KCND2

Chr 7

potassium voltage-gated channel subfamily D member 2

Also known as: KV4.2, RK5

NCBI Gene: 3751 ENSG00000184408 UniProt: Q9NZV8 OMIM: 605410

The protein forms voltage-gated potassium channels that regulate neuronal excitability by mediating A-type potassium currents, particularly important for controlling action potential firing patterns and back-propagation in brain neurons. Mutations cause autosomal dominant epileptic encephalopathy, early infantile, and seizures, benign familial infantile, affecting neuronal excitability and seizure threshold. This gene shows moderate constraint against loss-of-function variants (LOEUF 0.574) and has an established GeneReviews entry indicating clinical significance.

OMIM ResearchSummary from RefSeq, UniProt

Voltage-gated potassium (Kv) channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. Four sequence-related potassium channel genes - shaker, shaw, shab, and shal - have been identified in Drosophila, and each has been shown to have human homolog(s). This gene encodes a member of the potassium channel, voltage-gated, shal-related subfamily, members of which form voltage-activated A-type potassium ion channels and are prominent in the repolarization phase of the action potential. This member mediates a rapidly inactivating, A-type outward potassium current which is not under the control of the N terminus as it is in Shaker channels. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.57

Clinical Summary— KCND2

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Gene-Disease Validity (ClinGen)

KCND2-related neurodevelopmental disorder with or without seizures · ADModerate

Moderate evidence — consider for supplementary testing

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.32) despite low pLI — interpret in context.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Missense constrained — critical functional residues

LoF Constraint?

0.57LOEUF

pLI 0.012

Z-score 3.17

OE 0.32 (0.19–0.57)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

3.51Z-score

OE missense 0.49 (0.44–0.56)

189 obs / 382.3 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.32 (0.19–0.57)

0≤0.351.4

Missense OE?0.49 (0.44–0.56)

0≤0.61.4

Synonymous OE?0.95

0≤1.21.6

LoF obs/exp: 8 / 25.1Missense obs/exp: 189 / 382.3Syn Z: 0.45

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

moderateKCND2-related neurodevelopmental disorder with or without seizuresOTHERAD

This gene — mechanism propensity

0.81top 10%

GOF

0.82top 10%

LOF

0.2775th %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

DNprediction above median

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.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.