KCNA4

Chr 11AR

potassium voltage-gated channel subfamily A member 4

Also known as: HBK4, HK1, HPCN2, HUKII, KCNA4L, KCNA8, KV1.4, MCIDDS

NCBI Gene: 3739 ENSG00000182255 UniProt: P22459 OMIM: 176266

KCNA4 encodes a voltage-gated potassium channel that mediates potassium transport in excitable membranes and can form homotetrameric or heterotetrameric channels with other KCNA family members. Autosomal recessive mutations cause a neurodevelopmental disorder characterized by microcephaly, cataracts, intellectual disability, and dystonia with striatal abnormalities. The gene is highly constrained against loss-of-function variants (pLI = 0.98, LOEUF = 0.28), indicating intolerance to functional disruption.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Potassium 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, shaker-related subfamily. This member contains six membrane-spanning domains with a shaker-type repeat in the fourth segment. It belongs to the A-type potassium current class, the members of which may be important in the regulation of the fast repolarizing phase of action potentials in heart and thus may influence the duration of cardiac action potential.[provided by RefSeq, Mar 2011]

OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 0.281 OMIM phenotype

Clinical Summary— KCNA4

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.98). One damaged copy is likely sufficient to cause disease.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.28LOEUF

pLI 0.983

Z-score 3.58

OE 0.06 (0.02–0.28)

Highly constrained

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

Missense Constraint?

2.03Z-score

OE missense 0.71 (0.64–0.78)

267 obs / 377.8 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.06 (0.02–0.28)

0≤0.351.4

Missense OE?0.71 (0.64–0.78)

0≤0.61.4

Synonymous OE?1.16

0≤1.21.6

LoF obs/exp: 1 / 16.9Missense obs/exp: 267 / 377.8Syn Z: -1.55

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedKCNA4-related abnormal striatum, congenital cataract and intellectual disabilityOTHERAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.5870th %ile

GOF

0.6736th %ile

LOF

0.57top 25%

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

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