KCNH4
Chr 17potassium voltage-gated channel subfamily H member 4
Also known as: BEC2, ELK1, Kv12.3
The protein forms the pore-forming alpha subunit of voltage-gated delayed rectifier potassium channels that regulate neuronal excitability in the neocortex and striatum. Mutations cause autosomal dominant epilepsy through a gain-of-function mechanism, where altered channel properties disrupt normal neuronal firing patterns. The gene is highly intolerant to loss-of-function variants, consistent with the pathogenic mechanism being gain-of-function rather than haploinsufficiency.
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Highly LoF-intolerant (top ~10% of genes)
Moderately missense-constrained (top ~2.5%)
This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.
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.
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
141 submitted variants in ClinVar
Classification Summary
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 0 | 0 | 6 | 0 | 6 |
Likely Pathogenic | 0 | 0 | 0 | 0 | 0 |
VUS | 1 | 121 | 1 | 0 | 123 |
Likely Benign | 0 | 3 | 0 | 3 | 6 |
Benign | 0 | 0 | 0 | 1 | 1 |
| Total | 1 | 124 | 7 | 4 | 136 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
KCNH4 · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
No active trials found for this gene.
Search ClinicalTrials.gov →No open access results found
External Resources
Links to major genomics databases and tools