KCNC2

Summary

KCNC2 (potassium voltage-gated channel subfamily C member 2, HGNC:6234) is a protein-coding gene on chromosome 12q21.1, encoding Voltage-gated potassium channel KCNC2 (Q96PR1). Voltage-gated potassium channel that mediates transmembrane potassium transport in excitable membranes, primarily in the brain.

The Shaker gene family of Drosophila encodes components of voltage-gated potassium channels and is comprised of four subfamilies. Based on sequence similarity, this gene is similar to one of these subfamilies, namely the Shaw subfamily. The protein encoded by this gene belongs to the delayed rectifier class of channel proteins and is an integral membrane protein that mediates the voltage-dependent potassium ion permeability of excitable membranes. Several transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 3747 — RefSeq curated summary.

At a glance

• Gene–disease (curated): genetic developmental and epileptic encephalopathy (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 3
• Clinical variants (ClinVar): 156 total — 8 pathogenic, 9 likely-pathogenic
• Phenotypes (HPO): 78
• Druggable target: yes
• MANE Select transcript: NM_139137

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6234
Approved symbol	KCNC2
Name	potassium voltage-gated channel subfamily C member 2
Location	12q21.1
Locus type	gene with protein product
Status	Approved
Aliases	Kv3.2
Ensembl gene	ENSG00000166006
Ensembl biotype	protein_coding
OMIM	176256
Entrez	3747

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 9 protein_coding, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000298972, ENST00000350228, ENST00000393288, ENST00000540018, ENST00000546456, ENST00000548243, ENST00000548513, ENST00000549446, ENST00000550433, ENST00000647764, ENST00000888265, ENST00000962253

RefSeq mRNA: 17 — MANE Select: NM_139137 NM_001260497, NM_001260498, NM_001260499, NM_001414192, NM_001414193, NM_001414194, NM_001414195, NM_001414196, NM_001414197, NM_001414198, NM_001414199, NM_001414202, NM_001414206, NM_001414213, NM_139136, NM_139137, NM_153748

CCDS: CCDS58255, CCDS58256, CCDS58257, CCDS9005, CCDS9006, CCDS9007

Canonical transcript exons

ENST00000549446 — 5 exons

Exon	Start	End
ENSE00001098889	75050390	75051317
ENSE00001098896	75048153	75048317
ENSE00001376662	75207297	75208002
ENSE00001514733	75040078	75043241
ENSE00002373868	75209207	75209839

Expression profiles

Bgee: expression breadth broad, 69 present calls, max score 90.31.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 2.2572 / max 148.3476, expressed in 133 samples.

FANTOM5 promoters (16 alternative TSS)

Promoter ID	TPM avg	Samples expressed
132151	0.8025	94
132147	0.4853	82
132148	0.2614	70
132154	0.1746	63
132155	0.1704	59
132146	0.0671	43
132144	0.0609	32
206809	0.0434	32
132153	0.0339	23
132152	0.0326	21

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
prefrontal cortex	UBERON:0000451	90.31	gold quality
Brodmann (1909) area 9	UBERON:0013540	90.28	gold quality
anterior cingulate cortex	UBERON:0009835	89.60	gold quality
right frontal lobe	UBERON:0002810	86.98	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	86.04	gold quality
frontal cortex	UBERON:0001870	83.20	gold quality
neocortex	UBERON:0001950	82.98	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.72	gold quality
hypothalamus	UBERON:0001898	79.36	gold quality
cerebral cortex	UBERON:0000956	78.67	gold quality
amygdala	UBERON:0001876	77.36	gold quality
pituitary gland	UBERON:0000007	72.39	gold quality
forebrain	UBERON:0001890	72.25	gold quality
cortical plate	UBERON:0005343	70.96	gold quality
Ammon’s horn	UBERON:0001954	70.31	gold quality
adenohypophysis	UBERON:0002196	70.29	gold quality
amniotic fluid	UBERON:0000173	69.64	silver quality
brain	UBERON:0000955	68.10	gold quality
corpus callosum	UBERON:0002336	67.01	gold quality
temporal lobe	UBERON:0001871	65.89	gold quality
primary visual cortex	UBERON:0002436	64.94	gold quality
substantia nigra	UBERON:0002038	62.63	gold quality
superior frontal gyrus	UBERON:0002661	62.20	gold quality
cerebellar vermis	UBERON:0004720	60.68	gold quality
midbrain	UBERON:0001891	60.03	gold quality
pons	UBERON:0000988	59.80	gold quality
occipital lobe	UBERON:0002021	59.61	gold quality
caudate nucleus	UBERON:0001873	59.42	gold quality
nucleus accumbens	UBERON:0001882	58.78	gold quality
islet of Langerhans	UBERON:0000006	58.44	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	1996.86
E-HCAD-25	yes	1029.55
E-GEOD-93593	yes	288.82
E-GEOD-84465	yes	6.44
E-ANND-3	yes	4.42

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

101 targeting KCNC2, 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-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-548N	99.98	71.94	4170
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-4666A-3P	99.96	71.71	3434

Literature-anchored findings (GeneRIF, showing 9)

• In the absence of potassium ion, significant N-methyl-D-glucamine (NMDG)-positive currents could be recorded from human embryonic kidney cells expressing Kv3.1 or Kv3.2b channels and Kv1.5 Arg487Tyr/Val, but not wild-type channels. (PMID:19332619)
• Although all KV3 subunit transcripts are significantly expressed at embryonic age in whole brain extracts, only KV3.1, KV3.2 and KV3.4 subunit transgenic proteins are present. (PMID:21912965)
• This family’s complex phenotype is associated with a new chromosomal deletion, which suggests potential roles for the two genes, KCNC2 and ATXN7L3B, in human neurological disease. (PMID:23475819)
• Kv3.2 is not different in distribution or in level between normal and schizophrenia cases, nor influenced by antipsychotic drugs, in any brain region tested (PMID:23628987)
• these data suggest that reduction of KCNC2 is associated with modified hepatic gluconeogenesis and increased ER stress on obesity-mediated diabetic risk. (PMID:27623749)
• Mechanisms Underlying the Hyperexcitability of CA3 and Dentate Gyrus Hippocampal Neurons Derived From Patients With Bipolar Disorder. (PMID:31732108)
• A recurrent de novo variant supports KCNC2 involvement in the pathogenesis of developmental and epileptic encephalopathy. (PMID:34448338)
• Spectrum of Phenotypic, Genetic, and Functional Characteristics in Patients With Epilepsy With KCNC2 Pathogenic Variants. (PMID:35314505)
• Investigation of novel de novo KCNC2 variants causing severe developmental and early-onset epileptic encephalopathy. (PMID:36087422)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	si:ch73-334d15.4	ENSDARG00000056502
danio_rerio	kcnc2	ENSDARG00000057468
danio_rerio	kcnc4	ENSDARG00000061288
mus_musculus	Kcnc2	ENSMUSG00000035681
rattus_norvegicus	Kcnc2	ENSRNOG00000004077

Paralogs (31): KCNG1 (ENSG00000026559), KCNQ1 (ENSG00000053918), KCNQ2 (ENSG00000075043), KCND1 (ENSG00000102057), KCNA7 (ENSG00000104848), KCNA1 (ENSG00000111262), KCNC4 (ENSG00000116396), KCNQ4 (ENSG00000117013), KCNS1 (ENSG00000124134), KCNC1 (ENSG00000129159), KCNA5 (ENSG00000130037), KCNC3 (ENSG00000131398), KCNA10 (ENSG00000143105), KCNA6 (ENSG00000151079), KCNS2 (ENSG00000156486), KCNB1 (ENSG00000158445), KCNF1 (ENSG00000162975), KCNV1 (ENSG00000164794), KCNV2 (ENSG00000168263), KCNG4 (ENSG00000168418), KCNS3 (ENSG00000170745), KCNG3 (ENSG00000171126), KCND3 (ENSG00000171385), KCNA3 (ENSG00000177272), KCNA2 (ENSG00000177301), KCNG2 (ENSG00000178342), KCNA4 (ENSG00000182255), KCNB2 (ENSG00000182674), KCNQ3 (ENSG00000184156), KCND2 (ENSG00000184408), KCNQ5 (ENSG00000185760)

Protein

Protein identifiers

Voltage-gated potassium channel KCNC2 — Q96PR1 (reviewed: Q96PR1)

Alternative names: Potassium voltage-gated channel subfamily C member 2, Shaw-like potassium channel, Voltage-gated potassium channel Kv3.2

All UniProt accessions (2): A0A3B3ISR9, Q96PR1

UniProt curated annotations — full annotation on UniProt →

Function. Voltage-gated potassium channel that mediates transmembrane potassium transport in excitable membranes, primarily in the brain. Contributes to the regulation of the fast action potential repolarization and in sustained high-frequency firing in neurons of the central nervous system. Homotetramer channels mediate delayed-rectifier voltage-dependent potassium currents that activate rapidly at high-threshold voltages and inactivate slowly. Forms tetrameric channels through which potassium ions pass in accordance with their electrochemical gradient. The channel alternates between opened and closed conformations in response to the voltage difference across the membrane. Can form functional homotetrameric and heterotetrameric channels that contain variable proportions of KCNC1, and possibly other family members as well; channel properties depend on the type of alpha subunits that are part of the channel. Channel properties may be modulated either by the association with ancillary subunits, such as KCNE1, KCNE2 or KCNE3 or indirectly by nitric oxide (NO) through a cGMP- and PKG-mediated signaling cascade, slowing channel activation and deactivation of delayed rectifier potassium channels. Contributes to fire sustained trains of very brief action potentials at high frequency in retinal ganglion cells, thalamocortical and suprachiasmatic nucleus (SCN) neurons and in hippocampal and neocortical interneurons. Sustained maximal action potential firing frequency in inhibitory hippocampal interneurons is negatively modulated by histamine H2 receptor activation in a cAMP- and protein kinase (PKA) phosphorylation-dependent manner. Plays a role in maintaining the fidelity of synaptic transmission in neocortical GABAergic interneurons by generating action potential (AP) repolarization at nerve terminals, thus reducing spike-evoked calcium influx and GABA neurotransmitter release. Required for long-range synchronization of gamma oscillations over distance in the neocortex. Contributes to the modulation of the circadian rhythm of spontaneous action potential firing in suprachiasmatic nucleus (SCN) neurons in a light-dependent manner.

Subunit / interactions. Homotetramer and heterotetramer with other channel-forming alpha subunits, such as KCNC1. Interacts with KCNC1. Homotetramer or heterotetramer channel activity is regulated by association with modulating ancillary subunits such as KCNE1, KCNE2 and KCNE3, creating a functionally diverse range of channel complexes. Interacts with KCNE1, KCNE2 and KCNE3.

Subcellular location. Cell membrane. Membrane. Perikaryon. Cell projection. Axon. Dendrite. Postsynaptic cell membrane. Presynaptic cell membrane. Synapse. Synaptosome. Apical cell membrane. Basolateral cell membrane.

Post-translational modifications. Phosphorylated by PKA in cortical synaptosomes. cAMP-dependent phosphorylation inhibits channel activity. Histamine H2 receptor- and PKA-induced phosphorylation extends action potential spike duration, reduces action potential spike amplitude, sustains maximum firing frequency in hippocampal interneurons; also reduces the incidence of high-frequency oscillations in hippocampal CA3 pyramidal cell layers.

Disease relevance. A chromosomal aberration involving KCNC2 has been found in a mother and her two children with varying degrees of neurodevelopmental delay and cerebellar ataxia. One child also exhibits episodes of unresponsiveness suggestive of absence seizures and facial dysmorphism. Deletion at 12q21.1 deletes exons 3-5 of KCNC2. Developmental and epileptic encephalopathy 103 (DEE103) [MIM:619913] 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. DEE103 is an autosomal dominant form characterized by onset of various types of seizures in the first year of life. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Inhibited by Stichodactyla helianthus peptide ShK. Inhibited by millimolar levels of tetraethylammonium (TEA). Contrary to other channels, inhibited only by millimolar levels of 4-aminopyridine (4-AP).

Domain organisation. The transmembrane segment S4 functions as a voltage-sensor and is characterized by a series of positively charged amino acids at every third position. Channel opening and closing is effected by a conformation change that affects the position and orientation of the voltage-sensor paddle formed by S3 and S4 within the membrane. A transmembrane electric field that is positive inside would push the positively charged S4 segment outwards, thereby opening the pore, while a field that is negative inside would pull the S4 segment inwards and close the pore. Changes in the position and orientation of S4 are then transmitted to the activation gate formed by the inner helix bundle via the S4-S5 linker region.

Similarity. Belongs to the potassium channel family. C (Shaw) (TC 1.A.1.2) subfamily. Kv3.2/KCNC2 sub-subfamily.

Isoforms (6)

UniProt ID	Names	Canonical?
Q96PR1-1	1, Kv3.2b	yes
Q96PR1-2	2, Kv3.2d
Q96PR1-3	3, Kv3.2a
Q96PR1-4	4, Kv3.2c
Q96PR1-5	5
Q96PR1-6	6

RefSeq proteins (17): NP_001247426, NP_001247427, NP_001247428, NP_001401121, NP_001401122, NP_001401123, NP_001401124, NP_001401125, NP_001401126, NP_001401127, NP_001401128, NP_001401131, NP_001401135, NP_001401142, NP_631874, NP_631875, NP_715624 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000210	BTB/POZ_dom	Domain
IPR003131	T1-type_BTB	Domain
IPR003968	K_chnl_volt-dep_Kv	Family
IPR003974	K_chnl_volt-dep_Kv3	Family
IPR005821	Ion_trans_dom	Domain
IPR011333	SKP1/BTB/POZ_sf	Homologous_superfamily
IPR027359	Volt_channel_dom_sf	Homologous_superfamily
IPR028325	VG_K_chnl	Family

Pfam: PF00520, PF02214

Catalyzed reactions (Rhea), 1 shown:

• K(+)(in) = K(+)(out) (RHEA:29463)

UniProt features (46 total): sequence variant 9, binding site 8, transmembrane region 6, splice variant 6, topological domain 4, sequence conflict 4, region of interest 3, compositionally biased region 2, glycosylation site 2, chain 1, modified residue 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96PR1-F1	68.26	0.29

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 (8): 124; 130; 151; 152; 437; 438; 439; 440

Post-translational modifications (1): 600

Glycosylation sites (2): 259, 266

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-1296072	Voltage gated Potassium channels
R-HSA-381676	Glucagon-like Peptide-1 (GLP1) regulates insulin secretion
R-HSA-112316	Neuronal System
R-HSA-1296071	Potassium Channels
R-HSA-1430728	Metabolism
R-HSA-163685	Integration of energy metabolism
R-HSA-422356	Regulation of insulin secretion

MSigDB gene sets: 353 (showing top): GOBP_POTASSIUM_ION_TRANSPORT, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_RESPONSE_TO_ETHANOL, BENPORATH_ES_WITH_H3K27ME3, REACTOME_VOLTAGE_GATED_POTASSIUM_CHANNELS, GOBP_RESPONSE_TO_AMINE, GOBP_RESPONSE_TO_ACID_CHEMICAL, REACTOME_POTASSIUM_CHANNELS, GOBP_POSITIVE_REGULATION_OF_POTASSIUM_ION_TRANSPORT, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_CRANIAL_NERVE_DEVELOPMENT, GOBP_POSITIVE_REGULATION_OF_TRANSMEMBRANE_TRANSPORT, GOBP_FOREBRAIN_DEVELOPMENT, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_RESPONSE_TO_METAL_ION

GO Biological Process (25): action potential (GO:0001508), potassium ion transport (GO:0006813), response to light intensity (GO:0009642), response to amine (GO:0014075), optic nerve development (GO:0021554), globus pallidus development (GO:0021759), response to magnesium ion (GO:0032026), nitric oxide-cGMP-mediated signaling (GO:0038060), response to ethanol (GO:0045471), protein homooligomerization (GO:0051260), protein heterooligomerization (GO:0051291), membrane hyperpolarization (GO:0060081), cellular response to ammonium ion (GO:0071242), cellular response to nitric oxide (GO:0071732), potassium ion transmembrane transport (GO:0071805), cellular response to toxic substance (GO:0097237), regulation of action potential firing rate (GO:0099605), positive regulation of potassium ion transmembrane transport (GO:1901381), response to kainic acid (GO:1904373), response to nerve growth factor (GO:1990089), monoatomic ion transport (GO:0006811), response to toxic substance (GO:0009636), monoatomic ion transmembrane transport (GO:0034220), transmembrane transport (GO:0055085), regulation of presynaptic membrane potential (GO:0099505)

GO Molecular Function (9): voltage-gated potassium channel activity (GO:0005249), delayed rectifier potassium channel activity (GO:0005251), transmembrane transporter binding (GO:0044325), metal ion binding (GO:0046872), voltage-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential (GO:0099508), monoatomic ion channel activity (GO:0005216), potassium channel activity (GO:0005267), protein binding (GO:0005515), gated channel activity (GO:0022836)

GO Cellular Component (23): plasma membrane (GO:0005886), voltage-gated potassium channel complex (GO:0008076), membrane (GO:0016020), basolateral plasma membrane (GO:0016323), apical plasma membrane (GO:0016324), axon (GO:0030424), dendrite (GO:0030425), axolemma (GO:0030673), vesicle (GO:0031982), dendrite membrane (GO:0032590), neuronal cell body membrane (GO:0032809), presynaptic membrane (GO:0042734), terminal bouton (GO:0043195), perikaryon (GO:0043204), axon terminus (GO:0043679), cell body (GO:0044297), synapse (GO:0045202), postsynaptic membrane (GO:0045211), GABA-ergic synapse (GO:0098982), monoatomic ion channel complex (GO:0034702), cell projection (GO:0042995), neuron projection (GO:0043005), neuronal cell body (GO:0043025)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Potassium Channels	1
Regulation of insulin secretion	1
Neuronal System	1
Metabolism	1
Integration of energy metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
presynapse	3
regulation of membrane potential	2
response to nitrogen compound	2
protein complex oligomerization	2
channel activity	2
plasma membrane region	2
neuron projection	2
neuron projection membrane	2
neuronal cell body	2
synaptic membrane	2
metal ion transport	1
response to light stimulus	1
cranial nerve development	1
diencephalon development	1
neural nucleus development	1
response to metal ion	1
intracellular signaling cassette	1
response to alcohol	1
response to ammonium ion	1
cellular response to nitrogen compound	1
response to nitric oxide	1
cellular response to oxygen-containing compound	1
cellular response to reactive nitrogen species	1
potassium ion transport	1
monoatomic cation transmembrane transport	1
response to toxic substance	1
cellular response to chemical stimulus	1
regulation of action potential	1
positive regulation of potassium ion transport	1
potassium ion transmembrane transport	1
regulation of potassium ion transmembrane transport	1
positive regulation of cation transmembrane transport	1
response to amino acid	1
response to oxygen-containing compound	1
response to growth factor	1
potassium channel activity	1
voltage-gated monoatomic cation channel activity	1
voltage-gated potassium channel activity	1
protein binding	1

Protein interactions and networks

STRING

2435 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KCNC2	SCN1B	Q07699	741
KCNC2	SCN3A	Q9NY46	643
KCNC2	SCN1A	P35498	599
KCNC2	SCN2A	Q99250	583
KCNC2	SHPK	Q9UHJ6	577
KCNC2	SCN3B	Q9NY72	562
KCNC2	PVALB	P20472	522
KCNC2	KCNH8	Q96L42	493
KCNC2	KCNK17	Q96T54	493
KCNC2	SCN4A	P35499	480
KCNC2	KCNAB2	Q13303	476
KCNC2	KCNH3	Q9ULD8	458
KCNC2	DPY19L4	Q7Z388	453
KCNC2	KCNAB1	Q14722	450
KCNC2	TMEM9B	Q9NQ34	435

IntAct

0 interactions, top by confidence:

BioGRID (1): KCNC1 (Affinity Capture-Western)

ESM2 similar proteins: A4K2M4, A4K2N8, A4K2P6, A4K2Q6, A4K2R3, A4K2S2, A4K2T1, A4K2V2, A4K2W6, A4K2X4, A4K2Y2, D4ADX7, O35173, O35174, O88758, P15384, P15388, P16390, P17658, P17659, P19024, P22001, P22460, P22462, P25122, P48547, P50638, P59053, P59994, P79197, Q03719, Q03721, Q14B80, Q17ST2, Q61762, Q61923, Q63734, Q7TSH7, Q8CFS6, Q8R1C0

Diamond homologs: A2BDX4, A4K2M4, A4K2N8, A4K2P6, A4K2Q6, A4K2R3, A4K2S2, A4K2T1, A4K2V2, A4K2W6, A4K2X4, A4K2Y2, A6H8H5, D4AD53, D4ADX7, O18868, O35173, O35174, O73606, O88758, O88759, P10499, P15384, P15385, P15387, P15388, P16388, P16389, P16390, P17970, P19024, P22001, P22459, P22460, P22462, P25122, P48547, P50638, P59053, P59994

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
KCNC2	“down-regulates quantity”	potassium(1+)	relocalization

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	8
Likely pathogenic	9
Uncertain significance	121
Likely benign	11
Benign	3

Top pathogenic / likely-pathogenic (17)

Variant ID	HGVS	Classification
1411978	NM_139137.4(KCNC2):c.1052G>A (p.Arg351Lys)	Pathogenic
1693470	NM_139137.4(KCNC2):c.1411G>C (p.Val471Leu)	Pathogenic
1693471	NM_139137.4(KCNC2):c.499G>T (p.Asp167Tyr)	Pathogenic
1693472	NM_139137.4(KCNC2):c.375C>G (p.Cys125Trp)	Pathogenic
1693473	NM_139137.4(KCNC2):c.404A>G (p.Glu135Gly)	Pathogenic
1693475	NM_139137.4(KCNC2):c.1309A>G (p.Thr437Ala)	Pathogenic
2413122	NM_139137.4(KCNC2):c.1163T>C (p.Phe388Ser)	Pathogenic
3342853	NM_139137.4(KCNC2):c.1310C>A (p.Thr437Asn)	Pathogenic
1695909	NM_139137.4(KCNC2):c.1213A>G (p.Arg405Gly)	Likely pathogenic
1700164	NM_139137.4(KCNC2):c.1418T>A (p.Val473Asp)	Likely pathogenic
2662494	NM_139137.4(KCNC2):c.1418T>C (p.Val473Ala)	Likely pathogenic
3061800	NM_139137.4(KCNC2):c.487G>A (p.Glu163Lys)	Likely pathogenic
3234060	NM_139137.4(KCNC2):c.1210G>A (p.Glu404Lys)	Likely pathogenic
3773727	NM_139137.4(KCNC2):c.1181T>C (p.Leu394Ser)	Likely pathogenic
3775571	NM_139137.4(KCNC2):c.1405G>C (p.Val469Leu)	Likely pathogenic
3778672	NM_139137.4(KCNC2):c.879T>A (p.Phe293Leu)	Likely pathogenic
3911748	NM_139137.4(KCNC2):c.1405G>A (p.Val469Met)	Likely pathogenic

SpliceAI

2147 predictions. Top by Δscore:

Variant	Effect	Δscore
12:75113757:T:C	donor_gain	1.0000
12:75207998:CATGA:C	acceptor_gain	1.0000
12:75208000:TGA:T	acceptor_gain	1.0000
12:75208003:C:CC	acceptor_gain	1.0000
12:75051155:A:AC	donor_gain	0.9900
12:75051156:C:CC	donor_gain	0.9900
12:75051285:C:CT	acceptor_gain	0.9900
12:75051286:A:T	acceptor_gain	0.9900
12:75113893:C:CT	acceptor_gain	0.9900
12:75186362:C:G	acceptor_gain	0.9900
12:75192197:T:A	donor_gain	0.9900
12:75192203:T:TA	donor_gain	0.9900
12:75199876:T:C	donor_gain	0.9900
12:75207295:AC:A	donor_gain	0.9900
12:75207296:CC:C	donor_gain	0.9900
12:75207999:ATGA:A	acceptor_gain	0.9900
12:75208001:GA:G	acceptor_gain	0.9900
12:75208003:C:A	acceptor_loss	0.9900
12:75209202:GATAC:G	donor_loss	0.9900
12:75209204:TA:T	donor_loss	0.9900
12:75209205:ACCT:A	donor_loss	0.9900
12:75209211:A:C	donor_gain	0.9900
12:75043682:A:AC	donor_gain	0.9800
12:75051314:TAAA:T	acceptor_gain	0.9800
12:75051318:C:CC	acceptor_gain	0.9800
12:75113889:TCTCC:T	acceptor_gain	0.9800
12:75186361:TCTA:T	acceptor_gain	0.9800
12:75043683:A:C	donor_gain	0.9700
12:75114478:C:CT	donor_gain	0.9700
12:75114479:T:TT	donor_gain	0.9700

AlphaMissense

4133 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:75050552:C:G	A485P	1.000
12:75050558:C:G	A483P	1.000
12:75050560:A:G	L482S	1.000
12:75050564:A:G	S481P	1.000
12:75050567:A:C	Y480D	1.000
12:75050577:A:C	F476L	1.000
12:75050577:A:T	F476L	1.000
12:75050578:A:C	F476C	1.000
12:75050578:A:G	F476S	1.000
12:75050579:A:G	F476L	1.000
12:75050579:A:T	F476I	1.000
12:75050580:A:C	N475K	1.000
12:75050580:A:T	N475K	1.000
12:75050590:A:C	I472S	1.000
12:75050590:A:T	I472N	1.000
12:75050593:A:T	V471D	1.000
12:75050602:G:C	P468R	1.000
12:75050602:G:T	P468Q	1.000
12:75050605:A:T	M467K	1.000
12:75050608:G:T	A466D	1.000
12:75050611:A:C	I465R	1.000
12:75050611:A:T	I465K	1.000
12:75050617:A:G	L463P	1.000
12:75050623:C:A	G461V	1.000
12:75050623:C:T	G461E	1.000
12:75050624:C:G	G461R	1.000
12:75050624:C:T	G461R	1.000
12:75050632:G:T	A458D	1.000
12:75050634:A:C	C457W	1.000
12:75050635:C:T	C457Y	1.000

dbSNP variants (sampled 300 via entrez): RS1000005562 (12:75132152 C>A), RS1000021708 (12:75140693 A>T), RS1000032531 (12:75104058 C>G,T), RS1000058093 (12:75060104 C>G,T), RS1000076528 (12:75081031 T>A), RS1000091520 (12:75074316 A>G), RS1000101442 (12:75132499 C>A,G,T), RS1000143098 (12:75092776 A>G), RS1000143501 (12:75159635 C>G,T), RS1000150182 (12:75121364 T>C), RS1000158728 (12:75163652 T>C), RS1000183303 (12:75098756 T>A), RS1000221588 (12:75177629 A>G), RS1000235482 (12:75046564 A>G), RS1000272292 (12:75177438 C>T)

Disease associations

OMIM: gene MIM:176256 | disease phenotypes: MIM:619913, MIM:300088, MIM:612955

GenCC curated gene-disease

Disease	Classification	Inheritance
developmental and epileptic encephalopathy 103	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
genetic developmental and epileptic encephalopathy	Definitive	AD

Mondo (4): developmental and epileptic encephalopathy 103 (MONDO:0030957), developmental and epileptic encephalopathy (MONDO:0100620), developmental and epileptic encephalopathy, 9 (MONDO:0010246), long QT syndrome 12 (MONDO:0013062)

Orphanet (4): Female restricted epilepsy with intellectual disability (Orphanet:101039), X-linked intellectual disability-epilepsy syndrome (Orphanet:2076), Romano-Ward syndrome (Orphanet:101016), Congenital long QT syndrome (Orphanet:768)

HPO phenotypes

78 total (30 of 78 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000211	Trismus
HP:0000252	Microcephaly
HP:0000256	Macrocephaly
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:0000752	Hyperactivity
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:0001273	Abnormal corpus callosum morphology
HP:0001288	Gait disturbance
HP:0001290	Generalized hypotonia
HP:0001298	Encephalopathy
HP:0001315	Reduced tendon reflexes

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST003264_913	Post bronchodilator FEV1/FVC ratio	1.000000e-06
GCST006268_469	Reaction time	5.000000e-08
GCST008153_59	Lean body mass	2.000000e-07

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004713	FEV/FVC ratio
EFO:0008393	reaction time measurement
EFO:0004995	lean body mass

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
C564715	Epilepsy, Female-Restricted, with Mental Retardation (supp.)
C567842	Long Qt Syndrome 12 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2362996 (PROTEIN FAMILY), CHEMBL2363009 (SINGLE PROTEIN)

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 (4 total), top 4:

Ligand	Action	Affinity	Parameter
ShK Toxin	Channel blocker	9.5	pIC50
verapamil	Channel blocker	4.9	pEC50
fampridine	Channel blocker	4.6	pIC50
tetraethylammonium	Channel blocker	4.2	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 35 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	affects methylation	1
benzo(e)pyrene	increases methylation	1
Grape Seed Proanthocyanidins	affects cotreatment, decreases expression	1
bisphenol S	increases methylation	1
Acetaminophen	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Catechin	affects cotreatment, decreases expression	1
Lead	affects expression	1
Methapyrilene	increases methylation	1
8-Bromo Cyclic Adenosine Monophosphate	decreases expression	1
Aflatoxin B1	increases methylation	1
Acrylamide	decreases expression	1

ChEMBL screening assays

32 unique, capped per target: 31 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

Cellosaurus cell lines

1 cell lines: 1 spontaneously immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D1K5	PrecisION hKv3.2-CHO	Spontaneously immortalized cell line	Female

Clinical trials (associated diseases)

22 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).