KCNH4

Summary

KCNH4 (potassium voltage-gated channel subfamily H member 4, HGNC:6253) is a protein-coding gene on chromosome 17q21.2, encoding Voltage-gated delayed rectifier potassium channel KCNH4 (Q9UQ05). Pore-forming (alpha) subunit of a voltage-gated delayed rectifier.

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. The gene is brain-specific, and located in the neocortex and the striatum. It may be involved in cellular excitability of restricted neurons in the central nervous system.

Source: NCBI Gene 23415 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 135 total
• Regional missense constraint (gnomAD): 1 of 4 regions constrained (≈1% of expected missense variation)
• GTEx eGene: eQTL in 18 tissues, sQTL in 0 (q < 0.05)
• Constraint (gnomAD): pLI 0.95 (loss-of-function intolerant), LOEUF 0.50 (moderately constrained)
• MANE Select transcript: NM_012285
• Notable: 135 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6253
Approved symbol	KCNH4
Name	potassium voltage-gated channel subfamily H member 4
Location	17q21.2
Locus type	gene with protein product
Status	Approved
Aliases	Kv12.3, elk1
Ensembl gene	ENSG00000089558
Ensembl biotype	protein_coding
OMIM	604528
Entrez	23415

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

MANE Select: ENST00000264661

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1, TSL 5: 1

ENST00000264661, ENST00000607371, ENST00001138945

RefSeq mRNA: 1 — MANE Select: NM_012285 NM_012285

CCDS: CCDS11420

Canonical transcript exons

ENST00000264661 — 17 exons

Exon	Start	End
ENSE00001059058	42175579	42175736
ENSE00001059059	42171788	42171995
ENSE00001059060	42170107	42170301
ENSE00001059063	42178100	42178227
ENSE00001059065	42178331	42178477
ENSE00001059066	42176054	42176297
ENSE00001059067	42178793	42179026
ENSE00001136932	42180870	42181142
ENSE00001179445	42162248	42162321
ENSE00001179452	42163228	42163334
ENSE00001179483	42164130	42164168
ENSE00001179498	42166297	42166546
ENSE00001179505	42169477	42169676
ENSE00001231223	42163606	42163958
ENSE00001231237	42165449	42165693
ENSE00001231300	42159731	42160435
ENSE00003696982	42156891	42157118

Expression profiles

Bgee: expression breadth broad, 96 present calls, max score 82.80.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.1764 / max 36.3058, expressed in 77 samples.

Highest expression (Bgee): buccal mucosa cell, putamen, male germ line stem cell (sensu Vertebrata) in testis, caudate nucleus, nucleus accumbens.

Genetic regulation across tissues (GTEx eQTL / sQTL)

KCNH4 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 18 tissues and its splicing (sQTL) in 0 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

18 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Adipose Subcutaneous	eqtl	1.5e-16	+0.38	17:42122855:A:C
Esophagus Muscularis	eqtl	3.2e-08	+0.40	17:42136994:G:A
Adipose Visceral Omentum	eqtl	1.7e-07	+0.28	17:42119952:A:G
Breast Mammary Tissue	eqtl	1.8e-07	+0.25	17:42143379:G:A
Nerve Tibial	eqtl	4.8e-07	+0.32	17:42137747:C:T
Muscle Skeletal	eqtl	3.1e-06	+0.30	17:42122855:A:C
Heart Left Ventricle	eqtl	2.2e-04	+0.27	17:42129045:T:G
Skin Not Sun Exposed Suprapubic	eqtl	5.7e-04	+0.27	17:42141847:T:C
Colon Transverse	eqtl	6.7e-04	+0.32	17:42122182:G:A
Esophagus Gastroesophageal Junction	eqtl	7.8e-04	+0.34	17:42119952:A:G
Brain Caudate basal ganglia	eqtl	3.6e-03	+0.41	17:42180123:G:C
Thyroid	eqtl	5.5e-03	+0.23	17:42122855:A:C
Lung	eqtl	5.6e-03	+0.26	17:42122855:A:C
Colon Sigmoid	eqtl	1.0e-02	+0.28	17:42123884:C:T
Small Intestine Terminal Ileum	eqtl	1.2e-02	-0.83	17:42283439:A:G
Artery Tibial	eqtl	1.4e-02	+0.19	17:42137747:C:T
Skin Sun Exposed Lower leg	eqtl	2.1e-02	+0.22	17:42145640:C:G
Heart Atrial Appendage	eqtl	3.5e-02	+0.81	17:41960992:G:A

FANTOM5 promoters

2 alternative TSS:

Promoter ID	TPM avg	Samples expressed
166111	0.1072	53
166110	0.0692	36

Top tissues by expression

showing 100 of 215 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	82.80	gold quality
putamen	UBERON:0001874	77.67	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	75.97	silver quality
caudate nucleus	UBERON:0001873	75.46	gold quality
nucleus accumbens	UBERON:0001882	73.02	gold quality
myocardium	UBERON:0002349	69.28	gold quality
prefrontal cortex	UBERON:0000451	68.32	gold quality
right frontal lobe	UBERON:0002810	66.37	gold quality
Brodmann (1909) area 9	UBERON:0013540	64.36	gold quality
frontal cortex	UBERON:0001870	63.52	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	63.10	gold quality
primary visual cortex	UBERON:0002436	63.05	gold quality
nasal cavity epithelium	UBERON:0005384	62.97	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	62.13	gold quality
neocortex	UBERON:0001950	61.54	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	60.36	gold quality
biceps brachii	UBERON:0001507	60.16	gold quality
forebrain	UBERON:0001890	58.81	gold quality
cerebral cortex	UBERON:0000956	57.81	gold quality
secondary oocyte	CL:0000655	57.39	gold quality
superficial temporal artery	UBERON:0001614	57.29	gold quality
occipital lobe	UBERON:0002021	57.24	gold quality
anterior cingulate cortex	UBERON:0009835	57.08	gold quality
heart right ventricle	UBERON:0002080	57.01	gold quality
gingiva	UBERON:0001828	56.91	gold quality
vastus lateralis	UBERON:0001379	56.61	gold quality
quadriceps femoris	UBERON:0001377	56.25	gold quality
oral cavity	UBERON:0000167	56.10	gold quality
medial globus pallidus	UBERON:0002477	55.95	gold quality
vermiform appendix	UBERON:0001154	55.41	gold quality
gingival epithelium	UBERON:0001949	55.22	gold quality
brain	UBERON:0000955	55.07	gold quality
globus pallidus	UBERON:0001875	54.62	gold quality
decidua	UBERON:0002450	54.37	gold quality
trabecular bone tissue	UBERON:0002483	54.35	gold quality
caecum	UBERON:0001153	54.07	gold quality
lateral globus pallidus	UBERON:0002476	54.07	gold quality
tendon of biceps brachii	UBERON:0008188	53.82	gold quality
Brodmann (1909) area 23	UBERON:0013554	53.81	gold quality
middle temporal gyrus	UBERON:0002771	52.54	gold quality
cartilage tissue	UBERON:0002418	52.53	gold quality
amygdala	UBERON:0001876	52.12	gold quality
urinary bladder	UBERON:0001255	52.09	gold quality
skeletal muscle tissue	UBERON:0001134	52.06	gold quality
deltoid	UBERON:0001476	50.88	gold quality
hypothalamus	UBERON:0001898	50.53	gold quality
sperm	CL:0000019	49.87	gold quality
substantia nigra pars compacta	UBERON:0001965	49.81	gold quality
stromal cell of endometrium	CL:0002255	49.80	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	49.48	gold quality
temporal lobe	UBERON:0001871	49.17	gold quality
lymph node	UBERON:0000029	48.38	silver quality
subcutaneous adipose tissue	UBERON:0002190	48.38	gold quality
bone marrow cell	CL:0002092	48.27	gold quality
granulocyte	CL:0000094	48.19	silver quality
cardiac ventricle	UBERON:0002082	48.02	gold quality
heart left ventricle	UBERON:0002084	47.91	gold quality
omental fat pad	UBERON:0010414	47.62	gold quality
peritoneum	UBERON:0002358	47.60	gold quality
adipose tissue of abdominal region	UBERON:0007808	47.27	gold quality
superior frontal gyrus	UBERON:0002661	47.11	gold quality
adipose tissue	UBERON:0001013	46.60	gold quality
lateral nuclear group of thalamus	UBERON:0002736	46.19	gold quality
placenta	UBERON:0001987	46.12	gold quality
islet of Langerhans	UBERON:0000006	45.93	gold quality
right adrenal gland	UBERON:0001233	45.87	gold quality
colonic epithelium	UBERON:0000397	45.50	gold quality
saphenous vein	UBERON:0007318	45.32	gold quality
upper leg skin	UBERON:0004262	45.25	silver quality
amniotic fluid	UBERON:0000173	45.21	gold quality
Ammon’s horn	UBERON:0001954	45.20	gold quality
gall bladder	UBERON:0002110	45.17	silver quality
heart	UBERON:0000948	45.05	gold quality
right adrenal gland cortex	UBERON:0035827	44.76	gold quality
colonic mucosa	UBERON:0000317	44.68	gold quality
blood	UBERON:0000178	44.60	gold quality
apex of heart	UBERON:0002098	44.60	silver quality
adrenal gland	UBERON:0002369	44.58	gold quality
left adrenal gland	UBERON:0001234	44.38	gold quality
small intestine Peyer’s patch	UBERON:0003454	44.33	gold quality
small intestine	UBERON:0002108	44.23	gold quality
entorhinal cortex	UBERON:0002728	44.17	gold quality
tonsil	UBERON:0002372	44.10	silver quality
myometrium	UBERON:0001296	44.08	gold quality
left adrenal gland cortex	UBERON:0035825	43.76	gold quality
adrenal cortex	UBERON:0001235	43.69	gold quality
adult organism	UBERON:0007023	43.44	gold quality
inferior vagus X ganglion	UBERON:0005363	43.31	gold quality
ventricular zone	UBERON:0003053	43.28	gold quality
cauda epididymis	UBERON:0004360	43.26	gold quality
left uterine tube	UBERON:0001303	43.24	gold quality
trachea	UBERON:0003126	43.23	gold quality
cortical plate	UBERON:0005343	43.22	gold quality
anatomical system	UBERON:0000467	43.10	gold quality
oocyte	CL:0000023	43.09	gold quality
material anatomical entity	UBERON:0000465	43.07	gold quality
multicellular organism	UBERON:0000468	43.07	gold quality
uterine cervix	UBERON:0000002	43.06	silver quality
jejunum	UBERON:0002115	42.99	gold quality
pylorus	UBERON:0001166	42.89	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.08

HPA expression

RNA tissue specificity: Tissue enriched

52 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM
Nucleus accumbens	tissue	17.0
Basal ganglia	tissue	11.3
Olfactory bulb	tissue	10.6
Putamen	tissue	10.3
Caudate putamen	tissue	9.4
Cerebral cortex	tissue	7.9
Temporal cortex	tissue	7.9
Occipital cortex	tissue	7.5
Ventral forebrain	tissue	7.1
Somatosensory cortex	tissue	7.1
Insular cortex	tissue	6.9
Hippocampal formation	tissue	6.8
Entorhinal cortex	tissue	6.8
Prefrontal cortex	tissue	6.2
Motor cortex	tissue	5.7
Frontal cortex	tissue	5.7
Retrosplenial and cingulate cortex	tissue	5.7
Retrosplenial cortex	tissue	4.9
Septum	tissue	3.9
Amygdala	tissue	3.8
Medulla oblongata	tissue	3.0
Spinal cord	tissue	2.9
Substantia nigra	tissue	2.6
Hypothalamus	tissue	2.4
Postcentral gyrus	tissue	2.4
Midbrain	tissue	2.2
Periaqueductal gray	tissue	2.1
Pons	tissue	2.0
Thalamus	tissue	1.5
Corpus callosum	tissue	1.5
Superior colliculi	tissue	1.4
Hippocampus	tissue	1.1
Locus coeruleus	tissue	1.0
Cerebellum	tissue	0.8
Appendix	tissue	0.5
Urinary bladder	tissue	0.3
Pituitary gland	tissue	0.2
Lymph node	tissue	0.2
Adipose tissue	tissue	0.2
Choroid plexus	tissue	0.2
Tonsil	tissue	0.2
Cervix	tissue	0.1
Testis	tissue	0.1
Stomach 1	tissue	0.1
Heart muscle	tissue	0.1
Vagina	tissue	0.1
Tongue	tissue	0.1
Spleen	tissue	0.1
Small intestine	tissue	0.1
Duodenum	tissue	0.1
Adrenal gland	tissue	0.1
Bone marrow	tissue	0.1

Brain sub-regions (HPA Brain Atlas): detected in 189; highest nTPM — Caudate nucleus (25.0), Nucleus basalis of Meynert (22.3), Temporo-occipital transitional zone (9.7), Centromedial thalamic nucleus (8.5), Parietal operculum (7.5).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

Targeting KCNH4 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 46 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4425	100.00	67.59	1049
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-12136	99.98	72.81	5713
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-9902	99.89	69.15	2250
HSA-MIR-548AZ-5P	99.83	69.94	3230
HSA-MIR-548T-5P	99.83	69.91	3220
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-6794-5P	99.76	66.38	1048
HSA-MIR-6887-3P	99.66	67.83	1778
HSA-MIR-3175	99.65	66.30	2031
HSA-MIR-3147	99.52	66.34	388
HSA-MIR-671-5P	99.52	67.11	1277
HSA-MIR-1275	99.47	67.90	2749
HSA-MIR-125A-5P	99.36	70.59	1640
HSA-MIR-125B-5P	99.36	70.36	1662
HSA-MIR-6507-3P	99.35	67.32	1059
HSA-MIR-6852-5P	99.17	66.69	2073
HSA-MIR-939-3P	98.97	65.07	2347
HSA-MIR-4451	98.82	68.17	1455
HSA-MIR-4716-5P	98.82	68.57	1168
HSA-MIR-4763-5P	98.75	63.89	854
HSA-MIR-198	98.70	67.32	920
HSA-MIR-7155-5P	98.65	66.14	1290
HSA-MIR-4700-5P	98.63	67.43	1915
HSA-MIR-6878-5P	98.49	67.91	2142
HSA-MIR-5089-5P	98.45	66.06	1388

Functional genomics

gnomAD constraint: pLI 0.95, LOEUF 0.5, missense Z 3.38 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000264661 splits into 4 regions with different missense tolerance; 1 is missense-constrained (≈1% 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
17:42,160,043–42,165,667	441 / 512.3	0.86	no
17:42,165,668–42,175,709	318 / 479.6	0.66	no
17:42,175,710–42,176,065	2 / 16.7	0.12	yes (p 3.3e-04)
17:42,176,066–42,180,945	283 / 378.6	0.75	no

Cross-species orthologs

15 orthologs

Organism	Symbol	Gene ID
danio_rerio	kcnh4b	ENSDARG00000061990
danio_rerio	kcnh4a	ENSDARG00000062565
mus_musculus	Kcnh4	ENSMUSG00000035355
rattus_norvegicus	Kcnh4	ENSRNOG00000018790
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), 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)

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
Beauveria bassiana ARSEF 2860	J5J1K4	72.1%	Diamond
Neurospora crassa OR74A	Q01371	72.1%	Diamond
Brucella anthropi ATCC 49188	A6X554	69.0%	Diamond
Fusarium oxysporum f. sp. lycopersici 4287	A0A0J9UPF5	67.2%	Diamond
Aspergillus flavus	A0A364LYQ6	62.9%	Diamond
Gallus gallus	Q9PT84	61.4%	Diamond
Bacillus subtilis subsp. subtilis str. 168	O34627	50.4%	Diamond
Erythrobacter litoralis HTCC2594	Q2NCA3	48.1%	Diamond
Halobacterium salinarum NRC-1	Q9HPU8	47.5%	Diamond
Arabidopsis thaliana	O64511	44.6%	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
KAT2A	protein-coding	2648
HCRT	protein-coding	3060
RAB5C	protein-coding	5878
GHDC	protein-coding	84514
HSPB9	protein-coding	94086
RAB5C-AS1	ncRNA	105371781
DHX58	protein-coding	79132
STAT5A	protein-coding	6776
STAT5B	protein-coding	6777
STAT3	protein-coding	6774

Protein

Protein identifiers

Voltage-gated delayed rectifier potassium channel KCNH4 — Q9UQ05 (reviewed: Q9UQ05)

Alternative names: Brain-specific eag-like channel 2, Ether-a-go-go-like potassium channel 1, Potassium voltage-gated channel subfamily H member 4, Voltage-gated potassium channel subunit Kv12.3

All UniProt accessions (1): Q9UQ05

UniProt curated annotations — full annotation on UniProt →

Function. Pore-forming (alpha) subunit of a voltage-gated delayed rectifier. Activates at more negative voltages, exhibits fast prepulse-independent activation kinetics and deactivates much more slowly, but shows no inactivation.

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. Detected only in brain, in particular in the telencephalon. Detected in putamen and caudate nucleus, and at lower levels in cerebral cortex, occipital and hippocampus.

Similarity. Belongs to the potassium channel family. H (Eag) (TC 1.A.1.20) subfamily. Kv12.3/KCNH4 sub-subfamily.

RefSeq proteins (1): NP_036417* (*=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: PF00520, PF13426

Catalyzed reactions (Rhea)

• K(+)(in) = K(+)(out) (RHEA:29463)

UniProt features (34 total): topological domain 8, transmembrane region 6, region of interest 6, compositionally biased region 5, glycosylation site 3, domain 2, chain 1, intramembrane region 1, short sequence motif 1, sequence variant 1

Structure

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UQ05-F1	67.69	0.26

Human Protein Atlas

Protein class: Voltage-gated ion channels, Voltage-Gated Potassium Channels, Predicted membrane proteins, UniProt - Evidence at transcript level

Protein evidence: Evidence at transcript level

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 (3)

Type	Positions
N-linked (glcnac…) asparagine	326, 414, 473

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: 388 (showing top): PID_BCR_5PATHWAY, GOBP_POTASSIUM_ION_TRANSPORT, RNGTGGGC_UNKNOWN, GOBP_RESPONSE_TO_ETHANOL, GOBP_HEPATICOBILIARY_SYSTEM_DEVELOPMENT, GOBP_RESPONSE_TO_IONIZING_RADIATION, BIOCARTA_FMLP_PATHWAY, REACTOME_INNATE_IMMUNE_SYSTEM, REACTOME_VOLTAGE_GATED_POTASSIUM_CHANNELS, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_CELLULAR_RESPONSE_TO_LIPID, REACTOME_POTASSIUM_CHANNELS, KEGG_MAPK_SIGNALING_PATHWAY, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, AAGCCAT_MIR135A_MIR135B

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 (3): voltage-gated potassium channel activity (GO:0005249), monoatomic ion channel activity (GO:0005216), potassium channel activity (GO:0005267)

GO Cellular Component (4): plasma membrane (GO:0005886), voltage-gated potassium channel complex (GO:0008076), membrane (GO:0016020), monoatomic ion channel complex (GO:0034702)

Reactome top-level categories

2 top-level categories:

Category	Pathways
Potassium Channels	1
Neuronal System	1

GO top-level categories

21 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
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
potassium channel complex	1
plasma membrane protein complex	1
cellular anatomical structure	1
transmembrane transporter complex	1

Protein interactions and networks

STRING

showing 15 of 710 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KCNH4	GHDC	Q8N2G8	713
KCNH4	DHX58	Q96C10	679
KCNH4	KCNG1	Q9UIX4	523
KCNH4	KCNF1	Q9H3M0	516
KCNH4	HCRT	O43612	486
KCNH4	PRSS12	P56730	479
KCNH4	KCNS2	Q9ULS6	478
KCNH4	COL24A1	Q17RW2	473
KCNH4	TBC1D31	Q96DN5	455
KCNH4	KCNA10	Q16322	436
KCNH4	STAT5B	P51692	421
KCNH4	C1QL2	Q7Z5L3	404
KCNH4	KAT2A	Q92830	399
KCNH4	KCNV1	Q6PIU1	392
KCNH4	SCN3B	Q9NY72	384

IntAct

Human interaction partners of KCNH4 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

1 partners by confidence:

Partner	Interaction type	MIscore	Records
ARFGEF2	association	0.350	1

BioGRID (11 interactions; top human partners by supporting records): ARFGEF1 (Affinity Capture-MS), ARFGEF2 (Affinity Capture-MS), DDX39A (Affinity Capture-RNA), DDX58 (Affinity Capture-RNA), KCNH1 (Negative Genetic), KCNH2 (Negative Genetic), KCNH3 (Negative Genetic), KCNH5 (Negative Genetic), KCNH6 (Negative Genetic), KCNH8 (Negative Genetic), TUBB7P (Affinity Capture-MS)

Protein complexes (CORUM) (1)

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

1 complexes by size:

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

Disease & clinical

Genetic variants

Variant evidence for KCNH4: 135 ClinVar records (0 pathogenic / likely pathogenic); 4 GWAS associations.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	123
Likely benign	6
Benign	1

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 34 predictions of 1,717):

Position(s)	Effect	Δscore	Sites
17:42166295–42166296	donor_loss	1.0000	5
17:42169475–42169476	donor_loss	1.0000	4
17:42171997	acceptor_loss	1.0000	3
17:42175577–42175578	donor_loss	1.0000	5
17:42176052–42176053	donor_loss	1.0000	5
17:42178119	donor_gain	1.0000
17:42178791–42178792	donor_loss	1.0000	3
17:42178795	donor_gain	1.0000
17:42179027–42179028	acceptor_loss	1.0000	6
17:42166295	donor_loss	0.9900

AlphaMissense

2,122 missense substitutions predicted likely pathogenic (of 6,543 scored), across 498 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
M460	9	0.926	0.994
M61	9	0.883	0.979
D312	8	0.992	0.997
F442	8	0.992	1.000
F471	8	0.992	0.999
F274	8	0.985	0.997
D277	8	0.985	0.992
N12	8	0.977	0.995
F49	8	0.973	0.999
F369	8	0.973	0.998
H374	8	0.973	0.994
F29	8	0.972	0.998
D588	8	0.967	0.993
N444	8	0.966	0.999
D617	8	0.965	0.989
F14	8	0.964	0.998
F557	8	0.961	0.985
F455	8	0.957	0.993
D542	8	0.957	0.989
F69	8	0.956	0.996

HPA cancer prognostics

RNA cancer specificity: Not detected

Disease associations

OMIM: gene MIM:604528 | disease phenotypes:

GWAS associations

4 associations:

Study	Trait	p-value
GCST004278_26	Pulse pressure	3e-9
GCST004278_7	Pulse pressure	3e-9
GCST004278_35	Pulse pressure	6e-8
GCST004278_48	Pulse pressure	4e-7

EFO canonical traits (from GWAS)

1 canonical traits:

EFO ID	Trait name
EFO:0005763	pulse pressure 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)

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

12 total (human), top 12 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression	2
benzo(e)pyrene	increases methylation	1
CGP 52608	affects binding, increases reaction	1
Resveratrol	affects cotreatment, decreases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Ivermectin	increases expression	1
Methapyrilene	increases methylation	1
Plant Extracts	affects cotreatment, decreases expression	1
Tretinoin	increases expression	1
Valproic Acid	increases methylation	1
Sodium Selenite	decreases expression	1
Coal Ash	increases 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.