KCNT1

Chr 9AD

potassium sodium-activated channel subfamily T member 1

Also known as: DEE14, EIEE14, ENFL5, KCa4.1, KNa1.1, SLACK, Slo2.2, bA100C15.2

NCBI Gene: 57582ENSG00000107147UniProt: Q5JUK3

Potassium channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. This gene encodes a sodium-activated potassium channel subunit which is thought to function in ion conductance and developmental signaling pathways. Mutations in this gene cause the early-onset epileptic disorders, malignant migrating partial seizures of infancy and autosomal dominant nocturnal frontal lobe epilepsy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2012]

Primary Disease Associations & Inheritance

Developmental and epileptic encephalopathy 14MIM #614959
AD
Epilepsy nocturnal frontal lobe, 5MIM #615005
AD
UniProtEpilepsy, nocturnal frontal lobe, 5
593
ClinVar variants
32
Pathogenic / LP
0.00
pLI score
1
Active trials
Clinical Summary— KCNT1
🧬
Gene-Disease Validity (ClinGen)
childhood-onset epilepsy syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.32) despite low pLI — interpret in context.
📋
ClinVar Variants
32 Pathogenic / Likely Pathogenic· 339 VUS of 593 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
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.
0.47LOEUF
pLI 0.000
Z-score 4.92
OE 0.32 (0.23–0.47)
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.
2.86Z-score
OE missense 0.72 (0.67–0.77)
571 obs / 798.3 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

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.0.32 (0.23–0.47)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.72 (0.67–0.77)
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.1.25
0≤1.21.6
LoF obs/exp: 20 / 61.7Missense obs/exp: 571 / 798.3Syn Z: -3.71

ClinVar Variant Classifications

593 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic25
Likely Pathogenic7
VUS339
Likely Benign210
Benign9
Conflicting3
25
Pathogenic
7
Likely Pathogenic
339
VUS
210
Likely Benign
9
Benign
3
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
4
21
0
25
Likely Pathogenic
1
6
0
0
7
VUS
23
257
49
10
339
Likely Benign
2
4
104
100
210
Benign
0
0
9
0
9
Conflicting
—3
Total26271183110593

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

View in ClinVar →

Protein Context — Lollipop Plot

KCNT1 · protein map & ClinVar variants

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

Gene2Phenotype Curations

KCNT1-related epilepsy

definitive
ADUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

KCNT1-related malignant migrating partial seizures of infancy

definitive
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 14

MIM #614959

Molecular basis of disorder known

Autosomal dominant

Epilepsy nocturnal frontal lobe, 5

MIM #615005

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — KCNT1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
KCNT1-related epilepsies and epileptic encephalopathies: phenotypic and mutational spectrum.
Bonardi CM et al.·Brain
2021
Advances in epilepsy gene discovery and implications for epilepsy diagnosis and treatment.
Symonds JD et al.·Curr Opin Neurol
2017Review
Efficacy of anti-seizure medications and alternative therapies (ketogenic diet, CBD, and quinidine) in KCNT1-related epilepsy: A systematic review.
Gras M et al.·Epilepsia Open
2024Review
The Genetic Landscape of Epilepsy of Infancy with Migrating Focal Seizures.
Burgess R et al.·Ann Neurol
2019
Genetic determinants of global developmental delay and intellectual disability in Ukrainian children.
Shchubelka K et al.·J Neurodev Disord
2024
The epilepsy-autism phenotype associated with developmental and epileptic encephalopathies: New mechanism-based therapeutic options.
Specchio N et al.·Epilepsia
2025Review
KCNT1 gene variant-associated epilepsy: genetic insights, functional mechanisms, and emerging therapies.
Duan YZ et al.·J Neurol
2025Review
Rates of Status Epilepticus and Sudden Unexplained Death in Epilepsy in People With Genetic Developmental and Epileptic Encephalopathies.
Donnan AM et al.·Neurology
2023
Targeting K(Na)1.1 channels in KCNT1-associated epilepsy.
Cole BA et al.·Trends Pharmacol Sci
2021Review
Precision therapy with quinidine of KCNT1-related epileptic disorders: A systematic review.
Xu D et al.·Br J Clin Pharmacol
2022Review
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
Epilepsy

Precision Medicine in the Treatment of Epilepsy

RECRUITING
NCT05450822Gitte Moos KnudsenStarted 2022-02-18
LevetiracetamLevetiracetam TabletsLamotrigine tablet

External Resources

Links to major genomics databases and tools