KCNA2

Chr 1AD

potassium voltage-gated channel subfamily A member 2

ENSG00000177301 UniProt: P16389 OMIM: 176262

The protein forms voltage-gated potassium channels that allow neurons to repolarize following action potentials by functioning as delayed rectifiers. Mutations cause developmental and epileptic encephalopathy 32 through an autosomal dominant inheritance pattern, predominantly through gain-of-function mechanisms that disrupt normal neuronal excitability. The gene shows high constraint against loss-of-function variants, consistent with the importance of proper potassium channel dosage for neuronal function.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

GOF/LOFmechanismADLOEUF 0.381 OMIM phenotype

Clinical Summary— KCNA2

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Gene-Disease Validity (ClinGen)

developmental and epileptic encephalopathy · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.91). One damaged copy is likely sufficient to cause disease.

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

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GeneReview available — KCNA2

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint

0.38LOEUF

pLI 0.911

Z-score 3.32

OE 0.12 (0.05–0.38)

Highly constrained

More LoF-intolerant than ~75% of genes

Missense Constraint

3.83Z-score

OE missense 0.35 (0.30–0.42)

99 obs / 279.1 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios

LoF OE0.12 (0.05–0.38)

0≤0.351.4

Missense OE0.35 (0.30–0.42)

0≤0.61.4

Synonymous OE1.00

0≤1.21.6

LoF obs/exp: 2 / 16.6Missense obs/exp: 99 / 279.1Syn Z: -0.03

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveKCNA2-related epileptic encephalopathyGOFAD

definitiveKCNA2-related epileptic encephalopathyLOFAD

Mechanism Note (variant-dependent)

GOFLOF— mechanism depends on specific variant

Kv1.2 is tetrameric, but functional studies show mechanism is variant-specific. GOF variants cause DEE with increased current. LOF variants cause ataxia/ID with reduced current.

References:PMID:25656905

0.6357th %ile

GOF

0.78top 25%

LOF

0.4726th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function, dominant-negative and loss-of-function). 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

DNprediction above median · 1 literature citation

LOFLOEUF 0.38

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

DNRecently, de novo mutations in the gene KCNA2, causing either a dominant-negative loss-of-function or a gain-of-function of the voltage-gated K+ channel Kv1.2, were described to cause a new molecular entity within the epileptic encephalopathies.PMID:29050392

GOFThey carried mutations inducing a drastic gain-of-function effect leading to permanently open channels.PMID:25751627

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