KCNC3

Chr 19AD

potassium voltage-gated channel subfamily C member 3

Also known as: KSHIIID, KV3.3, SCA13

NCBI Gene: 3748 ENSG00000131398 UniProt: Q14003 OMIM: 176264

The protein forms a voltage-gated potassium channel that mediates rapid repolarization of fast-firing brain neurons, particularly regulating action potential frequency, shape and duration in Purkinje cells. Mutations cause spinocerebellar ataxia 13 through an autosomal dominant inheritance pattern. The pathogenic mechanism involves gain-of-function mutations that disrupt normal neuronal excitability and cerebellar function.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

The Shaker gene family of Drosophila encodes components of voltage-gated potassium channels and is comprised of four subfamilies. Based on sequence similarity, this gene is similar to one of these subfamilies, namely the Shaw subfamily. The protein encoded by this gene belongs to the delayed rectifier class of channel proteins and is an integral membrane protein that mediates the voltage-dependent potassium ion permeability of excitable membranes. Alternate splicing results in several transcript variants. [provided by RefSeq, Mar 2014]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.591 OMIM phenotype

Clinical Summary— KCNC3

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Gene-Disease Validity (ClinGen)

spinocerebellar ataxia type 13 · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.26) despite low pLI — interpret in context.

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ClinVar Variants

11 unique Pathogenic / Likely Pathogenic· 262 VUS of 475 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — KCNC3

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.59LOEUF

pLI 0.206

Z-score 2.72

OE 0.26 (0.13–0.59)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

3.04Z-score

OE missense 0.57 (0.51–0.64)

224 obs / 393.8 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.26 (0.13–0.59)

0≤0.351.4

Missense OE?0.57 (0.51–0.64)

0≤0.61.4

Synonymous OE?1.03

0≤1.21.6

LoF obs/exp: 4 / 15.6Missense obs/exp: 224 / 393.8Syn Z: -0.28

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongKCNC3-related spinocerebellar ataxiaOTHERAD

This gene — mechanism propensity

0.7033th %ile

GOF

0.84top 5%

LOF

0.4332th %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 · 1 literature citation · 82% of P/LP are missense

DNprediction above median · 1 literature citation

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.

Literature Evidence

DNKCNC3(R420H), located in the voltage sensor of the channel, has no detectable channel activity when expressed alone, and strong dominant negative effects when coexpressed with wild-type KCNC31

GOFGain-of function or dominant-negative mutations in the voltage-gated potassium channel KCNC3 (Kv3.3) were recently identified as a cause of autosomal dominant spinocerebellar ataxia.2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

ClinVar Variant Classifications

475 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic6

Likely Pathogenic5

VUS262

Likely Benign163

Benign18

Conflicting17

Pathogenic

Likely Pathogenic

262

VUS

163

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	5	0	0	6
Likely Pathogenic	1	4	0	0	5
VUS	14	240	6	2	262
Likely Benign	0	18	23	122	163
Benign	0	2	10	6	18
Conflicting	—				17
Total	16	269	39	130	471

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

View in ClinVar →

13 pathogenic / likely-pathogenic (of 21) ClinVar copy-number / structural variants overlap KCNC3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →