KCNS2

Chr 8

potassium voltage-gated channel modifier subfamily S member 2

Also known as: KV9.2

NCBI Gene: 3788 ENSG00000156486 UniProt: Q9ULS6 OMIM: 602906

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.

OMIM ResearchSummary from RefSeq, UniProt

Predicted to enable potassium channel regulator activity. Predicted to be involved in action potential; potassium ion transmembrane transport; and regulation of potassium ion transmembrane transport. Predicted to be located in perinuclear region of cytoplasm and plasma membrane. Predicted to be part of voltage-gated potassium channel complex. Predicted to be active in membrane. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.77

Clinical Summary— KCNS2

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Population Constraint (gnomAD)

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

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ClinVar Variants

1 unique Pathogenic / Likely Pathogenic· 41 VUS of 48 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 OE?0.34 (0.17–0.77)

0≤0.351.4

Missense OE?0.72 (0.64–0.81)

0≤0.61.4

Synonymous OE?0.94

0≤1.21.6

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

This gene — mechanism propensity

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.

ClinVar Variant Classifications

48 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

VUS41

Likely Benign2

Benign2

Pathogenic

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	1	0	1
Likely Pathogenic	0	0	0	0
VUS	41	0	0	41
Likely Benign	1	0	1	2
Benign	1	0	1	2
Total	43	1	2	46

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

View in ClinVar →

33 pathogenic / likely-pathogenic (of 38) ClinVar copy-number / structural variants overlap KCNS2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →