KCNT2

Summary

KCNT2 (potassium sodium-activated channel subfamily T member 2, HGNC:18866) is a protein-coding gene on chromosome 1q31.3, encoding Potassium channel subfamily T member 2 (Q6UVM3). Sodium-activated and chloride-activated potassium channel.

Enables chloride-activated potassium channel activity and intracellular sodium-activated potassium channel activity. Involved in potassium ion export across plasma membrane. Located in plasma membrane. Implicated in developmental and epileptic encephalopathy 57.

Source: NCBI Gene 343450 — RefSeq curated summary.

At a glance

• Gene–disease (curated): developmental and epileptic encephalopathy, 57 (Strong, GenCC)
• GWAS associations: 15
• Clinical variants (ClinVar): 319 total — 4 pathogenic, 11 likely-pathogenic
• Phenotypes (HPO): 18
• Druggable target: yes
• MANE Select transcript: NM_198503

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18866
Approved symbol	KCNT2
Name	potassium sodium-activated channel subfamily T member 2
Location	1q31.3
Locus type	gene with protein product
Status	Approved
Aliases	KCa4.2, SLICK, SLO2.1
Ensembl gene	ENSG00000162687
Ensembl biotype	protein_coding
OMIM	610044
Entrez	343450

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 5 protein_coding, 2 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000294725, ENST00000367433, ENST00000466914, ENST00000498426, ENST00000609185, ENST00000610076, ENST00000647658, ENST00000673703, ENST00000882026

RefSeq mRNA: 3 — MANE Select: NM_198503 NM_001287819, NM_001287820, NM_198503

CCDS: CCDS1384, CCDS72994, CCDS72995

Canonical transcript exons

ENST00000294725 — 28 exons

Exon	Start	End
ENSE00001315063	196326717	196326889
ENSE00001322278	196319484	196319555
ENSE00001899840	196225779	196228335
ENSE00003474978	196315892	196316026
ENSE00003484018	196305234	196305345
ENSE00003491711	196482331	196482379
ENSE00003499901	196489838	196489937
ENSE00003511859	196235986	196236070
ENSE00003515848	196468994	196469068
ENSE00003529785	196342079	196342228
ENSE00003537846	196465293	196465387
ENSE00003547717	196331156	196331261
ENSE00003554376	196492262	196492341
ENSE00003564818	196282273	196282356
ENSE00003596715	196333847	196334060
ENSE00003601301	196479179	196479238
ENSE00003625931	196340341	196340570
ENSE00003633392	196280860	196280988
ENSE00003637309	196429577	196429757
ENSE00003649251	196258194	196258494
ENSE00003653959	196428105	196428269
ENSE00003653977	196467703	196467786
ENSE00003662758	196373140	196373248
ENSE00003673819	196285657	196285758
ENSE00003705586	196425852	196425988
ENSE00003708350	196398563	196398671
ENSE00003709995	196423050	196423113
ENSE00003710992	196608215	196608440

Expression profiles

Bgee: expression breadth ubiquitous, 206 present calls, max score 92.48.

FANTOM5 (CAGE): breadth broad, TPM avg 6.9946 / max 419.6683, expressed in 818 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
16478	4.1775	532
16479	1.4916	568
201858	0.4156	199
16482	0.2909	152
16484	0.2606	143
16483	0.1521	81
16480	0.1183	57
16481	0.0879	34

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
parietal pleura	UBERON:0002400	92.48	gold quality
endothelial cell	CL:0000115	90.99	silver quality
cartilage tissue	UBERON:0002418	88.66	gold quality
Brodmann (1909) area 23	UBERON:0013554	88.34	gold quality
Brodmann (1909) area 46	UBERON:0006483	87.63	gold quality
middle temporal gyrus	UBERON:0002771	85.60	gold quality
germinal epithelium of ovary	UBERON:0001304	85.58	gold quality
calcaneal tendon	UBERON:0003701	83.26	gold quality
visceral pleura	UBERON:0002401	82.08	gold quality
cardiac muscle of right atrium	UBERON:0003379	81.57	silver quality
right coronary artery	UBERON:0001625	80.86	gold quality
left ovary	UBERON:0002119	80.57	gold quality
left coronary artery	UBERON:0001626	80.29	gold quality
ovary	UBERON:0000992	80.05	gold quality
urethra	UBERON:0000057	79.72	gold quality
coronary artery	UBERON:0001621	79.48	gold quality
superior frontal gyrus	UBERON:0002661	79.48	gold quality
ventricular zone	UBERON:0003053	79.08	gold quality
right ovary	UBERON:0002118	78.98	gold quality
popliteal artery	UBERON:0002250	78.62	gold quality
tibial artery	UBERON:0007610	78.62	gold quality
entorhinal cortex	UBERON:0002728	78.47	gold quality
pigmented layer of retina	UBERON:0001782	77.34	gold quality
liver	UBERON:0002107	77.34	gold quality
postcentral gyrus	UBERON:0002581	77.21	gold quality
tendon	UBERON:0000043	76.73	gold quality
primary visual cortex	UBERON:0002436	76.54	gold quality
mucosa of stomach	UBERON:0001199	76.52	gold quality
right lobe of liver	UBERON:0001114	76.26	gold quality
cortical plate	UBERON:0005343	75.94	gold quality

Single-cell (SCXA)

Detected in 9 experiment(s), a significant marker in 8.

Experiment	Marker?	Max mean expression
E-GEOD-131882	yes	1341.43
E-CURD-119	yes	984.82
E-HCAD-35	yes	11.21
E-MTAB-5061	yes	8.63
E-ANND-3	yes	6.14
E-GEOD-81547	yes	5.37
E-GEOD-81608	yes	5.11
E-ENAD-27	yes	3.95
E-CURD-11	no	73.63

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

120 targeting KCNT2, 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-4795-3P	100.00	74.62	4024
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-3682-5P	99.93	67.97	1163
HSA-MIR-552-5P	99.93	68.56	1583
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-10523-5P	99.91	69.22	2038
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-6809-3P	99.91	71.45	3814

Literature-anchored findings (GeneRIF, showing 15)

• Cloning and regulation of slick channel activity. (PMID:14684870)
• Together these findings suggest that (1) the selectivity filter and not the bundle crossing gates ion permeation and (2) dynamic coupling between the pore helix and the S5 and S6 segments mediates Slo2.1 channel activation. (PMID:24166878)
• Slick channels, in contrast to the similar Slack channels, are the only high-conductance K+ channels strongly sensitive to small changes in cell volume. (PMID:25347289)
• Charge reversal of Asp757 of Slo2.1 prevented activation of channels by intracellular Na+, whereas activation by niflumic acid was unaffected. (PMID:25903137)
• Together these results suggest that hydrophobic interactions between residues in S5 and the C-terminal end of the pore helix stabilize Slo2.1 channels in a closed state. (PMID:26724206)
• KCNT2 SNPs were associated with lifetime cannabis use, but the association did not reach genome-wide significance. [Meta-Analysis] (PMID:27023175)
• In the present study, we evaluated two other potential mechanisms for stabilization of Slo2 channels in a closed state: (1) dewetting and collapse of the inner pore (hydrophobic gating) and (2) constriction of the inner pore by tight criss-crossing of the cytoplasmic ends of the S6 alpha-helical segments. (PMID:27682982)
• mRNA of aquaporin 1 was co-expressed in Xenopus oocytes with homomeric or heteromeric Slick and Slack alpha-subunits. Hypotonic or hypertonic buffers caused changes in current. The heteromeric channel had a characteristic graded sensitivity to small and fast changes in cell volume. This the cell volume sensitivity is dependent on the number of volume sensitive Slick alpha-subunits in the tetrameric channels. (PMID:28222129)
• Pathogenic Phe240Leu mutation in KCNT2 channel changes ion selectivity. (PMID:29069600)
• The expression of three genes (STK26, KCNT2, CASP12) was correlated with the prognosis of skin cutaneous melanoma (SCM). STK26 and KCNT2 were significantly different between normal skin and SCM. These three hub genes have potential value as predictors for accurate diagnosis and prognosis of SCM in the future. (PMID:31557882)
• In silico and in vitro analysis of cation-activated potassium channels in human corneal endothelial cells. (PMID:32561484)
• An inducible circular RNA circKcnt2 inhibits ILC3 activation to facilitate colitis resolution. (PMID:32796851)
• New mutations in KCNT2 gene causing early infantile epileptic encephalopathy type 57: Case study and literature review. (PMID:32931186)
• Recurrent KCNT2 missense variants affecting p.Arg190 result in a recognizable phenotype. (PMID:34061450)
• KCNT2-Related Disorders: Phenotypes, Functional, and Pharmacological Properties. (PMID:37062836)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	kcnt2a	ENSDARG00000075812
mus_musculus	Kcnt2	ENSMUSG00000052726
rattus_norvegicus	Kcnt2	ENSRNOG00000013312
drosophila_melanogaster	SLO2	FBGN0261698
caenorhabditis_elegans		WBGENE00004831

Paralogs (3): KCNT1 (ENSG00000107147), KCNMA1 (ENSG00000156113), KCNU1 (ENSG00000215262)

Protein

Protein identifiers

Potassium channel subfamily T member 2 — Q6UVM3 (reviewed: Q6UVM3)

Alternative names: KNa1.2, Sequence like an intermediate conductance potassium channel subunit, Sodium and chloride-activated ATP-sensitive potassium channel Slo2.1

All UniProt accessions (5): A0A3B3IRL4, A0A669KBD9, A9LNM6, Q6UVM3, V9GZ63

UniProt curated annotations — full annotation on UniProt →

Function. Sodium-activated and chloride-activated potassium channel. Produces rapidly activating outward rectifier K(+) currents. Contributes to regulate neuronal excitability.

Subunit / interactions. Homotetramer. Forms heteromeric channels with KCNT1; these heterodimer channels differ from the homomers in their unitary conductance, kinetic behavior, subcellular localization, and response to activation of protein kinase C.

Subcellular location. Cell membrane.

Post-translational modifications. Phosphorylated by protein kinase C. Phosphorylation of the C-terminal domain inhibits channel activity.

Disease relevance. Developmental and epileptic encephalopathy 57 (DEE57) [MIM:617771] A form of epileptic encephalopathy, a heterogeneous group of severe early-onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. DEE57 is an autosomal dominant condition. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Are normally in a closed state unless activated by an increase in intracellular Na(+) and Cl(-). Inhibited upon stimulation of G-protein coupled receptors, such as CHRM1 and GRM1. There is conflicting data about the effect of ATP on KNCT2 channels activity. Intracellular ATP was initially report to inhibit the channel activity. However, others studies conclude that KNCT2 channels are not inhibited by intracellular ATP.

Domain organisation. The consensus ATP binding site (1025-GPKHSGKT-1032) seems to be non-functional.

Similarity. Belongs to the potassium channel family. Calcium-activated (TC 1.A.1.3) subfamily. KCa4.2/KCNT2 sub-subfamily.

Isoforms (4)

UniProt ID	Names	Canonical?
Q6UVM3-1	1	yes
Q6UVM3-2	2
Q6UVM3-3	3
Q6UVM3-4	4

RefSeq proteins (3): NP_001274748, NP_001274749, NP_940905* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003148	RCK_N	Domain
IPR003929	K_chnl_BK_asu	Domain
IPR013099	K_chnl_dom	Domain
IPR036291	NAD(P)-bd_dom_sf	Homologous_superfamily
IPR047871	K_chnl_Slo-like	Family

Pfam: PF03493, PF07885, PF22614

Catalyzed reactions (Rhea), 1 shown:

• K(+)(in) = K(+)(out) (RHEA:29463)

UniProt features (42 total): topological domain 8, transmembrane region 6, splice variant 6, sequence variant 6, mutagenesis site 6, region of interest 3, domain 2, compositionally biased region 2, chain 1, intramembrane region 1, glycosylation site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6UVM3-F1	76.42	0.35

Functional residue map

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

Glycosylation sites (1): 99

Mutagenesis-validated functional residues (6):

Position	Phenotype
267	constitutively open channel.
267	constitutively open channel; when associated with n-270.
270	does not affect channel activity. constitutively open channel; when associated with n-267.
270	constitutively open channel.
282	does not induce constitutive opening.
1031	does not affect kcnt2 channel activity.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 154 (showing top): GOBP_POTASSIUM_ION_TRANSPORT, MAZ_Q6, GOBP_MONOATOMIC_CATION_TRANSPORT, NFKB_Q6, NFKB_C, CDP_01, CORRE_MULTIPLE_MYELOMA_UP, P300_01, POU3F2_02, YY1_01, CUI_TCF21_TARGETS_2_UP, CHIANG_LIVER_CANCER_SUBCLASS_INTERFERON_UP, GOBP_TRANSMEMBRANE_TRANSPORT, SCGGAAGY_ELK1_02, GOMF_VOLTAGE_GATED_MONOATOMIC_CATION_CHANNEL_ACTIVITY

GO Biological Process (5): potassium ion transmembrane transport (GO:0071805), potassium ion export across plasma membrane (GO:0097623), monoatomic ion transport (GO:0006811), potassium ion transport (GO:0006813), monoatomic ion transmembrane transport (GO:0034220)

GO Molecular Function (4): intracellular sodium-activated potassium channel activity (GO:0005228), outward rectifier potassium channel activity (GO:0015271), chloride-activated potassium channel activity (GO:0070089), potassium channel activity (GO:0005267)

GO Cellular Component (2): plasma membrane (GO:0005886), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
potassium channel activity	2
monoatomic ion-gated channel activity	2
ligand-gated monoatomic cation channel activity	2
potassium ion transport	1
monoatomic cation transmembrane transport	1
potassium ion transmembrane transport	1
export across plasma membrane	1
transport	1
metal ion transport	1
monoatomic ion transport	1
transmembrane transport	1
voltage-gated potassium channel activity	1
monoatomic cation channel activity	1
potassium ion transmembrane transporter activity	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

818 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KCNT2	SCOC	Q9UIL1	680
KCNT2	KCNN1	Q92952	532
KCNT2	KCNA2	P16389	486
KCNT2	TTC12	Q9H892	485
KCNT2	KCNN2	Q9H2S1	474
KCNT2	KCNN4	O15554	467
KCNT2	CSN3	P07498	447
KCNT2	KCNA4	P22459	447
KCNT2	KCNV1	Q6PIU1	441
KCNT2	SLC35G1	Q2M3R5	436
KCNT2	KCNMB1	P78475	423
KCNT2	CRB1	P82279	420
KCNT2	CFHR4	Q92496	419
KCNT2	KCNH5	Q8NCM2	411
KCNT2	KCNN3	Q9UGI6	410

IntAct

158 interactions, top by confidence:

A	B	Type	Score
SCRIB	KCNT2	psi-mi:“MI:0407”(direct interaction)	0.610
KCNT2	PDZRN4	psi-mi:“MI:0407”(direct interaction)	0.610
KCNT2	MAST2	psi-mi:“MI:0407”(direct interaction)	0.610
KCNT2	SCRIB	psi-mi:“MI:0407”(direct interaction)	0.610
KCNT2	SCRIB	psi-mi:“MI:0915”(physical association)	0.610
PDZRN4	KCNT2	psi-mi:“MI:0407”(direct interaction)	0.610
MAST2	KCNT2	psi-mi:“MI:0407”(direct interaction)	0.610
KCNT2	MAST2	psi-mi:“MI:0915”(physical association)	0.610
PCDHB16	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
ZNRF4	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
TCIRG1	AP3D1	psi-mi:“MI:0914”(association)	0.530
IL4R	RHOBTB3	psi-mi:“MI:0914”(association)	0.530
PDZK1	KCNT2	psi-mi:“MI:0407”(direct interaction)	0.440
KCNT2	SNX27	psi-mi:“MI:0407”(direct interaction)	0.440
KCNT2	NHERF2	psi-mi:“MI:0407”(direct interaction)	0.440
KCNT2	MAST1	psi-mi:“MI:0407”(direct interaction)	0.440
KCNT2	RHPN1	psi-mi:“MI:0407”(direct interaction)	0.440
KCNT2	PDZRN3	psi-mi:“MI:0407”(direct interaction)	0.440
PTPN3	KCNT2	psi-mi:“MI:0407”(direct interaction)	0.440
KCNT2	ARHGEF12	psi-mi:“MI:0407”(direct interaction)	0.440
KCNT2	SHANK1	psi-mi:“MI:0407”(direct interaction)	0.440
KCNT2	SYNJ2BP	psi-mi:“MI:0407”(direct interaction)	0.440
KCNT2	GRID2IP	psi-mi:“MI:0407”(direct interaction)	0.440
KCNT2	MAGI1	psi-mi:“MI:0407”(direct interaction)	0.440
KCNT2	SNTB1	psi-mi:“MI:0407”(direct interaction)	0.440
KCNT2	FRMPD4	psi-mi:“MI:0407”(direct interaction)	0.440
KCNT2	DLG2	psi-mi:“MI:0407”(direct interaction)	0.440
PDZD7	KCNT2	psi-mi:“MI:0407”(direct interaction)	0.440
KCNT2	ARHGEF11	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (38): KCNT2 (Affinity Capture-MS), KCNT2 (Affinity Capture-MS), KCNT2 (Affinity Capture-MS), KCNT2 (Affinity Capture-MS), KCNT2 (Affinity Capture-MS), KCNT2 (Affinity Capture-MS), KCNT2 (Affinity Capture-MS), KCNT2 (Affinity Capture-MS), KCNT2 (Synthetic Lethality), KCNT2 (Affinity Capture-MS), KCNT2 (Affinity Capture-MS), KCNT2 (Affinity Capture-MS), KCNT2 (Affinity Capture-MS), KCNT2 (Affinity Capture-MS), KCNT2 (Affinity Capture-MS)

ESM2 similar proteins: A0A0G2JTR4, A0A2R8QFQ6, A0JM95, A4IFE4, A6QNS3, C1C3R6, D3Z649, D4ABL6, E9PV86, F1QH17, G3MWR8, O46404, Q0VAM2, Q12800, Q12979, Q13507, Q28EC1, Q3ULA2, Q3UNW5, Q4V860, Q5R6F2, Q5RB16, Q5RC04, Q5SSL4, Q5VWJ9, Q5ZLX4, Q63789, Q64143, Q6DHR3, Q6NZH6, Q6UVM3, Q6UVM4, Q6ZPR4, Q7RTP6, Q7T2U9, Q7Z6J6, Q8CE50, Q8CJ19, Q8JZL7, Q8N431

Diamond homologs: D3Z649, Q57603, Q5JUK3, Q69TN4, Q6UVM3, Q6UVM4, Q6ZPR4, Q850M0, Q8LBL1, Q8QFV0, Q9FWX6, Q9Z258, A0A509AS68, A5LFX5, A8MYU2, D4A6Z8, O17185, O35174, O43526, O54982, O88943, P31069, P56696, Q57604, Q8I5E6, Q8IKI3, Q8LIN5, Q92953, Q979Z2, Q9ER26, Q9JK45, Q9JK96, Q9JK97, Q9NR82, Q9ULS6, Q9YDF8, Q9Z351, P56509, Q58752, Q84568

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 122 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Ras activation upon Ca2+ influx through NMDA receptor	5	37.6×	1e-05
Unblocking of NMDA receptors, glutamate binding and activation	5	35.8×	1e-05
Negative regulation of NMDA receptor-mediated neuronal transmission	5	35.8×	1e-05
Long-term potentiation	5	31.3×	2e-05
Assembly and cell surface presentation of NMDA receptors	9	30.1×	2e-09
Neurexins and neuroligins	10	25.9×	1e-09
Protein-protein interactions at synapses	7	24.5×	1e-06
Neuronal System	8	4.7×	8e-03

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	10	53.8×	1e-12
protein localization to synapse	6	42.6×	1e-06
receptor clustering	7	40.5×	1e-07
regulation of postsynaptic membrane neurotransmitter receptor levels	6	27.5×	1e-05
establishment of cell polarity	5	17.7×	6e-04
cell-cell adhesion	11	10.3×	2e-06
protein-containing complex assembly	9	9.5×	4e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	11
Uncertain significance	229
Likely benign	40
Benign	6

Top pathogenic / likely-pathogenic (15)

Variant ID	HGVS	Classification
236299	NM_198503.5(KCNT2):c.720T>A (p.Phe240Leu)	Pathogenic
4530813	NM_198503.5(KCNT2):c.592C>G (p.Gln198Glu)	Pathogenic
695094	NM_198503.5(KCNT2):c.143_144del (p.Leu48fs)	Pathogenic
987968	NM_198503.5(KCNT2):c.569G>C (p.Arg190Pro)	Pathogenic
1177518	NM_198503.5(KCNT2):c.1731_1738del (p.Phe578fs)	Likely pathogenic
1320260	NM_198503.5(KCNT2):c.2501_2507del (p.Ser834fs)	Likely pathogenic
1339492	NM_198503.5(KCNT2):c.175+1G>T	Likely pathogenic
1679226	NM_198503.5(KCNT2):c.1096A>G (p.Lys366Glu)	Likely pathogenic
1685358	NM_198503.5(KCNT2):c.914G>C (p.Cys305Ser)	Likely pathogenic
1802558	NM_198503.5(KCNT2):c.1667C>T (p.Thr556Ile)	Likely pathogenic
3238854	NM_198503.5(KCNT2):c.800T>A (p.Leu267His)	Likely pathogenic
3383425	NM_198503.5(KCNT2):c.560C>A (p.Ala187Asp)	Likely pathogenic
4531370	NM_198503.5(KCNT2):c.2836A>T (p.Lys946Ter)	Likely pathogenic
4755521	NM_198503.5(KCNT2):c.1244del (p.Leu415fs)	Likely pathogenic
695093	NM_198503.5(KCNT2):c.1690A>T (p.Lys564Ter)	Likely pathogenic

SpliceAI

5866 predictions. Top by Δscore:

Variant	Effect	Δscore
1:196228336:C:CC	acceptor_gain	1.0000
1:196235984:A:AC	donor_gain	1.0000
1:196235985:C:CC	donor_gain	1.0000
1:196235985:CA:C	donor_gain	1.0000
1:196235985:CACA:C	donor_gain	1.0000
1:196235985:CACAA:C	donor_gain	1.0000
1:196236068:CAT:C	acceptor_gain	1.0000
1:196236071:C:CC	acceptor_gain	1.0000
1:196258495:C:CC	acceptor_gain	1.0000
1:196273467:C:CC	donor_gain	1.0000
1:196280887:AGT:A	donor_gain	1.0000
1:196282271:A:AC	donor_gain	1.0000
1:196282272:C:CC	donor_gain	1.0000
1:196282272:CAGA:C	donor_gain	1.0000
1:196282272:CAGAA:C	donor_gain	1.0000
1:196282288:AGAT:A	donor_gain	1.0000
1:196282291:T:TA	donor_gain	1.0000
1:196282354:TGA:T	acceptor_gain	1.0000
1:196282357:C:CC	acceptor_gain	1.0000
1:196315888:TTACC:T	donor_loss	1.0000
1:196315889:TAC:T	donor_loss	1.0000
1:196315890:A:AC	donor_gain	1.0000
1:196315890:AC:A	donor_gain	1.0000
1:196315890:ACCTG:A	donor_loss	1.0000
1:196315891:C:A	donor_loss	1.0000
1:196315891:C:CA	donor_gain	1.0000
1:196315891:CC:C	donor_gain	1.0000
1:196315891:CCT:C	donor_gain	1.0000
1:196315891:CCTG:C	donor_gain	1.0000
1:196315891:CCTGA:C	donor_gain	1.0000

AlphaMissense

7503 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:196305279:G:C	F850L	1.000
1:196305279:G:T	F850L	1.000
1:196305280:A:G	F850S	1.000
1:196305281:A:G	F850L	1.000
1:196305288:G:C	F847L	1.000
1:196305288:G:T	F847L	1.000
1:196305289:A:G	F847S	1.000
1:196305290:A:G	F847L	1.000
1:196305313:A:G	L839P	1.000
1:196326732:A:G	L754P	1.000
1:196326825:A:T	V723D	1.000
1:196398647:A:G	W404R	1.000
1:196398647:A:T	W404R	1.000
1:196429666:C:G	G244R	1.000
1:196465305:A:G	L209P	1.000
1:196465309:A:G	C208R	1.000
1:196467735:A:G	W171R	1.000
1:196467735:A:T	W171R	1.000
1:196258228:T:A	R1059S	0.999
1:196258228:T:G	R1059S	0.999
1:196258229:C:A	R1059I	0.999
1:196258241:A:G	L1055P	0.999
1:196280900:C:T	G957E	0.999
1:196280906:G:T	P955H	0.999
1:196280942:A:G	L943P	0.999
1:196282286:C:T	G923E	0.999
1:196282287:C:A	G923W	0.999
1:196282319:A:G	L912P	0.999
1:196285687:G:C	S889R	0.999
1:196285687:G:T	S889R	0.999

dbSNP variants (sampled 300 via entrez): RS1000005930 (1:196565891 A>C), RS1000006988 (1:196480114 G>A), RS1000008455 (1:196457747 C>T), RS1000016505 (1:196295569 T>G), RS1000016775 (1:196367770 A>G,T), RS1000017173 (1:196580751 G>T), RS1000022451 (1:196392769 T>C), RS1000038451 (1:196565629 T>C), RS1000044093 (1:196248036 T>C), RS1000053798 (1:196538248 C>T), RS1000060053 (1:196373908 G>A), RS1000067105 (1:196325542 A>G), RS1000068668 (1:196411627 T>C), RS1000074713 (1:196416709 A>G,T), RS1000080345 (1:196318941 T>A,C)

Disease associations

OMIM: gene MIM:610044 | disease phenotypes: MIM:617771

GenCC curated gene-disease

Disease	Classification	Inheritance
developmental and epileptic encephalopathy, 57	Strong	Autosomal dominant

Mondo (1): developmental and epileptic encephalopathy, 57 (MONDO:0033366)

Orphanet (0):

HPO phenotypes

18 total (18 of 18 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0002079	Hypoplasia of the corpus callosum
HP:0002123	Generalized myoclonic seizure
HP:0002376	Developmental regression
HP:0002521	Hypsarrhythmia
HP:0003593	Infantile onset
HP:0003623	Neonatal onset
HP:0007270	Atypical absence seizure
HP:0011097	Epileptic spasm
HP:0012736	Profound global developmental delay
HP:0025401	Staring gaze
HP:0032792	Tonic seizure
HP:0033725	Thin corpus callosum
HP:0034295	Reduced cerebral white matter volume
HP:0200134	Epileptic encephalopathy

GWAS associations

15 associations (top):

Study	Trait	p-value
GCST000898_3	Total ventricular volume	2.000000e-06
GCST001899_1	Age-related macular degeneration	1.000000e-16
GCST001986_1	Age-related macular degeneration	1.000000e-31
GCST001987_2	Age-related macular degeneration (extreme sampling)	9.000000e-24
GCST003262_334	Post bronchodilator FEV1	4.000000e-06
GCST003992_37	Photic sneeze reflex	1.000000e-18
GCST004749_54	Lung cancer in ever smokers	3.000000e-06
GCST005588_12	Idiopathic dilated cardiomyopathy	9.000000e-06
GCST006575_1	Takayasu arteritis	3.000000e-07
GCST007576_312	Chronotype	1.000000e-07
GCST007576_99	Chronotype	8.000000e-11
GCST010988_265	Adult body size	2.000000e-09
GCST010989_189	Body size at age 10	4.000000e-08
GCST012049_4	High density lipoprotein cholesterol levels	1.000000e-06
GCST90020027_1925	Waist-hip index	1.000000e-09

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0004314	forced expiratory volume
EFO:0007887	autosomal dominant compelling helio-ophthalmic outburst syndrome
EFO:0009094	idiopathic dilated cardiomyopathy
EFO:0008328	chronotype measurement
EFO:0009819	comparative body size at age 10, self-reported
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0007788	BMI-adjusted waist-hip ratio

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4739693 (SINGLE PROTEIN)

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs1886629	Toxicity	3	Bisphosphonates	Osteonecrosis

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1886629	KCNT2	3	0.00	1	Bisphosphonates

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 (6 total), top 6:

Ligand	Action	Affinity	Parameter
flufenamic acid	Agonist	8.85	pEC50
niflumic acid	Agonist	8.68	pEC50
phorbol 12-myristate 13-acetate	Inhibition	7.92	pIC50
CPK20	Channel blocker	5.9	pIC50
compound 43 [PMID: 37812884]	Channel blocker	5.64	pIC50
Ba2+	Inhibition	3.0	pIC50

ChEMBL bioactivities

4 potent at pChembl≥5 of 5 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.90	IC50	1270	nM	CHEMBL4476393
5.64	IC50	2300	nM	CHEMBL5420347
5.39	IC50	4100	nM	CHEMBL5220721
5.23	IC50	5900	nM	CHEMBL5394681

PubChem BioAssay actives

4 with measured affinity, of 40 total; 4 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
N-[1-[[2,4-bis(trifluoromethyl)phenyl]methyl]-2,3-dihydroindol-5-yl]cyclohexanesulfonamide	2077334: Inhibition of human KCNT2 expressed in HEK cells at +60 mV holding potential by whole-cell patch clamp electrophysiology method	ic50	1.2700	uM
5-[1-(2-ethoxyphenyl)sulfonylazetidin-3-yl]-3-(4-fluorophenyl)-1,2,4-oxadiazole	2036725: Inhibition of SLICK (unknown origin) expressed in HEK293 cells by thallium flux assay	ic50	2.3000	uM
N-[2-methoxy-5-(trifluoromethyl)phenyl]-2-[4-(4-methylpiperidin-1-yl)sulfonylpiperazin-1-yl]acetamide	1917579: Inhibition of Slick (unknown origin) expressed in HEK293 cells measured by thallium flux assay	ic50	4.1000	uM
3-(4-fluorophenyl)-5-(1-quinolin-8-ylsulfonylazetidin-3-yl)-1,2,4-oxadiazole	2036725: Inhibition of SLICK (unknown origin) expressed in HEK293 cells by thallium flux assay	ic50	5.9000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, decreases methylation, increases expression	9
sodium arsenite	increases expression	2
perfluorooctane sulfonic acid	decreases expression, increases expression	2
entinostat	decreases expression, affects cotreatment	2
aristolochic acid I	decreases expression	1
methyleugenol	decreases expression	1
bisphenol A	increases methylation	1
trichostatin A	increases expression	1
arsenite	increases methylation	1
mono-(2-ethylhexyl)phthalate	decreases expression	1
butyraldehyde	decreases expression	1
CGP 52608	affects binding, increases reaction	1
bazedoxifene	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	increases expression	1
Grape Seed Proanthocyanidins	increases expression, affects cotreatment	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	decreases methylation	1
NSC 689534	affects binding, decreases expression	1
Sunitinib	increases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	decreases expression	1
Arsenicals	increases methylation	1
Benzo(a)pyrene	affects methylation	1
Calcitriol	increases expression	1
Catechin	affects cotreatment, increases expression	1
Copper	affects binding, decreases expression	1
Oxygen	increases expression	1
Progesterone	increases expression	1
Dronabinol	increases expression	1

ChEMBL screening assays

7 unique, capped per target: 7 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4714794	Binding	Inhibition of KCNT2 (unknown origin) by patch clamp analysis	Discovery of the First Orally Available, Selective K1.1 Inhibitor: In Vitro and In Vivo Activity of an Oxadiazole Series. — ACS Med Chem Lett

Clinical trials (associated diseases)

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