETED	First Add-on vs. Mono-therapy Study of Topiramate in Neuro-Surgical Patients
NCT01689649	Phase 4	COMPLETED	A Study to Assess Tolerability and Efficacy of Topiramate Monotherapy in Recently Diagnosed Patients With Epilepsy
NCT01713777	Phase 4	COMPLETED	Equivalence Among Antiepileptic Drug Generic and Brand Products in People With Epilepsy: Chronic-Dose 4-Period Replicate Design
NCT01733394	Phase 4	COMPLETED	Equivalence Among Antiepileptic Drug Generic and Brand Products in People With Epilepsy: Single-Dose 6-Period Replicate Design (EQUIGEN Single-Dose Study)
NCT01804322	Phase 4	COMPLETED	Standardized Educational Plan for Epilepsy Patients With Comorbidities
NCT01932502	Phase 4	UNKNOWN	Evaluation of Onfi Conversion Therapy Replacing Clonazepam in Patients With Medically Refractory Epilepsy
NCT01995825	Phase 4	COMPLETED	Lamotrigine Bioequivalence
NCT02100644	Phase 4	COMPLETED	Valproate Dose Reduction and Its Clinical Evaluation by Introducing Lamotrigine in Japanese Women With Epilepsy - Single Arm, Multicenter, and Open-label Study
NCT02178995	Phase 4	COMPLETED	Methylphenidate Treatment of Attention Deficits in Epilepsy
NCT02205931	Phase 4	UNKNOWN	Ketogenic Diet in Infants With Epilepsy (KIWE)
NCT02362373	Phase 4	COMPLETED	Women With Epilepsy: a Pilot Study of PK and PD Anti-epileptic Drug Effects in Levonorgestrel Intrauterine System Users
NCT02404168	Phase 4	COMPLETED	BEEP Follow Up: Evaluation of Repeatability of Lamotrigine Pharmacokinetics in Epileptic Patients
NCT02429596	Phase 4	UNKNOWN	A Trial of Generic Substitution of Antiepileptic Drugs
NCT02633241	Phase 4	COMPLETED	A Pilot Study of Dexmedetomidine-Propofol in Children Undergoing Magnetic Resonance Imaging
NCT02645279	Phase 4	UNKNOWN	Comparison of Oral 30 % Dextrose and iv Midazolam Sedation During MRI in Neonates