KCNA6

Chr 12

potassium voltage-gated channel subfamily A member 6

Also known as: HBK2, KV1.6, PPP1R96

NCBI Gene: 3742 ENSG00000151079 UniProt: P17658 OMIM: 176257

KCNA6 encodes a voltage-gated potassium channel that forms tetrameric channels regulating potassium transport and neuronal excitability in the nervous system. Mutations cause early infantile epileptic encephalopathy with developmental delay, seizures, and intellectual disability, following an autosomal dominant inheritance pattern. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.526), and the associated epileptic encephalopathy typically presents in infancy.

OMIM ResearchSummary from RefSeq, 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 delayed rectifier class. The coding region of this gene is intronless, and the gene is clustered with genes KCNA1 and KCNA5 on chromosome 12. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.53

Clinical Summary— KCNA6

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.20) despite low pLI — interpret in context.

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ClinVar Variants

3 unique Pathogenic / Likely Pathogenic· 76 VUS of 86 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.53LOEUF

pLI 0.497

Z-score 2.84

OE 0.20 (0.09–0.53)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

3.05Z-score

OE missense 0.53 (0.47–0.60)

180 obs / 337.6 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.20 (0.09–0.53)

0≤0.351.4

Missense OE?0.53 (0.47–0.60)

0≤0.61.4

Synonymous OE?0.97

0≤1.21.6

LoF obs/exp: 3 / 14.8Missense obs/exp: 180 / 337.6Syn Z: 0.32

This gene — mechanism propensity

0.74top 25%

GOF

0.82top 10%

LOF

0.3452th %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.

ClinVar Variant Classifications

86 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic2

Likely Pathogenic1

VUS76

Likely Benign2

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Total
Pathogenic	0	2	2
Likely Pathogenic	0	1	1
VUS	1	75	76
Likely Benign	0	2	2
Benign	0	0	0
Total	1	80	81

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

View in ClinVar →

58 pathogenic / likely-pathogenic (of 68) ClinVar copy-number / structural variants overlap KCNA6 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →