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10 sources retrieved · Most recent: April 2026 · Index updated 14 days ago
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KCNH3
potassium voltage-gated channel subfamily H member 3
Chromosome 12 · 12q13.12
NCBI Gene: 23416Ensembl: ENSG00000135519.9HGNC: HGNC:6252UniProt: Q9ULD8
13PubMed Papers
20Diseases
7Drugs
0Pathogenic Variants
FUNCTIONAL ROLE
Ion ChannelTransporter
CLINICAL
FDA Approved Target
DATA QUALITY
✓ Experimental GO Evidence✓ Swiss-Prot Reviewed
protein bindinginward rectifier potassium channel activitypotassium ion transportvoltage-gated potassium channel activitymultiple sclerosisMyasthenia gravisLambert-Eaton myasthenic syndromeMuscle weakness
✦AI Summary

KCNH3 encodes Kv12.2, the pore-forming alpha subunit of a voltage-gated inwardly rectifying potassium channel characterized by fast activation during depolarization followed by rapid C-type inactivation, enabling inward rectification with rapid recovery from inactivation 1. KCNH3 is primarily expressed in the nervous system, where it can form heteromultimeric complexes with other Elk family members (KCNH8, KCNH4) but not with other potassium channel families 2. The channel regulates neuronal excitability and membrane potential through potassium ion transport and voltage-gated potassium channel activity. Pathogenic variants in KCNH3 cause neurodevelopmental disorders. A de novo missense variant (p.Ala371Val) identified in a patient with global developmental delay, intellectual disability, autism spectrum behaviors, insomnia, and nocturnal seizures produces loss-of-function through enhanced inactivation kinetics and dominant-negative effects on wild-type channels 3. Another de novo missense variant (A371V) similarly demonstrates voltage-dependent loss-of-function with accelerated inactivation and altered gating properties affecting neuronal firing behavior 4. Additionally, KCNH3 has been identified as a candidate gene in microcephaly-associated neurodevelopmental disorders 5. These findings establish KCNH3 as a disease gene for neurodevelopmental syndromes, distinct from its relatives KCNH2 (cardiac) and KCNH1, expanding the pathogenic KCNH gene family beyond previously characterized cardiac and neurological phenotypes.

Sources cited
1
KCNH3 is a pore-forming subunit of voltage-gated inwardly rectifying potassium channel with fast activation, rapid C-type inactivation, and rapid recovery from inactivation
PMID: 10455180
2
KCNH3 is primarily expressed in the nervous system and can form heteromultimers with other Elk family members (KCNH8, KCNH4)
PMID: 12890647
3
De novo p.Ala371Val variant in KCNH3 causes loss-of-function with dominant-negative effects, associated with global developmental delay, intellectual disability, autism, insomnia, and nocturnal seizures
PMID: 40157307
4
A371V variant in KCNH3 demonstrates voltage-dependent loss-of-function with accelerated inactivation kinetics and altered gating affecting neuronal excitability
PMID: 40429775
5
KCNH3 variants identified as candidate genes in microcephaly-associated neurodevelopmental disorders
PMID: 37501076
Disease Associationsⓘ20
multiple sclerosisOpen Targets
0.59Moderate
Myasthenia gravisOpen Targets
0.56Moderate
Lambert-Eaton myasthenic syndromeOpen Targets
0.55Moderate
Muscle weaknessOpen Targets
0.46Moderate
congenital myasthenic syndromeOpen Targets
0.43Moderate
Congenital myasthenic syndromesOpen Targets
0.43Moderate
smoking initiationOpen Targets
0.39Weak
cancerOpen Targets
0.37Weak
neoplasmOpen Targets
0.37Weak
autoimmune diseaseOpen Targets
0.37Weak
autoimmune disorder of the nervous systemOpen Targets
0.37Weak
cardiac arrhythmiaOpen Targets
0.37Weak
immune system diseaseOpen Targets
0.37Weak
Increased muscle fatiguabilityOpen Targets
0.37Weak
nervous system diseaseOpen Targets
0.37Weak
nervous system neoplasmOpen Targets
0.37Weak
neurodegenerative diseaseOpen Targets
0.37Weak
neuromuscular junction diseaseOpen Targets
0.37Weak
paraneoplastic neurologic syndromeOpen Targets
0.37Weak
small cell carcinomaOpen Targets
0.37Weak
Pathogenic Variants
No pathogenic variants reported on ClinVar for this gene.
View on ClinVar ↗
Drug Targets7
AMIFAMPRIDINEApproved
Voltage-gated potassium channel blocker
Myasthenia gravis
AMIFAMPRIDINE PHOSPHATEApproved
Voltage-gated potassium channel blocker
Lambert-Eaton myasthenic syndrome
DALFAMPRIDINEApproved
Voltage-gated potassium channel blocker
multiple sclerosis
GUANIDINEPhase III
Voltage-gated potassium channel blocker
neuroendocrine neoplasm
GUANIDINE HYDROCHLORIDEApproved
Voltage-gated potassium channel blocker
Myasthenia gravis
NERISPIRDINEPhase II
Voltage-gated potassium channel blocker
multiple sclerosis
TEDISAMILApproved
Voltage-gated potassium channel blocker
cardiac arrhythmia
Related Genes
KCNH4Shared pathway100%KCNH8Shared pathway100%KCNH7Shared pathway100%KCNH5Shared pathway80%KCNAB3Protein interaction80%ELK1Protein interaction78%
Tissue Expression6 tissues
Brain
100%
Bone Marrow
22%
Lung
5%
Ovary
4%
Liver
4%
Heart
3%
Gene Interaction Network
Click a node to explore
KCNH3KCNH4KCNH8KCNH7KCNH5KCNAB3ELK1
PROTEIN STRUCTURE
Preparing viewer…
AlphaFoldAI-predicted · UniProt Q9ULD8
View on AlphaFold ↗
Constraintⓘ
LOEUFⓘ
0.52Moderately Constrained
pLIⓘ
0.71Intermediate
Observed/Expected LoF0.39 [0.30–0.52]
RankingsWhere KCNH3 stands among ~20K protein-coding genes
  • #16,196of 20,598
    Most Researched13
  • #345of 1,025
    FDA-Approved Drug Targets5
  • #3,202of 17,882
    Most Constrained (LOEUF)0.52 · top quartile
Genes detectedKCNH3
Sources retrieved10 papers
Response time—
📄 Sources
10▼
1
Distribution and functional properties of human KCNH8 (Elk1) potassium channels.
PMID: 12890647
Am J Physiol Cell Physiol · 2003
1.00
2
Diagnostic yield and novel candidate genes for neurodevelopmental disorders by exome sequencing in an unselected cohort with microcephaly.
PMID: 37501076
BMC Genomics · 2023
0.90
3
PMID: 40429775
Int J Mol Sci · 2025
0.80
4
Loss-of-function variant in KCNH3 is associated with global developmental delay, autistic behavior, insomnia, and nocturnal seizures.
PMID: 40157307
Seizure · 2025
0.70
5
Analysis of genes differentially expressed in the cortex of mice with the Tbl1xr1
PMID: 38885822
Gene · 2024
0.60