KCNH6
Chr 17potassium voltage-gated channel subfamily H member 6
Also known as: ERG-2, ERG2, HERG2, Kv11.2, hERG-2
The protein forms the pore-forming alpha subunit of voltage-gated inwardly rectifying potassium channels that regulate neuronal excitability through unusual gating kinetics, producing small outward currents during depolarization and large inward currents during repolarization. Mutations cause neurodevelopmental disorder with seizures, microcephaly, and variable intellectual disability, inherited in an autosomal dominant pattern. The gene shows extremely low constraint against loss-of-function variants (pLI near zero), suggesting the associated disorder may not result from simple protein loss.
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Highly tolerant — LoF variants common in population
Tolerant to missense variation
This gene has evidence for multiple mechanisms of pathogenicity (gain-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.
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.
ClinVar Variant Classifications
210 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 | 10 | 0 | 10 |
Likely Pathogenic | 0 | 0 | 0 | 0 | 0 |
VUS | 0 | 184 | 1 | 0 | 185 |
Likely Benign | 0 | 9 | 0 | 2 | 11 |
Benign | 0 | 0 | 0 | 1 | 1 |
| Total | 0 | 193 | 11 | 3 | 207 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
KCNH6 · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
3D Protein StructureAlphaFold
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 →External Resources
Links to major genomics databases and tools