KCNN3

Summary

KCNN3 (potassium calcium-activated channel subfamily N member 3, HGNC:6292) is a protein-coding gene on chromosome 1q21.3, encoding Small conductance calcium-activated potassium channel protein 3 (Q9UGI6). Small conductance calcium-activated potassium channel that mediates the voltage-independent transmembrane transfer of potassium across the cell membrane through a constitutive interaction with calmodulin which binds the intracellular calcium allowing its opening.

Action potentials in vertebrate neurons are followed by an afterhyperpolarization (AHP) that may persist for several seconds and may have profound consequences for the firing pattern of the neuron. Each component of the AHP is kinetically distinct and is mediated by different calcium-activated potassium channels. This gene belongs to the KCNN family of potassium channels. It encodes an integral membrane protein that forms a voltage-independent calcium-activated channel, which is thought to regulate neuronal excitability by contributing to the slow component of synaptic AHP. This gene contains two CAG repeat regions in the coding sequence. It was thought that expansion of one or both of these repeats could lead to an increased susceptibility to schizophrenia or bipolar disorder, but studies indicate that this is probably not the case. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 3782 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Zimmermann-Laband syndrome 3 (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 39
• Clinical variants (ClinVar): 165 total — 4 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 68
• Druggable target: yes — 2 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_002249

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6292
Approved symbol	KCNN3
Name	potassium calcium-activated channel subfamily N member 3
Location	1q21.3
Locus type	gene with protein product
Status	Approved
Aliases	KCa2.3, hSK3, SKCA3
Ensembl gene	ENSG00000143603
Ensembl biotype	protein_coding
OMIM	602983
Entrez	3782

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 5 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000271915, ENST00000358505, ENST00000361147, ENST00000515643, ENST00000618040, ENST00000874071

RefSeq mRNA: 5 — MANE Select: NM_002249 NM_001204087, NM_001365837, NM_001365838, NM_002249, NM_170782

CCDS: CCDS1072, CCDS30880, CCDS72928, CCDS91063

Canonical transcript exons

ENST00000271915 — 8 exons

Exon	Start	End
ENSE00000961083	154771975	154772393
ENSE00000961086	154714876	154715003
ENSE00000961087	154713464	154713533
ENSE00001403931	154869032	154870281
ENSE00001632763	154733003	154733144
ENSE00001742485	154725916	154726026
ENSE00001853464	154697455	154708272
ENSE00003568203	154822089	154822184

Expression profiles

Bgee: expression breadth ubiquitous, 227 present calls, max score 94.58.

FANTOM5 (CAGE): breadth broad, TPM avg 5.2734 / max 190.5153, expressed in 610 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
14844	2.3061	505
14840	0.7674	216
14841	0.7604	108
14846	0.4952	225
14842	0.3331	81
14837	0.1800	27
14838	0.1662	26
14845	0.1203	62
14843	0.1154	65
14836	0.0195	11

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lateral globus pallidus	UBERON:0002476	94.58	gold quality
substantia nigra pars reticulata	UBERON:0001966	93.49	gold quality
medial globus pallidus	UBERON:0002477	92.81	gold quality
globus pallidus	UBERON:0001875	92.72	gold quality
substantia nigra pars compacta	UBERON:0001965	91.38	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	91.37	gold quality
ventral tegmental area	UBERON:0002691	90.96	gold quality
superior vestibular nucleus	UBERON:0007227	88.46	gold quality
entorhinal cortex	UBERON:0002728	88.18	gold quality
medulla oblongata	UBERON:0001896	87.72	gold quality
tendon of biceps brachii	UBERON:0008188	87.55	gold quality
lateral nuclear group of thalamus	UBERON:0002736	86.68	gold quality
inferior vagus X ganglion	UBERON:0005363	86.44	gold quality
subthalamic nucleus	UBERON:0001906	86.43	gold quality
inferior olivary complex	UBERON:0002127	84.66	gold quality
dorsal plus ventral thalamus	UBERON:0001897	84.52	gold quality
cranial nerve II	UBERON:0000941	84.40	gold quality
ventricular zone	UBERON:0003053	83.64	gold quality
buccal mucosa cell	CL:0002336	83.52	gold quality
temporal lobe	UBERON:0001871	82.58	gold quality
CA1 field of hippocampus	UBERON:0003881	82.26	gold quality
corpus callosum	UBERON:0002336	82.22	gold quality
nucleus accumbens	UBERON:0001882	81.95	gold quality
caudate nucleus	UBERON:0001873	81.44	gold quality
midbrain	UBERON:0001891	81.31	gold quality
putamen	UBERON:0001874	81.05	gold quality
postcentral gyrus	UBERON:0002581	80.83	gold quality
substantia nigra	UBERON:0002038	80.76	gold quality
parietal lobe	UBERON:0001872	80.49	gold quality
ganglionic eminence	UBERON:0004023	80.48	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-HCAD-25	yes	19.99
E-ANND-3	yes	17.93
E-GEOD-84465	yes	11.20
E-CURD-10	no	18.95

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ESR1, PAX3, SP1, SP3

miRNA regulators (miRDB)

401 targeting KCNN3, 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-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-432-3P	100.00	67.86	705
HSA-MIR-518D-5P	100.00	67.51	979
HSA-MIR-518E-5P	100.00	67.66	954
HSA-MIR-518F-5P	100.00	67.51	979
HSA-MIR-519A-5P	100.00	67.66	954
HSA-MIR-519B-5P	100.00	67.66	954
HSA-MIR-519C-5P	100.00	67.66	954
HSA-MIR-520C-5P	100.00	67.51	979
HSA-MIR-522-5P	100.00	67.66	954
HSA-MIR-523-5P	100.00	67.66	954
HSA-MIR-526A-5P	100.00	67.51	979
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-3613-3P	100.00	76.36	7965

Literature-anchored findings (GeneRIF, showing 40)

• The hSKCa3 potassium channel gene contains polymorphic CAG repeats in the coding region and is involved in the regulation of neuronal activity. The longer repeat alleles of the hSKCa3 gene may contribute to the genetic susceptibility to AN. (PMID:11803450)
• results do not support the involvement of the hKCa3 gene in schizophrenia, at least in the Japanese population (hKCa3; a calcium-activated potassium channel gene) (PMID:11807415)
• the combined effect of long CAG repeats and the differences in allele sizes contribute to symptom expression of schizophrenia, particularly on the anergia-activation-paranoid axis (PMID:12007452)
• Kit-negative fibroblast-like cells express this channel in smooth gut muscle in health and dissease. (PMID:12457234)
• Decreased expression of SK3 channels in the aganglionic bowel may contribute to motility dysfunction in Hirschsprung’s disease bowel. (PMID:12778407)
• novel SK3 transcript, SK3-1B that utilizes an alternative first exon (exon 1B), but is otherwise identical to SK3 and may contribute to pathogenesis of schizophrenia. (PMID:12808432)
• A contribution of the KCNN3 gene to genetic susceptibility to major psychosis and their phenotypic polymorphism may be related to the difference of allele length rather than to the number of CAG repeats. (PMID:12960745)
• the SK3 subunit of small conductance Ca2+-activated K+ channels interacts with both SK1 and SK2 subunits (PMID:14559917)
• SK3-1C is a dominant-negative suppressor of SKCa and IKCa channels (PMID:14638680)
• In this study a lower frequency for 1137-1140 Del homozygote of KCNN3 gene was observed, and the HHRR and TDT analyses suggested that the 1137-1140 Del alleles of KCNN3 gene be unlikely to confer susceptibility to schizophrenia. (PMID:16086287)
• Lack of evidence that length variations of the second polyglutamine array in the N-terminus of the KCNN3 channel exert an effect in migraine susceptibility. (PMID:16162291)
• The allelic frequency distribution of the CAG repeat in KCNN3 gene was compared in Serbian schizophrenic patients and controls. Data indicate a significant association between longer CAG repeats in second polymorphic KCNN3 region and schizophrenia. (PMID:16393881)
• The current work provides evidence for a fundamental role of the N-terminal domain and the calmodulin binding domain in SK3 trafficking in neurons. (PMID:17061167)
• Increased expression of SK3 has a critical role in the increased Ca(2+)-induced fragility in DM1 cells. (PMID:17101631)
• Endogenous ADMA may be an important factor for down-regulation of the expression of endothelial SK3 in atherosclerotic animals. (PMID:17869187)
• KCa3.1 and KCa2.3 are translocated out of the endoplasmic reticulum associated with Derlin-1. (PMID:18227067)
• No statistical association between the atrioventricular heart block phenotype and either the [CTG]n expansion length or the presence of specific single nucleotide polymorphisms in the SK3 gene were detected. (PMID:19472917)
• Membrane hyperpolarization increases melanoma cell motility via the KCa2.3 channel. The KCa2.3 channel might be the only member of the Ca(2+)-activated K(+) channel family involved in melanoma cell motility pathways. (PMID:19646982)
• rs13376333 is intronic to KCNN3, which encodes a potassium channel protein involved in atrial repolarization. (PMID:20173747)
• analysis of recycling of the Ca2+-activated K+ channel, KCa2.3, is dependent upon RME-1, Rab35/EPI64C, and an N-terminal domain (PMID:20360009)
• Oxaliplatin-neurotoxicity may be related to distribution of the polymorphic CAG motif of the SK3 gene, which might modulate nerve after-hyperpolarization. The 13-14 CAG repeat allele could mark patients susceptible to acute OXA neurotoxicity. (PMID:20872144)
• This study suggests that the SNPs within the kccn3 genes we examined do not play a major role in schizophrenia in the Han Chinese (PMID:20933057)
• Six SNPs (rs1218585, rs4845396, rs12058931, rs1218568, rs6426985, and rs4845394) in KCNN3 were associated with pretem birth. (PMID:21266667)
• There is an association between the synonymous single-nucleotide polymorphism rs1131820 in KCNN3 and lone atrial fibrillation. (PMID:21398315)
• The longer polyglutamine stretches are associated with reduced conductance of KCNN3 channel. (PMID:21433290)
• There is a significant association of rs13376333 in KCNN3 on chromosome 1q21 with atrial fibrillation in a Taiwanese population. (PMID:22019810)
• A total of four intronic single nucleotide polymorphisms in the KCNN3 gene display significant association with migraine. (PMID:22030984)
• SK3-mediated [Ca(2+)]i elevation and membrane potential hyperpolarization in trophectoderm cells are important for blastocyst hatching. (PMID:22416006)
• study shows SK3 channels are localized in CD34(+) cells and not in smooth muscle cells and that expression of SK3 channels is higher in non-pregnant compared to pregnant myometrium; propose SK3 activators reduce myometrium contractility by modulating telocyte function; first report to provide evidence for possible role of SK3 channels in uterine telocytes (PMID:22947283)
• Maternal association with preterm birth was found in small conductance calcium activated potassium channel isoform 3 (KCNN3, rs883319; P=0.01 (PMID:23018797)
• Atrial miR-499 is significantly upregulated in AF, leading to SK3 downregulation and possibly contributing to the electrical remodeling in AF. (PMID:23499625)
• Two conserved arginine residues from the SK3 potassium channel outer vestibule control selectivity of recognition by scorpion toxins. (PMID:23511633)
• SK3 channel is activated in neuroblastoma cells by overexpression of human endogenous retrovirus W family envelope gene. (PMID:23727510)
• We found that the SK3 channel triggers an association with the Orai1 channel within lipid rafts in primary human tumors and bone metastases (PMID:23774210)
• CaMKK/Akt/p300 cascade plays an important role in laminar stress-dependent induction of KCa2.3 and KCa3.1 expression, thereby regulating EC function and adaptation to hemodynamic changes. (PMID:23792675)
• Specific expression of hSK3 led to deficits in attention and sensory gating and heightened sensitivity to a psychomimetic drug (PMID:24206670)
• Differentiated dopaminergic neurons expressed low levels of SK2 channels and high levels of SK1 and SK3 channels. (PMID:24434522)
• Intermediate conductance Ca2+-activated K+ channels modulate human placental trophoblast syncytialization. (PMID:24595308)
• Reduced SK3 expression attenuates endometrial cell migration and is associated with unsuccessful pregnancy outcomes. (PMID:24978672)
• There was no significant difference in the genotype distributions or allele frequencies of the SNP rs1131820 between AF patients and controls. (PMID:24978901)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
mus_musculus	Kcnn3	ENSMUSG00000000794
rattus_norvegicus	Kcnn3	ENSRNOG00000020706
drosophila_melanogaster	SK	FBGN0029761
caenorhabditis_elegans		WBGENE00007176
caenorhabditis_elegans		WBGENE00008265
caenorhabditis_elegans	kcnl-2	WBGENE00008570
caenorhabditis_elegans		WBGENE00015387

Paralogs (3): KCNN2 (ENSG00000080709), KCNN4 (ENSG00000104783), KCNN1 (ENSG00000105642)

Protein

Protein identifiers

Small conductance calcium-activated potassium channel protein 3 — Q9UGI6 (reviewed: Q9UGI6)

Alternative names: KCa2.3

All UniProt accessions (2): Q9UGI6, A0A087WYJ0

UniProt curated annotations — full annotation on UniProt →

Function. Small conductance calcium-activated potassium channel that mediates the voltage-independent transmembrane transfer of potassium across the cell membrane through a constitutive interaction with calmodulin which binds the intracellular calcium allowing its opening. The current is characterized by a voltage-independent activation, an intracellular calcium concentration increase-dependent activation and a single-channel conductance of 10 picosiemens. Also presents an inwardly rectifying current, thus reducing its already small outward conductance of potassium ions, which is particularly the case when the membrane potential displays positive values, above + 20 mV. Activation is followed by membrane hyperpolarization. Thought to regulate neuronal excitability by contributing to the slow component of synaptic afterhyperpolarization. Does not function as a small conductance calcium-activated potassium channel. Selectively suppresses endogenous KCNN3 currents, in a dominant-negative fashion by decreasing the abundance of functional channels in the plasma membrane, possibly by selectively coassembling with and sequestering native KCNN3 protein in intracellular compartments. This dominant inhibitory effect extends to other members of the SK subfamily.

Subunit / interactions. Homodimer. Heteromultimer with KCNN2 or KCNN1; this modulates plasma membrane expression and consequently the small conductance calcium-activated potassium channel activity. The complex is composed of 4 channel subunits each of which binds to a calmodulin subunit which regulates the channel activity through calcium-binding. Interacts with CALM1.

Subcellular location. Cell membrane. Cytoplasm. Myofibril. Sarcomere. Z line.

Tissue specificity. Widely distributed in human tissues and is present at 20-60% of KCNN3 in the brain.

Disease relevance. Zimmermann-Laband syndrome 3 (ZLS3) [MIM:618658] A form of Zimmermann-Laband syndrome, a rare developmental disorder characterized by facial dysmorphism with bulbous nose and thick floppy ears, gingival enlargement, hypoplasia or aplasia of terminal phalanges and nails, hypertrichosis, joint hyperextensibility, and hepatosplenomegaly. Some patients manifest intellectual disability with or without epilepsy. ZLS3 inheritance is autosomal dominant. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Inhibited by bee venom neurotoxin apamin.

Domain organisation. The coiled-coil domaim mediates heteromeic assembly.

Polymorphism. The second poly-Gln region of KCNN3 is highly polymorphic and the number of Gln varies from 12 to 28 in the population.

Similarity. Belongs to the potassium channel KCNN family. KCa2.3/KCNN3 subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9UGI6-1	1	yes
Q9UGI6-2	2
Q9UGI6-3	3, SK3-1B

RefSeq proteins (5): NP_001191016, NP_001352766, NP_001352767, NP_002240, NP_740752 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004178	CaM-bd_dom	Domain
IPR013099	K_chnl_dom	Domain
IPR015449	K_chnl_Ca-activ_SK	Family
IPR036122	CaM-bd_dom_sf	Homologous_superfamily

Pfam: PF02888, PF03530, PF07885

Catalyzed reactions (Rhea), 1 shown:

• K(+)(in) = K(+)(out) (RHEA:29463)

UniProt features (37 total): compositionally biased region 8, transmembrane region 6, sequence variant 5, region of interest 4, sequence conflict 4, splice variant 3, mutagenesis site 3, chain 1, coiled-coil region 1, modified residue 1, intramembrane region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UGI6-F1	68.54	0.36

Functional residue map

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

Post-translational modifications (1): 167

Mutagenesis-validated functional residues (3):

Position	Phenotype
485	reduced inhibition by apamin. does not affect small conductance calcium-activated potassium channel activity.
509–511	impairs small conductance calcium-activated potassium channel activity of kcnn2.
516	no effect on inhibition by apamin.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-1296052	Ca2+ activated K+ channels
R-HSA-112316	Neuronal System
R-HSA-1296071	Potassium Channels

MSigDB gene sets: 458 (showing top): GOBP_POTASSIUM_ION_TRANSPORT, RNGTGGGC_UNKNOWN, REACTOME_POTASSIUM_CHANNELS, GCANCTGNY_MYOD_Q6, TGACCTY_ERR1_Q2, LHX3_01, GGGTGGRR_PAX4_03, AAAYRNCTG_UNKNOWN, CAGCTG_AP4_Q5, EFC_Q6, GOBP_MONOATOMIC_CATION_TRANSPORT, TTGGGAG_MIR150, NKX61_01, NKX62_Q2, MYOD_01

GO Biological Process (5): potassium ion transmembrane transport (GO:0071805), monoatomic ion transport (GO:0006811), potassium ion transport (GO:0006813), monoatomic ion transmembrane transport (GO:0034220), monoatomic cation transmembrane transport (GO:0098655)

GO Molecular Function (5): inward rectifier potassium channel activity (GO:0005242), calmodulin binding (GO:0005516), small conductance calcium-activated potassium channel activity (GO:0016286), protein binding (GO:0005515), calcium-activated potassium channel activity (GO:0015269)

GO Cellular Component (6): plasma membrane (GO:0005886), Z disc (GO:0030018), neuron projection (GO:0043005), neuronal cell body (GO:0043025), cytoplasm (GO:0005737), membrane (GO:0016020)

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	3
potassium ion transport	1
monoatomic cation transmembrane transport	1
transport	1
metal ion transport	1
monoatomic ion transport	1
transmembrane transport	1
monoatomic cation transport	1
monoatomic ion transmembrane transport	1
voltage-gated potassium channel activity	1
ligand-gated monoatomic cation channel activity	1
protein binding	1
calcium-activated potassium channel activity	1
binding	1
calcium-activated cation channel activity	1
potassium channel activity	1
membrane	1
cell periphery	1
I band	1
plasma membrane bounded cell projection	1
somatodendritic compartment	1
cell body	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1394 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KCNN3	ORAI1	Q96D31	918
KCNN3	CSN3	P07498	832
KCNN3	KCNMB4	Q86W47	830
KCNN3	TRPC1	P48995	807
KCNN3	NAALADL1	Q9UQQ1	774
KCNN3	CD4	P01730	720
KCNN3	ZFHX3	Q15911	717
KCNN3	CAV1	Q03135	697
KCNN3	KCNQ1	P51787	694
KCNN3	CD8A	P01732	694
KCNN3	KCNMA1	Q12791	672
KCNN3	KCNA5	P22460	666
KCNN3	CALM1	P02593	659
KCNN3	CALML4	Q96GE6	654
KCNN3	ADRA2A	P08913	649

IntAct

1 interactions, top by confidence:

BioGRID (12): KCNN3 (Reconstituted Complex), KCNN3 (Two-hybrid), KCNN3 (Two-hybrid), KCNN3 (Two-hybrid), KCNN3 (Two-hybrid), FCER1G (Two-hybrid), KCNN3 (Affinity Capture-RNA), CALM1 (Reconstituted Complex), APP (Reconstituted Complex), KCNN3 (Affinity Capture-Western), DNM2 (Affinity Capture-Western), RAB5A (Affinity Capture-Western)

ESM2 similar proteins: A1Z8N1, B3MG58, B3NSE1, B4GAP7, B4HNS0, B4J913, B4KR05, B4LPX5, B4MYA4, B4P624, B4QBN2, D4AYW0, G5EFJ9, O08678, O18868, P08510, P15385, P17970, P22459, P27448, P57789, P58390, P58391, P58392, P70605, Q02280, Q03141, Q05037, Q0P5V9, Q17NV8, Q19469, Q24563, Q28527, Q291H8, Q5BKX6, Q61423, Q7JQF1, Q7KVW5, Q7PIR5, Q8BUW1

Diamond homologs: O15554, O89109, P58390, P58391, P58392, P70604, P70605, P70606, Q02006, Q7KVW5, Q92952, Q9EQR3, Q9H2S1, Q9QYW1, Q9UGI6, O43525, O88944, P58126, Q11122, Q8K3F6, P17971

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
Riluzole	“up-regulates activity”	KCNN3	“chemical activation”
Naphtho[1,2-d]thiazol-2-amine	“up-regulates activity”	KCNN3	“chemical activation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	2
Uncertain significance	94
Likely benign	29
Benign	15

Top pathogenic / likely-pathogenic (6)

Variant ID	HGVS	Classification
1064423	NM_002249.6(KCNN3):c.1606G>A (p.Ala536Thr)	Pathogenic
804200	NM_002249.6(KCNN3):c.1306A>T (p.Ser436Cys)	Pathogenic
804201	NM_002249.6(KCNN3):c.805A>G (p.Lys269Glu)	Pathogenic
804202	NM_002249.6(KCNN3):c.1049G>A (p.Gly350Asp)	Pathogenic
2330091	NM_002249.6(KCNN3):c.1349T>C (p.Val450Ala)	Likely pathogenic
3910119	NM_002249.6(KCNN3):c.200AGC[25] (p.Gln80_Pro81insGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGln)	Likely pathogenic

SpliceAI

2378 predictions. Top by Δscore:

Variant	Effect	Δscore
1:154708067:A:AC	donor_gain	1.0000
1:154708068:C:CC	donor_gain	1.0000
1:154714874:A:AC	donor_gain	1.0000
1:154714875:C:CC	donor_gain	1.0000
1:154715004:C:CC	acceptor_gain	1.0000
1:154725915:CCCG:C	donor_gain	1.0000
1:154771974:CCTT:C	donor_gain	1.0000
1:154822181:AGTCC:A	acceptor_loss	1.0000
1:154822183:TCCTG:T	acceptor_loss	1.0000
1:154822184:CCTGC:C	acceptor_loss	1.0000
1:154822185:CT:C	acceptor_loss	1.0000
1:154822186:T:G	acceptor_loss	1.0000
1:154869161:ATAG:A	donor_gain	1.0000
1:154708069:TGC:T	donor_gain	0.9900
1:154713459:CTCA:C	donor_loss	0.9900
1:154713460:TCA:T	donor_loss	0.9900
1:154713461:CA:C	donor_loss	0.9900
1:154713463:C:CT	donor_loss	0.9900
1:154713532:ACC:A	acceptor_loss	0.9900
1:154713533:CCTG:C	acceptor_loss	0.9900
1:154713535:T:A	acceptor_loss	0.9900
1:154714898:T:TA	donor_gain	0.9900
1:154715003:TC:T	acceptor_loss	0.9900
1:154715004:CTAAG:C	acceptor_loss	0.9900
1:154725909:ATCTT:A	donor_loss	0.9900
1:154725910:TCTTA:T	donor_loss	0.9900
1:154725911:CTTA:C	donor_loss	0.9900
1:154725912:TTA:T	donor_loss	0.9900
1:154725913:TACCC:T	donor_loss	0.9900
1:154725914:A:AC	donor_gain	0.9900

AlphaMissense

4837 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:154708238:A:G	L645P	1.000
1:154713471:A:G	L631P	1.000
1:154713501:A:G	L621P	1.000
1:154713510:T:G	Q618P	1.000
1:154713518:C:A	K615N	1.000
1:154713518:C:G	K615N	1.000
1:154713527:C:A	R612S	1.000
1:154713527:C:G	R612S	1.000
1:154713528:C:A	R612M	1.000
1:154713528:C:G	R612T	1.000
1:154713531:A:G	L611S	1.000
1:154714882:A:C	I608S	1.000
1:154714882:A:G	I608T	1.000
1:154714882:A:T	I608N	1.000
1:154714886:C:G	A607P	1.000
1:154714891:A:G	L605P	1.000
1:154714891:A:T	L605H	1.000
1:154714893:G:C	F604L	1.000
1:154714893:G:T	F604L	1.000
1:154714894:A:C	F604C	1.000
1:154714894:A:G	F604S	1.000
1:154714895:A:G	F604L	1.000
1:154714899:C:A	R602S	1.000
1:154714899:C:G	R602S	1.000
1:154714903:T:G	Q601P	1.000
1:154714906:T:G	H600P	1.000
1:154714907:G:C	H600D	1.000
1:154714911:C:A	R598S	1.000
1:154714911:C:G	R598S	1.000
1:154714912:C:A	R598M	1.000

dbSNP variants (sampled 300 via entrez): RS1000000159 (1:154725462 T>A), RS1000049926 (1:154845512 C>A,G,T), RS1000050290 (1:154848255 A>G), RS1000069199 (1:154791852 C>T), RS1000091532 (1:154733980 G>A,C), RS1000093122 (1:154714474 G>A,C,T), RS1000095022 (1:154766917 G>A), RS1000099279 (1:154831038 A>G), RS1000127259 (1:154751451 A>C,G), RS1000159382 (1:154731041 T>C,G), RS1000162226 (1:154812032 T>G), RS1000166767 (1:154832485 G>A), RS1000220636 (1:154814988 G>A,T), RS1000260661 (1:154768583 C>T), RS1000300761 (1:154839900 T>C)

Disease associations

OMIM: gene MIM:602983 | disease phenotypes: MIM:618658

GenCC curated gene-disease

Disease	Classification	Inheritance
Zimmermann-Laband syndrome 3	Strong	Autosomal dominant
Zimmermann-Laband syndrome	Supportive	Autosomal recessive
schizophrenia	Limited	Unknown

Mondo (6): Zimmermann-Laband syndrome 3 (MONDO:0032854), prostate cancer (MONDO:0008315), esophageal atresia (MONDO:0001044), pyloric stenosis (MONDO:0001561), schizophrenia (MONDO:0005090), Zimmermann-Laband syndrome (MONDO:0000200)

Orphanet (1): Familial prostate cancer (Orphanet:1331)

HPO phenotypes

68 total (30 of 68 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000154	Wide mouth
HP:0000158	Macroglossia
HP:0000169	Gingival fibromatosis
HP:0000175	Cleft palate
HP:0000179	Thick lower lip vermilion
HP:0000193	Bifid uvula
HP:0000212	Gingival overgrowth
HP:0000218	High palate
HP:0000280	Coarse facial features
HP:0000294	Low anterior hairline
HP:0000316	Hypertelorism
HP:0000347	Micrognathia
HP:0000407	Sensorineural hearing impairment
HP:0000414	Bulbous nose
HP:0000431	Wide nasal bridge
HP:0000445	Wide nose
HP:0000455	Broad nasal tip
HP:0000470	Short neck
HP:0000494	Downslanted palpebral fissures
HP:0000506	Telecanthus
HP:0000518	Cataract
HP:0000527	Long eyelashes
HP:0000574	Thick eyebrow
HP:0000664	Synophrys
HP:0000668	Hypodontia
HP:0000811	Abnormal external genitalia morphology
HP:0000977	Soft skin
HP:0000998	Hypertrichosis
HP:0001199	Triphalangeal thumb

GWAS associations

39 associations (top):

Study	Trait	p-value
GCST000602_2	Atrial fibrillation	2.000000e-21
GCST001499_1	Atrial fibrillation	2.000000e-14
GCST001762_489	Obesity-related traits	7.000000e-06
GCST001762_574	Obesity-related traits	9.000000e-06
GCST001942_19	Prostate cancer	2.000000e-08
GCST002817_18	Alzheimer’s disease in APOE e4- carriers	2.000000e-06
GCST004296_3	Atrial fibrillation	4.000000e-15
GCST004297_10	Atrial fibrillation	3.000000e-17
GCST004300_1	Incident atrial fibrillation	4.000000e-09
GCST004301_8	Prevalent atrial fibrillation	4.000000e-10
GCST004750_91	Squamous cell lung carcinoma	6.000000e-06
GCST005306_6	Atrial fibrillation	7.000000e-09
GCST006061_123	Atrial fibrillation	5.000000e-59
GCST006061_124	Atrial fibrillation	1.000000e-57
GCST006061_6	Atrial fibrillation	1.000000e-56
GCST006061_87	Atrial fibrillation	6.000000e-16
GCST006414_108	Atrial fibrillation	3.000000e-79
GCST006414_45	Atrial fibrillation	2.000000e-23
GCST006414_95	Atrial fibrillation	1.000000e-18
GCST008103_81	Bipolar disorder	1.000000e-06
GCST008161_129	Waist circumference adjusted for body mass index	9.000000e-06
GCST008163_58	Height	5.000000e-06
GCST008362_141	Birth weight	7.000000e-11
GCST008362_91	Birth weight	3.000000e-19
GCST008363_17	Offspring birth weight	3.000000e-08
GCST008363_22	Offspring birth weight	1.000000e-07
GCST010696_19	Cortical thickness (min-P)	2.000000e-10
GCST010697_10	Cortical surface area (min-P)	3.000000e-10
GCST010698_59	Subcortical volume (min-P)	9.000000e-10
GCST010699_20	Brain morphology (min-P)	7.000000e-10

EFO canonical traits (10, from GWAS)

EFO ID	Trait name
EFO:0004736	aspartate aminotransferase measurement
EFO:0007789	BMI-adjusted waist circumference
EFO:0004344	birth weight
EFO:0005939	parental genotype effect measurement
EFO:0004346	neuroimaging measurement
EFO:0004840	cortical thickness
EFO:0004810	interleukin-6 measurement
EFO:0004531	urate measurement
EFO:0009270	heel bone mineral density
EFO:0007788	BMI-adjusted waist-hip ratio

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D004933	Esophageal Atresia	C06.198.330; C06.405.117.260; C16.131.314.330
D017219	Gastric Outlet Obstruction	C06.405.748.340
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750
D011707	Pyloric Stenosis	C06.405.748.340.690
C536725	Zimmerman Laband syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL3381 (SINGLE PROTEIN), CHEMBL4524132 (PROTEIN FAMILY)

Molecules with ChEMBL bioactivity

2 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 7,290 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL121663	DEQUALINIUM CHLORIDE	4	4,224
CHEMBL449782	CEPHARANTHINE	2	3,066

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: vgic — Calcium- and sodium-activated potassium channels (K_Ca, K_Na)

Most potent curated ligand interactions (23 total), top 23:

Ligand	Action	Affinity	Parameter
leiurotoxin I	Antagonist	9.0	pIC50
UCL1684	Inhibitor	9.0	pIC50
tamapin	Antagonist	8.8	pIC50
UCL1848	Antagonist	8.7	pIC50
apamin	Antagonist	8.64	pIC50
Lei-Dab7	Antagonist	8.42	pKd
NS11757	Gating inhibitor	8.1	pKd
RA-2	Antagonist	7.7	pIC50
P05	Antagonist	7.6	pIC50
NS13001	Agonist	6.85	pEC50
Ca2+	Agonist	6.5	pEC50
tetrandrine	Inhibition	6.34	pKi
NS8593	Antagonist	6.1	pIC50
AP14145	Channel blocker	5.96	pIC50
AP30663	Channel blocker	5.96	pIC50
SKA-31	Agonist	5.52	pEC50
CyPPA	Agonist	5.3	pEC50
DC-EBIO	Agonist	4.9	pEC50
riluzole	Agonist	4.9	pEC50
tubocurarine	Antagonist	4.5	pIC50
dequalinium	Antagonist	4.5	pIC50
EBIO	Agonist	3.8	pEC50
tetraethylammonium	Channel blocker	2.7	pIC50

ChEMBL bioactivities

56 potent at pChembl≥5 of 63 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.19	IC50	0.064	nM	APAMIN
9.78	IC50	0.168	nM	APAMIN
9.44	EC50	0.36	nM	CHEMBL4749661
9.42	EC50	0.38	nM	CHEMBL4785313
8.96	EC50	1.1	nM	CHEMBL4762592
8.96	EC50	1.1	nM	CHEMBL4749661
8.77	EC50	1.7	nM	CHEMBL4787693
8.59	EC50	2.6	nM	CHEMBL4786321
8.42	EC50	3.8	nM	CHEMBL4760396
8.40	IC50	4	nM	CHEMBL476339
8.11	Kd	7.8	nM	CHEMBL511710
7.70	EC50	20	nM	CHEMBL2324346
7.60	IC50	25	nM	CHEMBL489770
7.51	IC50	31	nM	CHEMBL3040285
7.34	Ki	46	nM	CHEMBL1909931
7.25	IC50	56	nM	CHEMBL476339
7.23	IC50	59	nM	CHEMBL476339
7.22	IC50	60	nM	CHEMBL360621
7.22	Kd	60	nM	CHEMBL511710
7.00	Kd	100	nM	CHEMBL510780
6.85	EC50	140	nM	CHEMBL5421015
6.72	EC50	190	nM	CHEMBL5078247
6.70	EC50	200	nM	CHEMBL5403198
6.67	Ki	214	nM	CHEMBL1909929
6.54	IC50	290	nM	CHEMBL489770
6.46	IC50	350	nM	CHEMBL472452
6.43	Ki	370	nM	CHEMBL1182632
6.40	EC50	400	nM	CHEMBL510780
6.34	Ki	461	nM	FANCHININ
6.26	IC50	543	nM	CHEMBL489770
6.24	IC50	580	nM	CHEMBL472452
6.24	Ki	575	nM	CHEMBL1909930
6.22	EC50	600	nM	CHEMBL5086997
6.17	Ki	679	nM	BERBAMINE
6.08	Ki	837	nM	CHEMBL1909928
6.05	EC50	900	nM	CHEMBL499968
6.00	IC50	1000	nM	CHEMBL469732
5.96	IC50	1100	nM	CHEMBL452406
5.96	Ki	1091	nM	CEPHARANTHINE
5.90	Ki	1268	nM	CHEMBL1909932
5.89	IC50	1300	nM	DEQUALINIUM CHLORIDE
5.80	IC50	1600	nM	CHEMBL452406
5.79	Ki	1625	nM	CHEMBL1182643
5.75	Ki	1791	nM	CHEMBL1185254
5.74	EC50	1810	nM	CHEMBL511710
5.70	IC50	2000	nM	DEQUALINIUM CHLORIDE
5.66	EC50	2200	nM	CHEMBL510780
5.53	IC50	2970	nM	CHEMBL1909931
5.52	IC50	3000	nM	CHEMBL257156
5.28	IC50	5200	nM	CHEMBL469756

PubChem BioAssay actives

56 with measured affinity, of 171 total; 40 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,4S,7S,13S,16S,19S,22S,25S,28R,31S,34S,37S,40R,47S,50R)-50-amino-40-[[(2S)-5-amino-1-[[(2S)-5-amino-1-[[(2S)-1-amino-3-(1H-imidazol-5-yl)-1-oxopropan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-1,5-dioxopentan-2-yl]carbamoyl]-4-(4-aminobutyl)-47-(2-amino-2-oxoethyl)-34,37-bis(3-carbamimidamidopropyl)-19-[(1R)-1-hydroxyethyl]-7,22,31-trimethyl-25-(2-methylpropyl)-2,5,8,14,17,20,23,26,29,32,35,38,46,49-tetradecaoxo-42,43,52,53-tetrathia-3,6,9,15,18,21,24,27,30,33,36,39,45,48-tetradecazatricyclo[26.16.10.09,13]tetrapentacontan-16-yl]propanoic acid	349489: Inhibition of Kca2.3 channel expressed in HEK293 cells by electrophysiology assay	ic50	0.0001	uM
3-[(1R,4S,7S,13R,16S,19S,22S,25S,28R,31S,34S,37S,40R,47S,50R)-50-amino-40-[[(2S)-5-amino-1-[[(2S)-5-amino-1-[[(2S)-1-amino-3-(1H-imidazol-4-yl)-1-oxopropan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-1,5-dioxopentan-2-yl]carbamoyl]-4-(4-aminobutyl)-47-(2-amino-2-oxoethyl)-34,37-bis(3-carbamimidamidopropyl)-19-[(1R)-1-hydroxyethyl]-7,22,31-trimethyl-25-(2-methylpropyl)-2,5,8,14,17,20,23,26,29,32,35,38,46,49-tetradecaoxo-42,43,52,53-tetrathia-3,6,9,15,18,21,24,27,30,33,36,39,45,48-tetradecazatricyclo[26.16.10.09,13]tetrapentacontan-16-yl]propanoic acid	1724190: Inhibition of recombinant human SK3 expressed in HEK293T cells assessed as reduction in channel current with holding potential 0 mV and ramp voltage from -100 to 100 mV by whole cell patch clamp method	ec50	0.0004	uM
(2S)-2-[[(2S)-1-[(2S)-2-[[(1R,4S,7R,12R,15S,18S,21S,27S,30S,36S,39R,44R,47S,50S,53S,56S,59R,66S,69S,75S,80S,83S,86S)-36,66-bis(4-aminobutyl)-47-(2-amino-2-oxoethyl)-44-[[(2S)-2-[[(2S)-2-aminopropanoyl]amino]-3-phenylpropanoyl]amino]-75-[(2S)-butan-2-yl]-15,53,56-tris(3-carbamimidamidopropyl)-4,69,80-tris(2-carboxyethyl)-18,86-bis(hydroxymethyl)-21,27,30,50,83-pentakis(2-methylpropyl)-2,5,13,16,19,22,25,28,31,34,37,45,48,51,54,57,65,68,71,74,77,78,81,84,87-pentacosaoxo-9,10,41,42,61,62-hexathia-3,6,14,17,20,23,26,29,32,35,38,46,49,52,55,58,64,67,70,73,76,79,82,85,88-pentacosazatricyclo[37.24.14.1112,59]octaoctacontane-7-carbonyl]amino]-3-methylbutanoyl]pyrrolidine-2-carbonyl]amino]-3-(4-hydroxyphenyl)propanoic acid	1724190: Inhibition of recombinant human SK3 expressed in HEK293T cells assessed as reduction in channel current with holding potential 0 mV and ramp voltage from -100 to 100 mV by whole cell patch clamp method	ec50	0.0004	uM
(2S)-2-[[(2S)-6-amino-2-[[(2S)-2-[[(1R,4S,7R,12R,15S,18S,21S,27S,30S,36S,39R,44R,47S,50S,53S,56S,59R,66S,69S,75S,80S,83S,86S)-36,66-bis(4-aminobutyl)-47-(2-amino-2-oxoethyl)-80-(3-amino-3-oxopropyl)-44-[[(2S)-2-[[(2S)-2-aminopropanoyl]amino]-3-phenylpropanoyl]amino]-75-[(2S)-butan-2-yl]-15,53-bis(3-carbamimidamidopropyl)-4-(2-carboxyethyl)-69-(carboxymethyl)-18,86-bis(hydroxymethyl)-21,27,30,50,83-pentakis(2-methylpropyl)-56-(2-methylsulfanylethyl)-2,5,13,16,19,22,25,28,31,34,37,45,48,51,54,57,65,68,71,74,77,78,81,84,87-pentacosaoxo-9,10,41,42,61,62-hexathia-3,6,14,17,20,23,26,29,32,35,38,46,49,52,55,58,64,67,70,73,76,79,82,85,88-pentacosazatricyclo[37.24.14.1112,59]octaoctacontane-7-carbonyl]amino]-3-methylbutanoyl]amino]hexanoyl]amino]-3-(1H-imidazol-4-yl)propanoic acid	1724184: Inhibition of recombinant human SK3 expressed in HEK293T cells assessed as decrease in intracellular calcium level at membrane potential -120 mV for 50 ms followed by 400 ms voltage ramp to 60 mV by whole cell patch clamp method	ec50	0.0011	uM
3-[(1R,4S,7R,12R,15S,18S,21S,27S,30S,36S,39R,44R,47S,50S,53S,56S,59R,66S,69S,75S,80S,83S,86S)-4,36-bis(4-aminobutyl)-7-[[(2S)-1-[(2S)-2-[[(2S)-1-amino-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]carbamoyl]pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]carbamoyl]-47-(2-amino-2-oxoethyl)-44-[[(2S)-2-[[(2S)-2-aminopropanoyl]amino]-3-phenylpropanoyl]amino]-75-[(2S)-butan-2-yl]-15,53,56-tris(3-carbamimidamidopropyl)-66,80-bis(2-carboxyethyl)-18,86-bis(hydroxymethyl)-21,27,30,50,83-pentakis(2-methylpropyl)-2,5,13,16,19,22,25,28,31,34,37,45,48,51,54,57,65,68,71,74,77,78,81,84,87-pentacosaoxo-9,10,41,42,61,62-hexathia-3,6,14,17,20,23,26,29,32,35,38,46,49,52,55,58,64,67,70,73,76,79,82,85,88-pentacosazatricyclo[37.24.14.1112,59]octaoctacontan-69-yl]propanoic acid	1724184: Inhibition of recombinant human SK3 expressed in HEK293T cells assessed as decrease in intracellular calcium level at membrane potential -120 mV for 50 ms followed by 400 ms voltage ramp to 60 mV by whole cell patch clamp method	ec50	0.0017	uM
(2S)-2-[[(2S)-1-[(2S)-2-[[(1R,4S,7R,12R,15S,18S,21S,27S,30S,36S,39R,44R,47S,50S,53S,56S,59R,66S,69S,75S,80S,83S,86S)-4,36-bis(4-aminobutyl)-47-(2-amino-2-oxoethyl)-44-[[(2S)-2-[[(2S)-2-aminopropanoyl]amino]-3-phenylpropanoyl]amino]-75-[(2S)-butan-2-yl]-15,53,56-tris(3-carbamimidamidopropyl)-66,69,80-tris(2-carboxyethyl)-18,86-bis(hydroxymethyl)-21,27,30,50,83-pentakis(2-methylpropyl)-2,5,13,16,19,22,25,28,31,34,37,45,48,51,54,57,65,68,71,74,77,78,81,84,87-pentacosaoxo-9,10,41,42,61,62-hexathia-3,6,14,17,20,23,26,29,32,35,38,46,49,52,55,58,64,67,70,73,76,79,82,85,88-pentacosazatricyclo[37.24.14.1112,59]octaoctacontane-7-carbonyl]amino]-3-methylbutanoyl]pyrrolidine-2-carbonyl]amino]-3-(4-hydroxyphenyl)propanoic acid	1724190: Inhibition of recombinant human SK3 expressed in HEK293T cells assessed as reduction in channel current with holding potential 0 mV and ramp voltage from -100 to 100 mV by whole cell patch clamp method	ec50	0.0026	uM
3-[(1R,4S,7R,12R,15S,18S,21S,27S,30S,36S,39R,44R,47S,50S,53S,56S,59R,66S,69S,75S,80S,83S,86S)-7-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-1-amino-3-(1H-imidazol-4-yl)-1-oxopropan-2-yl]amino]-1-oxohexan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]carbamoyl]-36,53,66-tris(4-aminobutyl)-47-(2-amino-2-oxoethyl)-80-(3-amino-3-oxopropyl)-44-[[(2S)-2-[[(2S)-2-aminopropanoyl]amino]-3-methylbutanoyl]amino]-75-[(2S)-butan-2-yl]-15,56-bis(3-carbamimidamidopropyl)-69-(carboxymethyl)-18,86-bis(hydroxymethyl)-21,27,30,50,83-pentakis(2-methylpropyl)-2,5,13,16,19,22,25,28,31,34,37,45,48,51,54,57,65,68,71,74,77,78,81,84,87-pentacosaoxo-9,10,41,42,61,62-hexathia-3,6,14,17,20,23,26,29,32,35,38,46,49,52,55,58,64,67,70,73,76,79,82,85,88-pentacosazatricyclo[37.24.14.1112,59]octaoctacontan-4-yl]propanoic acid	1724184: Inhibition of recombinant human SK3 expressed in HEK293T cells assessed as decrease in intracellular calcium level at membrane potential -120 mV for 50 ms followed by 400 ms voltage ramp to 60 mV by whole cell patch clamp method	ec50	0.0038	uM
N-(4-methyl-2-pyridinyl)-4-pyridin-2-yl-1,3-thiazol-2-amine	387518: Displacement of [125I]apamin from Kca2.3 channel expressed in HEK293 cells by scintillation proximity assay	ic50	0.0040	uM
N-(6,7-dichloro-1,2,3,4-tetrahydronaphthalen-1-yl)-1H-benzimidazol-2-amine	346956: Inhibition of human SK3 channel expressed in HEK293 cells assessed as Ca2+ induced current after drug wash out by whole cell patch clamp technique in presence of bicuculline methobromide	kd	0.0078	uM
N-(4-fluorophenyl)-9-methyl-2-(3-methylpyrazol-1-yl)purin-6-amine	726262: Inhibition of human Kca 2.3 expressed in HEK293 cells by patch clamp technique	ec50	0.0200	uM
N,4-dipyridin-2-yl-1,3-thiazol-2-amine	387518: Displacement of [125I]apamin from Kca2.3 channel expressed in HEK293 cells by scintillation proximity assay	ic50	0.0250	uM
2,10-diaza-18,24-diazoniahexacyclo[22.6.2.211,18.14,8.012,17.025,30]pentatriaconta-1(31),4(35),5,7,11(34),12,14,16,18(33),24(32),25,27,29-tridecaene	754047: Inhibition of KCa2.3 (unknown origin)	ic50	0.0310	uM
2-methyl-1-[[3-[(2-methyl-8-propan-2-ylisoquinolin-2-ium-1-yl)methyl]phenyl]methyl]-8-propan-2-ylisoquinolin-2-ium diiodide	626506: Displacement of [125I]-apamin from cloned SK3 channel expressed in human HEK293 cells after 1 hr by liquid scintillation counting	ki	0.0460	uM
2,9-diaza-17,23-diazoniahexacyclo[21.6.2.24,7.210,17.011,16.024,29]pentatriaconta-1(30),4,6,10(33),11,13,15,17(32),23(31),24,26,28,34-tridecaene	754047: Inhibition of KCa2.3 (unknown origin)	ic50	0.0600	uM
N-[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]-1H-benzimidazol-2-amine	346951: Inhibition of wild type human SK3 channel expressed in HEK293 cells	kd	0.1000	uM
N-(4-chlorophenyl)-2-(3,5-dimethylpyrazol-1-yl)-9-methylpurin-6-amine	1974166: Positive modulation of SK3 in HEK293 cells in presence of Ca2+ by patch-clamp method	ec50	0.1400	uM
N-(3-chloro-4-fluorophenyl)-2-(3,5-dimethylpyrazol-1-yl)-6-methylpyrimidin-4-amine	1818835: Potentiation of human KCa2.3 expressed in HEK293 cells at -90 mV holding potential measured at 1 to 2 days by patch clamp electrophysiology relative to calcium	ec50	0.1900	uM
N-(4-fluorophenyl)-7-methyl-2-(3-methylpyrazol-1-yl)pyrrolo[2,3-d]pyrimidin-4-amine	1974179: Activation of SK3 (unknown origin) expressed in HEK293 cells coexpressing CaM/GFP in presence of Ca2+ by electrophysiological method	ec50	0.2000	uM
2-methyl-1-[4-(2-methyl-8-propan-2-ylisoquinolin-2-ium-1-yl)butyl]-8-propan-2-ylisoquinolin-2-ium diiodide	626506: Displacement of [125I]-apamin from cloned SK3 channel expressed in human HEK293 cells after 1 hr by liquid scintillation counting	ki	0.2140	uM
5-chloro-N-(thiophen-2-ylmethyl)pyrazolo[1,5-a]pyrimidin-7-amine	349488: Inhibition of Kca2.3 channel expressed in HEK293 cells by thallium flux assay	ic50	0.3500	uM
(1S)-1-[3-[(1S)-6,7-dimethoxy-2-methyl-3,4-dihydro-1H-isoquinolin-1-yl]propyl]-6,7-dimethoxy-2-methyl-3,4-dihydro-1H-isoquinoline	2006727: Displacement of [125I]apamin from SK3 (unknown origin) expressed in HEK293 cells assessed as inhibition constant incubated for 1 hr by liquid scintillation counting analysis	ki	0.3700	uM
(1S,14S)-9,20,21,25-tetramethoxy-15,30-dimethyl-7,23-dioxa-15,30-diazaheptacyclo[22.6.2.23,6.18,12.114,18.027,31.022,33]hexatriaconta-3(36),4,6(35),8,10,12(34),18,20,22(33),24,26,31-dodecaene	2006727: Displacement of [125I]apamin from SK3 (unknown origin) expressed in HEK293 cells assessed as inhibition constant incubated for 1 hr by liquid scintillation counting analysis	ki	0.4610	uM
2-methyl-1-[5-(2-methyl-8-propan-2-ylisoquinolin-2-ium-1-yl)pentyl]-8-propan-2-ylisoquinolin-2-ium diiodide	626506: Displacement of [125I]-apamin from cloned SK3 channel expressed in human HEK293 cells after 1 hr by liquid scintillation counting	ki	0.5750	uM
N-(5-chloro-2-fluorophenyl)-2-(3,5-dimethylpyrazol-1-yl)-6-methylpyrimidin-4-amine	1818838: Potentiation of human KCa2.3 expressed in HEK293 cells at -90 mV holding potential measured at 1 to 2 days by patch clamp electrophysiology	ec50	0.6000	uM
(1S,14R)-20,21,25-trimethoxy-15,30-dimethyl-7,23-dioxa-15,30-diazaheptacyclo[22.6.2.23,6.18,12.114,18.027,31.022,33]hexatriaconta-3(36),4,6(35),8,10,12(34),18,20,22(33),24,26,31-dodecaen-9-ol	2006724: Displacement of [125I]apamin from human SK3 expressed in HEK293 cells assessed as inhibition constant incubated for 1 hr by liquid scintillation counting analysis	ki	0.6790	uM
2-methyl-1-[3-(2-methyl-8-propan-2-ylisoquinolin-2-ium-1-yl)propyl]-8-propan-2-ylisoquinolin-2-ium diiodide	626506: Displacement of [125I]-apamin from cloned SK3 channel expressed in human HEK293 cells after 1 hr by liquid scintillation counting	ki	0.8370	uM
6,7-dichloro-3-nitroso-1H-indol-2-ol	1974166: Positive modulation of SK3 in HEK293 cells in presence of Ca2+ by patch-clamp method	ec50	0.9000	uM
5-chloro-N-[(1R)-1-phenylethyl]pyrazolo[1,5-a]pyrimidin-7-amine	349488: Inhibition of Kca2.3 channel expressed in HEK293 cells by thallium flux assay	ic50	1.0000	uM
(14S,27R)-22,33-dimethoxy-13,28-dimethyl-2,5,7,20-tetraoxa-13,28-diazaoctacyclo[25.6.2.216,19.13,10.121,25.04,8.031,35.014,39]nonatriaconta-1(33),3(39),4(8),9,16(38),17,19(37),21,23,25(36),31,34-dodecaene	2006724: Displacement of [125I]apamin from human SK3 expressed in HEK293 cells assessed as inhibition constant incubated for 1 hr by liquid scintillation counting analysis	ki	1.0910	uM
N-benzyl-5-chloropyrazolo[1,5-a]pyrimidin-7-amine	349488: Inhibition of Kca2.3 channel expressed in HEK293 cells by thallium flux assay	ic50	1.1000	uM
2-methyl-1-[[4-[(2-methyl-8-propan-2-ylisoquinolin-2-ium-1-yl)methyl]phenyl]methyl]-8-propan-2-ylisoquinolin-2-ium diiodide	626506: Displacement of [125I]-apamin from cloned SK3 channel expressed in human HEK293 cells after 1 hr by liquid scintillation counting	ki	1.2680	uM
1-[10-(4-amino-2-methylquinolin-1-ium-1-yl)decyl]-2-methylquinolin-1-ium-4-amine dichloride	387515: Inhibition of Kca2.3 channel expressed in HEK293 cells by thallium flux assay	ic50	1.3000	uM
(1R)-1-[3-[(1R)-6,7-dimethoxy-2-methyl-3,4-dihydro-1H-isoquinolin-1-yl]propyl]-6,7-dimethoxy-2-methyl-3,4-dihydro-1H-isoquinoline	2006727: Displacement of [125I]apamin from SK3 (unknown origin) expressed in HEK293 cells assessed as inhibition constant incubated for 1 hr by liquid scintillation counting analysis	ki	1.6250	uM
(1S)-1-[3-[(1R)-6,7-dimethoxy-2-methyl-3,4-dihydro-1H-isoquinolin-1-yl]propyl]-6,7-dimethoxy-2-methyl-3,4-dihydro-1H-isoquinoline	2006727: Displacement of [125I]apamin from SK3 (unknown origin) expressed in HEK293 cells assessed as inhibition constant incubated for 1 hr by liquid scintillation counting analysis	ki	1.7910	uM
(1S)-1-[3-[(1S)-6,7-dimethoxy-2-methyl-3,4-dihydro-1H-isoquinolin-1-yl]propyl]-6,7-dimethoxy-2-methyl-3,4-dihydro-1H-isoquinoline;dihydrochloride	332058: Inhibition of SK3 expressed in CHO FlipIn cells by whole cell patch-clamp assay	ic50	3.0000	uM
5-chloro-N-[(3-chlorophenyl)methyl]pyrazolo[1,5-a]pyrimidin-7-amine	349488: Inhibition of Kca2.3 channel expressed in HEK293 cells by thallium flux assay	ic50	5.2000	uM
N-cyclohexyl-2-(3,5-dimethylpyrazol-1-yl)-6-methylpyrimidin-4-amine	1974169: Positive modulation of SK3 (unknown origin)	ec50	5.6000	uM
5-chloro-N-(1,2-diphenylethyl)pyrazolo[1,5-a]pyrimidin-7-amine	349488: Inhibition of Kca2.3 channel expressed in HEK293 cells by thallium flux assay	ic50	7.5000	uM
5-chloro-N-[(3-nitrophenyl)methyl]pyrazolo[1,5-a]pyrimidin-7-amine	349488: Inhibition of Kca2.3 channel expressed in HEK293 cells by thallium flux assay	ic50	7.9000	uM
5-chloro-N-[[2-(trifluoromethoxy)phenyl]methyl]pyrazolo[1,5-a]pyrimidin-7-amine	349488: Inhibition of Kca2.3 channel expressed in HEK293 cells by thallium flux assay	ic50	10.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, increases methylation	3
Panobinostat	affects cotreatment, decreases expression	2
Benzo(a)pyrene	affects methylation	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Silicon Dioxide	decreases expression, increases expression	2
Aflatoxin B1	affects methylation, increases methylation	2
methylmercuric chloride	decreases expression	1
propionaldehyde	increases expression	1
bisphenol A	affects cotreatment, decreases methylation	1
sodium arsenite	increases expression	1
benzo(e)pyrene	affects methylation	1
aflatoxin B2	affects methylation	1
bicuculline methobromide	decreases reaction, increases activity, decreases activity	1
S-(1,2-dichlorovinyl)cysteine	increases expression, affects response to substance	1
1-ethyl-2-benzimidazolinone	increases activity	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
6,7-dichloro-1H-indole-2,3-dione 3-oxime	increases activity, increases reaction, decreases reaction	1
abrine	increases expression	1
5,6-dichloro-1-ethyl-1,3-dihydro-2H-benzimidazol-2-one	increases activity	1
dorsomorphin	affects cotreatment, decreases expression	1
cyclohexyl-(2-(3,5-dimethylpyrazol-1-yl)-6-methylpyrimidin-4-yl)amine	decreases reaction, increases activity, increases import, increases reaction	1
Sunitinib	decreases expression	1
Fulvestrant	decreases methylation, affects cotreatment	1
Acetaminophen	decreases expression	1
Apamin	decreases reaction, increases activity, increases import	1
Calcium	increases activity, increases reaction	1
Diethylhexyl Phthalate	decreases expression	1
Doxorubicin	decreases expression	1
Ethyl Methanesulfonate	increases expression	1
Lipopolysaccharides	affects response to substance, increases expression	1

ChEMBL screening assays

51 unique, capped per target: 51 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1008048	Binding	Inhibition of wild type human SK3 channel expressed in HEK293 cells at 100 nM by whole cell assay	Synthesis and structure-activity relationship studies of 2-(N-substituted)-aminobenzimidazoles as potent negative gating modulators ofsmall conductance Ca2+-activated K+ channels. — J Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00000374	PHASE4	COMPLETED	Treatment for First-Episode Schizophrenia
NCT00001656	PHASE4	COMPLETED	Comparison of Clozapine vs Olanzapine in Childhood-Onset Psychotic Disorders
NCT00007774	PHASE4	COMPLETED	To Determine if Olanzapine is More Cost Effective Than Haloperidol for the Treatment of Schizophrenia
NCT00014001	PHASE4	COMPLETED	CATIE- Schizophrenia Trial
NCT00018668	PHASE4	COMPLETED	Antipsychotic Response in Schizophrenia
NCT00034801	PHASE4	COMPLETED	Olanzapine Versus Active Comparator in the Treatment of Depression in Patients With Schizophrenia
NCT00034905	PHASE4	COMPLETED	A Comparison of Seroquel vs. Risperidone in Schizophrenia
NCT00036088	PHASE4	COMPLETED	Olanzapine Versus An Active Comparator in the Treatment of Schizophrenia
NCT00044187	PHASE4	COMPLETED	The Assessment of a Weight-Gain Agent for the Treatment of Olanzapine-Associated Anti-Obesity Agent in Patients With Schizophrenia, Schizophreniform Disorder, Schizoaffective Disorder, and Bipolar I Disorder
NCT00044655	PHASE4	COMPLETED	Switching Medication to Treat Schizophrenia
NCT00048828	PHASE4	COMPLETED	Treating Drug-Resistant Childhood Schizophrenia
NCT00053703	PHASE4	COMPLETED	Treatment of Early Onset Schizophrenia Spectrum Disorders (TEOSS)
NCT00056498	PHASE4	COMPLETED	Risperidone Treatment in Schizophrenia Patients Who Are Currently Taking Clozapine
NCT00061802	PHASE4	COMPLETED	Efficacy and Safety of Two Atypical Antipsychotics vs. Placebo in Patients With an Acute Exacerbation of Either Schizophrenia or Schizoaffective Disorder
NCT00080327	PHASE4	COMPLETED	Study of Three Doses of Aripiprazole in Patients With Acute Schizophrenia
NCT00088049	PHASE4	COMPLETED	Study of Olanzapine vs. Aripiprazole in the Treatment of Schizophrenia
NCT00090012	PHASE4	COMPLETED	Comparison of Continuing Olanzapine to Switching to Quetiapine in Overweight or Obese Patients With Schizophrenia and Schizoaffective Disorder
NCT00100776	PHASE4	COMPLETED	Efficacy of High Dose Olanzapine for the Treatment of Schizophrenia and Schizoaffective Disorder
NCT00103571	PHASE4	COMPLETED	Olanzapine Versus Aripiprazole in the Treatment of Acutely Ill Patients With Schizophrenia
NCT00108368	PHASE4	COMPLETED	The Effects of Risperidone and Olanzapine on Thinking
NCT00114595	PHASE4	COMPLETED	Ethyl-Eicosapentaenoic Acid and Tardive Dyskinesia
NCT00130923	PHASE4	COMPLETED	Risperidone Long-acting Versus Oral Risperidone in Patients With Schizophrenia and Alcohol Use Disorder
NCT00137020	PHASE4	COMPLETED	Clinical Effect Of Cross Titration Of Antipsychotics With Ziprasidone In Schizophrenia Or Schizoaffective Disorder
NCT00140166	PHASE4	COMPLETED	Treatment of Acute Schizophrenia With Vitamin Therapy
NCT00145847	PHASE4	COMPLETED	Naltrexone Treatment of Alcohol Abuse in Schizophrenia
NCT00148564	PHASE4	COMPLETED	Energy Homeostasis Under Treatment With Atypical Antipsychotics
NCT00156715	PHASE4	COMPLETED	Efficacy of Quetiapine in the Treatment of Patients With Schizophrenia and a Comorbid Substance Use Disorder
NCT00158223	PHASE4	COMPLETED	Effectiveness of Pimozide in Augmenting the Effects of Clozapine in the Treatment of Schizophrenia
NCT00159081	PHASE4	COMPLETED	One Year Drug Treatment in First-Episode Schizophrenia
NCT00159120	PHASE4	COMPLETED	Maintenance Treatment vs. Stepwise Drug Discontinuation in First-Episode Schizophrenia
NCT00159133	PHASE4	COMPLETED	Prodrome-Based Early Intervention With Antipsychotics vs. Benzodiazepines in First-Episode Schizophrenia
NCT00159757	PHASE4	TERMINATED	12 Week Open, Non-Comparative Switch Study Of Oral Ziprazidone In Previously Treated Schizophrenic Patients
NCT00167817	PHASE4	COMPLETED	Effect of Switch to Aripiprazole on Health and Smoking Parameters in Patients With Schizophrenia: A Pilot Study
NCT00169026	PHASE4	TERMINATED	Alcoholism and Schizophrenia: Effects of Clozapine
NCT00169039	PHASE4	TERMINATED	Clozapine Versus Chlorpromazine for Treatment-Unresponsive Schizophrenia
NCT00169065	PHASE4	COMPLETED	Effectiveness of Clozapine Versus Olanzapine for Treatment-resistant Schizophrenia
NCT00169091	PHASE4	TERMINATED	Clozapine Versus Haloperidol for Treating the First Episode of Schizophrenia
NCT00176423	PHASE4	COMPLETED	Efficacy Study of Galantamine for Cognitive Impairments in Schizophrenia
NCT00176436	PHASE4	COMPLETED	Atomoxetine for Treatment of Weight Gain in Olanzapine or Clozapine Patients
NCT00177008	PHASE4	COMPLETED	Aripiprazole for the Treatment of Schizophrenia With Co-Morbid Social Anxiety