KCNH5

Summary

KCNH5 (potassium voltage-gated channel subfamily H member 5, HGNC:6254) is a protein-coding gene on chromosome 14q23.2, encoding Voltage-gated delayed rectifier potassium channel KCNH5 (Q8NCM2). Pore-forming (alpha) subunit of a voltage-gated delayed rectifier potassium channel that mediates outward-rectifying potassium currents which, on depolarization, reaches a steady-state level and do not inactivate.

This gene encodes a member of voltage-gated potassium channels. Members of this family have diverse functions, including regulating neurotransmitter and hormone release, cardiac function, and cell volume. This protein is an outward-rectifying, noninactivating channel. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 27133 — RefSeq curated summary.

At a glance

• Gene–disease (curated): infantile-onset epilepsy (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 9
• Clinical variants (ClinVar): 865 total — 6 pathogenic, 6 likely-pathogenic
• Phenotypes (HPO): 73
• Druggable target: yes
• MANE Select transcript: NM_139318

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6254
Approved symbol	KCNH5
Name	potassium voltage-gated channel subfamily H member 5
Location	14q23.2
Locus type	gene with protein product
Status	Approved
Aliases	Kv10.2, H-EAG2, eag2, hEAG2
Ensembl gene	ENSG00000140015
Ensembl biotype	protein_coding
OMIM	605716
Entrez	27133

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 3 protein_coding, 1 retained_intron

ENST00000322893, ENST00000394964, ENST00000394968, ENST00000420622

RefSeq mRNA: 2 — MANE Select: NM_139318 NM_139318, NM_172375

CCDS: CCDS45122, CCDS9756

Canonical transcript exons

ENST00000322893 — 11 exons

Exon	Start	End
ENSE00001172080	62779728	62779924
ENSE00001194217	62699464	62708455
ENSE00001304563	62950133	62950559
ENSE00001773437	62849653	62849852
ENSE00001781141	62802329	62802581
ENSE00001931443	63045114	63045458
ENSE00003681757	63016831	63016954
ENSE00003719681	62987072	62987187
ENSE00003721518	63001331	63001459
ENSE00003721941	63006366	63006472
ENSE00003741504	62980872	62981264

Expression profiles

Bgee: expression breadth broad, 83 present calls, max score 96.34.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.3183 / max 15.0185, expressed in 136 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
143588	0.2015	95
143587	0.1168	62

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	96.34	gold quality
secondary oocyte	CL:0000655	82.08	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	79.26	gold quality
oocyte	CL:0000023	74.48	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	72.83	gold quality
pigmented layer of retina	UBERON:0001782	71.06	gold quality
prefrontal cortex	UBERON:0000451	70.58	gold quality
lateral nuclear group of thalamus	UBERON:0002736	68.41	silver quality
Brodmann (1909) area 9	UBERON:0013540	67.51	gold quality
cortical plate	UBERON:0005343	67.19	gold quality
primary visual cortex	UBERON:0002436	67.11	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	66.70	gold quality
colonic epithelium	UBERON:0000397	66.60	gold quality
frontal cortex	UBERON:0001870	65.53	gold quality
neocortex	UBERON:0001950	64.35	gold quality
right frontal lobe	UBERON:0002810	61.54	gold quality
superior frontal gyrus	UBERON:0002661	61.42	gold quality
occipital lobe	UBERON:0002021	61.40	gold quality
cerebral cortex	UBERON:0000956	61.15	gold quality
Brodmann (1909) area 46	UBERON:0006483	60.41	gold quality
anterior cingulate cortex	UBERON:0009835	59.75	gold quality
Brodmann (1909) area 23	UBERON:0013554	59.24	silver quality
ventricular zone	UBERON:0003053	58.70	silver quality
parotid gland	UBERON:0001831	58.15	gold quality
postcentral gyrus	UBERON:0002581	57.80	silver quality
hypothalamus	UBERON:0001898	57.29	gold quality
corpus callosum	UBERON:0002336	56.76	gold quality
parietal lobe	UBERON:0001872	55.85	silver quality
middle temporal gyrus	UBERON:0002771	55.65	gold quality
pons	UBERON:0000988	55.16	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	62.42
E-ANND-3	yes	5.85

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

70 targeting KCNH5, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-329-3P	99.91	66.56	1234
HSA-MIR-362-3P	99.91	66.38	1267
HSA-MIR-6499-3P	99.90	66.38	1212
HSA-MIR-3941	99.86	70.54	2735
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-6844	99.82	70.69	2423
HSA-MIR-2052	99.79	69.37	2031
HSA-MIR-132-3P	99.73	70.56	1424
HSA-MIR-212-3P	99.73	70.65	1424
HSA-MIR-452-5P	99.65	69.63	1762

Literature-anchored findings (GeneRIF, showing 14)

• molecular identification and characterisation (PMID:12135768)
• Methylation of KCNH5 was present in 80% of NSCLC tissues but only in 14% of noncancerous tissues. (PMID:18349282)
• data suggest that the ‘Per-Ant-Sim’ (PAS) and cyclic nucleotide binding (cNBD) domains at the N- and C-termini form interacting oligomers that have roles in channel function (PMID:19172261)
• Three-dimensional structure of human Kv10.2 ion channel studied by single particle electron microscopy and molecular modeling (PMID:22792721)
• This study performed whole exome sequencing demonistrated that the true de novo variants represent mutations in genes (KCNH5, CLCN4, and ARHGEF15) not previously associated with epilepsies in humans. (PMID:23647072)
• Our results demonstrate the critical role of the Arg327 residue in stabilizing the channel closed state and explicate for the first time the structural and functional change of a Kv10.2 channel mutation associated with neurological disease. (PMID:24133262)
• Study propose that hypomethylation of the placental-specific KCNH5 promoter is frequently associated with KCNH5 expression in melanoma cells. (PMID:24759919)
• The observed Ca(2+)-induced proteolytic cleavage of EAG2 channel may act as an adaptive response under physiological and/or pathological conditions. (PMID:25542181)
• EAG2 potassium channel has an evolutionarily conserved function for promoting brain tumor growth. (PMID:26258683)
• Chloride intracellular channel 1 cooperates with potassium channel EAG2 to promote medulloblastoma growth. (PMID:32097463)
• Regional heritability mapping identifies several novel loci (STAT4, ULK4, and KCNH5) for primary biliary cholangitis in the Japanese population. (PMID:33833419)
• A novel loss-of-function mutation of the voltage-gated potassium channel Kv10.2 involved in epilepsy and autism. (PMID:36068614)
• Neurodevelopmental and Epilepsy Phenotypes in Individuals With Missense Variants in the Voltage-Sensing and Pore Domains of KCNH5. (PMID:36307226)
• Mechanism underlying delayed rectifying in human voltage-mediated activation Eag2 channel. (PMID:36928654)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	kcnh5a	ENSDARG00000043220
danio_rerio	kcnh5b	ENSDARG00000069117
mus_musculus	Kcnh5	ENSMUSG00000034402
rattus_norvegicus	Kcnh5	ENSRNOG00000009542
drosophila_melanogaster	Elk	FBGN0011589
drosophila_melanogaster	Cngl	FBGN0263257
caenorhabditis_elegans		WBGENE00001171

Paralogs (17): KCNH2 (ENSG00000055118), CNGB1 (ENSG00000070729), KCNH4 (ENSG00000089558), HCN2 (ENSG00000099822), CNGA4 (ENSG00000132259), KCNH3 (ENSG00000135519), HCN4 (ENSG00000138622), KCNH1 (ENSG00000143473), HCN3 (ENSG00000143630), CNGA3 (ENSG00000144191), HCN1 (ENSG00000164588), CNGB3 (ENSG00000170289), KCNH6 (ENSG00000173826), CNGA2 (ENSG00000183862), KCNH8 (ENSG00000183960), KCNH7 (ENSG00000184611), CNGA1 (ENSG00000198515)

Protein

Protein identifiers

Voltage-gated delayed rectifier potassium channel KCNH5 — Q8NCM2 (reviewed: Q8NCM2)

Alternative names: Ether-a-go-go potassium channel 2, Potassium voltage-gated channel subfamily H member 5, Voltage-gated potassium channel subunit Kv10.2

All UniProt accessions (1): Q8NCM2

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 which, on depolarization, reaches a steady-state level and do not inactivate. The kinetic is characterized by a slow activation time course and a small voltage dependence of the activation time constants, therefore, starts to open at more negative voltages. The activation kinetics depend on the prepulse potential and external divalent cation concentration. The time course of activation is biphasic with a fast and a slowly activating current component. With negative prepulses, the current activation is delayed and slowed down several fold, whereas more positive prepulses speed up activation, therefore the activation rate depends on holding potential.

Subunit / interactions. Homotetramer. The potassium channel is probably composed of a homo- or heterotetrameric complex of pore-forming alpha subunits that can associate with modulating beta subunits. Heteromultimer with KCNH1/EAG.

Subcellular location. Membrane.

Tissue specificity. Detected in brain, skeletal muscle, heart, placenta, lung and liver, and at low levels in kidney.

Disease relevance. Developmental and epileptic encephalopathy 112 (DEE112) [MIM:620537] A form of epileptic encephalopathy, a heterogeneous group of early-onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. DEE112 is an autosomal dominant form characterized by onset in infancy, and a wide range of seizure types including focal and generalized seizures. Cognitive outcomes range from normal intellect to profound intellectual development impairment. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Contains a voltage sensor domain (VSD) formed from the S1-S4 transmembrane helices, a pore domain formed from the S5-pore loop-S6 domain and the C-terminal cyclic nucleotide binding homology domain (CNBHD). The segment S4 is probably the voltage-sensor and is characterized by a series of positively charged amino acids at every third position.

Similarity. Belongs to the potassium channel family. H (Eag) (TC 1.A.1.20) subfamily. Kv10.2/KCNH5 sub-subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
Q8NCM2-1	1	yes
Q8NCM2-2	2, 2b
Q8NCM2-3	3

RefSeq proteins (2): NP_647479, NP_758963 (=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
IPR003949	K_chnl_volt-dep_EAG	Family
IPR005821	Ion_trans_dom	Domain
IPR014710	RmlC-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), 1 shown:

• K(+)(in) = K(+)(out) (RHEA:29463)

UniProt features (108 total): helix 29, strand 23, turn 9, topological domain 8, sequence variant 8, transmembrane region 6, region of interest 5, splice variant 5, compositionally biased region 3, mutagenesis site 3, domain 2, chain 1, intramembrane region 1, short sequence motif 1, binding site 1, modified residue 1, glycosylation site 1, cross-link 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
7YID	ELECTRON MICROSCOPY	3.4
7YIE	ELECTRON MICROSCOPY	3.4
7YIF	ELECTRON MICROSCOPY	3.5
7YIH	ELECTRON MICROSCOPY	3.5
7YIG	ELECTRON MICROSCOPY	3.6
7YIJ	ELECTRON MICROSCOPY	3.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8NCM2-F1	72.67	0.39

Functional residue map

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

Ligand- & substrate-binding residues (1): 550–667

Post-translational modifications (2): 883, 785

Glycosylation sites (1): 403

Mutagenesis-validated functional residues (3):

Position	Phenotype
337	left-shifts the half-activation membrane potential.
468	reduces the delayed rectifier potassium channel activity. has little effect on the voltage sensitivity.
472	almost loss of the delayed rectifier potassium channel activity. has little effect on the voltage sensitivity.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

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

MSigDB gene sets: 262 (showing top): GOBP_POTASSIUM_ION_TRANSPORT, REACTOME_VOLTAGE_GATED_POTASSIUM_CHANNELS, NKX25_02, REACTOME_POTASSIUM_CHANNELS, GOBP_CELL_CYCLE_PHASE_TRANSITION, GOCC_CELL_SURFACE, ATGCAGT_MIR217, LHX3_01, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_REGULATION_OF_CELL_CYCLE_G2_M_PHASE_TRANSITION, MYOD_01, GATA6_01, GOBP_REGULATION_OF_CELL_CYCLE, GOBP_MITOTIC_CELL_CYCLE, MYOD_Q6

GO Biological Process (7): potassium ion transport (GO:0006813), regulation of G2/M transition of mitotic cell cycle (GO:0010389), 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 (7): voltage-gated potassium channel activity (GO:0005249), delayed rectifier potassium channel activity (GO:0005251), calmodulin binding (GO:0005516), transmembrane transporter binding (GO:0044325), protein-containing complex binding (GO:0044877), monoatomic ion channel activity (GO:0005216), potassium channel activity (GO:0005267)

GO Cellular Component (5): plasma membrane (GO:0005886), voltage-gated potassium channel complex (GO:0008076), cell surface (GO:0009986), membrane (GO:0016020), monoatomic ion channel complex (GO:0034702)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Potassium Channels	1
Neuronal System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transport	2
protein binding	2
cellular anatomical structure	2
metal ion transport	1
G2/M transition of mitotic cell cycle	1
regulation of mitotic cell cycle phase transition	1
regulation of cell cycle G2/M phase transition	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
binding	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
transmembrane transporter complex	1

Protein interactions and networks

STRING

908 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KCNH5	KCNQ3	O43525	517
KCNH5	KCND1	Q9NSA2	504
KCNH5	KCNQ2	O43526	488
KCNH5	KCNT1	Q5JUK3	480
KCNH5	KCND2	Q9NZV8	475
KCNH5	KCNB1	Q14721	468
KCNH5	KCNA2	P16389	465
KCNH5	KCNMA1	Q12791	455
KCNH5	KCNB2	Q92953	449
KCNH5	KCND3	Q9UK17	431
KCNH5	KCNQ5	Q9NR82	419
KCNH5	KCNA1	Q09470	415
KCNH5	KCNT2	Q6UVM3	411
KCNH5	KCNC1	P48547	407
KCNH5	KCNQ1	P51787	403

IntAct

3 interactions, top by confidence:

A	B	Type	Score
KCNH5	HNRNPL	psi-mi:“MI:0915”(physical association)	0.400
M		psi-mi:“MI:0914”(association)	0.350

BioGRID (10): KCNH5 (Synthetic Lethality), TUBA1B (Affinity Capture-MS), TUBB4B (Affinity Capture-MS), HSPA8 (Affinity Capture-MS), TUBB (Affinity Capture-MS), MBP (Affinity Capture-MS), KCNH5 (Affinity Capture-Western), KCNH5 (Proximity Label-MS), KCNH5 (Negative Genetic), KCNH5 (Proximity Label-MS)

ESM2 similar proteins: A0A1S4GYH6, A0A1S4H2E2, A8XF54, A8XNX8, D4AYW0, G5EBR3, G5ECT0, G5EDN0, G5EG88, H2L006, H2QAR6, O18276, O18965, O76554, O95259, P20781, P24612, P25123, P34271, P41849, P48167, P48168, P54244, P54245, P54246, Q02280, Q09274, Q09453, Q10025, Q17298, Q18812, Q21005, Q27394, Q5BKX6, Q60603, Q60NC0, Q63472, Q75NA5, Q86DA5, Q8NCM2

Diamond homologs: A5K0N4, G5EFJ9, O08703, O08962, O18965, O35219, O54852, O54853, O89047, O95259, P29281, P59111, Q02280, Q12809, Q60603, Q63472, Q8I719, Q8NCM2, Q8WNY2, Q920E3, Q96L42, Q9EPI9, Q9ER47, Q9H252, Q9NS40, Q9PT84, Q9QWS8, Q9R1T9, Q9TSZ3, Q9TUI4, Q9ULD8, Q9UQ05, Q9WVJ0, W7JX98, A0A509AKL0, O64511, P93025, Q1M667, Q2NCA3, Q2QYY8

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	6
Uncertain significance	426
Likely benign	339
Benign	52

Top pathogenic / likely-pathogenic (12)

Variant ID	HGVS	Classification
100784	NM_139318.5(KCNH5):c.980G>A (p.Arg327His)	Pathogenic
1042182	NM_139318.5(KCNH5):c.998G>A (p.Arg333His)	Pathogenic
2583108	NM_139318.5(KCNH5):c.2020-4A>G	Pathogenic
2583110	NM_139318.5(KCNH5):c.1402A>C (p.Thr468Pro)	Pathogenic
2583111	NM_139318.5(KCNH5):c.1412T>C (p.Phe471Ser)	Pathogenic
2713328	NM_139318.5(KCNH5):c.908A>G (p.Tyr303Cys)	Pathogenic
1488521	NM_139318.5(KCNH5):c.979C>T (p.Arg327Cys)	Likely pathogenic
2583163	NM_139318.5(KCNH5):c.1382C>A (p.Ala461Glu)	Likely pathogenic
2835906	NM_139318.5(KCNH5):c.979C>A (p.Arg327Ser)	Likely pathogenic
4041567	NM_139318.5(KCNH5):c.998G>T (p.Arg333Leu)	Likely pathogenic
4278299	NM_139318.5(KCNH5):c.1679G>A (p.Arg560His)	Likely pathogenic
4833037	NM_139318.5(KCNH5):c.388G>C (p.Asp130His)	Likely pathogenic

SpliceAI

3149 predictions. Top by Δscore:

Variant	Effect	Δscore
14:62779721:AACAT:A	donor_loss	1.0000
14:62779722:ACATA:A	donor_loss	1.0000
14:62779723:CATA:C	donor_loss	1.0000
14:62779724:ATACC:A	donor_loss	1.0000
14:62779725:TACCC:T	donor_loss	1.0000
14:62779726:A:AC	donor_gain	1.0000
14:62779726:AC:A	donor_gain	1.0000
14:62779727:C:CC	donor_gain	1.0000
14:62779727:CC:C	donor_gain	1.0000
14:62779760:T:TA	donor_gain	1.0000
14:62779920:CTTCC:C	acceptor_gain	1.0000
14:62779922:TCC:T	acceptor_gain	1.0000
14:62779923:CCC:C	acceptor_gain	1.0000
14:62849647:CCATA:C	donor_loss	1.0000
14:62849648:CATA:C	donor_loss	1.0000
14:62849650:TAC:T	donor_loss	1.0000
14:62849652:C:G	donor_loss	1.0000
14:62849853:C:CC	acceptor_gain	1.0000
14:62950131:A:AC	donor_gain	1.0000
14:62950131:ACAG:A	donor_gain	1.0000
14:62950132:C:CC	donor_gain	1.0000
14:62950132:CAG:C	donor_gain	1.0000
14:62950132:CAGC:C	donor_gain	1.0000
14:62987066:A:AC	donor_gain	1.0000
14:62987066:ACTT:A	donor_loss	1.0000
14:62987067:C:CC	donor_gain	1.0000
14:62987067:CTTA:C	donor_gain	1.0000
14:62987068:TTACT:T	donor_loss	1.0000
14:62987069:TA:T	donor_loss	1.0000
14:62987070:A:AC	donor_gain	1.0000

AlphaMissense

6534 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:62708346:A:G	F710S	1.000
14:62708358:A:T	V706D	1.000
14:62708363:G:C	H704Q	1.000
14:62708363:G:T	H704Q	1.000
14:62708364:T:C	H704R	1.000
14:62708447:A:C	F676L	1.000
14:62708447:A:T	F676L	1.000
14:62708448:A:G	F676S	1.000
14:62708449:A:G	F676L	1.000
14:62779735:C:A	R671M	1.000
14:62779738:A:G	L670P	1.000
14:62779756:A:G	L664P	1.000
14:62779767:G:C	F660L	1.000
14:62779767:G:T	F660L	1.000
14:62779768:A:G	F660S	1.000
14:62779769:A:G	F660L	1.000
14:62779779:A:C	F656L	1.000
14:62779779:A:T	F656L	1.000
14:62779780:A:C	F656C	1.000
14:62779780:A:G	F656S	1.000
14:62779781:A:G	F656L	1.000
14:62779791:A:C	F652L	1.000
14:62779791:A:T	F652L	1.000
14:62779793:A:G	F652L	1.000
14:62779798:A:G	L650P	1.000
14:62779810:A:G	L646S	1.000
14:62779825:A:T	I641N	1.000
14:62779834:A:G	L638P	1.000
14:62779839:A:C	C636W	1.000
14:62779840:C:T	C636Y	1.000

dbSNP variants (sampled 300 via entrez): RS1000002596 (14:62980806 C>A), RS1000015333 (14:62897958 G>A,C), RS1000016446 (14:62910414 A>G), RS1000021948 (14:62821323 A>C), RS1000054447 (14:62821693 A>G), RS1000091322 (14:62751811 A>T), RS1000091341 (14:62792531 G>T), RS1000098561 (14:62928909 T>C), RS1000106083 (14:62958485 T>C), RS1000106622 (14:63017167 A>T), RS1000112534 (14:63041653 A>G), RS1000118495 (14:62903749 T>C), RS1000125467 (14:62730189 G>T), RS1000127786 (14:62873727 T>C,G), RS1000129058 (14:62837605 C>A)

Disease associations

OMIM: gene MIM:605716 | disease phenotypes: MIM:620537, MIM:618416

GenCC curated gene-disease

Disease	Classification	Inheritance
developmental and epileptic encephalopathy 112	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
infantile-onset epilepsy	Definitive	AD

Mondo (4): developmental and epileptic encephalopathy (MONDO:0100620), early-infantile DEE (MONDO:0800491), developmental and epileptic encephalopathy 112 (MONDO:0957812), metabolic crises, recurrent, with variable encephalomyopathic features and neurologic regression (MONDO:0032736)

Orphanet (2): Early infantile developmental and epileptic encephalopathy (Orphanet:1934), Early myoclonic encephalopathy (Orphanet:1935)

HPO phenotypes

73 total (30 of 73 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000158	Macroglossia
HP:0000252	Microcephaly
HP:0000348	High forehead
HP:0000494	Downslanted palpebral fissures
HP:0000504	Abnormality of vision
HP:0000508	Ptosis
HP:0000546	Retinal degeneration
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000668	Hypodontia
HP:0000708	Atypical behavior
HP:0000717	Autism
HP:0000729	Autistic behavior
HP:0000750	Delayed speech and language development
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001265	Hyporeflexia
HP:0001268	Mental deterioration
HP:0001270	Motor delay
HP:0001273	Abnormal corpus callosum morphology
HP:0001288	Gait disturbance
HP:0001290	Generalized hypotonia
HP:0001298	Encephalopathy
HP:0001315	Reduced tendon reflexes
HP:0001336	Myoclonus

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST001521_17	Subcutaneous adipose tissue	2.000000e-06
GCST001850_30	Major depressive disorder	4.000000e-06
GCST002301_4	Body mass index	5.000000e-07
GCST002347_2	Response to protease inhibitor treatment in hepatitis c (bilirubin toxicity)	6.000000e-06
GCST002652_11	Cotinine glucuronidation	2.000000e-09
GCST005316_532	Intelligence (MTAG)	5.000000e-08
GCST006914_1	Sleep duration	9.000000e-06
GCST009391_1975	Metabolite levels	4.000000e-06
GCST012490_539	Femur bone mineral density x serum urate levels interaction	4.000000e-09

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0004570	bilirubin measurement
EFO:0005657	response to protease inhibitor
EFO:0006508	cotinine glucuronidation measurement
EFO:0004337	intelligence
EFO:0008534	tryptophan measurement
EFO:0004531	urate measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2362996 (PROTEIN FAMILY)

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

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 (2 total), top 2:

Ligand	Action	Affinity	Parameter
LY97241	Pore blocker	5.8	pIC50
quinidine	Pore blocker	3.8	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

20 total (human), top 20 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, increases expression	4
Panobinostat	affects cotreatment, decreases expression	2
Benzo(a)pyrene	affects methylation, increases expression, increases methylation	2
Phenylmercuric Acetate	decreases expression, affects cotreatment	2
afuresertib	decreases expression	1
methyleugenol	decreases expression	1
potassium perchlorate	increases expression	1
trichostatin A	decreases expression, increases expression	1
arsenite	affects binding, decreases reaction	1
sulforaphane	decreases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
quinocetone	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
licochalcone B	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Acetaminophen	decreases expression	1
Copper	affects cotreatment, decreases expression	1
Malathion	increases expression	1
Tretinoin	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)

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

Trial	Phase	Status	Title
NCT03347526	PHASE3	SUSPENDED	A Novel Approach to Infantile Spasms
NCT03421496	PHASE3	TERMINATED	A Study to Assess Cannabidiol Oral Solution With Vigabatrin as Initial Therapy in Participants With Infantile Spasms
NCT06719141	PHASE3	RECRUITING	A Study to Investigate LP352 in Children and Adults With Developmental and Epileptic Encephalopathies (DEE)
NCT06908226	PHASE3	ENROLLING_BY_INVITATION	A Study to Investigate LP352 in Children and Adults With Developmental and Epileptic Encephalopathy (DEE)
NCT04289467	PHASE2	RECRUITING	Treatment of Refractory Infantile Spasms With Fenfluramine
NCT05626634	PHASE2	COMPLETED	Open-label, Long-term Safety Study of LP352 in Subjects With Developmental and Epileptic Encephalopathy
NCT04727970	PHASE1	COMPLETED	Tricaprilin Infantile Spasms Pilot Study
NCT06700811	PHASE1	RECRUITING	Ketogenic Diet for Prevention of Epileptic Spasms in Infantile Onset Genetic Epilepsies
NCT03876444	PHASE2/PHASE3	UNKNOWN	Intravenous Methylprednisolone Versus Oral Prednisolone for Infantile Spasms
NCT05279118	PHASE2/PHASE3	ACTIVE_NOT_RECRUITING	Ketogenic Diet vs ACTH for the Treatment of Children With West Syndrome
NCT05364021	PHASE1/PHASE2	COMPLETED	Study to Investigate LP352 in Subjects With Developmental and Epileptic Encephalopathies
NCT06983158	PHASE1/PHASE2	SUSPENDED	A Clinical Trial of CAP-002 Gene Therapy in Pediatric Patients With Syntaxin-Binding Protein 1 (STXBP1) Encephalopathy
NCT04937062	EARLY_PHASE1	ACTIVE_NOT_RECRUITING	Phenylbutyrate for Monogenetic Developmental and Epileptic Encephalopathy
NCT04302116	Not specified	RECRUITING	Vigabatrin With High Dose Prednisolone Combination Therapy vs Vigabatrin Alone for Infantile Spasm
NCT05538936	Not specified	COMPLETED	The Effect of Spa and Massage on Babies on Colic Symptoms
NCT06149663	Not specified	AVAILABLE	Intermediate-Size Expanded Access Protocol (EAP) for LP352
NCT06266234	Not specified	RECRUITING	Characterization by Automated System on Infantile Spasmes
NCT06380192	Not specified	RECRUITING	Developmental and Epileptic Encephalopathy of Genetic Etiology: Natural History Through Reuse of Clinical Data
NCT07396883	Not specified	NOT_YET_RECRUITING	Developmental and Epileptic Encephalopathies Diagnosed Via Long-read Genome Sequencing
NCT07413211	Not specified	RECRUITING	Genetic Developmental and Epileptic Encephalopathy Natural History Study for Clinical Trial Readiness
NCT07531511	Not specified	NOT_YET_RECRUITING	SLC6A1-NDD Prospective Longitudinal Natural History Study
NCT07585643	Not specified	NOT_YET_RECRUITING	IBIS - Investigating Reliability of BIS and SEDLINE Monitoring in Children With Developmental and Epileptic Encephalopathies (DEE).
NCT00006191	Not specified	COMPLETED	Effect of Levetiracetam on Brain Excitability
NCT02960347	Not specified	COMPLETED	Examining the Efficacy of tDCS in the Attenuation of Epileptic Paroxysmal Discharges and Clinical Seizures
NCT06938542	Not specified	ENROLLING_BY_INVITATION	Palliative Care Needs of Children With Rare Diseases and Their Families