KCND3

Chr 1AD

potassium voltage-gated channel subfamily D member 3

Also known as: BRGDA9, KCND3L, KCND3S, KSHIVB, KV4.3, SCA19, SCA22

NCBI Gene: 3752 ENSG00000171385 UniProt: Q9UK17

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 includes two isoforms with different sizes, which are encoded by alternatively spliced transcript variants of this gene. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Brugada syndrome 9MIM #616399

Spinocerebellar ataxia 19MIM #607346

728

ClinVar variants

Pathogenic / LP

0.99

pLI score· haploinsufficient

Active trials

Clinical Summary— KCND3

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Gene-Disease Validity (ClinGen)

Brugada syndrome 1 · ADDisputed

Disputed — evidence questions this relationship

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.99). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

41 Pathogenic / Likely Pathogenic· 298 VUS of 728 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

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.

0.28LOEUF

pLI 0.990

Z-score 4.01

OE 0.09 (0.04–0.28)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

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.

3.85Z-score

OE missense 0.48 (0.43–0.54)

209 obs / 435.3 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.0.09 (0.04–0.28)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.48 (0.43–0.54)

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.0.95

0≤1.21.6

LoF obs/exp: 2 / 22.6Missense obs/exp: 209 / 435.3Syn Z: 0.55