KCNH4

Chr 17

potassium voltage-gated channel subfamily H member 4

Also known as: BEC2, ELK1, Kv12.3

NCBI Gene: 23415 ENSG00000089558 UniProt: Q9UQ05

The protein forms the pore-forming alpha subunit of voltage-gated delayed rectifier potassium channels that regulate neuronal excitability in the neocortex and striatum. Mutations cause autosomal dominant epilepsy through a gain-of-function mechanism, where altered channel properties disrupt normal neuronal firing patterns. The gene is highly intolerant to loss-of-function variants, consistent with the pathogenic mechanism being gain-of-function rather than haploinsufficiency.

ResearchSummary from RefSeq, UniProt, Mechanism

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. This gene encodes a member of the potassium channel, voltage-gated, subfamily H. This member is a pore-forming (alpha) subunit. The gene is brain-specific, and located in the neocortex and the striatum. It may be involved in cellular excitability of restricted neurons in the central nervous system. [provided by RefSeq, Jul 2008]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.21

Clinical Summary— KCNH4

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

122 VUS of 134 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.21LOEUF

pLI 1.000

Z-score 5.48

OE 0.09 (0.04–0.21)

Highly constrained

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

Missense Constraint?

2.94Z-score

OE missense 0.67 (0.62–0.73)

435 obs / 645.3 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.09 (0.04–0.21)

0≤0.351.4

Missense OE?0.67 (0.62–0.73)

0≤0.61.4

Synonymous OE?0.96

0≤1.21.6

LoF obs/exp: 4 / 42.6Missense obs/exp: 435 / 645.3Syn Z: 0.56

This gene — mechanism propensity

0.6064th %ile

GOF

0.77top 25%

LOF

0.58top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFLOEUF 0.21

GOFprediction 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. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

134 submitted variants in ClinVar

ClinVar

Classification Summary

VUS122

Likely Benign6

Benign1

122

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	1	121	0	122
Likely Benign	0	3	3	6
Benign	0	0	1	1
Total	1	124	4	129

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

View in ClinVar →

6 pathogenic / likely-pathogenic (of 7) ClinVar copy-number / structural variants overlap KCNH4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →