KCNK1

Summary

KCNK1 (potassium two pore domain channel subfamily K member 1, HGNC:6272) is a protein-coding gene on chromosome 1q42.2, encoding Potassium channel subfamily K member 1 (O00180). Ion channel that contributes to passive transmembrane potassium transport and to the regulation of the resting membrane potential in brain astrocytes, but also in kidney and in other tissues.

This gene encodes one of the members of the superfamily of potassium channel proteins containing two pore-forming P domains. The product of this gene has not been shown to be a functional channel, however, it may require other non-pore-forming proteins for activity.

Source: NCBI Gene 3775 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 52 total
• MANE Select transcript: NM_002245

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6272
Approved symbol	KCNK1
Name	potassium two pore domain channel subfamily K member 1
Location	1q42.2
Locus type	gene with protein product
Status	Approved
Aliases	K2p1.1, DPK, TWIK-1
Ensembl gene	ENSG00000135750
Ensembl biotype	protein_coding
OMIM	601745
Entrez	3775

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 4 protein_coding_CDS_not_defined, 3 protein_coding

ENST00000366620, ENST00000366621, ENST00000446915, ENST00000472190, ENST00000472869, ENST00000487728, ENST00000918244

RefSeq mRNA: 1 — MANE Select: NM_002245 NM_002245

CCDS: CCDS1599

Canonical transcript exons

ENST00000366621 — 3 exons

Exon	Start	End
ENSE00001442190	233614106	233614526
ENSE00001628238	233671271	233672514
ENSE00003603068	233666595	233666990

Expression profiles

Bgee: expression breadth ubiquitous, 279 present calls, max score 99.11.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 8.2549 / max 637.6606, expressed in 1057 samples.

FANTOM5 promoters (18 alternative TSS)

Promoter ID	TPM avg	Samples expressed
9087	2.3792	557
9080	1.9329	547
9084	0.9210	447
9085	0.7384	448
9086	0.6796	388
9082	0.2894	187
9088	0.2200	101
9083	0.1806	92
9079	0.1733	56
9096	0.1678	31

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cerebellar vermis	UBERON:0004720	99.11	gold quality
pons	UBERON:0000988	97.99	gold quality
cerebellum	UBERON:0002037	97.93	gold quality
endothelial cell	CL:0000115	97.90	gold quality
cerebellar cortex	UBERON:0002129	97.81	gold quality
cerebellar hemisphere	UBERON:0002245	97.78	gold quality
orbitofrontal cortex	UBERON:0004167	97.72	gold quality
right hemisphere of cerebellum	UBERON:0014890	97.59	gold quality
paraflocculus	UBERON:0005351	97.41	gold quality
cartilage tissue	UBERON:0002418	96.78	gold quality
corpus epididymis	UBERON:0004359	96.73	gold quality
cardiac muscle of right atrium	UBERON:0003379	96.48	gold quality
Brodmann (1909) area 23	UBERON:0013554	96.40	gold quality
buccal mucosa cell	CL:0002336	96.39	gold quality
mucosa of sigmoid colon	UBERON:0004993	96.38	gold quality
caput epididymis	UBERON:0004358	96.31	gold quality
jejunal mucosa	UBERON:0000399	96.24	gold quality
choroid plexus epithelium	UBERON:0003911	96.24	gold quality
inferior vagus X ganglion	UBERON:0005363	96.04	gold quality
colonic mucosa	UBERON:0000317	95.73	gold quality
middle temporal gyrus	UBERON:0002771	95.67	gold quality
nasal cavity epithelium	UBERON:0005384	95.59	gold quality
prefrontal cortex	UBERON:0000451	95.31	gold quality
epithelial cell of pancreas	CL:0000083	95.26	gold quality
pancreatic ductal cell	CL:0002079	94.94	gold quality
Brodmann (1909) area 46	UBERON:0006483	94.86	gold quality
frontal pole	UBERON:0002795	94.84	gold quality
parietal lobe	UBERON:0001872	94.73	gold quality
superior frontal gyrus	UBERON:0002661	94.73	gold quality
Brodmann (1909) area 9	UBERON:0013540	94.57	gold quality

Single-cell (SCXA)

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

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

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

70 targeting KCNK1, 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-340-5P	100.00	72.50	4437
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-129-5P	99.88	70.26	3273
HSA-LET-7A-2-3P	99.87	70.53	1921
HSA-LET-7G-3P	99.85	70.43	1929
HSA-MIR-4799-5P	99.82	70.60	2663
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-26A-5P	99.78	73.52	2303
HSA-MIR-26B-5P	99.78	73.51	2305
HSA-MIR-4320	99.75	65.80	793
HSA-MIR-3680-3P	99.75	72.51	3095
HSA-MIR-6885-3P	99.75	70.36	3187
HSA-MIR-12129	99.72	67.45	1311
HSA-MIR-4465	99.71	72.56	2096
HSA-MIR-33A-3P	99.70	70.27	3362

Literature-anchored findings (GeneRIF, showing 14)

• Removal of the peptide adduct by SUMO protease reveals K2P1 to be a K+-selective, pH-sensitive, openly rectifying channel regulated by reversible peptide linkage. (PMID:15820677)
• support TWIK-1 and TREK-1 as being the major components of the long-sought K(+) channels underlying the passive conductance of mature hippocampal astrocytes (PMID:19571146)
• TWIK1 is internalized via a dynamin-dependent mechanism and addressed to the recycling endosomal compartment. Mutation in its cytoplasmic C terminus (I293A,I294A) stabilizes TWIK1 at the plasma membrane, resulting in robust currents. (PMID:19959478)
• ion selectivity of TWIK-1 K+ channels during pathological hypokalemia; a molecular basis for inward leak Na+ currents that could trigger or contribute to cardiac paradoxical depolarization in lowered [K+]o; mechanism for regulating cardiac excitability. (PMID:21653227)
• Potassium channels, in particular K2P channels, are expressed and functional in the apical membrane of airway epithelial cells (PMID:21964404)
• study presents the 3.4 angstrom resolution crystal structure of a human K2P channel, K2P1; an extracellular cap domain located above the selectivity filter forms an ion pathway in which K(+) ions flow through side portals (PMID:22282804)
• TWIK-1 protein possesses a hydrophobic barrier deep within the inner pore (PMID:25001086)
• Our data indicate that TWIK-1 has a highly conserved role in cardiac function and is required for normal heart rate and atrial morphology. Despite the functional importance of TWIK-1 in the atrium, genetic variation in KCNK1 is not a common primary cause of human AF. (PMID:27103460)
• Dynamics of the TWIK-1 Channel (PMID:27558721)
• Selectivity filter instability dominates the low intrinsic activity of the TWIK-1 K2P K(+) channel. (PMID:31806709)
• Identification of KCNK1 as a potential prognostic biomarker and therapeutic target of breast cancer. (PMID:36566598)
• Overexpressed KCNK1 regulates potassium channels affecting molecular mechanisms and biological pathways in bladder cancer. (PMID:38689322)
• KCNK1 promotes proliferation and metastasis of breast cancer cells by activating lactate dehydrogenase A (LDHA) and up-regulating H3K18 lactylation. (PMID:38905316)
• Evidence for an Association Between a pH-Dependent Potassium Channel, TWIK-1, and the Accuracy of Smooth Pursuit Eye Movements. (PMID:39012638)

Cross-species orthologs

17 orthologs

Organism	Symbol	Gene ID
danio_rerio	kcnk1b	ENSDARG00000017254
danio_rerio	kcnk1a	ENSDARG00000045067
mus_musculus	Kcnk1	ENSMUSG00000033998
rattus_norvegicus	Kcnk1	ENSRNOG00000019937
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), KCNK13 (ENSG00000152315), KCNK5 (ENSG00000164626), KCNK9 (ENSG00000169427), KCNK3 (ENSG00000171303), KCNK7 (ENSG00000173338), KCNK4 (ENSG00000182450), KCNK12 (ENSG00000184261), KCNK18 (ENSG00000186795)

Protein

Protein identifiers

Potassium channel subfamily K member 1 — O00180 (reviewed: O00180)

Alternative names: Inward rectifying potassium channel protein TWIK-1, Potassium channel K2P1, Potassium channel KCNO1

All UniProt accessions (2): O00180, Q5T5E6

UniProt curated annotations — full annotation on UniProt →

Function. Ion channel that contributes to passive transmembrane potassium transport and to the regulation of the resting membrane potential in brain astrocytes, but also in kidney and in other tissues. Forms dimeric channels through which potassium ions pass in accordance with their electrochemical gradient. The channel is selective for K(+) ions at physiological potassium concentrations and at neutral pH, but becomes permeable to Na(+) at subphysiological K(+) levels and upon acidification of the extracellular medium. The homodimer has very low potassium channel activity, when expressed in heterologous systems, and can function as weakly inward rectifying potassium channel. Channel activity is modulated by activation of serotonin receptors. Heterodimeric channels containing KCNK1 and KCNK2 have much higher activity, and may represent the predominant form in astrocytes. Heterodimeric channels containing KCNK1 and KCNK3 or KCNK9 have much higher activity. Heterodimeric channels formed by KCNK1 and KCNK9 may contribute to halothane-sensitive currents. Mediates outward rectifying potassium currents in dentate gyrus granule cells and contributes to the regulation of their resting membrane potential. Contributes to the regulation of action potential firing in dentate gyrus granule cells and down-regulates their intrinsic excitability. In astrocytes, the heterodimer formed by KCNK1 and KCNK2 is required for rapid glutamate release in response to activation of G-protein coupled receptors, such as F2R and CNR1. Required for normal ion and water transport in the kidney. Contributes to the regulation of the resting membrane potential of pancreatic beta cells. The low channel activity of homodimeric KCNK1 may be due to sumoylation. The low channel activity may be due to rapid internalization from the cell membrane and retention in recycling endosomes. Permeable to monovalent cations with ion selectivity for K(+) > Rb(+) » NH4(+) » Cs(+) = Na(+) = Li(+).

Subunit / interactions. Homodimer; disulfide-linked. Heterodimer with KCNK2; disulfide-linked. In astrocytes, forms mostly heterodimeric potassium channels with KCNK2, with only a minor proportion of functional channels containing homodimeric KCNK1. Interacts with KCNK3 and KCNK9, forming functional heterodimeric channels. Interacts with GNG4. Identified in a complex with PSD and ARF6; interacts only with PSD that is bound to ARF6. Interacts with UBE2I.

Subcellular location. Cell membrane. Recycling endosome. Synaptic cell membrane. Cytoplasmic vesicle. Perikaryon. Cell projection. Dendrite. Apical cell membrane.

Tissue specificity. Detected in bronchial epithelial cells. Detected in heart left atrium and left ventricle. Detected in cardiac myocytes (at protein level). Widely expressed with high levels in heart, brain and kidney, and lower levels in colon, ovary, placenta, lung and liver. Highly expressed in cerebellum, and detected at lower levels in amygdala, caudate nucleus, brain cortex, hippocampus, putamen, substantia nigra, thalamus, dorsal root ganglion, spinal cord, pituitary, heart, kidney, lung, placenta, pancreas, stomach, small intestine, uterus and prostate. Detected in right and left heart ventricle and atrium, and in heart Purkinje fibers.

Post-translational modifications. Sumoylation is controversial. Sumoylated by UBE2I. Not sumoylated when expressed in xenopus oocytes or mammalian cells. Sumoylation inactivates the channel, but does not interfere with expression at the cell membrane. Sumoylation of a single subunit is sufficient to silence the dimeric channel. Sumoylation of KCNK1 is sufficient to silence heterodimeric channels formed by KCNK1 and KCNK3 or KCNK9. Desumoylated by SENP1; this activates the channel. Desumoylated by SENP1; this strongly increases halothane-mediated activation of heterodimeric channels formed with KCNK9. SENP1 treatment has no effect.

Activity regulation. Inhibited by Ba(2+) ions and quinidine. Inhibited by quinine. Is slightly inhibited by 10 mM tetraethylammonium (TEA), and only marginally inhibited by 4-aminopyridine, charybdotoxin and dendrotoxin. Lowering the extracellular pH to below 6.5 transiently activates the channel, and then inhibits channel activity. Inhibited when the intracellular pH is decreased down to pH 6.0, but this may be due to indirect effects.

Miscellaneous. When the external K(+) concentration is lowered to subphysiological levels, it takes several minutes till the channel has reached a new, stable state characterized by increased Na(+) permeability. Likewise, when the external pH is lowered to values below 6.5, it takes several minutes till the channel has reached a new, stable state characterized by increased Na(+) permeability. When raising the K(+) concentration back to 5 mM, it takes 40 to 70 minutes for the channel to regain its original selectivity for K(+). Likewise, it takes more that 25 minutes for the channel to regain its original K(+) selectivity when the pH is raised back to 7.4.

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

RefSeq proteins (1): NP_002236* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001779	2pore_dom_K_chnl_TWIK1	Family
IPR003092	2pore_dom_K_chnl_TASK	Family
IPR003280	2pore_dom_K_chnl	Family
IPR005408	2pore_dom_K_chnl_TWIK	Family
IPR013099	K_chnl_dom	Domain

Pfam: PF07885

Catalyzed reactions (Rhea), 8 shown:

• NH4(+)(in) = NH4(+)(out) (RHEA:28747)
• K(+)(in) = K(+)(out) (RHEA:29463)
• chloride(in) = chloride(out) (RHEA:29823)
• Na(+)(in) = Na(+)(out) (RHEA:34963)
• L-glutamate(out) = L-glutamate(in) (RHEA:66336)
• Rb(+)(in) = Rb(+)(out) (RHEA:78547)
• Li(+)(in) = Li(+)(out) (RHEA:78551)
• Cs(+)(in) = Cs(+)(out) (RHEA:78555)

UniProt features (59 total): mutagenesis site 20, helix 9, topological domain 7, intramembrane region 4, transmembrane region 4, region of interest 3, site 3, turn 2, strand 2, chain 1, modified residue 1, glycosylation site 1, disulfide bond 1, cross-link 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
3UKM	X-RAY DIFFRACTION	3.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O00180-F1	83.34	0.61

Functional residue map

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

Catalytic / active sites (3): 118 (important for increased permeability to na(+) when k(+) levels are subphysiological); 146 (part of a hydrophobic barrier that is stochastically dewetted and limits ion permeability); 261 (part of a hydrophobic barrier that is stochastically dewetted and limits ion permeability)

Post-translational modifications (2): 326, 274

Disulfide bonds (1): 69

Glycosylation sites (1): 95

Mutagenesis-validated functional residues (20):

Position	Phenotype
69	abolishes channel activity and formation of disulfide-linked homodimers.
95	abolishes n-glycosylation.
108–109	impairs selectivity for k(+) ions and increases permeability to na(+) ions, both at ph 7.4 and at ph 6.
118	abolishes change in ion selectivity in the presence of subphysiological k(+) levels.
122	increases channel activity, and has only a minor effect on the inhibition by acidification of the extracellular medium.
122	decreases channel activity and abolishes inhibition by acidification of the extracellular medium.
146	does not increase the low intrinsic channel activity.
146	increases channel activity.
146	increases channel activity. strongly increases channel activity; when associated with s-261.
161	no effect on channel activity.
228	no effect on selectivity for k(+) ions.
231	strongly decreases activity of homodimeric channels and of heterodimeric channels formed with kcnk3 and with kcnk9. no e
250	slightly decreases the increased permeability to na(+) ions at ph 6.
261	increases channel activity.
261	increases channel activity. strongly increases channel activity; when associated with s-146.
274	converts the electrically silent channel that is present at the cell membrane to an active channel.
274	converts the electrically silent channel that is present at the cell membrane to an active channel. no effect on retenti
293–294	strongly increases location at the cell membrane.
299–336	no effect on intracellular retention in recycling endosomes.

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-1299308	Tandem of pore domain in a weak inwardly rectifying K+ channels (TWIK)
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: 295 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_UP, GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_UP, GOBP_POTASSIUM_ION_TRANSPORT, GOBP_GLUTAMATE_SECRETION, REACTOME_TANDEM_PORE_DOMAIN_POTASSIUM_CHANNELS, REACTOME_POTASSIUM_CHANNELS, GOBP_SODIUM_ION_TRANSMEMBRANE_TRANSPORT, TTTGTAG_MIR520D, MODULE_64, WANG_RECURRENT_LIVER_CANCER_UP, KAAB_HEART_ATRIUM_VS_VENTRICLE_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_INORGANIC_ANION_TRANSPORT, CREBP1_Q2, BROWNE_HCMV_INFECTION_16HR_UP

GO Biological Process (11): potassium ion transport (GO:0006813), glutamate secretion (GO:0014047), response to nicotine (GO:0035094), sodium ion transmembrane transport (GO:0035725), regulation of resting membrane potential (GO:0060075), cellular response to acidic pH (GO:0071468), potassium ion transmembrane transport (GO:0071805), chloride transmembrane transport (GO:1902476), monoatomic ion transport (GO:0006811), monoatomic ion transmembrane transport (GO:0034220), regulation of postsynaptic membrane potential (GO:0060078)

GO Molecular Function (9): inward rectifier potassium channel activity (GO:0005242), potassium channel activity (GO:0005267), sodium channel activity (GO:0005272), ligand-gated channel activity (GO:0022834), potassium ion leak channel activity (GO:0022841), identical protein binding (GO:0042802), protein heterodimerization activity (GO:0046982), voltage-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential (GO:1905030), protein binding (GO:0005515)

GO Cellular Component (15): plasma membrane (GO:0005886), voltage-gated potassium channel complex (GO:0008076), membrane (GO:0016020), dendrite (GO:0030425), brush border membrane (GO:0031526), potassium channel complex (GO:0034705), perikaryon (GO:0043204), recycling endosome (GO:0055037), synaptic membrane (GO:0097060), inward rectifier potassium channel complex (GO:1902937), endosome (GO:0005768), apical plasma membrane (GO:0016324), cytoplasmic vesicle (GO:0031410), cell projection (GO:0042995), synapse (GO:0045202)

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
monoatomic cation transmembrane transport	2
regulation of membrane potential	2
monoatomic cation channel activity	2
plasma membrane region	2
metal ion transport	1
dicarboxylic acid transport	1
acidic amino acid transport	1
secretion by cell	1
nitrogen compound transport	1
response to chemical	1
sodium ion transport	1
response to acidic pH	1
cellular response to pH	1
potassium ion transport	1
chloride transport	1
monoatomic anion transmembrane transport	1
transport	1
monoatomic ion transport	1
transmembrane transport	1
voltage-gated potassium channel activity	1
ligand-gated monoatomic cation channel activity	1
potassium ion transmembrane transporter activity	1
sodium ion transmembrane transporter activity	1
gated channel activity	1
potassium channel activity	1
leak channel activity	1
protein binding	1
protein dimerization activity	1
voltage-gated monoatomic ion channel activity	1
regulation of postsynaptic membrane potential	1
binding	1
membrane	1
cell periphery	1
potassium channel complex	1
plasma membrane protein complex	1
neuron projection	1
dendritic tree	1
brush border	1
apical plasma membrane	1

Protein interactions and networks

STRING

1062 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KCNK1	KRT76	Q01546	975
KCNK1	KCNK2	O95069	953
KCNK1	SENP1	Q9P0U3	729
KCNK1	SAE1	Q9UBE0	631
KCNK1	KCNK3	O14649	617
KCNK1	KCNJ10	P78508	582
KCNK1	KCNK9	Q9NPC2	575
KCNK1	KCNJ3	P48549	566
KCNK1	KCNA5	P22460	559
KCNK1	KCNJ16	Q9NPI9	552
KCNK1	SUMO1	P55856	534
KCNK1	UBA2	Q9UBT2	533
KCNK1	KCNB1	Q14721	532
KCNK1	UBE2I	P50550	525
KCNK1	KCNA4	P22459	523
KCNK1	KCNA2	P16389	523

IntAct

41 interactions, top by confidence:

A	B	Type	Score
KCNK1	KCNK1	psi-mi:“MI:2364”(proximity)	0.570
KCNK1	KCNK1	psi-mi:“MI:0407”(direct interaction)	0.570
	KCNK1	psi-mi:“MI:0915”(physical association)	0.560
KCNK1		psi-mi:“MI:0915”(physical association)	0.560
KCNK1	TMEM139	psi-mi:“MI:0915”(physical association)	0.560
KCNK1	CREB3L1	psi-mi:“MI:0915”(physical association)	0.560
KCNK1	STOM	psi-mi:“MI:0915”(physical association)	0.560
KCNK1	AQP6	psi-mi:“MI:0915”(physical association)	0.560
KCNK1	TMEM14B	psi-mi:“MI:0915”(physical association)	0.560
KCNK1	CDIPT	psi-mi:“MI:0915”(physical association)	0.560
KCNK1	ERGIC3	psi-mi:“MI:0915”(physical association)	0.560
KCNK1	SUMO1	psi-mi:“MI:2364”(proximity)	0.510
SUMO1	KCNK1	psi-mi:“MI:0195”(covalent binding)	0.510
CREB3	KCNK1	psi-mi:“MI:0915”(physical association)	0.370
KCNK1	CREB3	psi-mi:“MI:0915”(physical association)	0.370
TCIRG1	KCNK1	psi-mi:“MI:0915”(physical association)	0.370
KCNK1	TMEM223	psi-mi:“MI:0914”(association)	0.350
PTPRN	KCNK1	psi-mi:“MI:0914”(association)	0.350
VSIG1	RIMOC1	psi-mi:“MI:0914”(association)	0.350
SLC44A1	UPK3BL1	psi-mi:“MI:0914”(association)	0.350
SLC44A5	UPK3BL1	psi-mi:“MI:0914”(association)	0.350
KCNK1	UBE2I	psi-mi:“MI:2364”(proximity)	0.270
KCNK1	CREB3L1	psi-mi:“MI:0915”(physical association)	0.000
KCNK1	STOM	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (76): KRTAP10-3 (Two-hybrid), KCNK1 (Two-hybrid), KCNK1 (Two-hybrid), KCNK1 (Two-hybrid), KCNK1 (Two-hybrid), KCNK1 (Two-hybrid), TMEM14B (Two-hybrid), STOM (Two-hybrid), CREB3L1 (Two-hybrid), TMEM139 (Two-hybrid), KCNK1 (Reconstituted Complex), KIAA2013 (Affinity Capture-MS), RAB18 (Affinity Capture-MS), LPCAT3 (Affinity Capture-MS), TM9SF4 (Affinity Capture-MS)

ESM2 similar proteins: A0A8C2M425, A0JPN2, A4IGI5, B0BNF0, B1H1N7, D3ZYP5, O00180, O08581, O88496, P38435, Q07175, Q0P4Y8, Q0P5A0, Q1L911, Q2YDJ2, Q32LM8, Q3U0Y2, Q3UUA0, Q497J1, Q498W5, Q49LS7, Q4R5F4, Q53FP2, Q58EL2, Q5E9T5, Q5KR61, Q5RD07, Q5RF50, Q5UE96, Q640M6, Q6DFQ7, Q6JAM9, Q6MG14, Q6NVG1, Q78IQ7, Q8BPS4, Q8BXT9, Q8C0T0, Q8K0H7, Q8NCS4

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

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	49
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1280 predictions. Top by Δscore:

Variant	Effect	Δscore
1:233614527:GTAGG:G	donor_loss	1.0000
1:233630625:A:G	donor_gain	0.9900
1:233634911:GAAA:G	donor_gain	0.9900
1:233634914:A:AG	donor_gain	0.9900
1:233666591:GCAG:G	acceptor_loss	0.9900
1:233666592:CA:C	acceptor_loss	0.9900
1:233666593:A:AG	acceptor_gain	0.9900
1:233666594:G:GG	acceptor_gain	0.9900
1:233666594:GGTT:G	acceptor_gain	0.9900
1:233666861:G:GT	donor_gain	0.9900
1:233666879:G:GT	donor_gain	0.9900
1:233666880:A:T	donor_gain	0.9900
1:233671266:CACAG:C	acceptor_loss	0.9900
1:233671268:CA:C	acceptor_loss	0.9900
1:233671269:A:AG	acceptor_gain	0.9900
1:233671269:A:C	acceptor_loss	0.9900
1:233671270:G:GC	acceptor_loss	0.9900
1:233671270:G:GG	acceptor_gain	0.9900
1:233634861:GCATA:G	donor_gain	0.9800
1:233634914:A:G	donor_gain	0.9800
1:233671266:C:G	acceptor_gain	0.9800
1:233630587:G:GT	donor_gain	0.9700
1:233666593:AG:A	acceptor_gain	0.9700
1:233666594:GG:G	acceptor_gain	0.9700
1:233666989:GT:G	donor_gain	0.9700
1:233671267:A:AG	acceptor_gain	0.9700
1:233671269:AG:A	acceptor_gain	0.9700
1:233671270:GG:G	acceptor_gain	0.9700
1:233614527:G:GG	donor_gain	0.9600
1:233660800:AGCG:A	donor_gain	0.9600

AlphaMissense

2186 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:233614281:G:A	G37D	1.000
1:233614475:T:A	W102R	1.000
1:233614475:T:C	W102R	1.000
1:233614477:G:C	W102C	1.000
1:233614477:G:T	W102C	1.000
1:233614526:G:C	G119R	1.000
1:233666660:G:C	G141R	1.000
1:233666661:G:A	G141D	1.000
1:233666891:T:C	F218L	1.000
1:233666893:T:A	F218L	1.000
1:233666893:T:G	F218L	1.000
1:233666909:A:C	S224R	1.000
1:233666911:C:A	S224R	1.000
1:233666911:C:G	S224R	1.000
1:233666919:G:A	G227D	1.000
1:233666924:G:A	G229R	1.000
1:233666924:G:C	G229R	1.000
1:233666924:G:T	G229W	1.000
1:233666925:G:A	G229E	1.000
1:233671285:G:C	G256R	1.000
1:233614280:G:C	G37R	0.999
1:233614304:G:A	E45K	0.999
1:233614499:T:C	F110L	0.999
1:233614501:C:A	F110L	0.999
1:233614501:C:G	F110L	0.999
1:233614505:A:C	S112R	0.999
1:233614507:C:A	S112R	0.999
1:233614507:C:G	S112R	0.999
1:233614515:T:A	L115H	0.999
1:233614521:C:T	T117I	0.999

dbSNP variants (sampled 300 via entrez): RS1000019055 (1:233646861 A>G), RS1000041845 (1:233646559 T>A,C), RS1000125682 (1:233628650 C>T), RS1000152106 (1:233614686 C>G,T), RS1000156622 (1:233656812 C>T), RS1000193819 (1:233653278 C>A), RS1000265396 (1:233646178 A>G), RS1000350671 (1:233658812 T>G), RS1000376430 (1:233659616 C>T), RS1000407565 (1:233659417 T>A), RS1000422691 (1:233659074 T>G), RS1000493832 (1:233612423 C>G), RS1000567617 (1:233652859 C>A,T), RS1000627807 (1:233652832 C>T), RS1000655029 (1:233658536 T>C)

Disease associations

OMIM: gene MIM:601745 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST001017_19	Diabetic retinopathy	6.000000e-06
GCST001588_1	Periodontal microbiota	3.000000e-07
GCST001588_9	Periodontal microbiota	4.000000e-06
GCST003830_15	Response to bronchodilator in chronic obstructive pulmonary disease (change in FEV1)	2.000000e-07
GCST004823_12	Cognitive function	9.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0005921	FEV change measurement
EFO:0008354	cognitive function measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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)

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
magnolol	Inhibition	5.21	pIC50

CTD chemical–gene interactions

44 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, affects expression, affects cotreatment	7
trichostatin A	affects cotreatment, increases expression	3
mercuric bromide	affects cotreatment, increases expression	2
entinostat	affects cotreatment, increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Silicon Dioxide	increases expression, affects expression	2
Tretinoin	decreases expression, increases expression	2
Tunicamycin	decreases expression, increases expression	2
Cyclosporine	increases expression	2
methylmercuric chloride	increases expression	1
bisphenol A	decreases expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
sodium arsenite	increases expression	1
cobaltous chloride	increases expression	1
deguelin	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	increases expression	1
clothianidin	decreases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
bisphenol S	decreases expression	1
Temozolomide	increases expression	1
Decitabine	decreases expression, decreases reaction	1
Panobinostat	affects cotreatment, increases expression	1
Acetaminophen	increases expression	1
Air Pollutants	increases abundance, decreases expression	1
Benzo(a)pyrene	increases expression	1
Carbamazepine	affects expression	1
Cisplatin	affects response to substance	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_SU03	HAP1 KCNK1 (-) 1	Cancer cell line	Male
CVCL_SU04	HAP1 KCNK1 (-) 2	Cancer cell line	Male
CVCL_SU05	HAP1 KCNK1 (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

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