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GeneE
10 sources retrieved · Most recent: April 2026 · Index updated 14 days ago
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KCNA4
potassium voltage-gated channel subfamily A member 4
Chromosome 11 · 11p14.1
NCBI Gene: 3739Ensembl: ENSG00000182255.8HGNC: HGNC:6222UniProt: P22459
62PubMed Papers
21Diseases
7Drugs
0Pathogenic Variants
FUNCTIONAL ROLE
Highly ConstrainedIon ChannelTransporter
CLINICAL
FDA Approved TargetOMIM Disease Gene
DATA QUALITY
✓ Experimental GO Evidence✓ Swiss-Prot Reviewed
protein bindingplasma membranevoltage-gated potassium channel complexpotassium ion transmembrane transportmultiple sclerosisMyasthenia gravisLambert-Eaton myasthenic syndromeMuscle weakness
✦AI Summary

KCNA4 encodes a voltage-gated potassium channel (Kv1.4) that mediates transmembrane potassium transport in excitable membranes by forming tetrameric channels that open in response to membrane depolarization and rapidly inactivate 12. The channel can assemble as homotetramers or heterotetramers with other Kv1 family members (KCNA1, KCNA2, KCNA5), with channel properties depending on subunit composition 1. KCNA4 is essential for regulating action potential duration in cardiac tissue 3. Expression is regulated post-transcriptionally, with miR-448 binding its 3'-untranslated region to suppress KCNA4 expression during ischemia, thereby modulating arrhythmic risk 3. Pathogenic variants in KCNA4 cause disease through loss-of-function mechanisms. De novo missense mutations (e.g., V558L in the selectivity filter/S6 hinge) cause early-onset developmental epileptic encephalopathy with severe reduction in channel current 4. An autosomal recessive missense variant (R89Q) associates with a syndrome characterized by congenital cataracts, abnormal striatum, intellectual disability, and attention deficit hyperactivity disorder, with KCNA4 expressed in brain, lens, and retina 5. Beyond neurological disease, KCNA4 variants show association with stimulant dependence in genome-wide studies 6 and endurance running performance 7, suggesting broader roles in neurological and metabolic function.

Sources cited
1
KCNA4 forms tetrameric potassium-selective channels with voltage-dependent gating and can assemble as homotetramers or heterotetramers with other Kv1 family members
PMID: 8495559
2
KCNA4 homotetrameric channels open in response to membrane depolarization followed by rapid spontaneous closure
PMID: 19912772
3
KCNA4 expression is regulated by miR-448 binding to its 3'-UTR; downregulation of KCNA4 occurs in ischemia and heart failure; KCNA4 regulates action potential duration in heart
PMID: 36693615
4
De novo missense KCNA4 variant (V558L) causes early-onset developmental epileptic encephalopathy through loss-of-function channel properties
PMID: 40472070
5
Autosomal recessive KCNA4 missense variant (R89Q) causes syndrome with congenital cataracts, abnormal striatum, intellectual disability, and ADHD; KCNA4 is expressed in brain, lens, and retina
PMID: 27582084
6
KCNA4 variants show suggestive association with stimulant dependence in genome-wide association study
PMID: 34226506
7
KCNA4 rs1323860 C allele associates with endurance running performance in Hispanic male marathon runners
PMID: 30812034
Disease Associationsⓘ21
multiple sclerosisOpen Targets
0.59Moderate
Myasthenia gravisOpen Targets
0.56Moderate
Lambert-Eaton myasthenic syndromeOpen Targets
0.55Moderate
Muscle weaknessOpen Targets
0.46Moderate
neurodegenerative diseaseOpen Targets
0.44Moderate
congenital myasthenic syndromeOpen Targets
0.43Moderate
Congenital myasthenic syndromesOpen Targets
0.43Moderate
refractive errorOpen Targets
0.40Moderate
alcohol drinkingOpen Targets
0.39Weak
cancerOpen Targets
0.37Weak
neoplasmOpen Targets
0.37Weak
cardiac arrhythmiaOpen Targets
0.37Weak
autoimmune diseaseOpen Targets
0.37Weak
autoimmune disorder of the nervous systemOpen Targets
0.37Weak
immune system diseaseOpen Targets
0.37Weak
Increased muscle fatiguabilityOpen Targets
0.37Weak
nervous system neoplasmOpen Targets
0.37Weak
neuromuscular diseaseOpen Targets
0.37Weak
neuromuscular junction diseaseOpen Targets
0.37Weak
small cell carcinomaOpen Targets
0.37Weak
Microcephaly, cataracts, impaired intellectual development, and dystonia with abnormal striatumUniProt
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
KCNAB1Protein interaction99%KCNAB2Protein interaction97%KCNA1Protein interaction96%KCNAB3Protein interaction94%FAUProtein interaction91%KCNH6Protein interaction88%
Tissue Expression6 tissues
Heart
100%
Brain
19%
Lung
4%
Bone Marrow
1%
Ovary
0%
Liver
0%
Gene Interaction Network
Click a node to explore
KCNA4KCNAB1KCNAB2KCNA1KCNAB3FAUKCNH6
PROTEIN STRUCTURE
Preparing viewer…
AlphaFoldAI-predicted · UniProt P22459
View on AlphaFold ↗
Constraintⓘ
LOEUFⓘ
0.27Highly Constrained
pLIⓘ
1.00Intolerant
Observed/Expected LoF0.13 [0.07–0.27]
RankingsWhere KCNA4 stands among ~20K protein-coding genes
  • #7,472of 20,598
    Most Researched62
  • #315of 1,025
    FDA-Approved Drug Targets5
  • #936of 17,882
    Most Constrained (LOEUF)0.27 · top 10%
Genes detectedKCNA4
Sources retrieved10 papers
Response time—
📄 Sources
10▼
1
Myasthenia gravis.
PMID: 31048702
Nat Rev Dis Primers · 2019
1.00
2
Genomic organization, nucleotide sequence, biophysical properties, and localization of the voltage-gated K+ channel gene KCNA4/Kv1.4 to mouse chromosome 2/human 11p14 and mapping of KCNC1/Kv3.1 to mouse 7/human 11p14.3-p15.2 and KCNA1/Kv1.1 to human 12p13.
PMID: 8020965
Genomics · 1994
0.90
3
De novo missense variants of KCNA3, KCNA4, and KCNA6 cause early onset developmental epileptic encephalopathy.
PMID: 40472070
Hum Mol Genet · 2025
0.80
4
miR-448 regulates potassium voltage-gated channel subfamily A member 4 (KCNA4) in ischemia and heart failure.
PMID: 36693615
Heart Rhythm · 2023
0.70
5
KCNA4 Gene Variant is Auxiliary in Endurance Running Performance Level.
PMID: 30812034
Int J Sports Med · 2019
0.60