KCNV1

Chr 8

potassium voltage-gated channel modifier subfamily V member 1

Also known as: HNKA, KCNB3, KV2.3, KV8.1

NCBI Gene: 27012 ENSG00000164794 UniProt: Q6PIU1

This protein is a voltage-gated potassium channel subunit that modulates the activity of other potassium channels (KCNB1, KCNB2, KCNC4, and KCND1) by altering their inactivation properties and potentially reducing their function by retaining them in intracellular membranes. Mutations cause autosomal dominant epilepsy, typically with infantile or early childhood onset. KCNV1 is highly constrained against loss-of-function variants (pLI = 0.98, LOEUF = 0.30), indicating that functional copies are essential for normal neurological development.

Summary from RefSeq, UniProt

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Active trials

Pubs (1 yr)

P/LP submissions

P/LP missense

0.29

LOEUF· LoF intol.

Multiple*

Mechanism· predicted

Clinical Summary— KCNV1

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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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ClinVar Variants

37 unique Pathogenic / Likely Pathogenic· 23 VUS of 66 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint

0.29LOEUF

pLI 0.978

Z-score 3.49

OE 0.06 (0.02–0.29)

Highly constrained

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

Missense Constraint

4.07Z-score

OE missense 0.33 (0.28–0.39)

95 obs / 289.9 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios

LoF OE0.06 (0.02–0.29)

0≤0.351.4

Missense OE0.33 (0.28–0.39)

0≤0.61.4

Synonymous OE1.08

0≤1.21.6

LoF obs/exp: 1 / 16.1Missense obs/exp: 95 / 289.9Syn Z: -0.66

0.5869th %ile

GOF

0.78top 25%

LOF

0.4233th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and loss-of-function). 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

LOFLOEUF 0.29

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.