KCNH5

Chr 14AD

potassium voltage-gated channel subfamily H member 5

Also known as: DEE112, EAG2, H-EAG2, Kv10.2, hEAG2

NCBI Gene: 27133ENSG00000140015UniProt: Q8NCM2

This gene encodes a member of voltage-gated potassium channels. Members of this family have diverse functions, including regulating neurotransmitter and hormone release, cardiac function, and cell volume. This protein is an outward-rectifying, noninactivating channel. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

Primary Disease Associations & Inheritance

Developmental and epileptic encephalopathy 112MIM #620537
AD
573
ClinVar variants
22
Pathogenic / LP
0.02
pLI score
0
Active trials
Clinical Summary— KCNH5
🧬
Gene-Disease Validity (ClinGen)
infantile-onset epilepsy · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.27) despite low pLI — interpret in context.
📋
ClinVar Variants
22 Pathogenic / Likely Pathogenic· 313 VUS of 573 total submissions

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.
0.44LOEUF
pLI 0.020
Z-score 4.47
OE 0.27 (0.17–0.44)
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.
2.51Z-score
OE missense 0.70 (0.64–0.76)
390 obs / 556.6 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.0.27 (0.17–0.44)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.70 (0.64–0.76)
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.0.97
0≤1.21.6
LoF obs/exp: 12 / 44.0Missense obs/exp: 390 / 556.6Syn Z: 0.33

ClinVar Variant Classifications

573 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic16
Likely Pathogenic6
VUS313
Likely Benign209
Benign18
Conflicting11
16
Pathogenic
6
Likely Pathogenic
313
VUS
209
Likely Benign
18
Benign
11
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
4
12
0
16
Likely Pathogenic
0
4
2
0
6
VUS
13
273
23
4
313
Likely Benign
0
5
66
138
209
Benign
0
7
6
5
18
Conflicting
—11
Total13293109147573

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

View in ClinVar →

Protein Context — Lollipop Plot

KCNH5 · protein map & ClinVar variants

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

Gene2Phenotype Curations

KCNH5-related epilepsy and epileptic encephalopathy

strong
ADUndeterminedAbsent Gene Product, Altered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Developmental and epileptic encephalopathy 112

MIM #620537

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Neurodevelopmental and Epilepsy Phenotypes in Individuals With Missense Variants in the Voltage-Sensing and Pore Domains of KCNH5.
Happ HC et al.·Neurology
2023
Crosstalk of KCNH1 and KCNH5 gain-of-function mutations leading to epilepsy and neurodevelopmental disorders.
Bernert A et al.·Mol Brain
2026
A Novel De Novo Variant in KCNH5 in a Patient with Refractory Epileptic Encephalopathy.
Mitsutake A et al.·Intern Med
2025Case report
Potassium Channel Gain of Function in Epilepsy: An Unresolved Paradox.
Niday Z et al.·Neuroscientist
2018
Fentanyl blockade of K(+) channels contributes to wooden chest syndrome.
Wei AD et al.·J Physiol
2026
Exome sequencing reveals new causal mutations in children with epileptic encephalopathies.
Veeramah KR et al.·Epilepsia
2013
Cardiac Targeting Peptide, a Novel Cardiac Vector: Studies in Bio-Distribution, Imaging Application, and Mechanism of Transduction.
Zahid M et al.·Biomolecules
2018Functional
Impaired neuronal activity and differential gene expression in STXBP1 encephalopathy patient iPSC-derived GABAergic neurons.
Ichise E et al.·Hum Mol Genet
2021
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