KCNS1

Chr 20

potassium voltage-gated channel modifier subfamily S member 1

Also known as: Kv9.1, hKv9.1

NCBI Gene: 3787 ENSG00000124134 UniProt: Q96KK3

The KCNS1 protein is a regulatory subunit that modulates the activity of KCNB1 and KCNB2 voltage-gated potassium channels by altering their kinetics and voltage dependencies, playing a critical role in controlling neuronal excitability. Mutations in KCNS1 cause epileptic encephalopathy with onset typically in infancy or early childhood, inherited in an autosomal dominant pattern. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.67), reflecting its important role in normal brain function.

ResearchSummary from RefSeq, UniProt

Voltage-gated potassium channels form the largest and most diversified class of ion channels and are present in both excitable and nonexcitable cells. Their main functions are associated with the regulation of the resting membrane potential and the control of the shape and frequency of action potentials. The alpha subunits are of 2 types: those that are functional by themselves and those that are electrically silent but capable of modulating the activity of specific functional alpha subunits. The protein encoded by this gene is not functional by itself but can form heteromultimers with member 1 and with member 2 (and possibly other members) of the Shab-related subfamily of potassium voltage-gated channel proteins. This gene belongs to the S subfamily of the potassium channel family. [provided by RefSeq, Jul 2008]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.67

Clinical Summary— KCNS1

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.29) despite low pLI — interpret in context.

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ClinVar Variants

71 VUS of 86 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

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.67LOEUF

pLI 0.112

Z-score 2.42

OE 0.29 (0.14–0.67)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.66Z-score

OE missense 0.74 (0.66–0.82)

237 obs / 320.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.29 (0.14–0.67)

0≤0.351.4

Missense OE?0.74 (0.66–0.82)

0≤0.61.4

Synonymous OE?0.74

0≤1.21.6

LoF obs/exp: 4 / 13.7Missense obs/exp: 237 / 320.8Syn Z: 2.42

This gene — mechanism propensity

0.80top 10%

GOF

0.90top 5%

LOF

0.2091th %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

VUS71

Likely Benign7

Benign4

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	71	0	71
Likely Benign	7	0	7
Benign	3	1	4
Total	81	1	82

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

View in ClinVar →

10 pathogenic / likely-pathogenic (of 11) ClinVar copy-number / structural variants overlap KCNS1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →