KCNH8

Summary

KCNH8 (potassium voltage-gated channel subfamily H member 8, HGNC:18864) is a protein-coding gene on chromosome 3p24.3, encoding Voltage-gated delayed rectifier potassium channel KCNH8 (Q96L42). Pore-forming (alpha) subunit of a voltage-gated delayed rectifier potassium channel that mediates outward-rectifying potassium currents.

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.

Source: NCBI Gene 131096 — RefSeq curated summary.

At a glance

• GWAS associations: 18
• Clinical variants (ClinVar): 218 total — 1 pathogenic, 1 likely-pathogenic
• GTEx eGene: eQTL in 8 tissues, sQTL in 0 (q < 0.05)
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 0.81 (unconstrained)
• MANE Select transcript: NM_144633
• Notable: 218 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18864
Approved symbol	KCNH8
Name	potassium voltage-gated channel subfamily H member 8
Location	3p24.3
Locus type	gene with protein product
Status	Approved
Aliases	Kv12.1, elk3
Ensembl gene	ENSG00000183960
Ensembl biotype	protein_coding
OMIM	608260
Entrez	131096

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 3 protein_coding, 3 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

MANE Select: ENST00000328405

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 2, TSL 4: 1

ENST00000328405, ENST00000452398, ENST00000475063, ENST00000938024, ENST00001093534, ENST00001093535, ENST00001144840

RefSeq mRNA: 1 — MANE Select: NM_144633 NM_144633

CCDS: CCDS2632

Canonical transcript exons

ENST00000328405 — 16 exons

Exon	Start	End
ENSE00001295800	19281198	19281329
ENSE00001299391	19148510	19148795
ENSE00001300020	19342587	19342714
ENSE00001300111	19451155	19451404
ENSE00001301382	19253654	19253887
ENSE00001324320	19450106	19450305
ENSE00001326716	19533395	19535642
ENSE00003486388	19517998	19518074
ENSE00003532935	19515322	19515428
ENSE00003538650	19438164	19438361
ENSE00003541902	19456768	19456982
ENSE00003595401	19347725	19347965
ENSE00003597538	19512970	19513325
ENSE00003603123	19510363	19510401
ENSE00003645883	19395104	19395311
ENSE00003677338	19390481	19390638

Expression profiles

Bgee: expression breadth ubiquitous, 168 present calls, max score 90.49.

FANTOM5 (CAGE): breadth broad, TPM avg 2.5113 / max 162.8225, expressed in 285 samples.

Highest expression (Bgee): corpus callosum, endothelial cell, C1 segment of cervical spinal cord, substantia nigra, pituitary gland.

Genetic regulation across tissues (GTEx eQTL / sQTL)

KCNH8 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 8 tissues and its splicing (sQTL) in 0 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

8 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Testis	eqtl	7.7e-22	-0.99	3:19148202:C:G
Skin Sun Exposed Lower leg	eqtl	5.6e-08	-0.40	3:19148202:C:G
Skin Not Sun Exposed Suprapubic	eqtl	1.6e-05	-0.33	3:19148202:C:G
Pancreas	eqtl	1.7e-03	-0.81	3:19147074:G:C
Lung	eqtl	5.8e-03	+0.28	3:19102655:C:T
Brain Putamen basal ganglia	eqtl	6.4e-03	-0.36	3:18867608:A:G
Adipose Subcutaneous	eqtl	2.6e-02	+0.20	3:19102655:C:T
Nerve Tibial	eqtl	2.7e-02	-0.19	3:20070695:C:G

FANTOM5 promoters

6 alternative TSS:

Promoter ID	TPM avg	Samples expressed
35642	1.3892	154
35644	0.4092	39
35641	0.2791	134
35640	0.2358	108
35639	0.1468	68
35646	0.0511	10

Top tissues by expression

showing 100 of 239 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
corpus callosum	UBERON:0002336	90.49	gold quality
endothelial cell	CL:0000115	85.29	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	80.75	gold quality
substantia nigra	UBERON:0002038	80.39	gold quality
pituitary gland	UBERON:0000007	80.37	gold quality
adenohypophysis	UBERON:0002196	79.83	gold quality
putamen	UBERON:0001874	79.80	gold quality
midbrain	UBERON:0001891	79.11	gold quality
spinal cord	UBERON:0002240	78.78	gold quality
Ammon’s horn	UBERON:0001954	78.47	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	77.96	gold quality
amygdala	UBERON:0001876	77.59	gold quality
inferior vagus X ganglion	UBERON:0005363	77.58	gold quality
Brodmann (1909) area 9	UBERON:0013540	77.38	gold quality
ganglionic eminence	UBERON:0004023	77.22	gold quality
cortical plate	UBERON:0005343	76.79	gold quality
Brodmann (1909) area 46	UBERON:0006483	76.60	gold quality
right frontal lobe	UBERON:0002810	76.31	gold quality
lateral globus pallidus	UBERON:0002476	76.28	gold quality
caudate nucleus	UBERON:0001873	76.11	gold quality
buccal mucosa cell	CL:0002336	74.84	silver quality
hypothalamus	UBERON:0001898	74.26	gold quality
primary visual cortex	UBERON:0002436	74.16	gold quality
forebrain	UBERON:0001890	73.88	gold quality
substantia nigra pars reticulata	UBERON:0001966	73.87	gold quality
occipital lobe	UBERON:0002021	73.05	gold quality
ventricular zone	UBERON:0003053	72.53	gold quality
postcentral gyrus	UBERON:0002581	72.48	gold quality
temporal lobe	UBERON:0001871	72.25	gold quality
brain	UBERON:0000955	72.24	gold quality
cerebral cortex	UBERON:0000956	71.84	gold quality
frontal cortex	UBERON:0001870	71.62	gold quality
neocortex	UBERON:0001950	71.34	gold quality
nucleus accumbens	UBERON:0001882	71.33	gold quality
parietal lobe	UBERON:0001872	71.06	gold quality
subthalamic nucleus	UBERON:0001906	70.62	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	70.33	gold quality
prefrontal cortex	UBERON:0000451	70.14	gold quality
anterior cingulate cortex	UBERON:0009835	69.91	gold quality
dorsal plus ventral thalamus	UBERON:0001897	69.86	gold quality
superior frontal gyrus	UBERON:0002661	69.28	gold quality
superior vestibular nucleus	UBERON:0007227	68.61	gold quality
medulla oblongata	UBERON:0001896	67.89	gold quality
sural nerve	UBERON:0015488	67.73	gold quality
right adrenal gland cortex	UBERON:0035827	66.97	gold quality
tibial nerve	UBERON:0001323	66.68	gold quality
right adrenal gland	UBERON:0001233	66.20	gold quality
substantia nigra pars compacta	UBERON:0001965	66.05	gold quality
ventral tegmental area	UBERON:0002691	66.05	gold quality
body of pancreas	UBERON:0001150	65.28	gold quality
globus pallidus	UBERON:0001875	65.05	gold quality
left adrenal gland cortex	UBERON:0035825	64.24	gold quality
entorhinal cortex	UBERON:0002728	63.79	gold quality
oviduct epithelium	UBERON:0004804	63.45	gold quality
colonic epithelium	UBERON:0000397	63.16	gold quality
adrenal cortex	UBERON:0001235	63.09	gold quality
left adrenal gland	UBERON:0001234	63.01	gold quality
Brodmann (1909) area 23	UBERON:0013554	62.93	silver quality
pancreas	UBERON:0001264	62.49	gold quality
right hemisphere of cerebellum	UBERON:0014890	62.21	gold quality
adrenal gland	UBERON:0002369	61.88	gold quality
body of stomach	UBERON:0001161	61.49	gold quality
mucosa of stomach	UBERON:0001199	61.26	gold quality
lateral nuclear group of thalamus	UBERON:0002736	61.22	silver quality
medial globus pallidus	UBERON:0002477	60.96	gold quality
granulocyte	CL:0000094	60.86	gold quality
lymph node	UBERON:0000029	60.61	gold quality
middle temporal gyrus	UBERON:0002771	60.45	gold quality
rectum	UBERON:0001052	60.39	gold quality
gall bladder	UBERON:0002110	60.26	gold quality
minor salivary gland	UBERON:0001830	60.21	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	60.18	gold quality
small intestine Peyer’s patch	UBERON:0003454	59.92	gold quality
spleen	UBERON:0002106	59.72	gold quality
stomach	UBERON:0000945	59.65	gold quality
saliva-secreting gland	UBERON:0001044	59.32	gold quality
cerebellar hemisphere	UBERON:0002245	59.25	gold quality
cerebellar cortex	UBERON:0002129	59.24	gold quality
muscle layer of sigmoid colon	UBERON:0035805	58.80	gold quality
cerebellum	UBERON:0002037	58.55	gold quality
islet of Langerhans	UBERON:0000006	58.53	gold quality
small intestine	UBERON:0002108	58.36	gold quality
vermiform appendix	UBERON:0001154	58.29	gold quality
right uterine tube	UBERON:0001302	58.06	gold quality
pons	UBERON:0000988	57.66	gold quality
mouth mucosa	UBERON:0003729	57.62	gold quality
right testis	UBERON:0004534	57.41	gold quality
testis	UBERON:0000473	57.23	gold quality
left testis	UBERON:0004533	56.98	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	56.28	gold quality
tonsil	UBERON:0002372	56.10	gold quality
transverse colon	UBERON:0001157	55.92	gold quality
intestine	UBERON:0000160	55.61	gold quality
colon	UBERON:0001155	54.97	gold quality
large intestine	UBERON:0000059	54.54	gold quality
parotid gland	UBERON:0001831	54.43	gold quality
lower esophagus muscularis layer	UBERON:0035833	54.32	gold quality
caecum	UBERON:0001153	54.30	gold quality
lower esophagus	UBERON:0013473	54.29	gold quality
bone marrow cell	CL:0002092	54.12	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-GEOD-180759	yes	1389.28
E-HCAD-35	yes	88.04
E-ANND-3	yes	5.21

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 148 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Spleen	tissue	39.3	not detected
Esophagus	tissue	35.7	low
Lymph node	tissue	35.4	low
Smooth muscle	tissue	35.4	not detected
Tonsil	tissue	35.0	medium
Adipose tissue	tissue	34.8	low
Endometrium 1	tissue	32.7	low
Appendix	tissue	32.2	medium
Choroid plexus	tissue	31.5
Gallbladder	tissue	28.1	not detected
Urinary bladder	tissue	27.3	low
Cervix	tissue	26.2	low
Lung	tissue	25.8	medium
Placenta	tissue	25.3	low
Vagina	tissue	23.4	not detected
Heart muscle	tissue	22.2	medium
Locus coeruleus	tissue	21.0
Tongue	tissue	20.6
Thymus	tissue	18.3
Thyroid gland	tissue	18.2	low
Breast	tissue	17.9	low
Nucleus accumbens	tissue	17.9
Hippocampus	tissue	17.7	not detected
Ovary	tissue	17.4	low
Bone marrow	tissue	16.5	medium
Fallopian tube	tissue	15.1	low
Seminal vesicle	tissue	14.3	medium
Postcentral gyrus	tissue	14.0
Stomach 1	tissue	13.8	not detected
Adrenal gland	tissue	13.5	not detected
Rectum	tissue	12.9	not detected
Prostate	tissue	12.3	low
Colon	tissue	11.7	low
Skin 1	tissue	11.5	medium
Parathyroid gland	tissue	10.9	low
Small intestine	tissue	10.8	low
Kidney	tissue	10.6	medium
Skeletal muscle	tissue	10.5	low
Pituitary gland	tissue	10.5
Liver	tissue	10.1	low
Putamen	tissue	9.2
Nucleus accumbens	tissue	9.0
Duodenum	tissue	8.7	low
Epididymis	tissue	8.6	low
Substantia nigra	tissue	8.6
Pancreas	tissue	8.5	low
Spinal cord	tissue	8.4
Ventral forebrain	tissue	8.2
Septum	tissue	8.2
Hypothalamus	tissue	8.1
Salivary gland	tissue	8.0	low
Testis	tissue	7.9	medium
Basal ganglia	tissue	7.8	low
Medulla oblongata	tissue	7.8
Corpus callosum	tissue	7.8
Periaqueductal gray	tissue	7.7
Pons	tissue	7.4
Midbrain	tissue	7.4
Thalamus	tissue	6.8
Superior colliculi	tissue	6.7

Brain sub-regions (HPA Brain Atlas): detected in 381; highest nTPM — Flocculonodular lobe (36.5), Vermis (33.3), Cerebellar cortex (33.2), Area postrema (27.0), Temporal white matter (27.0).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CEBPA, EGR1

miRNA regulators (miRDB)

Targeting KCNH8 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 112 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-219A-5P	99.91	73.36	735
HSA-MIR-8087	99.90	69.55	1351
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-4782-3P	99.88	73.31	735
HSA-MIR-6766-3P	99.88	73.38	732
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-8067	99.86	69.59	2260
HSA-MIR-221-3P	99.86	71.56	1329
HSA-MIR-222-3P	99.86	71.35	1337
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-664B-3P	99.84	71.65	3590
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-6844	99.82	70.69	2423
HSA-MIR-548AZ-3P	99.82	70.56	3549
HSA-MIR-548BC	99.82	70.61	3524

Functional genomics

gnomAD constraint: pLI 2.77e-14, LOEUF 0.81, missense Z 1.78 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000328405 splits into 3 regions with different missense tolerance; 0 are missense-constrained. Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
3:19,148,720–19,347,797	244 / 256.8	0.95	no
3:19,347,798–19,456,979	415 / 577.4	0.72	no
3:19,456,980–19,534,096	558 / 495.8	1.13	no

Literature-anchored findings (GeneRIF, showing 1)

• Kv12.1 channels add to the growing list of K(+) channels that are insensitive to phospholipase C beta signaling (PMID:30136882)

Cross-species orthologs

14 orthologs

Organism	Symbol	Gene ID
danio_rerio	kcnh8	ENSDARG00000062640
mus_musculus	Kcnh8	ENSMUSG00000035580
rattus_norvegicus	Kcnh8	ENSRNOG00000058626
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), KCNH7 (ENSG00000184611), CNGA1 (ENSG00000198515)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:2445160) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 13 distinct phenotype terms.

Mouse phenotype (MP)	Records
enlarged heart	1
abnormal liver morphology	1
abnormal spleen morphology	1
enlarged spleen	1
enlarged lymph nodes	1
abnormal ovary morphology	1
abnormal testis morphology	1
enlarged testis	1
abnormal skin morphology	1
abnormal eye morphology	1
abnormal single cell response	1
behavior/neurological phenotype	1
hydrometra	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 syringae pv. tomato str. DC3000	Q881J7	92.7%	Diamond
Pseudomonas savastanoi pv. phaseolicola 1448A	Q48IV1	92.1%	Diamond
Brucella anthropi ATCC 49188	A6X554	69.0%	Diamond
Gallus gallus	Q9PT84	61.4%	Diamond
Bacillus subtilis subsp. subtilis str. 168	O34627	50.4%	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
LINC03180	ncRNA	105376981
LINC03179	ncRNA	107986066
MIR4791	ncRNA	100616291
EFHB	protein-coding	151651
PP2D1	protein-coding	151649
RAB5A	protein-coding	5868

Protein

Protein identifiers

Voltage-gated delayed rectifier potassium channel KCNH8 — Q96L42 (reviewed: Q96L42)

Alternative names: ELK1, Ether-a-go-go-like potassium channel 3, Potassium voltage-gated channel subfamily H member 8, Voltage-gated potassium channel subunit Kv12.1

All UniProt accessions (2): F8WCG6, Q96L42

UniProt curated annotations — full annotation on UniProt →

Function. Pore-forming (alpha) subunit of a voltage-gated delayed rectifier potassium channel that mediates outward-rectifying potassium currents. Elicits a slowly activating, non-inactivating and slowly deactivation outwards potassium current at depolarizating voltages from -30 mV to +50mV. Shows no obvious change in the activation rate from different holding potentials. Activation is strongly dependent on the pH of the external solution.

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.

Subcellular location. Membrane.

Tissue specificity. Primarily expressed in the nervous system.

Similarity. Belongs to the potassium channel family. H (Eag) (TC 1.A.1.20) subfamily. Kv12.1/KCNH8 sub-subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q96L42-1	1	yes
Q96L42-2	2

RefSeq proteins (1): NP_653234* (*=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
IPR003950	K_chnl_volt-dep_ELK	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 (36 total): topological domain 8, transmembrane region 6, region of interest 5, splice variant 4, compositionally biased region 3, domain 2, glycosylation site 2, sequence variant 2, chain 1, intramembrane region 1, short sequence motif 1, sequence conflict 1

Structure

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96L42-F1	64.41	0.25

Human Protein Atlas

Protein class: Predicted intracellular proteins, Plasma proteins, Transcription factors, Helix-turn-helix domains, Cancer-related genes, Candidate cancer biomarkers

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): nucleoplasm; mitochondria

Antibody reliability (HPA): IH approved · IF supported

Functional residue map

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

Glycosylation sites (2)

Type	Positions
N-linked (glcnac…) asparagine	320, 409

Function

Pathways and Gene Ontology

Reactome pathways

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

3 pathways:

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

MSigDB gene sets: 453 (showing top): AHRARNT_01, GOBP_POTASSIUM_ION_TRANSPORT, MYOGENIN_Q6, REACTOME_VOLTAGE_GATED_POTASSIUM_CHANNELS, TGCACTT_MIR519C_MIR519B_MIR519A, REACTOME_POTASSIUM_CHANNELS, AAGCCAT_MIR135A_MIR135B, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GGGTGGRR_PAX4_03, GOBP_MONOATOMIC_CATION_TRANSPORT, BILD_HRAS_ONCOGENIC_SIGNATURE, GOBP_WOUND_HEALING, GTGCCTT_MIR506, TCF4_Q5, AP1_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 (4): voltage-gated potassium channel activity (GO:0005249), delayed rectifier potassium channel activity (GO:0005251), monoatomic ion channel activity (GO:0005216), 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

20 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
potassium channel activity	1
voltage-gated monoatomic cation channel activity	1
voltage-gated potassium channel activity	1
monoatomic ion transmembrane transporter activity	1
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 13 annotations. The rest are phylogenetic / computational / electronic (IEA).

3 experimentally-supported GO terms:

GO term	NS	Evidence
potassium ion transport	BP	direct assay
plasma membrane	CC	direct assay
delayed rectifier potassium channel activity	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 860 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KCNH8	ELK4	P28323	946
KCNH8	ELK3	P41970	850
KCNH8	KCNF1	Q9H3M0	499
KCNH8	TMC5	Q6UXY8	472
KCNH8	KCNK17	Q96T54	463
KCNH8	KCNC2	Q96PR1	460
KCNH8	FKBP9	O95302	452
KCNH8	DPY19L4	Q7Z388	450
KCNH8	KCNG1	Q9UIX4	447
KCNH8	KCNC1	P48547	440
KCNH8	IGHV4-38-2	P0DP08	427
KCNH8	KCNB2	Q92953	425
KCNH8	ETV3	P41162	422
KCNH8	CLIC4	Q9Y696	418
KCNH8	TBC1D5	Q92609	400

IntAct

Human interaction partners of KCNH8 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

1 partners by confidence:

Partner	Interaction type	MIscore	Records
FMR1	physical association	0.000	1

BioGRID (9 interactions; top human partners by supporting records): HNRNPL (Affinity Capture-RNA), KCNH4 (Negative Genetic), NUDT21 (Affinity Capture-RNA), PARP16 (Proximity Label-MS), PARP2 (Proximity Label-MS), PARP3 (Proximity Label-MS), PARP4 (Proximity Label-MS), SOX2 (Affinity Capture-MS)

Protein complexes (CORUM) (2)

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

2 complexes by size:

Complex	Subunits	Members
★ KCNH3-KCNH8 complex	2	KCNH3, KCNH8
★ KCNH4-KCNH8 complex	2	KCNH4, KCNH8

Disease & clinical

Genetic variants

Variant evidence for KCNH8: 218 ClinVar records (2 pathogenic / likely pathogenic); 18 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	1
Uncertain significance	185
Likely benign	6
Benign	6

Top pathogenic / likely-pathogenic (2)

Showing all 2 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
1700685	NM_144633.3(KCNH8):c.298T>C (p.Tyr100His)	Likely pathogenic	criteria provided, single submitter	1
1330209	GRCh37/hg19 3p24.3(chr3:18004128-19575641)x1	Pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

Explore KCNH8’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; 28 predictions of 3,262):

Position(s)	Effect	Δscore	Sites
12:96223563–96223564	acceptor_loss	1.0000	3
12:96223741	donor_gain	1.0000
12:96223774–96223775	donor_loss	1.0000	4
3:19253652–19253653	acceptor_loss	1.0000	5
3:19253888–19253889	donor_loss	1.0000	4
3:19281189–19281190	acceptor_gain	1.0000	2
3:19281193	acceptor_gain	1.0000
3:19281196–19281197	acceptor_loss	1.0000	2
3:19281197	acceptor_gain	1.0000
3:19281330–19281331	donor_loss	1.0000	5

AlphaMissense

3,111 missense substitutions predicted likely pathogenic (of 7,277 scored), across 617 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
M455	9	0.992	1.000
M61	9	0.985	0.999
M360	9	0.926	0.999
M461	9	0.925	0.998
D306	8	0.999	1.000
D261	8	0.998	0.999
F268	8	0.998	1.000
D271	8	0.998	0.999
D314	8	0.998	0.999
D612	8	0.998	1.000
N12	8	0.997	1.000
F29	8	0.997	1.000
H368	8	0.997	0.999
F437	8	0.997	1.000
F466	8	0.997	1.000
D583	8	0.997	0.999
F14	8	0.996	1.000
D23	8	0.996	0.999
D225	8	0.996	0.999
N439	8	0.995	1.000

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

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

4 prognostic cancer types:

Cancer	Prognostic	p-value
Ovary Serous Cystadenocarcinoma (TCGA)	unfavorable	1.95e-05
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	0.000131
Stomach Adenocarcinoma (TCGA)	unfavorable	0.000178
Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma (TCGA)	unfavorable	0.00033

Disease associations

OMIM: gene MIM:608260 | disease phenotypes: MIM:254900

GenCC curated gene-disease

Mondo (1): action myoclonus-renal failure syndrome (MONDO:0009699)

Orphanet (1): Action myoclonus-renal failure syndrome (Orphanet:163696)

GWAS associations

18 associations:

Study	Trait	p-value
GCST010653_95	Thyroid stimulating hormone levels	6e-29
GCST011494_82	Daytime nap	5e-12
GCST010653_96	Thyroid stimulating hormone levels	2e-11
GCST004343_2	Chronic venous disease	5e-11
GCST008295_26	Number of decayed, missing and filled tooth surfaces or use of dentures	9e-10
GCST004861_91	Itch intensity from mosquito bite	1e-9
GCST008306_13	Dentures	2e-9
GCST003786_1	Small intestine neuroendocrine tumor	3e-9
GCST003798_1	Acute lymphoblastic leukemia in childhood (B cell precursor)	8e-9
GCST005848_4	Heart rate response to recovery post exercise (50 sec)	8e-9
GCST90000047_218	Age at first sexual intercourse	3e-8
GCST005832_10	Acute lymphoblastic leukemia in childhood (B cell precursor)	3e-7
GCST009638_3	B-cell acute lymphoblastic leukaemia	4e-7
GCST004162_14	Carotid plaque burden	1e-6
GCST012485_3	Cerebral amyloid angiopathy x sex interaction in Alzheimer’s disease	1e-6
GCST011384_1	Vaginal microbiome composition (community state type)	3e-6
GCST000101_9	Hip geometry	4e-6
GCST002432_6	Response to inhaled corticosteroid treatment in asthma (change in FEV1)	6e-6

EFO canonical traits (from GWAS)

10 canonical traits:

EFO ID	Trait name
EFO:0004685	hip geometry
EFO:0005921	FEV change measurement
EFO:0006501	carotid plaque build
EFO:0008377	mosquito bite reaction itch intensity measurement
EFO:0009185	heart rate response to recovery post exercise
EFO:0010078	dentures
EFO:0011013	vaginal microbiome measurement
EFO:0007828	daytime rest measurement
EFO:0008343	sex interaction measurement
EFO:0009749	age at first sexual intercourse measurement

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 (1 total), top 1:

Ligand	Action	Affinity	Parameter
Ba2+	Channel blocker	3.7	pIC50

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

21 total (human), top 21 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Aflatoxin B1	decreases methylation, increases methylation	2
bisphenol F	increases methylation	1
methyleugenol	decreases expression	1
bisphenol A	affects methylation	1
trichostatin A	decreases expression	1
beta-lapachone	increases expression	1
arsenite	increases methylation	1
tobacco tar	decreases expression, decreases reaction	1
benzo(e)pyrene	increases methylation	1
allyl sulfide	decreases reaction, decreases expression	1
CGP 52608	affects binding, increases reaction	1
abrine	increases expression	1
Acetaminophen	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Estradiol	decreases expression	1
Lead	decreases expression	1
Methapyrilene	increases methylation	1
N-Nitrosopyrrolidine	decreases expression	1
Nickel	decreases expression	1
Valproic Acid	affects 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 238 trials:

NCT	Phase	Status	Title
NCT00439699	Phase 4	COMPLETED	A Pilot Clinical Trial Of Memantine for Essential Tremor
NCT00584376	Phase 4	COMPLETED	Pregabalin (Lyrica) for the Treatment of Essential Tremor
NCT00998660	Phase 4	COMPLETED	RECHARGE Sub-Study to the Implantable Systems Performance Registry (ISPR)
NCT02111369	Phase 4	COMPLETED	Propranolol and Botulinum Toxin for Essential Vocal Tremor
NCT02495883	Phase 4	COMPLETED	Functional Imaging of Tremor Circuits and Mechanisms of Treatment Response
NCT00018564	Phase 3	COMPLETED	Novel Therapies for Essential Tremor
NCT00236496	Phase 3	COMPLETED	A Comparison of the Efficacy and Safety of Topiramate Versus Placebo in Treating Tremor of Unknown Cause.
NCT01441284	Phase 3	WITHDRAWN	Efficacy of Pramipexole Extended Release in the Treatment of Essential Tremor
NCT04193527	Phase 3	COMPLETED	A Study to Evaluate the Diagnostic Efficacy of DaTSCAN™ Ioflupane (123I) Injection in Single Photon Emission Computed Tomography (SPECT) for the Diagnosis of Parkinsonian Syndrome (PS) in Chinese Patients
NCT04265209	Phase 3	COMPLETED	[18F] LBT-999 PET Compared to [123I]-FP/CIT SPECT to Distinguish Between Parkinson’s Diseases and Essential Tremor
NCT06087276	Phase 3	ACTIVE_NOT_RECRUITING	Essential 3 - Decentralized, Phase 3 Study Evaluating the Safety and Efficacy of Ulixacaltamide in Essential Tremor (ET)
NCT00080366	Phase 2	COMPLETED	Octanol to Treat Essential Tremor
NCT00102596	Phase 2	COMPLETED	Clinical Trial Characterizing the Bioavailability of 1-Octanol in Adults With Ethanol-responsive Essential Tremor
NCT00223743	Phase 2	COMPLETED	A Safety/Efficacy Trial of Zonisamide for Essential Tremor
NCT00321087	Phase 2	TERMINATED	A Study of T2000 in Essential Tremor
NCT00598078	Phase 2	COMPLETED	Multiple-dose,Double-blind,Placebo-controlled Study of Sodium Oxybate in Patients With Essential Tremor
NCT00655278	Phase 2	TERMINATED	T2000 in Essential Tremor - Open Label Continuation
NCT01332695	Phase 2	COMPLETED	A Pilot Efficacy and Safety Study of ST101 in Essential Tremor
NCT02277106	Phase 2	COMPLETED	Evaluate SAGE-547 in Participants With Essential Tremor
NCT02551848	Phase 2	UNKNOWN	Kinematic-based BoNT-A Injections for Bilateral ET
NCT02668146	Phase 2	UNKNOWN	An Efficacy/Safety Study of Perampanel for Reducing Essential Tremor
NCT02978781	Phase 2	COMPLETED	A Study to Evaluate SAGE-217 in Participants With Essential Tremor
NCT03101241	Phase 2	COMPLETED	A Phase 2 RCT Study of CX-8998 for Essential Tremor
NCT03688685	Phase 2	COMPLETED	A Clinical Study to Evaluate CAD-1883 in Essential Tremor
NCT03780426	Phase 2	COMPLETED	tSMS in Essential Tremor
NCT04305275	Phase 2	COMPLETED	A Study to Evaluate the Efficacy, Safety, and Tolerability of SAGE-324 in Participants With Essential Tremor
NCT04727658	Phase 2	TERMINATED	Linac FRACtionated Radiosurgical THALamotomie in Tremors (FRACTHAL)
NCT04880616	Phase 2	COMPLETED	Safety, Efficacy, and Tolerability of NBI-827104 for the Treatment of Essential Tremor
NCT05021978	Phase 2	COMPLETED	A Clinical Trial of PRAX-944 in Participants With Essential Tremor
NCT05021991	Phase 2	COMPLETED	A Clinical Trial of 2 Doses of PRAX-944 in Participants With Essential Tremor
NCT05122650	Phase 2	COMPLETED	A Study To Assess the Safety and Efficacy of JZP385 in the Treatment of Adults With Moderate to Severe Essential Tremor (ET)
NCT05173012	Phase 2	COMPLETED	Study to Evaluate SAGE-324 in Participants With Essential Tremor
NCT05387642	Phase 2	WITHDRAWN	A Clinical Trial of PRAX-114 in Participants With Essential Tremor
NCT06312800	Phase 2	WITHDRAWN	Acamprosate and Methazolamide for Essential Tremor
NCT06821906	Phase 2	RECRUITING	Stereotactic Radiosurgery in the Treatment of Essential Tremor
NCT07074002	Phase 2	RECRUITING	Proof of Concept Study on BP1.4979 Effect on Essential Tremor
NCT07103265	Phase 2	NOT_YET_RECRUITING	Developing a New LIFU Neuromodulation Method to Suppress Tremor
NCT00001986	Phase 1	COMPLETED	1-Octanol to Treat Essential Tremor
NCT00016679	Phase 1	COMPLETED	1-Octanol to Treat Essential Tremor
NCT01304758	Phase 1	COMPLETED	ExAblate Transcranial MR Guided Focused Ultrasound in the Treatment of Essential Tremor
NCT01468948	Phase 1	COMPLETED	Octanoic Acid for Essential Tremor
NCT01698450	Phase 1	COMPLETED	Magnetic Resonance (MR) Guided Functional Ultrasound-Neurosurgery for Movement Disorders
NCT02037217	Phase 1	COMPLETED	ExAblate Transcranial MR Guided Focused Ultrasound in the Treatment of Essential Tremor
NCT05897775	Phase 1	RECRUITING	Coordinated Reset Deep Brain Stimulation for Essential Tremor
NCT07049003	Phase 1	RECRUITING	Deep Brain Stimulation of the Deep Cerebellar Nuclei for Refractory Tremor
NCT00608231	Phase 2/3	WITHDRAWN	Dexmedetomidine Effects on Microelectrode Recording in Deep Brain Stimulation
NCT04748640	Phase 2/3	RECRUITING	Bilateral Essential Tremor Treatment With Gamma Knife
NCT05366751	Phase 2/3	TERMINATED	A Study to Evaluate the Long-term Safety and Tolerability of SAGE-324 in Participants With Essential Tremor
NCT00620165	Phase 1/2	COMPLETED	Efficacy of Levetiracetam in Essential Tremor
NCT00848172	Phase 1/2	COMPLETED	Double-Blind, Placebo Controlled Pilot Study of Octanoic Acid in Essential Tremor
NCT03805750	Phase 1/2	COMPLETED	Trial of Cannabis for Essential Tremor
NCT07344194	Phase 1/2	RECRUITING	Dual-Site Transcranial Magnetic Stimulation of the Supplementary Motor Area and Cerebellum for the Treatment of Essential Tremor.
NCT07484152	Phase 1/2	NOT_YET_RECRUITING	Motor and Non-Motor Effects of Low-Intensity Focused Ultrasound (LIFU) as a Neuromodulation Tool in Essential Tremor
NCT00646451	Early Phase 1	COMPLETED	Pregabalin in the Treatment of Essential Tremor
NCT05475340	Early Phase 1	UNKNOWN	Open Label Study for the Use of Transcranial Ultrasound Treatment of Tremor
NCT07599592	Early Phase 1	RECRUITING	Open Label Study for the Use of Low Intensity Focused Ultrasound for Essential Tremor
NCT07721272	Early Phase 1	NOT_YET_RECRUITING	Human Cognition During Surgery: Stimulation-based and Cholinergic Modulation
NCT00368199	Not specified	COMPLETED	Transcranial Duplex Scanning and Single Photon Emission Computer Tomography (SPECT) in Parkinsonian Syndromes
NCT00575081	Not specified	RECRUITING	Physiological Brain Atlas Development
NCT00616343	Not specified	TERMINATED	Zonisamide in the Treatment of Essential Tremor