KCNK4

Summary

KCNK4 (potassium two pore domain channel subfamily K member 4, HGNC:6279) is a protein-coding gene on chromosome 11q13.1, encoding Potassium channel subfamily K member 4 (Q9NYG8). K(+) channel that conducts voltage-dependent outward rectifying currents upon membrane depolarization.

This gene encodes a member of the TWIK-related arachidonic acid-stimulated two pore potassium channel subfamily. The encoded protein homodimerizes and functions as an outwardly rectifying channel. This channel is regulated by polyunsaturated fatty acids, temperature and mechanical deformation of the lipid membrane. This protein is expressed primarily in neural tissues and may be involved in regulating the noxious input threshold in dorsal root ganglia neurons. Alternate splicing results in multiple transcript variants. Naturally occurring read-through transcripts also exist between this gene and the downstream testis expressed 40 (TEX40) gene, as represented in GeneID: 106780802.

Source: NCBI Gene 50801 — RefSeq curated summary.

At a glance

• Gene–disease (curated): facial dysmorphism, hypertrichosis, epilepsy, intellectual/developmental delay, and gingival overgrowth syndrome (Strong, GenCC)
• GWAS associations: 3
• Clinical variants (ClinVar): 448 total — 1 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 38
• Druggable target: yes
• MANE Select transcript: NM_033310

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6279
Approved symbol	KCNK4
Name	potassium two pore domain channel subfamily K member 4
Location	11q13.1
Locus type	gene with protein product
Status	Approved
Aliases	K2p4.1, TRAAK
Ensembl gene	ENSG00000182450
Ensembl biotype	protein_coding
OMIM	605720
Entrez	50801

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 10 protein_coding, 4 retained_intron, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000394525, ENST00000422670, ENST00000453423, ENST00000536690, ENST00000538767, ENST00000538846, ENST00000539216, ENST00000539651, ENST00000541349, ENST00000545838, ENST00000696753, ENST00000906048, ENST00000906049, ENST00000967307, ENST00000967308, ENST00000967309

RefSeq mRNA: 2 — MANE Select: NM_033310 NM_001317090, NM_033310

CCDS: CCDS8067

Canonical transcript exons

ENST00000422670 — 7 exons

Exon	Start	End
ENSE00002257059	64299346	64300031
ENSE00002282026	64291302	64291566
ENSE00003487466	64292942	64293207
ENSE00003544589	64297467	64297653
ENSE00003661916	64296878	64297001
ENSE00003671153	64297119	64297279
ENSE00003692382	64298110	64298249

Expression profiles

Bgee: expression breadth broad, 66 present calls, max score 81.98.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.2841 / max 23.6491, expressed in 85 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
114935	0.0881	45
114938	0.0788	51
114936	0.0436	24
114937	0.0422	32
114939	0.0314	19

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
nucleus accumbens	UBERON:0001882	81.98	gold quality
temporal lobe	UBERON:0001871	80.70	gold quality
amygdala	UBERON:0001876	80.67	gold quality
Ammon’s horn	UBERON:0001954	79.94	gold quality
superior frontal gyrus	UBERON:0002661	79.78	gold quality
prefrontal cortex	UBERON:0000451	79.55	gold quality
anterior cingulate cortex	UBERON:0009835	79.36	gold quality
frontal cortex	UBERON:0001870	79.17	gold quality
right frontal lobe	UBERON:0002810	78.77	gold quality
cerebral cortex	UBERON:0000956	78.31	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	77.98	gold quality
caudate nucleus	UBERON:0001873	77.80	gold quality
Brodmann (1909) area 9	UBERON:0013540	77.34	gold quality
putamen	UBERON:0001874	77.06	gold quality
primary visual cortex	UBERON:0002436	76.68	gold quality
brain	UBERON:0000955	71.45	gold quality
hypothalamus	UBERON:0001898	68.28	gold quality
right hemisphere of cerebellum	UBERON:0014890	66.48	gold quality
cerebellar cortex	UBERON:0002129	65.19	gold quality
cerebellum	UBERON:0002037	65.14	gold quality
cerebellar hemisphere	UBERON:0002245	65.02	gold quality
cortical plate	UBERON:0005343	61.01	gold quality
placenta	UBERON:0001987	59.77	gold quality
substantia nigra	UBERON:0002038	59.75	gold quality
endometrium	UBERON:0001295	49.84	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	47.27	gold quality
bone marrow cell	CL:0002092	46.71	gold quality
myometrium	UBERON:0001296	44.05	gold quality
sural nerve	UBERON:0015488	42.26	gold quality
descending thoracic aorta	UBERON:0002345	42.13	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.98

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 15)

• Human TASK-3 was cloned and expressed; protein sequence and activity compared to similar two pore domain potassium channels, including KCNK4 (TRAAK). (PMID:11042359)
• role for TREK-1 in contributing to uterine quiescence during gestation (PMID:20811500)
• crystal structure of TRAAK at 3.8 angstroms resolution; channel comprises 2 protomers that create 2-fold symmetric K(+) channel; extracellular surface has a helical cap; 2 diagonally opposed gate-forming inner helices form membrane-interacting structures (PMID:22282805)
• structure reveals a domain-swapped chain connectivity enabled by the helical cap that exchanges two opposing outer helices 180 degrees around the channel (PMID:23341632)
• TRAAK is responsive to mechanical forces similar to the ion channel Piezo1; mechanical activation of TRAAK can electrically counter Piezo1 activation. (PMID:24550493)
• findings uncover a unique aspect of potassium channel modulation, indicate a means for how the channel C-terminal cytoplasmic domain affects the C-type gate, and suggest how lipids and bilayer inner leaflet deformations gate the channel. (PMID:25500157)
• KCNK4 promoter methylation is associated with Breast Cancer. (PMID:25809865)
• How ion channels sense mechanical force: insights from mechanosensitive K2P channels TRAAK, TREK1, and TREK2. (PMID:26332952)
• Functional alanine-mutagenesis screens of TASK-1 and TRAAK were used to build an in silico model of the TASK-1 cap. (PMID:26794006)
• The pleiotropic effect of dysregulated KCNK4 function. (PMID:30290154)
• TRAAK, TREK1 and TREK2 are robustly mechanosensitive K+-selective channels of the K2P family and are modulated by chemical and physical stimuli including lipids, lysolipids, arachidonic acid and other polyunsaturated fatty acids. (PMID:31542828)
• Selective regulation of human TRAAK channels by biologically active phospholipids. (PMID:32989299)
• Syndromic disorders caused by gain-of-function variants in KCNH1, KCNK4, and KCNN3-a subgroup of K(+) channelopathies. (PMID:33594261)
• Physical basis for distinct basal and mechanically gated activity of the human K(+) channel TRAAK. (PMID:34390650)
• A recurrent KCNK4 variant in a dominant pedigree with hypertrichosis and gingival fibromatosis syndrome: Variable phenotypic expressivity and insights on patients’ dental management. (PMID:37750049)

Cross-species orthologs

16 orthologs

Organism	Symbol	Gene ID
danio_rerio	kcnk4a	ENSDARG00000103286
mus_musculus	Kcnk4	ENSMUSG00000024957
rattus_norvegicus	Kcnk4	ENSRNOG00000021140
drosophila_melanogaster	Ork1	FBGN0017561
drosophila_melanogaster	Task7	FBGN0037690
drosophila_melanogaster	Task6	FBGN0038165
drosophila_melanogaster	CG10864	FBGN0038621
drosophila_melanogaster	CG42340	FBGN0259242
caenorhabditis_elegans		WBGENE00006661
caenorhabditis_elegans		WBGENE00006674
caenorhabditis_elegans		WBGENE00006675
caenorhabditis_elegans		WBGENE00006679
caenorhabditis_elegans		WBGENE00006685
caenorhabditis_elegans		WBGENE00006686
caenorhabditis_elegans		WBGENE00006695
caenorhabditis_elegans		WBGENE00006696

Paralogs (14): KCNK2 (ENSG00000082482), KCNK16 (ENSG00000095981), KCNK6 (ENSG00000099337), KCNK10 (ENSG00000100433), KCNK15 (ENSG00000124249), KCNK17 (ENSG00000124780), KCNK1 (ENSG00000135750), KCNK13 (ENSG00000152315), KCNK5 (ENSG00000164626), KCNK9 (ENSG00000169427), KCNK3 (ENSG00000171303), KCNK7 (ENSG00000173338), KCNK12 (ENSG00000184261), KCNK18 (ENSG00000186795)

Protein

Protein identifiers

Potassium channel subfamily K member 4 — Q9NYG8 (reviewed: Q9NYG8)

Alternative names: TWIK-related arachidonic acid-stimulated potassium channel protein, Two pore potassium channel KT4.1

All UniProt accessions (3): Q9NYG8, F5GYE0, F5GZ20

UniProt curated annotations — full annotation on UniProt →

Function. K(+) channel that conducts voltage-dependent outward rectifying currents upon membrane depolarization. Voltage sensing is coupled to K(+) electrochemical gradient in an ‘ion flux gating’ mode where outward but not inward ion flow opens the gate. Converts to voltage-independent ’leak’ conductance mode upon stimulation by various stimuli including mechanical membrane stretch, basic pH, heat and lipids. Homo- and heterodimerizes to form functional channels with distinct regulatory and gating properties. At trigeminal A-beta afferent nerves, the heterodimer of KCNK2/TREK-1 and KCNK4/TRAAK is mostly coexpressed at nodes of Ranvier where it conducts voltage-independent mechanosensitive and thermosensitive currents, allowing rapid action potential repolarization, high speed and high frequence saltatory conduction on myelinated nerves to ensure prompt sensory responses. Permeable to other monovalent cations such as Rb(+) and Cs(+).

Subunit / interactions. Homodimer; disulfide-linked. Forms heterodimers with other 2-pore domain K(+) channel subunits, such as KCNK2 and KCNK10.

Subcellular location. Cell membrane. Cell projection. Axon.

Post-translational modifications. N-glycosylated.

Disease relevance. Facial dysmorphism, hypertrichosis, epilepsy, intellectual and developmental delay, and gingival overgrowth syndrome (FHEIG) [MIM:618381] An autosomal dominant syndrome characterized by delayed motor and intellectual development, poor speech, seizures, generalized hypertrichosis and facial dysmorphic features, including hypotonic facies, bitemporal narrowing, micrognathia, deep-set eyes, bushy eyebrows and long eyelashes, low-set ears, short deep philtrum, gingival overgrowth, prominent upper and lower vermilion, and everted upper lip. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Activated by mechanical stretch and arachidonic acid.

Domain organisation. Each subunit contributes two pore-forming domains 1 and 2 which assemble to form a single pore with M2 and M4 transmembrane helices lining the central cavity and M1 and M3 facing the lipid bilayer. The transmembrane helices are bridged by the selectivity filters 1 and 2 carrying a signature sequence TxTTxGYGD that coordinate the permeant ions. Up to four ions can simultaneously occupy the selectivity filter and at least two elementary charges must translocate across the filter to convert it into the open conformation. Channel opening is brought about by a conformation change that involves buckling of the second transmembrane helix and affects the position and orientation of the fourth transmembrane helix.

Miscellaneous. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Similarity. Belongs to the two pore domain potassium channel (TC 1.A.1.8) family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9NYG8-1	1, KT4.1a	yes
Q9NYG8-2	2, KT4.1b

RefSeq proteins (2): NP_001304019, NP_201567* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003280	2pore_dom_K_chnl	Family
IPR008074	2pore_dom_K_chnl_TRAAK	Family
IPR013099	K_chnl_dom	Domain

Pfam: PF07885

Catalyzed reactions (Rhea), 3 shown:

• K(+)(in) = K(+)(out) (RHEA:29463)
• Rb(+)(in) = Rb(+)(out) (RHEA:78547)
• Cs(+)(in) = Cs(+)(out) (RHEA:78555)

UniProt features (62 total): binding site 14, helix 10, topological domain 7, mutagenesis site 5, intramembrane region 4, transmembrane region 4, strand 4, region of interest 3, sequence variant 3, compositionally biased region 2, glycosylation site 2, chain 1, disulfide bond 1, splice variant 1, turn 1

Structure

Experimental structures (PDB)

12 structures.

PDB	Method	Resolution (Å)
7LJ5	X-RAY DIFFRACTION	2.26
4WFE	X-RAY DIFFRACTION	2.5
4WFF	X-RAY DIFFRACTION	2.5
4I9W	X-RAY DIFFRACTION	2.75
7LJA	X-RAY DIFFRACTION	2.77
7LJ4	X-RAY DIFFRACTION	2.78
7LJB	X-RAY DIFFRACTION	2.97
4WFG	X-RAY DIFFRACTION	3
4WFH	X-RAY DIFFRACTION	3.01
4RUE	X-RAY DIFFRACTION	3.3
3UM7	X-RAY DIFFRACTION	3.31
4RUF	X-RAY DIFFRACTION	3.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NYG8-F1	79.11	0.50

Antibody-complex structures (SAbDab): 9 — 4I9W, 4WFE, 4WFF, 4WFG, 4WFH, 7LJ4, 7LJ5, 7LJA, 7LJB

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 (14): 103; 103; 104; 104; 105; 105; 106; 212; 212; 213; 213; 214 …

Disulfide bonds (1): 52

Glycosylation sites (2): 78, 82

Mutagenesis-validated functional residues (5):

Position	Phenotype
98	strongly increases basal level of channel activity, decreases further activation by pressure and abolishes further activ
103	loss of voltage-dependent channel gating. displays linear current-voltage relationship.
212	loss of voltage-dependent channel gating. abolishes activation by arachidonic acid and pip2.
232	gain of a cryptic cation-pi interaction that activates channel gating.
236	increases basal level of channel activity and decreases further activation by pressure, but has little effect on further

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-1299503	TWIK related potassium channel (TREK)
R-HSA-5576886	Phase 4 - resting membrane potential
R-HSA-112316	Neuronal System
R-HSA-1296071	Potassium Channels
R-HSA-1296346	Tandem pore domain potassium channels
R-HSA-397014	Muscle contraction
R-HSA-5576891	Cardiac conduction

MSigDB gene sets: 209 (showing top): GOBP_POTASSIUM_ION_TRANSPORT, GOBP_MEMORY, BENPORATH_ES_WITH_H3K27ME3, GOBP_COGNITION, GOBP_SENSORY_PERCEPTION_OF_TEMPERATURE_STIMULUS, GOBP_BEHAVIOR, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_SENSORY_PERCEPTION_OF_MECHANICAL_STIMULUS, REACTOME_TANDEM_PORE_DOMAIN_POTASSIUM_CHANNELS, GOBP_CELLULAR_RESPONSE_TO_EXTERNAL_STIMULUS, REACTOME_POTASSIUM_CHANNELS, GOBP_DETECTION_OF_MECHANICAL_STIMULUS_INVOLVED_IN_SENSORY_PERCEPTION, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, chr11q13, GOBP_MONOATOMIC_CATION_TRANSPORT

GO Biological Process (17): potassium ion transport (GO:0006813), memory (GO:0007613), neuronal action potential (GO:0019228), sensory perception of pain (GO:0019233), sensory perception of temperature stimulus (GO:0050951), detection of mechanical stimulus involved in sensory perception of touch (GO:0050976), cellular response to mechanical stimulus (GO:0071260), cellular response to fatty acid (GO:0071398), cellular response to acidic pH (GO:0071468), cellular response to alkaline pH (GO:0071469), cellular response to temperature stimulus (GO:0071502), potassium ion transmembrane transport (GO:0071805), cellular response to arachidonate (GO:1904551), response to ultrasound (GO:1990478), monoatomic ion transport (GO:0006811), response to mechanical stimulus (GO:0009612), monoatomic ion transmembrane transport (GO:0034220)

GO Molecular Function (8): potassium channel activity (GO:0005267), outward rectifier potassium channel activity (GO:0015271), potassium ion leak channel activity (GO:0022841), identical protein binding (GO:0042802), metal ion binding (GO:0046872), temperature-gated cation channel activity (GO:0097604), mechanosensitive potassium channel activity (GO:0098782), protein binding (GO:0005515)

GO Cellular Component (7): plasma membrane (GO:0005886), node of Ranvier (GO:0033268), potassium channel complex (GO:0034705), membrane (GO:0016020), axon (GO:0030424), monoatomic ion channel complex (GO:0034702), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Tandem pore domain potassium channels	1
Cardiac conduction	1
Neuronal System	1
Potassium Channels	1
Muscle contraction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
sensory perception	2
response to mechanical stimulus	2
cellular response to pH	2
monoatomic cation channel activity	2
potassium channel activity	2
metal ion transport	1
learning or memory	1
action potential	1
transmission of nerve impulse	1
detection of mechanical stimulus involved in sensory perception	1
sensory perception of touch	1
cellular response to abiotic stimulus	1
cellular response to external stimulus	1
response to fatty acid	1
cellular response to lipid	1
cellular response to oxygen-containing compound	1
response to acidic pH	1
response to alkaline pH	1
response to temperature stimulus	1
potassium ion transport	1
monoatomic cation transmembrane transport	1
cellular response to fatty acid	1
response to arachidonate	1
transport	1
response to external stimulus	1
response to abiotic stimulus	1
monoatomic ion transport	1
transmembrane transport	1
potassium ion transmembrane transporter activity	1
voltage-gated potassium channel activity	1
leak channel activity	1
protein binding	1
cation binding	1
temperature-gated ion channel activity	1
mechanosensitive monoatomic cation channel activity	1
binding	1
membrane	1
cell periphery	1
main axon	1

Protein interactions and networks

STRING

1044 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KCNK4	KRT76	Q01546	883
KCNK4	PIEZO1	Q92508	715
KCNK4	KCNK2	O95069	700
KCNK4	TRPM8	Q7Z2W7	630
KCNK4	KCNMA1	Q12791	628
KCNK4	PIEZO2	Q9H5I5	623
KCNK4	TRPA1	O75762	615
KCNK4	TRPV1	Q8NER1	595
KCNK4	TRPV4	Q9HBA0	583
KCNK4	TRPV2	Q9Y5S1	492
KCNK4	PRKACG	P22612	492
KCNK4	KCNA2	P16389	491
KCNK4	PRKACB	P22694	490
KCNK4	PRKACA	P17612	488
KCNK4	GPR137	Q96N19	488

IntAct

5 interactions, top by confidence:

A	B	Type	Score
KCNK4	RPL14	psi-mi:“MI:0915”(physical association)	0.370
DIDO1	KCNK4	psi-mi:“MI:0915”(physical association)	0.370
M		psi-mi:“MI:0914”(association)	0.350
KCNK4	CRYGB	psi-mi:“MI:0914”(association)	0.350

BioGRID (8): KCNK4 (Two-hybrid), GOLGA5 (Affinity Capture-MS), TMEM161A (Affinity Capture-MS), TMEM87A (Affinity Capture-MS), NDFIP1 (Affinity Capture-MS), CRYGB (Affinity Capture-MS), KCNK4 (Two-hybrid), RPL14 (Two-hybrid)

ESM2 similar proteins: A0A3Q2HW92, A1A5B4, A2ADF7, A5D787, A6NFX1, A6NGC4, D3ZVU9, F1PZV2, O96011, P19258, Q04671, Q13286, Q148K5, Q3T0A0, Q3T9M1, Q3U481, Q3UGX3, Q501J2, Q567V2, Q5BK62, Q5JZQ7, Q5R9A1, Q5RFI0, Q5U419, Q5ZJX0, Q60HH0, Q66GV0, Q6DGV7, Q6NUT3, Q6UXD7, Q6ZMD2, Q7Z403, Q8BMT9, Q8CE47, Q8CHK3, Q8TB61, Q8TBR7, Q8TCT7, Q8VC74, Q8VIK2

Diamond homologs: G3V8R8, G3V8V5, G5E845, O00180, O08581, O14649, O17185, O35111, O54912, O88454, O95069, O95279, P57789, P97438, Q0P5A0, Q23435, Q3LS21, Q3TBV4, Q5RD07, Q5UE96, Q5VSE6, Q63ZI0, Q6Q1P3, Q6VV64, Q7Z418, Q8BUW1, Q8R454, Q8R5I0, Q920B6, Q96T54, Q96T55, Q9ERS1, Q9ES08, Q9H427, Q9HB14, Q9HB15, Q9JIS4, Q9JL58, Q9NPC2, Q9NYG8

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	2
Uncertain significance	210
Likely benign	181
Benign	18

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
1803302	NM_033310.3(KCNK4):c.428G>A (p.Gly143Asp)	Pathogenic
1438188	NM_033310.3(KCNK4):c.739G>T (p.Ala247Ser)	Likely pathogenic
3772055	NM_033310.3(KCNK4):c.728T>C (p.Leu243Pro)	Likely pathogenic

SpliceAI

1028 predictions. Top by Δscore:

Variant	Effect	Δscore
11:64297549:C:CA	acceptor_gain	1.0000
11:64297549:C:G	acceptor_gain	1.0000
11:64298096:T:A	acceptor_gain	1.0000
11:64298097:G:A	acceptor_gain	1.0000
11:64298099:T:TA	acceptor_gain	1.0000
11:64298100:G:A	acceptor_gain	1.0000
11:64298245:CAGAG:C	donor_loss	1.0000
11:64298247:GAG:G	donor_gain	1.0000
11:64298249:GGTA:G	donor_loss	1.0000
11:64293129:G:GT	donor_gain	0.9900
11:64293208:G:GC	donor_loss	0.9900
11:64297276:CTTGG:C	donor_loss	0.9900
11:64297277:TTGG:T	donor_loss	0.9900
11:64297278:TGGTG:T	donor_loss	0.9900
11:64297279:GGTGA:G	donor_loss	0.9900
11:64297280:G:GG	donor_gain	0.9900
11:64297280:GTG:G	donor_loss	0.9900
11:64297281:T:G	donor_loss	0.9900
11:64297282:GAGCT:G	donor_loss	0.9900
11:64297462:CGCA:C	acceptor_loss	0.9900
11:64297463:GCA:G	acceptor_loss	0.9900
11:64297464:CAGAA:C	acceptor_loss	0.9900
11:64297465:A:AG	acceptor_gain	0.9900
11:64297465:A:G	acceptor_loss	0.9900
11:64297466:G:GA	acceptor_gain	0.9900
11:64297466:G:T	acceptor_loss	0.9900
11:64297466:GAA:G	acceptor_gain	0.9900
11:64297466:GAAGT:G	acceptor_gain	0.9900
11:64297522:T:A	acceptor_gain	0.9900
11:64297548:A:AG	acceptor_gain	0.9900

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000079532 (11:64293184 C>A), RS1000451236 (11:64293623 C>T), RS1000676012 (11:64292303 C>G), RS1000811738 (11:64292137 G>A), RS1001526080 (11:64294355 T>C), RS1001549061 (11:64291681 C>T), RS1001570831 (11:64297974 C>A,T), RS1001856394 (11:64292741 C>T), RS1001907775 (11:64299628 C>G,T), RS1001914869 (11:64291398 T>C), RS1002285930 (11:64293002 C>G,T), RS1002571486 (11:64295758 G>A,C), RS1002963449 (11:64299254 G>A,T), RS1003428745 (11:64290366 C>CA), RS1003496263 (11:64299053 A>G)

Disease associations

OMIM: gene MIM:605720 | disease phenotypes: MIM:618381

GenCC curated gene-disease

Disease	Classification	Inheritance
facial dysmorphism, hypertrichosis, epilepsy, intellectual/developmental delay, and gingival overgrowth syndrome	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
facial dysmorphism, hypertrichosis, epilepsy, intellectual/developmental delay, and gingival overgrowth syndrome	Moderate	AD

Mondo (3): facial dysmorphism, hypertrichosis, epilepsy, intellectual/developmental delay, and gingival overgrowth syndrome (MONDO:0032714), intellectual disability (MONDO:0001071), gingival overgrowth (MONDO:0002507)

Orphanet (3): Facial dysmorphism-hypertrichosis-epilepsy-intellectual disability/developmental delay-gingival overgrowth syndrome (Orphanet:598603), Self-limited epilepsy with centrotemporal spikes (Orphanet:1945), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

38 total (30 of 38 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000154	Wide mouth
HP:0000201	Pierre-Robin sequence
HP:0000212	Gingival overgrowth
HP:0000219	Thin upper lip vermilion
HP:0000297	Facial hypotonia
HP:0000322	Short philtrum
HP:0000341	Narrow forehead
HP:0000347	Micrognathia
HP:0000369	Low-set ears
HP:0000490	Deeply set eye
HP:0000527	Long eyelashes
HP:0000574	Thick eyebrow
HP:0000609	Optic nerve hypoplasia
HP:0000639	Nystagmus
HP:0000664	Synophrys
HP:0000750	Delayed speech and language development
HP:0000998	Hypertrichosis
HP:0001156	Brachydactyly
HP:0001249	Intellectual disability
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001347	Hyperreflexia
HP:0001385	Hip dysplasia
HP:0002002	Deep philtrum
HP:0002069	Bilateral tonic-clonic seizure
HP:0002079	Hypoplasia of the corpus callosum
HP:0002080	Intention tremor
HP:0002119	Ventriculomegaly
HP:0002194	Delayed gross motor development

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST001622_1	Sarcoidosis	3.000000e-18
GCST004132_98	Crohn’s disease	5.000000e-06
GCST004785_38	Vitiligo	5.000000e-08

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D019214	Gingival Overgrowth	C07.465.714.258.428
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3714486 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: vgic — Two-pore domain potassium channels (K_2P)

CTD chemical–gene interactions

16 total (human), top 16 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases methylation	2
Potassium	increases reaction, increases transport	2
Aflatoxin B1	decreases methylation, increases methylation	2
Arachidonic Acid	increases reaction, increases transport	2
benzo(e)pyrene	decreases methylation	1
aflatoxin B2	decreases methylation	1
licochalcone B	increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Cadmium	increases expression	1
Flufenamic Acid	increases reaction, increases transport	1
Mefenamic Acid	increases reaction, increases transport	1
Methapyrilene	decreases methylation	1
Niflumic Acid	increases transport, increases reaction	1
Plant Extracts	affects cotreatment, decreases expression	1
Smoke	decreases expression	1
Testosterone	decreases expression	1

ChEMBL screening assays

18 unique, capped per target: 18 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3819944	Binding	Activation of TRAAK (unknown origin) expressed in Xenopus oocytes assessed as increase in channel currents	Perspectives on the Two-Pore Domain Potassium Channel TREK-1 (TWIK-Related K(+) Channel 1). A Novel Therapeutic Target? — J Med Chem

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_YA67	IDG-HEK293T-KCNK4-V5-OE	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT00781196	PHASE3	COMPLETED	Folic Acid Supplementation in Phenytoin Induced Gingival Overgrowth
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT06806319	PHASE2	COMPLETED	Assessment of Growth Factors Levels Associated with Wound Healing After Soft Tissue Crown Lengthening
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT04030767	PHASE1	UNKNOWN	Evaluating Lip Repositioning for the Treatment of Excess Gingival Display With and Without Pretreatment With Botox
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study
NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD
NCT02591446	Not specified	COMPLETED	Transcranial Magnetic Stimulation Studies in Autism Spectrum Disorders
NCT02714868	Not specified	COMPLETED	Evaluation of Project TEAM (Teens Making Environmental and Activity Modifications)