KCNC3

Summary

KCNC3 (potassium voltage-gated channel subfamily C member 3, HGNC:6235) is a protein-coding gene on chromosome 19q13.33, encoding Voltage-gated potassium channel KCNC3 (Q14003). Voltage-gated potassium channel that plays an important role in the rapid repolarization of fast-firing brain neurons.

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. Alternate splicing results in several transcript variants.

Source: NCBI Gene 3748 — RefSeq curated summary.

At a glance

• Gene–disease (curated): spinocerebellar ataxia type 13 (Definitive, ClinGen)
• Clinical variants (ClinVar): 475 total — 6 pathogenic, 5 likely-pathogenic
• Phenotypes (HPO): 44
• Druggable target: yes
• MANE Select transcript: NM_004977

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6235
Approved symbol	KCNC3
Name	potassium voltage-gated channel subfamily C member 3
Location	19q13.33
Locus type	gene with protein product
Status	Approved
Aliases	Kv3.3
Ensembl gene	ENSG00000131398
Ensembl biotype	protein_coding
OMIM	176264
Entrez	3748

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 4 protein_coding

ENST00000376959, ENST00000474951, ENST00000477616, ENST00000670667

RefSeq mRNA: 2 — MANE Select: NM_004977 NM_001372305, NM_004977

CCDS: CCDS12793

Canonical transcript exons

ENST00000477616 — 5 exons

Exon	Start	End
ENSE00001937373	50320223	50320349
ENSE00002233598	50322975	50324082
ENSE00002283554	50328213	50329377
ENSE00002529285	50311937	50316091
ENSE00003471278	50320593	50320784

Expression profiles

Bgee: expression breadth ubiquitous, 192 present calls, max score 95.92.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.3837 / max 166.7517, expressed in 922 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
182149	4.5644	828
182151	0.8434	315
182152	0.4188	230
182155	0.3788	216
182153	0.2768	188
182148	0.2595	141
182146	0.2040	104
182147	0.1700	73
182154	0.1678	76
182150	0.1002	57

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
kidney epithelium	UBERON:0004819	95.92	silver quality
right uterine tube	UBERON:0001302	95.51	gold quality
cerebellar vermis	UBERON:0004720	94.84	gold quality
right hemisphere of cerebellum	UBERON:0014890	93.96	gold quality
cerebellar cortex	UBERON:0002129	93.02	gold quality
cerebellar hemisphere	UBERON:0002245	92.95	gold quality
cerebellum	UBERON:0002037	92.46	gold quality
left lobe of thyroid gland	UBERON:0001120	91.69	gold quality
right lobe of thyroid gland	UBERON:0001119	91.53	gold quality
vena cava	UBERON:0004087	90.39	silver quality
lateral nuclear group of thalamus	UBERON:0002736	90.18	gold quality
thyroid gland	UBERON:0002046	90.08	gold quality
pons	UBERON:0000988	89.93	gold quality
left ventricle myocardium	UBERON:0006566	89.62	gold quality
cardiac muscle of right atrium	UBERON:0003379	89.57	gold quality
inferior vagus X ganglion	UBERON:0005363	88.42	gold quality
lateral globus pallidus	UBERON:0002476	87.82	gold quality
right frontal lobe	UBERON:0002810	87.63	gold quality
parietal lobe	UBERON:0001872	87.25	gold quality
epithelial cell of pancreas	CL:0000083	87.03	silver quality
dorsal plus ventral thalamus	UBERON:0001897	86.96	gold quality
ventral tegmental area	UBERON:0002691	86.80	gold quality
body of tongue	UBERON:0011876	86.60	silver quality
medulla oblongata	UBERON:0001896	86.36	gold quality
postcentral gyrus	UBERON:0002581	86.19	gold quality
superior vestibular nucleus	UBERON:0007227	86.04	gold quality
frontal cortex	UBERON:0001870	85.62	gold quality
prefrontal cortex	UBERON:0000451	85.45	gold quality
myocardium	UBERON:0002349	85.38	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	85.02	silver quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.37

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CREB1

miRNA regulators (miRDB)

40 targeting KCNC3, 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-6867-5P	100.00	82.21	3464
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-544A	99.84	68.66	1965
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-7109-5P	99.18	66.13	1057
HSA-MIR-422A	99.18	65.83	550
HSA-MIR-328-5P	99.08	64.65	1000
HSA-MIR-6846-5P	98.81	65.86	1121
HSA-MIR-6848-5P	98.81	65.49	1126
HSA-MIR-6885-5P	98.71	64.33	902
HSA-MIR-6887-5P	98.56	68.49	1295
HSA-MIR-6795-5P	98.52	68.51	1277
HSA-MIR-378H	98.43	66.16	545
HSA-MIR-378A-3P	98.43	66.10	548
HSA-MIR-378B	98.43	65.36	573
HSA-MIR-378C	98.43	66.10	548
HSA-MIR-378D	98.43	66.10	548

Literature-anchored findings (GeneRIF, showing 19)

• results establish a role for KCNC3 in phenotypes ranging from developmental disorders to adult-onset neurodegeneration and suggest voltage-gated K+ channels as candidates for additional neurodegenerative diseases (PMID:16501573)
• Mutations in the voltage-gated potassium channel KCNC3 are causative for spinocerebellar ataxia 13. (PMID:18592334)
• The p.Arg420His mutation, which results in a nonfunctional channel subunit, was recurrent and associated with late-onset progressive ataxia. (PMID:19953606)
• Mutations in KCNC3 are a rare cause of spinocerebellar ataxia with a frequency of less than 1%. (PMID:21479265)
• The spinocerebellar ataxia type 13 mutation of the KV3.3 gene specifically suppresses the excitability of Kv3.3-expressing, fast-spiking neurons in zebrafish (PMID:21543613)
• The KCNC3 mutation casued Spinocerebellar ataxia 13. (PMID:21827913)
• Kv3.3 gating contributes significantly to an early age of onset in spinocerebellar ataxia type 13 (PMID:22289912)
• no disease-related KCNC3 mutation was identified, suggesting that spinocerebellar ataxia type 13 is a rare form of SCA in mainland China (PMID:23293936)
• Data suggest that mutant forms of Kv3.3 (as seem in subjects with spinocerebellar ataxia-13) are unstable, are degraded through proteasomes at faster rates, and can be stabilized by a chemical chaperone. (PMID:23734863)
• This study presented the results of a detailed neurological clinical and diagnostic testing on 21 mutation-positive members of a four-generation Filipino family to further define this disease, aiding diagnosis and prognosis. (PMID:23912307)
• Data indicate that an autosomal dominant mutation in the gene encoding Kv3.3 has been identified in a large Filipino kindred manifesting as spinocerebellar ataxia type 13 (SCA13). (PMID:24116147)
• These results are specific to the KCNC3(R420H) allele and provide new insight into the molecular basis of disease manifestation in SCA13. (PMID:25152487)
• Functional and in silico analysis identified at least one novel pathogenic mutation in KCNC3 that cause Spinocerebellar ataxia type 13 (SCA13) and two additionally potential ones. (PMID:25756792)
• investigated using either targeted next generation sequencing or trio-based exome sequencing and were found to have mutations in three different genes, KCNC3, ITPR1 and SPTBN2 (PMID:25981959)
• This review covers the localization and physiological function of Kv3.3 in the central nervous system and how the normal function of the channel is altered by the disease-causing mutations (PMID:26442672)
• The Kv channels, or at least Kv3.3, appear to be associated with cell differentiation (PMID:26849432)
• Kv3.3 regulates Arp2/3-dependent cortical actin nucleation mediated by Hax-1; resulting cortical actin structures interact with the channel’s gating machinery to slow its inactivation rate during sustained membrane depolarizations; a mutation that leads to late-onset spinocerebellar ataxia type 13. (PMID:26997484)
• results therefore confirm the KCNC3R423H allele as causative for SCA13, through a dominant negative effect on KCNC3WT and links with EGFR that account for dominant inheritance, congenital onset, and disease pathology (PMID:28467418)
• Study expanded the genotype-phenotype-pathophysiology repertoire of SCA13 by addition of a causative KCNC3 mutation, p.Pro583_Pro585del, its associated phenotype of profound spasticity, and the decreased inactivation rate of the mutant channel. (PMID:29949095)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Kcnc3	ENSMUSG00000062785
rattus_norvegicus	Kcnc3	ENSRNOG00000019959

Paralogs (31): KCNG1 (ENSG00000026559), KCNQ1 (ENSG00000053918), KCNQ2 (ENSG00000075043), KCND1 (ENSG00000102057), KCNA7 (ENSG00000104848), KCNA1 (ENSG00000111262), KCNC4 (ENSG00000116396), KCNQ4 (ENSG00000117013), KCNS1 (ENSG00000124134), KCNC1 (ENSG00000129159), KCNA5 (ENSG00000130037), KCNA10 (ENSG00000143105), KCNA6 (ENSG00000151079), 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

Voltage-gated potassium channel KCNC3 — Q14003 (reviewed: Q14003)

Alternative names: KSHIIID, Potassium voltage-gated channel subfamily C member 3, Voltage-gated potassium channel subunit Kv3.3

All UniProt accessions (4): A0A590UJ62, E7ETH1, E9PQY4, Q14003

UniProt curated annotations — full annotation on UniProt →

Function. Voltage-gated potassium channel that plays an important role in the rapid repolarization of fast-firing brain neurons. The channel opens in response to the voltage difference across the membrane, forming a potassium-selective channel through which potassium ions pass in accordance with their electrochemical gradient. The channel displays rapid activation and inactivation kinetics. It plays a role in the regulation of the frequency, shape and duration of action potentials in Purkinje cells. Required for normal survival of cerebellar neurons, probably via its role in regulating the duration and frequency of action potentials that in turn regulate the activity of voltage-gated Ca(2+) channels and cellular Ca(2+) homeostasis. Required for normal motor function. Plays a role in the reorganization of the cortical actin cytoskeleton and the formation of actin veil structures in neuronal growth cones via its interaction with HAX1 and the Arp2/3 complex.

Subunit / interactions. Homotetramer. Heterotetramer with KCNC1. Interacts (via C-terminus) with HAX1; this interaction modulates channel gating. Identified in a complex with ACTR3, a subunit of the Arp2/3 complex; this interaction is indirect and depends on the presence of HAX1.

Subcellular location. Cell membrane. Presynaptic cell membrane. Perikaryon. Cell projection. Axon. Dendrite. Dendritic spine membrane. Cytoplasm. Cell cortex. Cytoskeleton.

Post-translational modifications. N-glycosylated.

Disease relevance. Spinocerebellar ataxia 13 (SCA13) [MIM:605259] Spinocerebellar ataxia is a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCA13 is an autosomal dominant cerebellar ataxia (ADCA) characterized by slow progression and variable age at onset, ranging from childhood to late adulthood. Intellectual disability can be present in some patients. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The segment S4 is probably the voltage-sensor and is characterized by a series of positively charged amino acids at every third position. The cytoplasmic N-terminus mediates N-type inactivation. The C-terminal cytoplasmic tail contributes to the regulation of channel inactivation and to the interaction with HAX1 and the Arp2/3 complex.

Similarity. Belongs to the potassium channel family. C (Shaw) (TC 1.A.1.2) subfamily. Kv3.3/KCNC3 sub-subfamily.

RefSeq proteins (2): NP_001359234, NP_004968* (*=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
IPR005404	K_chnl_volt-dep_Kv3.3	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 (54 total): sequence variant 14, binding site 8, transmembrane region 6, region of interest 5, mutagenesis site 5, topological domain 4, compositionally biased region 4, modified residue 3, glycosylation site 3, chain 1, short sequence motif 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q14003-F1	66.01	0.27

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): 157; 163; 184; 185; 503; 504; 505; 506

Post-translational modifications (3): 625, 686, 691

Glycosylation sites (3): 320, 336, 483

Mutagenesis-validated functional residues (5):

Position	Phenotype
1–78	loss of n-type inactivation.
366	decreases protein abundance.
420	decreases protein abundance.
423	decreases protein abundance.
592	loss of interaction with actr3. no effect on voltage-dependent channel opening or current amplitude, but decreased rate

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: 208 (showing top): GOBP_POTASSIUM_ION_TRANSPORT, REACTOME_VOLTAGE_GATED_POTASSIUM_CHANNELS, REACTOME_POTASSIUM_CHANNELS, MODULE_64, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_PROTEIN_HOMOOLIGOMERIZATION, GOCC_NEURON_PROJECTION, GOBP_PROTEIN_TETRAMERIZATION, GOBP_TRANSMEMBRANE_TRANSPORT, GOBP_CORTICAL_CYTOSKELETON_ORGANIZATION, GOCC_NEURON_PROJECTION_TERMINUS, GOCC_CELL_PROJECTION_MEMBRANE, GOCC_POSTSYNAPSE, GOCC_POTASSIUM_CHANNEL_COMPLEX, GOCC_NEURON_SPINE

GO Biological Process (9): action potential (GO:0001508), potassium ion transport (GO:0006813), cortical actin cytoskeleton organization (GO:0030866), protein homooligomerization (GO:0051260), protein tetramerization (GO:0051262), 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), metal ion binding (GO:0046872), monoatomic ion channel activity (GO:0005216), potassium channel activity (GO:0005267), protein binding (GO:0005515), gated channel activity (GO:0022836)

GO Cellular Component (18): cytoskeleton (GO:0005856), plasma membrane (GO:0005886), cell cortex (GO:0005938), voltage-gated potassium channel complex (GO:0008076), dendrite (GO:0030425), dendrite membrane (GO:0032590), dendritic spine membrane (GO:0032591), neuronal cell body membrane (GO:0032809), presynaptic membrane (GO:0042734), perikaryon (GO:0043204), axon terminus (GO:0043679), postsynaptic membrane (GO:0045211), cytoplasm (GO:0005737), membrane (GO:0016020), axon (GO:0030424), monoatomic ion channel complex (GO:0034702), cell projection (GO:0042995), synapse (GO:0045202)

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
cellular anatomical structure	4
synaptic membrane	3
protein complex oligomerization	2
transport	2
channel activity	2
cell periphery	2
neuron projection	2
neuron projection membrane	2
neuronal cell body	2
presynapse	2
regulation of membrane potential	1
metal ion transport	1
actin cytoskeleton organization	1
cortical cytoskeleton organization	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
cation binding	1
monoatomic ion transmembrane transporter activity	1
monoatomic cation channel activity	1
potassium ion transmembrane transporter activity	1
binding	1
intracellular membraneless organelle	1
membrane	1
cytoplasm	1
potassium channel complex	1
plasma membrane protein complex	1
dendritic tree	1
dendrite	1
dendrite membrane	1
dendritic spine	1
cell body membrane	1
neuron projection terminus	1
distal axon	1
postsynapse	1

Protein interactions and networks

STRING

2064 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KCNC3	SLC17A7	Q9P2U7	777
KCNC3	SCN1B	Q07699	735
KCNC3	SPTBN2	O15020	726
KCNC3	CACNA1A	P78510	710
KCNC3	ATXN10	Q9UBB4	695
KCNC3	ATXN7	O15265	664
KCNC3	TTBK2	Q6IQ55	661
KCNC3	PRKCG	P05129	644
KCNC3	FGF14	Q92915	628
KCNC3	SCN3A	Q9NY46	619
KCNC3	SCN4A	P35499	608
KCNC3	SCN1A	P35498	602
KCNC3	PPP2R2B	Q00005	599
KCNC3	AFG3L2	Q9Y4W6	593
KCNC3	ITPR1	Q14643	562

IntAct

5 interactions, top by confidence:

A	B	Type	Score
KCNC4	GXYLT2	psi-mi:“MI:0914”(association)	0.350
KCNC4	SMPD2	psi-mi:“MI:0914”(association)	0.350
KCNC3	ATF6	psi-mi:“MI:0914”(association)	0.350
KCNC3	FYN	psi-mi:“MI:0914”(association)	0.350

BioGRID (30): KCNC3 (Affinity Capture-MS), RHBDD3 (Affinity Capture-MS), ATF6B (Affinity Capture-MS), NDFIP1 (Affinity Capture-MS), ATF6 (Affinity Capture-MS), C17orf70 (Affinity Capture-MS), KCNC3 (Affinity Capture-MS), PAX6 (Affinity Capture-MS), KCNC1 (Affinity Capture-MS), PTPRF (Affinity Capture-MS), FYN (Affinity Capture-MS), EPHX1 (Affinity Capture-MS), KDELR1 (Affinity Capture-MS), TNS1 (Affinity Capture-MS), OSMR (Affinity Capture-MS)

ESM2 similar proteins: A2A699, A2XVC2, A8MVW0, B0F2B4, D3ZE55, O09017, O14492, O62763, O95206, P10588, P21836, P22303, P23795, P36196, P37136, P43029, P43136, P50427, Q14003, Q29RK8, Q2QXZ2, Q2RAQ5, Q3U0S6, Q495W5, Q4ACU6, Q5T442, Q5U651, Q5ZMM1, Q62888, Q62889, Q63959, Q69ZK9, Q6UXK2, Q76KP1, Q7FA29, Q7Z4P5, Q80WV3, Q80XF7, Q869C3, Q8BQU6

Diamond homologs: A2BDX4, A4K2M4, A4K2N8, A4K2P6, A4K2Q6, A4K2R3, A4K2S2, A4K2T1, A4K2V2, A4K2W6, A4K2X4, A4K2Y2, A6H8H5, D4AD53, D4ADX7, G5EFC3, O18868, O35173, O35174, O73606, O88758, O88759, P10499, P15384, P15385, P15387, P15388, P16388, P16390, P17970, P17971, P17972, P22001, P22459, P22739, P25122, P48547, P59053, P59994, P59995

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
KCNC3	“down-regulates quantity”	potassium(1+)	relocalization

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	5
Uncertain significance	263
Likely benign	130
Benign	18

Top pathogenic / likely-pathogenic (11)

Variant ID	HGVS	Classification
13473	NM_004977.3(KCNC3):c.1259G>A (p.Arg420His)	Pathogenic
13474	NM_004977.3(KCNC3):c.1344C>A (p.Phe448Leu)	Pathogenic
208671	NM_004977.3(KCNC3):c.1268G>A (p.Arg423His)	Pathogenic
245604	NM_004977.3(KCNC3):c.1283C>T (p.Thr428Ile)	Pathogenic
522615	NM_004977.3(KCNC3):c.11_12del (p.Ser4fs)	Pathogenic
545048	NM_004977.3(KCNC3):c.1344C>G (p.Phe448Leu)	Pathogenic
1679940	NM_004977.3(KCNC3):c.2077A>C (p.Ile693Leu)	Likely pathogenic
3251038	NM_004977.3(KCNC3):c.1267C>T (p.Arg423Cys)	Likely pathogenic
422460	NM_004977.3(KCNC3):c.2079C>G (p.Ile693Met)	Likely pathogenic
808628	NM_004977.3(KCNC3):c.2113C>T (p.Arg705Ter)	Likely pathogenic
976029	NM_004977.3(KCNC3):c.1223A>G (p.Asp408Gly)	Likely pathogenic

SpliceAI

710 predictions. Top by Δscore:

Variant	Effect	Δscore
19:50320587:CCTCA:C	donor_loss	1.0000
19:50320588:CTCA:C	donor_loss	1.0000
19:50320589:TCA:T	donor_loss	1.0000
19:50320590:CAC:C	donor_loss	1.0000
19:50320592:C:CG	donor_loss	1.0000
19:50320783:ATCT:A	acceptor_loss	1.0000
19:50320784:TC:T	acceptor_loss	1.0000
19:50320785:C:CC	acceptor_gain	1.0000
19:50320785:C:CG	acceptor_loss	1.0000
19:50320786:T:G	acceptor_loss	1.0000
19:50320793:C:CT	acceptor_gain	1.0000
19:50320793:C:T	acceptor_gain	1.0000
19:50320794:A:T	acceptor_gain	1.0000
19:50320802:C:CT	acceptor_gain	1.0000
19:50320803:A:T	acceptor_gain	1.0000
19:50320806:C:CT	acceptor_gain	1.0000
19:50324079:CATA:C	acceptor_gain	1.0000
19:50324083:C:CC	acceptor_gain	1.0000
19:50320591:A:AC	donor_gain	0.9900
19:50320591:AC:A	donor_gain	0.9900
19:50320592:C:CC	donor_gain	0.9900
19:50320592:CC:C	donor_gain	0.9900
19:50320780:AGGAT:A	acceptor_gain	0.9900
19:50320781:GGAT:G	acceptor_gain	0.9900
19:50320782:GAT:G	acceptor_gain	0.9900
19:50320783:AT:A	acceptor_gain	0.9900
19:50320807:A:T	acceptor_gain	0.9900
19:50324078:ACATA:A	acceptor_gain	0.9900
19:50324079:CATAC:C	acceptor_gain	0.9900
19:50324081:TA:T	acceptor_gain	0.9900

AlphaMissense

4891 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:50323289:A:G	L555P	1.000
19:50323297:C:A	K552N	1.000
19:50323297:C:G	K552N	1.000
19:50323301:G:T	A551D	1.000
19:50323302:C:G	A551P	1.000
19:50323307:G:T	A549D	1.000
19:50323308:C:G	A549P	1.000
19:50323310:A:G	L548P	1.000
19:50323310:A:T	L548Q	1.000
19:50323314:A:G	S547P	1.000
19:50323317:A:C	Y546D	1.000
19:50323317:A:G	Y546H	1.000
19:50323319:T:C	Y545C	1.000
19:50323320:A:C	Y545D	1.000
19:50323320:A:G	Y545H	1.000
19:50323325:C:T	G543D	1.000
19:50323327:A:C	F542L	1.000
19:50323327:A:T	F542L	1.000
19:50323328:A:C	F542C	1.000
19:50323328:A:G	F542S	1.000
19:50323329:A:C	F542V	1.000
19:50323329:A:G	F542L	1.000
19:50323329:A:T	F542I	1.000
19:50323330:G:C	N541K	1.000
19:50323330:G:T	N541K	1.000
19:50323331:T:A	N541I	1.000
19:50323332:T:C	N541D	1.000
19:50323333:G:C	N540K	1.000
19:50323333:G:T	N540K	1.000
19:50323334:T:A	N540I	1.000

dbSNP variants (sampled 300 via entrez): RS1000121439 (19:50335519 G>A,T), RS1000194711 (19:50322532 G>A), RS1000249704 (19:50330207 C>T), RS1000388702 (19:50317450 T>A), RS1000435321 (19:50323915 G>A), RS1000491360 (19:50318062 G>A), RS1000514004 (19:50312330 G>A), RS1000663008 (19:50312443 T>G), RS1000725538 (19:50330005 G>T), RS1000736190 (19:50312123 C>T), RS1000738623 (19:50317630 G>A), RS1000933812 (19:50331467 C>G,T), RS1000981975 (19:50326162 G>C), RS1001096626 (19:50326372 C>T), RS1001121966 (19:50334223 C>A,T)

Disease associations

OMIM: gene MIM:176264 | disease phenotypes: MIM:605259, MIM:612591

GenCC curated gene-disease

Disease	Classification	Inheritance
spinocerebellar ataxia type 13	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
spinocerebellar ataxia type 13	Definitive	AD

Mondo (4): spinocerebellar ataxia type 13 (MONDO:0011529), hereditary ataxia (MONDO:0100309), cleft palate (MONDO:0016064), colorectal cancer, susceptibility to, 10 (MONDO:0012953)

Orphanet (4): Spinocerebellar ataxia type 13 (Orphanet:98768), Hereditary ataxia (Orphanet:183518), Cleft palate (Orphanet:2014), Attenuated familial adenomatous polyposis (Orphanet:220460)

HPO phenotypes

44 total (30 of 44 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000012	Urinary urgency
HP:0000020	Urinary incontinence
HP:0000365	Hearing impairment
HP:0000473	Torticollis
HP:0000543	Optic disc pallor
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001256	Mild intellectual disability
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001270	Motor delay
HP:0001272	Cerebellar atrophy
HP:0001288	Gait disturbance
HP:0001290	Generalized hypotonia
HP:0001336	Myoclonus
HP:0001347	Hyperreflexia
HP:0001999	Abnormal facial shape
HP:0002015	Dysphagia
HP:0002062	Abnormal pyramidal tract morphology
HP:0002066	Gait ataxia
HP:0002067	Bradykinesia
HP:0002070	Limb ataxia
HP:0002073	Progressive cerebellar ataxia
HP:0002172	Postural instability
HP:0002312	Clumsiness

GWAS associations

0 associations (top):

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D002972	Cleft Palate	C05.500.460.185; C05.660.207.540.460.185; C07.320.440.185; C07.465.525.185; C07.650.500.460.185; C07.650.525.185; C16.131.621.207.540.460.185; C16.131.850.500.460.185; C16.131.850.525.185
C531684	Hereditary spinal ataxia (supp.)
C537195	Spinocerebellar ataxia 13 (supp.)

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
tetraethylammonium	Channel blocker	3.9	pIC50
fampridine	Channel blocker	2.9	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

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
(+)-JQ1 compound	increases expression	2
Valproic Acid	affects cotreatment, decreases expression	2
aristolochic acid I	decreases expression	1
OTX015	increases expression	1
mivebresib	increases expression	1
dicrotophos	increases expression	1
arsenite	increases methylation	1
butyraldehyde	increases expression	1
pentanal	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	decreases expression	1
dorsomorphin	decreases expression, affects cotreatment	1
bisphenol S	decreases expression	1
jinfukang	decreases expression	1
Acetaminophen	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Benzo(a)pyrene	decreases methylation, increases methylation	1
Hydrogen Peroxide	affects cotreatment, decreases expression	1
T-2 Toxin	increases expression	1
Theophylline	affects cotreatment, decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Urethane	increases expression	1
Okadaic Acid	increases expression	1
Particulate Matter	increases expression, increases abundance	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

Cellosaurus cell lines

5 cell lines: 3 induced pluripotent stem cell, 1 spontaneously immortalized cell line, 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D1K6	PrecisION hKv3.3-CHO	Spontaneously immortalized cell line	Female
CVCL_E4WA	KOLF2.1J KCNC3 8.9kbdel DEL/DEL	Induced pluripotent stem cell	Male
CVCL_E7LD	KOLF2.1J KCNC3 R420H SNV/SNV	Induced pluripotent stem cell	Male
CVCL_E7LE	KOLF2.1J KCNC3 R420H SNV/WT	Induced pluripotent stem cell	Male
CVCL_XP94	HAP1 KCNC3 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02422056	PHASE4	COMPLETED	Acid Tranexamic Effectiveness in Reducing the Intraoperative Bleeding in Palatoplasty
NCT02915042	PHASE4	WITHDRAWN	Dexmedetomidine vs Placebo for Pediatric Cleft Palate Repair
NCT02953145	PHASE4	WITHDRAWN	The Use of Fibrin Sealant to Reduce Post Operative Pain in Cleft Palate Surgery
NCT03632044	PHASE4	ACTIVE_NOT_RECRUITING	Evaluation of Trigeminal Nerve Blockade
NCT06962306	PHASE4	RECRUITING	Optimizing Perioperative Analgesia to Lower Pain Following Cleft Palate Surgery
NCT00098319	PHASE3	COMPLETED	Oral Cleft Prevention Trial in Brazil
NCT00397917	PHASE3	COMPLETED	Oral Cleft Prevention Program
NCT04928352	PHASE3	RECRUITING	Nebulized Bupivacaine Analgesia for Cleft Palate Repair
NCT04928391	PHASE3	COMPLETED	A Single Bolus of Dexmedetomidine Versus Normal Saline in Postoperative Agitation
NCT00202397	PHASE2	COMPLETED	Effect of Riluzole as a Symptomatic Approach in Patients With Chronic Cerebellar Ataxia
NCT00004639	PHASE2	COMPLETED	Cleft Palate Surgery and Speech Development
NCT00760006	PHASE2	COMPLETED	Preventing Complications in Cleft Palate Repair With Antibiotics
NCT01760330	PHASE2	WITHDRAWN	IV Acetaminophen in Children Undergoing Palatoplasty
NCT02350803	PHASE2	COMPLETED	Does Use of Rigid Fixation After Removing Distraction Osteogenesis Device Reduce the Relapse?
NCT03412474	PHASE2	COMPLETED	Suprazygomatic Block in Cleft Palate Surgery in Children
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT01360164	PHASE1/PHASE2	UNKNOWN	Safety and Efficacy of Umbilical Cord Mesenchymal Stem Cell Therapy for Patients With Hereditary Ataxia
NCT00004306	Not specified	COMPLETED	Clinical and Molecular Correlations in Spinocerebellar Ataxia Type 10 (SCA10)
NCT04750850	Not specified	COMPLETED	Core Stability Exercises and Hereditary Ataxia
NCT05160870	Not specified	UNKNOWN	Genotype-phenotype Correlation and Pathogenic Mechanism in Hereditary Ataxia
NCT05160883	Not specified	UNKNOWN	Neuroimaging Changes in Hereditary Ataxia
NCT06034886	Not specified	AVAILABLE	Expanded Access Protocol of Troriluzole in Patients With Spinocerebellar Ataxia (SCA)
NCT06152133	Not specified	COMPLETED	Telerehabilitation, Core Stability Exercises and Hereditary Ataxia (TRCore-ataxia)
NCT06267222	Not specified	ENROLLING_BY_INVITATION	Trans-spinal Electrical Stimulation in Individuals With Spinocerebellar Ataxia
NCT07092358	Not specified	RECRUITING	Hereditary Ataxia Research on Multi-Omics and Neuroclinical Insights in the Yangtze Delta
NCT07200505	Not specified	NOT_YET_RECRUITING	Telerehabilitation for Core Stability and Strength in Hereditary Ataxia
NCT01616953	PHASE1/PHASE2	COMPLETED	Cell Therapy for Craniofacial Bone Defects
NCT02247193	PHASE1/PHASE2	COMPLETED	Botulinum Toxin to Improve Cosmesis of Primary Cleft Lip Repair
NCT00097149	Not specified	COMPLETED	Systematic Pediatric Care for Oral Clefts - South America
NCT00285714	Not specified	UNKNOWN	3D Imaging of Hard and Soft Tissue in Orthognathic Surgery
NCT00340977	Not specified	COMPLETED	Svangerskap, Arv, Og Miljo (Pregnancy, Heredity and Environment)
NCT00423072	Not specified	COMPLETED	Middle Ear Pressure Disregulation in Cleft Palate Patients
NCT00584272	Not specified	COMPLETED	Retrospective Study on the Outcome of Cleft Palate Repair: Comparing US Surgical and Ethicon Suture Materials
NCT00773994	Not specified	COMPLETED	Pilot Study Evaluating Characteristic Closure Patterns of the Normal Velopharyngeal Portal
NCT00779961	Not specified	UNKNOWN	An Investigation for the Optimal Timing of a Cleft Palate Repair
NCT00829101	Not specified	COMPLETED	Articulation and Phonology in Children With Unilateral Cleft Lip and Palate
NCT00993551	Not specified	COMPLETED	Timing of Primary Surgery for Cleft Palate
NCT00993993	Not specified	COMPLETED	Relational Development in Children With Cleft Lips and Palates: Influence of the Waiting Period Prior to the First Surgical Intervention and the Parents’ Psychological Perception of the Abnormality
NCT01046591	Not specified	COMPLETED	Sleep and Behavior in Children With Cleft Palate
NCT01252264	Not specified	COMPLETED	FaceBase Biorepository