KCNC1

Chr 11AD

potassium voltage-gated channel subfamily C member 1

Also known as: EPM7, KV3.1, KV4, NGK2

This gene encodes a voltage-gated potassium channel that controls potassium ion permeability across excitable cell membranes. Mutations cause progressive myoclonic epilepsy type 7, inherited in an autosomal dominant pattern. The high pLI score (0.99) and low LOEUF score (0.26) indicate the gene is highly intolerant to loss-of-function variants, suggesting haploinsufficiency as the likely pathogenic mechanism.

GeneReviewsOMIMResearchSummary from RefSeq, OMIM, UniProt
GOFmechanismADLOEUF 0.261 OMIM phenotype
Clinical SummaryKCNC1
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Gene-Disease Validity (ClinGen)
progressive myoclonus epilepsy · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.99). One damaged copy is likely sufficient to cause disease.
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GeneReview available — KCNC1
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

Dual constrained — LoF & missense intolerant
LoF Constraint
0.26LOEUF
pLI 0.990
Z-score 3.73
OE 0.06 (0.020.26)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint
4.52Z-score
OE missense 0.36 (0.310.41)
139 obs / 390.2 exp
Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios
LoF OE0.06 (0.020.26)
00.351.4
Missense OE0.36 (0.310.41)
00.61.4
Synonymous OE0.88
01.21.6
LoF obs/exp: 1 / 18.1Missense obs/exp: 139 / 390.2Syn Z: 1.28
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
definitiveKCNC1-related epilepsy, progressive myoclonicGOFAD
DN
0.5869th %ile
GOF
0.75top 25%
LOF
0.59top 25%

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function, loss-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median · 1 literature citation
LOFLOEUF 0.26
DN1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNFunctional analysis of the Arg320His mutant channel showed a dominant-negative loss-of-function effect.PMID:25401298
GOFA novel KCNC1 gain-of-function variant causing developmental and epileptic encephalopathy: Precision medicine approach with fluoxetine.PMID:37203213

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

0 submitted variants in ClinVar

Protein Context — Lollipop Plot

KCNC1 · protein map & ClinVar variants

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

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

No active trials found for this gene.

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Clinical Literature
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Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC