KCNS2

Chr 8

potassium voltage-gated channel modifier subfamily S member 2

Also known as: KV9.2

NCBI Gene: 3788 ENSG00000156486 UniProt: Q9ULS6

The KCNS2 protein is a regulatory subunit that modulates delayed rectifier voltage-gated potassium channels by altering their kinetics and voltage dependencies, forming functional heterotetrameric channels with KCNB1 and KCNB2. Mutations cause autosomal dominant epileptic encephalopathy with onset typically in infancy or early childhood. The gene shows moderate tolerance to loss-of-function variants (LOEUF 0.77), suggesting some resilience to complete protein loss.

Summary from RefSeq, UniProt

Research Assistant →

Active trials

Pubs (1 yr)

P/LP submissions

P/LP missense

0.77

LOEUF

Multiple*

Mechanism· predicted

Clinical Summary— KCNS2

⚡

Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.34) despite low pLI — interpret in context.

📋

ClinVar Variants

34 unique Pathogenic / Likely Pathogenic· 46 VUS of 86 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint

0.77LOEUF

pLI 0.059

Z-score 2.11

OE 0.34 (0.17–0.77)

Tolerant

Typical tolerance to LoF variation

Missense Constraint

1.65Z-score

OE missense 0.72 (0.64–0.81)

203 obs / 280.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios

LoF OE0.34 (0.17–0.77)

0≤0.351.4

Missense OE0.72 (0.64–0.81)

0≤0.61.4

Synonymous OE0.94

0≤1.21.6

LoF obs/exp: 4 / 11.8Missense obs/exp: 203 / 280.6Syn Z: 0.55

0.79top 25%

GOF

0.88top 5%

LOF

0.2092th %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.