KCNA1

Chr 12AD

potassium voltage-gated channel subfamily A member 1

Also known as: AEMK, EA1, HBK1, HUK1, KV1.1, MBK1, MK1, RBK1

NCBI Gene: 3736ENSG00000111262UniProt: Q09470

This gene encodes a voltage-gated delayed potassium channel that is phylogenetically related to the Drosophila Shaker channel. The encoded protein has six putative transmembrane segments (S1-S6), and the loop between S5 and S6 forms the pore and contains the conserved selectivity filter motif (GYGD). The functional channel is a homotetramer. The N-terminus of the channel is associated with beta subunits that can modify the inactivation properties of the channel as well as affect expression levels. The C-terminus of the channel is complexed to a PDZ domain protein that is responsible for channel targeting. Mutations in this gene have been associated with myokymia with periodic ataxia (AEMK). [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Episodic ataxia/myokymia syndromeMIM #160120
AD
UniProtEpisodic ataxia 1
UniProtMyokymia isolated 1
699
ClinVar variants
78
Pathogenic / LP
0.08
pLI score
0
Active trials
Clinical Summary— KCNA1
🧬
Gene-Disease Validity (ClinGen)
episodic ataxia type 1 · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.32) despite low pLI — interpret in context.
📋
ClinVar Variants
78 Pathogenic / Likely Pathogenic· 394 VUS of 699 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Missense constrained — critical functional residues
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.
0.73LOEUF
pLI 0.076
Z-score 2.23
OE 0.32 (0.16–0.73)
Tolerant

Typical tolerance to LoF variation

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.
3.33Z-score
OE missense 0.47 (0.41–0.54)
148 obs / 313.8 exp
Constrained

Highly missense-constrained (top ~0.1%)

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.0.32 (0.16–0.73)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.47 (0.41–0.54)
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.1.10
0≤1.21.6
LoF obs/exp: 4 / 12.5Missense obs/exp: 148 / 313.8Syn Z: -0.95

ClinVar Variant Classifications

699 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic60
Likely Pathogenic18
VUS394
Likely Benign186
Benign28
Conflicting13
60
Pathogenic
18
Likely Pathogenic
394
VUS
186
Likely Benign
28
Benign
13
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
22
38
0
60
Likely Pathogenic
0
15
3
0
18
VUS
7
291
89
7
394
Likely Benign
0
3
9
174
186
Benign
0
1
22
5
28
Conflicting
—13
Total7332161186699

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

View in ClinVar →

Protein Context — Lollipop Plot

KCNA1 · protein map & ClinVar variants

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

Gene2Phenotype Curations

KCNA1-related epileptic encephalopathy

limited
ADUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

KCNA1-related epileptic encephalopathy

limited
ARUndeterminedAltered 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

Episodic ataxia/myokymia syndrome

MIM #160120

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — KCNA1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Episodic Ataxias: Primary and Secondary Etiologies, Treatment, and Classification Approaches.
Hassan A·Tremor Other Hyperkinet Mov (N Y)
2023Case report
The episodic ataxias.
Graves TD et al.·Handb Clin Neurol
2024Review
Episodic ataxias.
Jen JC et al.·Handb Clin Neurol
2018Review
Clinical Spectrum of KCNA1 Mutations: New Insights into Episodic Ataxia and Epilepsy Comorbidity.
Paulhus K et al.·Int J Mol Sci
2020Review
Both gain- and loss-of-function variants of KCNA1 are associated with paroxysmal kinesigenic dyskinesia.
Sun WB et al.·J Genet Genomics
2024
Novel Genetic Variants Expand the Functional, Molecular, and Pathological Diversity of KCNA1 Channelopathy.
Paulhus K et al.·Int J Mol Sci
2023Review
[Hereditary episodic ataxia].
Riant F et al.·Rev Neurol (Paris)
2011Review
[Episodic ataxias].
Herrmann A et al.·Tidsskr Nor Laegeforen
2005Review
Distinct epilepsy phenotypes and response to drugs in KCNA1 gain- and loss-of function variants.
Miceli F et al.·Epilepsia
2022
Episodic Ataxias: Faux or Real?
Giunti P et al.·Int J Mol Sci
2020Review
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