KCNT2

Chr 1AD

potassium sodium-activated channel subfamily T member 2

Also known as: DEE57, EIEE57, KCa4.2, KNa1.2, SLICK, SLO2.1

NCBI Gene: 343450ENSG00000162687UniProt: Q6UVM3

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. [provided by Alliance of Genome Resources, Jul 2025]

Primary Disease Associations & Inheritance

Developmental and epileptic encephalopathy 57MIM #617771
AD
317
ClinVar variants
38
Pathogenic / LP
0.04
pLI score
0
Active trials
Clinical Summary— KCNT2
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.25) despite low pLI — interpret in context.
📋
ClinVar Variants
38 Pathogenic / Likely Pathogenic· 231 VUS of 317 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Missense constrained — critical functional residues
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.37LOEUF
pLI 0.042
Z-score 5.74
OE 0.25 (0.17–0.37)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
3.56Z-score
OE missense 0.58 (0.53–0.64)
340 obs / 581.7 exp
Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.25 (0.17–0.37)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.58 (0.53–0.64)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.10
0≤1.21.6
LoF obs/exp: 17 / 68.1Missense obs/exp: 340 / 581.7Syn Z: -1.10

ClinVar Variant Classifications

317 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic23
Likely Pathogenic15
VUS231
Likely Benign39
Benign5
Conflicting4
23
Pathogenic
15
Likely Pathogenic
231
VUS
39
Likely Benign
5
Benign
4
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
3
19
0
23
Likely Pathogenic
5
5
5
0
15
VUS
10
195
24
2
231
Likely Benign
0
16
4
19
39
Benign
0
0
3
2
5
Conflicting
—4
Total162195523317

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

KCNT2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

KCNT2-related developmental and infantile epileptic encephalopathy

limited
ADGain Of FunctionAltered Gene Product Structure
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Developmental and epileptic encephalopathy 57

MIM #617771

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — KCNT2
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
KCNT2-Related Disorders: Phenotypes, Functional, and Pharmacological Properties.
Cioclu MC et al.·Ann Neurol
2023Functional
Genetics of epilepsy.
Nolan D et al.·Handb Clin Neurol
2018Review
Genetic associations of neuropathic pain and sensory profile in a deeply phenotyped neuropathy cohort.
Åkerlund M et al.·Pain
2025Cohort
Lhermitte-Duclos disease with concomitant KCNT2 gene mutation: report of an extremely rare combination.
Assi J et al.·Childs Nerv Syst
2023Case report
Recurrent KCNT2 missense variants affecting p.Arg190 result in a recognizable phenotype.
Jackson A et al.·Am J Med Genet A
2021Case report
In Silico Assisted Identification, Synthesis, and In Vitro Pharmacological Characterization of Potent and Selective Blockers of the Epilepsy-Associated KCNT1 Channel.
Iraci N et al.·J Med Chem
2024
New mutations in KCNT2 gene causing early infantile epileptic encephalopathy type 57: Case study and literature review.
Alagoz M et al.·Acta Biochim Pol
2020Review
Prediction of Lymph Node Metastasis in Non-Small Cell Lung Carcinoma Using Primary Tumor Somatic Mutation Data.
Lee V et al.·JCO Clin Cancer Inform
2025
Additional observation of a de novo pathogenic variant in KCNT2 leading to epileptic encephalopathy with clinical features of frontal lobe epilepsy.
Inuzuka LM et al.·Brain Dev
2020Case report
Genetic susceptibility to oral and atherosclerotic cardiovascular diseases based on dental and heart SCORE studies.
Bezamat M et al.·Sci Rep
2025
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools