KCNA6

Summary

KCNA6 (potassium voltage-gated channel subfamily A member 6, HGNC:6225) is a protein-coding gene on chromosome 12p13.32, encoding Potassium voltage-gated channel subfamily A member 6 (P17658). Voltage-gated potassium channel that mediates transmembrane potassium transport in excitable membranes.

Potassium 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. Four sequence-related potassium channel genes - shaker, shaw, shab, and shal - have been identified in Drosophila, and each has been shown to have human homolog(s). This gene encodes a member of the potassium channel, voltage-gated, shaker-related subfamily. This member contains six membrane-spanning domains with a shaker-type repeat in the fourth segment. It belongs to the delayed rectifier class. The coding region of this gene is intronless, and the gene is clustered with genes KCNA1 and KCNA5 on chromosome 12.

Source: NCBI Gene 3742 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complex neurodevelopmental disorder (Moderate, GenCC)
• GWAS associations: 3
• Clinical variants (ClinVar): 85 total — 2 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 2
• Druggable target: yes
• MANE Select transcript: NM_002235

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6225
Approved symbol	KCNA6
Name	potassium voltage-gated channel subfamily A member 6
Location	12p13.32
Locus type	gene with protein product
Status	Approved
Aliases	Kv1.6, HBK2, PPP1R96
Ensembl gene	ENSG00000151079
Ensembl biotype	protein_coding
OMIM	176257
Entrez	3742

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000280684

RefSeq mRNA: 1 — MANE Select: NM_002235 NM_002235

CCDS: CCDS8534

Canonical transcript exons

ENST00000280684 — 1 exons

Exon	Start	End
ENSE00000997517	4809334	4813318

Expression profiles

Bgee: expression breadth ubiquitous, 123 present calls, max score 85.59.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.4152 / max 34.5455, expressed in 72 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
123587	1.2781	357
123590	0.4152	72
123586	0.1561	88
123589	0.0531	20
123588	0.0312	15

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	85.59	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	79.31	silver quality
prefrontal cortex	UBERON:0000451	78.34	gold quality
islet of Langerhans	UBERON:0000006	74.63	gold quality
ventricular zone	UBERON:0003053	72.07	gold quality
frontal cortex	UBERON:0001870	71.32	gold quality
neocortex	UBERON:0001950	70.66	gold quality
Brodmann (1909) area 9	UBERON:0013540	70.65	gold quality
calcaneal tendon	UBERON:0003701	70.35	gold quality
right frontal lobe	UBERON:0002810	69.41	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	69.41	gold quality
anterior cingulate cortex	UBERON:0009835	69.27	gold quality
ganglionic eminence	UBERON:0004023	68.62	gold quality
cerebral cortex	UBERON:0000956	67.36	gold quality
hypothalamus	UBERON:0001898	65.03	gold quality
caudate nucleus	UBERON:0001873	63.88	gold quality
forebrain	UBERON:0001890	63.47	gold quality
superior frontal gyrus	UBERON:0002661	62.45	gold quality
Brodmann (1909) area 46	UBERON:0006483	61.72	silver quality
amygdala	UBERON:0001876	61.71	gold quality
tendon	UBERON:0000043	61.20	gold quality
postcentral gyrus	UBERON:0002581	60.98	silver quality
brain	UBERON:0000955	60.80	gold quality
Ammon’s horn	UBERON:0001954	60.62	gold quality
central nervous system	UBERON:0001017	60.49	gold quality
putamen	UBERON:0001874	60.19	gold quality
parietal lobe	UBERON:0001872	58.37	silver quality
smooth muscle tissue	UBERON:0001135	57.90	gold quality
temporal lobe	UBERON:0001871	57.72	gold quality
ascending aorta	UBERON:0001496	57.11	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

181 targeting KCNA6, 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-3163	100.00	77.23	8605
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-545-3P	99.95	70.74	2783

Literature-anchored findings (GeneRIF, showing 3)

• analysis of how the RCK2 domain of the human BKCa channel is a calcium sensor (PMID:18162557)
• The spectrum of neurologic manifestations and neoplasms associated with voltage-gated potassium channel (VGKC) autoimmunity is broader than previously recognized (PMID:18474843)
• De novo KCNA6 variants with attenuated KV 1.6 channel deactivation in patients with epilepsy. (PMID:36318112)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Kcna6	ENSMUSG00000038077
rattus_norvegicus	Kcna6	ENSRNOG00000052486

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), KCNS2 (ENSG00000156486), KCNB1 (ENSG00000158445), KCNF1 (ENSG00000162975), KCNV1 (ENSG00000164794), KCNC2 (ENSG00000166006), 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

Potassium voltage-gated channel subfamily A member 6 — P17658 (reviewed: P17658)

Alternative names: Voltage-gated potassium channel HBK2, Voltage-gated potassium channel subunit Kv1.6

All UniProt accessions (1): P17658

UniProt curated annotations — full annotation on UniProt →

Function. Voltage-gated potassium channel that mediates transmembrane potassium transport in excitable membranes. Forms tetrameric potassium-selective 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 channels and heterotetrameric channels that contain variable proportions of KCNA1, KCNA2, KCNA4, KCNA6, and possibly other family members as well; channel properties depend on the type of alpha subunits that are part of the channel. Channel properties are modulated by cytoplasmic beta subunits that regulate the subcellular location of the alpha subunits and promote rapid inactivation. Homotetrameric channels display rapid activation and slow inactivation.

Subunit / interactions. Homotetramer and heterotetramer of potassium channel proteins. Interacts with KCNAB1 and KCNAB2.

Subcellular location. Cell membrane.

Domain organisation. The N-terminus may be important in determining the rate of inactivation of the channel while the tail may play a role in modulation of channel activity and/or targeting of the channel to specific subcellular compartments. 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. A (Shaker) (TC 1.A.1.2) subfamily. Kv1.6/KCNA6 sub-subfamily.

RefSeq proteins (1): NP_002226* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000210	BTB/POZ_dom	Domain
IPR003131	T1-type_BTB	Domain
IPR003968	K_chnl_volt-dep_Kv	Family
IPR003972	K_chnl_volt-dep_Kv1	Family
IPR004053	KCNA6	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
IPR046988	KCNA6_BTB_POZ	Domain

Pfam: PF00520, PF02214

Catalyzed reactions (Rhea), 1 shown:

• K(+)(in) = K(+)(out) (RHEA:29463)

UniProt features (32 total): topological domain 8, transmembrane region 6, region of interest 4, sequence variant 4, intramembrane region 2, short sequence motif 2, compositionally biased region 2, modified residue 2, chain 1, lipid moiety-binding region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P17658-F1	75.42	0.53

Functional residue map

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

Post-translational modifications (3): 3, 511, 285

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: 150 (showing top): GOBP_POTASSIUM_ION_TRANSPORT, E2F_Q4, MYAATNNNNNNNGGC_UNKNOWN, E2F_Q4_01, E2F4DP1_01, REACTOME_VOLTAGE_GATED_POTASSIUM_CHANNELS, REACTOME_POTASSIUM_CHANNELS, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GRAESSMANN_RESPONSE_TO_MC_AND_SERUM_DEPRIVATION_UP, AP2_Q3, CTATGCA_MIR153, GOBP_MONOATOMIC_CATION_TRANSPORT, E2F1DP1_01, E2F1DP2_01, ATF1_Q6

GO Biological Process (7): action potential (GO:0001508), potassium ion transport (GO:0006813), protein homooligomerization (GO:0051260), potassium ion transmembrane transport (GO:0071805), monoatomic ion transport (GO:0006811), monoatomic ion transmembrane transport (GO:0034220), transmembrane transport (GO:0055085)

GO Molecular Function (5): voltage-gated potassium channel activity (GO:0005249), delayed rectifier potassium channel activity (GO:0005251), monoatomic ion channel activity (GO:0005216), potassium channel activity (GO:0005267), protein binding (GO:0005515)

GO Cellular Component (8): cytosol (GO:0005829), plasma membrane (GO:0005886), voltage-gated potassium channel complex (GO:0008076), membrane (GO:0016020), potassium channel complex (GO:0034705), axon terminus (GO:0043679), axon (GO:0030424), 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
cellular anatomical structure	2
regulation of membrane potential	1
metal ion transport	1
protein complex oligomerization	1
potassium ion transport	1
monoatomic cation transmembrane transport	1
monoatomic ion transport	1
transmembrane transport	1
cellular process	1
potassium channel activity	1
voltage-gated monoatomic cation channel activity	1
voltage-gated potassium channel activity	1
monoatomic ion transmembrane transporter activity	1
channel activity	1
monoatomic cation channel activity	1
potassium ion transmembrane transporter activity	1
binding	1
cytoplasm	1
membrane	1
cell periphery	1
potassium channel complex	1
plasma membrane protein complex	1
cation channel complex	1
neuron projection terminus	1
presynapse	1
distal axon	1
neuron projection	1
transmembrane transporter complex	1

Protein interactions and networks

STRING

1246 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KCNA6	KCNA2	P16389	978
KCNA6	KCNA1	Q09470	976
KCNA6	KCNAB2	Q13303	785
KCNA6	TPI1	P00938	766
KCNA6	KCNAB1	Q14722	737
KCNA6	SHPK	Q9UHJ6	716
KCNA6	KCNH2	Q12809	553
KCNA6	RFPL1	O75677	522
KCNA6	KCNA3	P22001	522
KCNA6	SCN2A	Q99250	506
KCNA6	SCN8A	Q9UQD0	500
KCNA6	KCNMA1	Q12791	498
KCNA6	KCNN4	O15554	496
KCNA6	SCN4A	P35499	474
KCNA6	KCNAB3	O43448	439

IntAct

127 interactions, top by confidence:

A	B	Type	Score
KCNA6	DOLK	psi-mi:“MI:0915”(physical association)	0.740
KCNA6	KCNA3	psi-mi:“MI:0914”(association)	0.530
KCNA6	MAST2	psi-mi:“MI:0407”(direct interaction)	0.440
KCNA6	ARHGEF11	psi-mi:“MI:0407”(direct interaction)	0.440
KCNA6	PDZD7	psi-mi:“MI:0407”(direct interaction)	0.440
KCNA6	ARHGEF12	psi-mi:“MI:0407”(direct interaction)	0.440
KCNA6	MAST1	psi-mi:“MI:0407”(direct interaction)	0.440
KCNA6	MAGI3	psi-mi:“MI:0407”(direct interaction)	0.440
KCNA6	DLG3	psi-mi:“MI:0407”(direct interaction)	0.440
MAGI1	KCNA6	psi-mi:“MI:0407”(direct interaction)	0.440
KCNA6	HTRA4	psi-mi:“MI:0407”(direct interaction)	0.440
KCNA6	MAGI2	psi-mi:“MI:0407”(direct interaction)	0.440
KCNA6	PDZD2	psi-mi:“MI:0407”(direct interaction)	0.440
KCNA6	PTPN3	psi-mi:“MI:0407”(direct interaction)	0.440
KCNA6	TAMALIN	psi-mi:“MI:0407”(direct interaction)	0.440
KCNA6	TAX1BP3	psi-mi:“MI:0407”(direct interaction)	0.440
KCNA6	DLG1	psi-mi:“MI:0407”(direct interaction)	0.440
DLG4	KCNA6	psi-mi:“MI:0407”(direct interaction)	0.440
KCNA6	WHRN	psi-mi:“MI:0407”(direct interaction)	0.440
KCNA6	DLG2	psi-mi:“MI:0407”(direct interaction)	0.440
KCNA6	SYNJ2BP	psi-mi:“MI:0407”(direct interaction)	0.440
KCNA6	LNX2	psi-mi:“MI:0407”(direct interaction)	0.440
KCNA6	TIAM2	psi-mi:“MI:0407”(direct interaction)	0.440
KCNA6	RADIL	psi-mi:“MI:0407”(direct interaction)	0.440
KCNA6	GORASP2	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (26): GET4 (Affinity Capture-MS), KCNAB2 (Affinity Capture-MS), HADHB (Affinity Capture-MS), SLC4A2 (Affinity Capture-MS), ITIH3 (Affinity Capture-MS), KCNA3 (Affinity Capture-MS), HERC3 (Affinity Capture-MS), RHBDD1 (Affinity Capture-MS), GOLM1 (Affinity Capture-MS), DOLK (Affinity Capture-MS), KCNA3 (Affinity Capture-MS), DOLK (Affinity Capture-MS), KCNAB2 (Affinity Capture-MS), GOLM1 (Affinity Capture-MS), DOLK (Two-hybrid)

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: A4K2M4, A4K2P6, A4K2T1, A4K2Y2, A6H8H5, B2RQA1, G5EFC3, O18868, O35174, O43526, O88759, O88943, O97531, P08510, P10499, P15384, P15385, P15387, P15388, P16388, P16389, P16390, P17658, P17659, P17970, P17971, P17972, P19024, P22001, P22459, P22460, P22462, P22739, P25122, P48547, P50638, P56696, P59994, P59995, P63141

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 82 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Ras activation upon Ca2+ influx through NMDA receptor	5	51.9×	2e-06
Unblocking of NMDA receptors, glutamate binding and activation	5	49.4×	2e-06
Negative regulation of NMDA receptor-mediated neuronal transmission	5	49.4×	2e-06
Long-term potentiation	5	43.3×	3e-06
Assembly and cell surface presentation of NMDA receptors	8	36.9×	4e-09
Neurexins and neuroligins	9	32.2×	1e-09
Protein-protein interactions at synapses	5	24.1×	6e-05
RHOB GTPase cycle	5	14.0×	6e-04

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	11	80.9×	2e-16
protein localization to synapse	6	58.2×	8e-08
receptor clustering	7	55.3×	9e-09
regulation of postsynaptic membrane neurotransmitter receptor levels	7	43.9×	3e-08
cell-cell adhesion	10	12.8×	5e-07
protein-containing complex assembly	8	11.5×	3e-05
regulation of small GTPase mediated signal transduction	5	9.1×	4e-03
protein homooligomerization	5	7.7×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	1
Uncertain significance	75
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
4282460	NM_002235.5(KCNA6):c.1366G>C (p.Val456Leu)	Pathogenic
4540020	NM_002235.5(KCNA6):c.1346C>T (p.Thr449Ile)	Pathogenic
2430245	NM_002235.5(KCNA6):c.1367T>A (p.Val456Asp)	Likely pathogenic

SpliceAI

130 predictions. Top by Δscore:

Variant	Effect	Δscore
12:4810229:C:A	acceptor_gain	0.9600
12:4809649:G:T	donor_gain	0.8200
12:4810230:G:A	acceptor_gain	0.8200
12:4810235:C:G	acceptor_gain	0.7600
12:4810198:G:C	acceptor_gain	0.7500
12:4809597:ACC:A	donor_gain	0.7100
12:4809649:G:GT	donor_gain	0.7100
12:4809781:G:GG	donor_gain	0.6500
12:4809575:G:T	donor_gain	0.5900
12:4809393:G:T	donor_gain	0.5700
12:4809780:A:AG	donor_gain	0.5600
12:4809393:G:GT	donor_gain	0.5500
12:4809399:G:A	donor_gain	0.5500
12:4810197:TG:T	acceptor_gain	0.5500
12:4810234:ACGCT:A	acceptor_gain	0.5400
12:4809401:T:TA	donor_gain	0.4900
12:4810234:AC:A	acceptor_gain	0.4900
12:4810235:C:CA	acceptor_gain	0.4900
12:4809398:G:A	donor_gain	0.4600
12:4810197:T:TA	acceptor_gain	0.4600
12:4809574:G:GT	donor_gain	0.4500
12:4810223:T:A	acceptor_gain	0.4400
12:4809593:C:CA	donor_gain	0.4300
12:4810281:G:GC	acceptor_gain	0.4300
12:4810803:TGGGG:T	acceptor_gain	0.4200
12:4810804:GGGGG:G	acceptor_gain	0.4200
12:4809785:GCTC:G	donor_gain	0.3900
12:4809598:C:CG	donor_gain	0.3800
12:4810234:A:AG	acceptor_gain	0.3800
12:4811419:A:AG	acceptor_gain	0.3800

AlphaMissense

3440 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:4810179:T:A	N46K	1.000
12:4810179:T:G	N46K	1.000
12:4810187:G:A	G49E	1.000
12:4810195:T:C	F52L	1.000
12:4810197:T:A	F52L	1.000
12:4810197:T:G	F52L	1.000
12:4810241:T:A	L67H	1.000
12:4810244:G:A	G68E	1.000
12:4810294:T:C	F85L	1.000
12:4810296:C:A	F85L	1.000
12:4810296:C:G	F85L	1.000
12:4810298:T:C	F86S	1.000
12:4810303:C:A	R88S	1.000
12:4810315:A:C	S92R	1.000
12:4810317:C:A	S92R	1.000
12:4810317:C:G	S92R	1.000
12:4810318:T:C	F93L	1.000
12:4810320:C:A	F93L	1.000
12:4810320:C:G	F93L	1.000
12:4810328:T:A	I96N	1.000
12:4810331:T:C	L97P	1.000
12:4810339:T:G	Y100D	1.000
12:4810391:T:C	F117S	1.000
12:4810604:T:A	I188K	1.000
12:4810612:T:C	F191L	1.000
12:4810614:T:A	F191L	1.000
12:4810614:T:G	F191L	1.000
12:4810615:T:C	C192R	1.000
12:4810841:A:T	E267V	1.000
12:4810849:T:C	C270R	1.000

dbSNP variants (sampled 300 via entrez): RS1000079031 (12:4851390 G>A), RS1000160483 (12:4814278 A>G), RS1000165901 (12:4826732 G>T), RS1000344612 (12:4832753 C>G,T), RS1000439932 (12:4809306 T>G), RS1000497966 (12:4828110 T>C), RS1000557706 (12:4833117 G>T), RS1000736833 (12:4815495 G>A,T), RS1000815598 (12:4816300 G>A), RS1000817659 (12:4839989 G>A), RS1000868110 (12:4816146 C>T), RS1001038480 (12:4822309 C>A,T), RS1001221887 (12:4820483 A>G), RS1001361917 (12:4826773 T>C), RS1001446513 (12:4827095 CCT>C)

Disease associations

OMIM: gene MIM:176257 | disease phenotypes: MIM:163600

GenCC curated gene-disease

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Moderate	Autosomal dominant

Mondo (7): cerebellar ataxia (MONDO:0000437), hyperopia (MONDO:0004891), flatfoot (MONDO:0005293), nipples inverted (MONDO:0008100), esophageal atresia (MONDO:0001044), pyloric stenosis (MONDO:0001561), complex neurodevelopmental disorder (MONDO:0100038)

Orphanet (1): Rare ataxia (Orphanet:102002)

HPO phenotypes

2 total (2 of 2 shown, HPO-id order):

HPO	Term
HP:0002032	Esophageal atresia
HP:0002021	Pyloric stenosis

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST005025_40	Anti-saccade response	7.000000e-06
GCST006915_1	Physical activity (moderate intensity activity duration)	2.000000e-08
GCST010002_205	Refractive error	2.000000e-08

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0006874	antisaccade response measurement
EFO:0008002	physical activity measurement

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D002524	Cerebellar Ataxia	C10.228.140.252.190; C10.597.350.090.500; C23.888.592.350.090.200
D004933	Esophageal Atresia	C06.198.330; C06.405.117.260; C16.131.314.330
D005413	Flatfoot	C05.330.488.655.250; C05.330.495.681.250; C05.660.585.512.380.813.250; C16.131.621.585.512.500.681.250
D017219	Gastric Outlet Obstruction	C06.405.748.340
D006956	Hyperopia	C11.744.479
D011707	Pyloric Stenosis	C06.405.748.340.690

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2362996 (PROTEIN FAMILY), CHEMBL5279 (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 (9 total), top 9:

Ligand	Action	Affinity	Parameter
[125I]BgK (W5Y / Y26F)	Channel blocker	11.4	pKd
hongotoxin-1	Channel blocker	11.0	pKd
[125I]α-DTX	Channel blocker	10.4	pKd
ShK Toxin	Channel blocker	9.8	pIC50
charybdotoxin	Channel blocker	9.0	pIC50
mast cell degranulating peptide	Channel blocker	8.0	pIC50
α-dendrotoxin	Channel blocker	7.7	pIC50
conopeptide Y-PI1	Pore blocker	6.8	pIC50
tetraethylammonium	Channel blocker	2.2	pIC50

ChEMBL bioactivities

7 potent at pChembl≥5 of 12 total, top 7 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
6.89	IC50	130	nM	CHEMBL444449
5.80	IC50	1600	nM	CHEMBL4207745
5.43	IC50	3700	nM	CHEMBL3621636
5.31	IC50	4900	nM	OROIDIN
5.10	IC50	7900	nM	CHEMBL3261431

PubChem BioAssay actives

7 with measured affinity, of 57 total; 6 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
4-(4-phenoxybutoxy)furo[3,2-g]chromen-7-one	1379140: Inhibition of human Kv1.6 expressed in CHO cells at -80 mV holding potential by whole cell automated patch clamp method	ic50	0.1300	uM
N-[(E)-3-(2-amino-1H-imidazol-5-yl)prop-2-enyl]-4,5-dichloro-1H-pyrrole-2-carboxamide	1379140: Inhibition of human Kv1.6 expressed in CHO cells at -80 mV holding potential by whole cell automated patch clamp method	ic50	1.6000	uM
N-[(E)-3-(2-amino-1H-imidazol-5-yl)prop-2-enyl]-4-bromo-1H-pyrrole-2-carboxamide	1379140: Inhibition of human Kv1.6 expressed in CHO cells at -80 mV holding potential by whole cell automated patch clamp method	ic50	3.7000	uM
N-[(E)-3-(2-amino-1H-imidazol-5-yl)prop-2-enyl]-4,5-dibromo-1H-pyrrole-2-carboxamide	1379140: Inhibition of human Kv1.6 expressed in CHO cells at -80 mV holding potential by whole cell automated patch clamp method	ic50	4.9000	uM
N-[(E)-3-(2-amino-1H-imidazol-5-yl)prop-2-enyl]-5-fluoro-1H-indole-2-carboxamide	1379140: Inhibition of human Kv1.6 expressed in CHO cells at -80 mV holding potential by whole cell automated patch clamp method	ic50	7.9000	uM

CTD chemical–gene interactions

9 total (human), top 9 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
GSK-J4	decreases expression	1
aflatoxin B2	increases methylation	1
CGP 52608	increases reaction, affects binding	1
Glyphosate	affects methylation	1
Benzo(a)pyrene	decreases methylation, increases methylation, affects methylation	1
Lead	affects expression	1
Valproic Acid	increases methylation	1
Antirheumatic Agents	increases expression	1
Copper Sulfate	increases expression	1

ChEMBL screening assays

29 unique, capped per target: 24 binding, 3 functional, 1 toxicity, 1 admet

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
CHEMBL4407441	ADMET	Inhibition of Kv1.6 (unknown origin) at 3 uM relative to control	Discovery of 3,4,6-Trisubstituted Piperidine Derivatives as Orally Active, Low hERG Blocking Akt Inhibitors via Conformational Restriction and Structure-Based Design. — J Med Chem

Cellosaurus cell lines

3 cell lines: 2 spontaneously immortalized cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_C0Y2	B’SYS CHO Kv1.6	Spontaneously immortalized cell line	Female
CVCL_D1JY	PrecisION hKv1.6-CHO	Spontaneously immortalized cell line	Female
CVCL_YA57	IDG-HEK293T-KCNA6-V5-OE	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00950196	PHASE4	COMPLETED	Amantadine for Improving Neurologic Symptoms in Ataxia-Telangiectasia
NCT04107740	PHASE4	COMPLETED	C-Trelin Orally Disintegrated(OD) Tablet 5mg in Ataxia Due to Spinocerebellar Degeneration
NCT00347204	PHASE4	COMPLETED	Comparison of Acular LS Versus Nevanac for Pain Control in Eyes Undergoing PRK
NCT00455455	PHASE4	COMPLETED	Corneal and Conjunctival Sensitivity and Staining Study
NCT00937105	PHASE4	COMPLETED	Daily Wear Corneal Infiltrative Event Study
NCT01387360	PHASE4	COMPLETED	Presbyopic Supracor Treatment for Near Myopic/Hyperopic Pseudophakic Eyes
NCT01977807	PHASE4	UNKNOWN	A Prospective Safety and Effectiveness Study of the 500 Hz Technolas Perfect Vision Excimer Laser in Asian Eyes Using LASIK
NCT02071576	PHASE4	UNKNOWN	A Prospective Safety and Effectiveness Study of the 500 Hz Technolas Perfect Vision Excimer Laser Using LASIK
NCT02112968	PHASE4	UNKNOWN	A Prospective Safety and Effectiveness Study of a New High Repetition Rate Excimer Laser Using LASIK for the Correction of Ammetropia and Presbyopia
NCT03881670	PHASE4	COMPLETED	On-Eye Optical Quality of Lotrafilcon B Lenses Over 12 Hours
NCT04208750	PHASE4	COMPLETED	Clinical Investigation of the Vision-R800 Device.
NCT04283331	PHASE4	UNKNOWN	Anesthetic Impregnated Bandage Soft Contact Lens (BSCL) in Pain Management After Photorefractive Keratectomy (PRK)
NCT02414087	PHASE4	UNKNOWN	Therapeutic Effects of Customized Insoles on Children With Flat Foot
NCT04564430	PHASE4	UNKNOWN	Clonidine for Tourniquet-related Pain in Children
NCT06211504	PHASE4	RECRUITING	Sinus Tarsi Implant as an Adjuvant Procedure to Medial Displacement Calcaneal Osteotomy in the Treatment of Mobile Adult Acquired Flatfoot Deformity
NCT01970098	PHASE3	COMPLETED	A Confirmatory Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT01970111	PHASE3	COMPLETED	An Extension Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT01970124	PHASE3	COMPLETED	A Long-Term Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT01970137	PHASE3	COMPLETED	A 24-week Open-label Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT02889302	PHASE3	COMPLETED	An Additional Confirmatory Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT03408080	PHASE3	ACTIVE_NOT_RECRUITING	Open Pilot Trial of BHV-4157
NCT03701399	PHASE3	ACTIVE_NOT_RECRUITING	Troriluzole in Adult Participants With Spinocerebellar Ataxia
NCT03901638	PHASE3	TERMINATED	Tllsh2910 for Ataxia and Gut Microbiota Alteration in Patients of Multiple System Atrophy
NCT07040137	PHASE3	RECRUITING	Confirmatory Study 3 of KPS-0373 in Patients With Spinocerebellar Degeneration
NCT00520689	PHASE3	COMPLETED	Multipurpose Disinfecting Solution Compatibility With a Silicone Hydrogel Contact Lens
NCT00910403	PHASE3	COMPLETED	Multicenter Evaluation of Safety and Effectiveness of Presbyopic LASIK for Hyperopes
NCT00928122	PHASE3	UNKNOWN	Intrastromal Correction of Ametropia by a Femtosecond Laser
NCT01028378	PHASE3	COMPLETED	Safety and Efficacy Study of Topography-Guided LASIK to Treat Myopia and Hyperopia
NCT01322919	PHASE3	COMPLETED	Safety and Efficacy Study to Evaluate the Treatment of Both Near and Distance Vision in a Simultaneous Laser Procedure
NCT05247658	PHASE3	TERMINATED	Use of a Disk of Amniotic Membrane (Visio-AMTRIX) in Postoperative Care After PKR
NCT00034242	PHASE2	COMPLETED	High-Dose Intravenous Immunoglobulin to Treat Cerebellar Degeneration
NCT00202397	PHASE2	COMPLETED	Effect of Riluzole as a Symptomatic Approach in Patients With Chronic Cerebellar Ataxia
NCT00863538	PHASE2	COMPLETED	Phase II Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT01004016	PHASE2	COMPLETED	A Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT01350440	PHASE2	COMPLETED	Safety and Efficacy of Intravenous Immune Globulin in Treating Spinocerebellar Ataxia
NCT02540655	PHASE2	COMPLETED	Efficacy and Safety Study of Stemchymal® in Polyglutamine Spinocerebellar Ataxia
NCT03932669	PHASE2	COMPLETED	Effect of Nilotinib in Cerebellar Ataxia Patients
NCT04301284	PHASE2	WITHDRAWN	Study of CAD-1883 for Spinocerebellar Ataxia
NCT05125666	PHASE2	UNKNOWN	Efficacy of Dual Task Training on Children With Ataxia After Medulloblastoma Resection
NCT06397274	PHASE2	NOT_YET_RECRUITING	Stemchymal® for Polyglutamine Spinocerebellar Ataxia