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: 3736 ENSG00000111262 UniProt: Q09470 OMIM: 176260

This protein forms a voltage-gated delayed rectifier potassium channel that controls neuronal excitability through tetrameric complexes in cell membranes. Mutations cause episodic ataxia with myokymia syndrome through an autosomal dominant inheritance pattern. The pathogenic mechanism involves gain-of-function effects that disrupt normal potassium channel activity.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.731 OMIM phenotype

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

44 unique Pathogenic / Likely Pathogenic· 433 VUS of 736 total submissions

Explore recent and relevant literature in Research Assistant →

📖

GeneReview available — KCNA1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Missense constrained — critical functional residues

LoF Constraint?

0.73LOEUF

pLI 0.076

Z-score 2.23

OE 0.32 (0.16–0.73)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

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?

LoF OE?0.32 (0.16–0.73)

0≤0.351.4

Missense OE?0.47 (0.41–0.54)

0≤0.61.4

Synonymous OE?1.10

0≤1.21.6

LoF obs/exp: 4 / 12.5Missense obs/exp: 148 / 313.8Syn Z: -0.95

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveKCNA1-related episodic ataxia with or without seizuresOTHERAD

limitedKCNA1-related epileptic encephalopathyOTHERAR

This gene — mechanism propensity

0.81top 10%

GOF

0.86top 5%

LOF

0.2289th %ile

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.

GOFprediction above median · 1 literature citation · 95% of P/LP are missense

DNprediction above median · 1 literature citation

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.

Literature Evidence

DNDominant-negative mutation p.Arg324Thr in KCNA1 impairs Kv1.1 channel function in episodic ataxia.1

GOFThe excellent clinical response to carbamazepine observed in the patients carrying the A261T variant suggests an exquisite sensitivity of KCNA1 GoF to sodium channel inhibition that should be further explored.2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

ClinVar Variant Classifications

736 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic25

Likely Pathogenic19

VUS433

Likely Benign198

Benign40

Conflicting20

Pathogenic

Likely Pathogenic

433

VUS

198

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	2	23	0	0	25
Likely Pathogenic	0	19	0	0	19
VUS	19	316	89	9	433
Likely Benign	0	3	16	179	198
Benign	0	1	34	5	40
Conflicting	—				20
Total	21	362	139	193	735

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

View in ClinVar →

56 pathogenic / likely-pathogenic (of 69) ClinVar copy-number / structural variants overlap KCNA1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →