KCNC3

Chr 19AD

potassium voltage-gated channel subfamily C member 3

Also known as: KSHIIID, KV3.3, SCA13

NCBI Gene: 3748ENSG00000131398UniProt: Q14003

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]

Primary Disease Associations & Inheritance

Spinocerebellar ataxia 13MIM #605259
AD
489
ClinVar variants
24
Pathogenic / LP
0.21
pLI score
1
Active trials
Clinical Summary— KCNC3
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.26) despite low pLI — interpret in context.
📋
ClinVar Variants
24 Pathogenic / Likely Pathogenic· 264 VUS of 489 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
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?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.26 (0.13–0.59)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.57 (0.51–0.64)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.03
0≤1.21.6
LoF obs/exp: 4 / 15.6Missense obs/exp: 224 / 393.8Syn Z: -0.28

ClinVar Variant Classifications

489 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic17
Likely Pathogenic7
VUS264
Likely Benign158
Benign20
Conflicting17
17
Pathogenic
7
Likely Pathogenic
264
VUS
158
Likely Benign
20
Benign
17
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
5
11
0
17
Likely Pathogenic
0
4
3
0
7
VUS
10
228
24
2
264
Likely Benign
0
16
24
118
158
Benign
0
3
10
7
20
Conflicting
—17
Total1125672127483

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

View in ClinVar →

Protein Context — Lollipop Plot

KCNC3 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

KCNC3-related spinocerebellar ataxia

strong
ADUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Spinocerebellar ataxia 13

MIM #605259

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Extreme phenotypic heterogeneity in non-expansion spinocerebellar ataxias.
Cunha P et al.·Am J Hum Genet
2023
The natural history of progressive myoclonus ataxia.
van der Veen S et al.·Neurobiol Dis
2024Natural history
Diagnosis of hereditary ataxias: a real-world single center experience.
Meli A et al.·J Neurol
2025
KCNC3(R420H), a K(+) channel mutation causative in spinocerebellar ataxia 13 displays aberrant intracellular trafficking.
Gallego-Iradi C et al.·Neurobiol Dis
2014
Kv3.3 Expression Enhanced by a Novel Variant in the Kozak Sequence of KCNC3.
Reis MC et al.·Int J Mol Sci
2024Case report
Functional analysis helps to define KCNC3 mutational spectrum in Dutch ataxia cases.
Duarri A et al.·PLoS One
2015Cohort
A KCNC3 mutation causes a neurodevelopmental, non-progressive SCA13 subtype associated with dominant negative effects and aberrant EGFR trafficking.
Khare S et al.·PLoS One
2017
Negative Myoclonus: Neurophysiological Study and Clinical Impact in Progressive Myoclonus Ataxia.
Pollini L et al.·Mov Disord
2024
A novel early onset spinocerebellar ataxia 13 BAC mouse model with cerebellar atrophy, tremor, and ataxic gait.
Yin J et al.·Exp Anim
2025Functional
C-terminal proline deletions in KCNC3 cause delayed channel inactivation and an adult-onset progressive SCA13 with spasticity.
Khare S et al.·Cerebellum
2018Case report
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Rare DisordersUndiagnosed DisordersDisorders of Unknown Prevalence

Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford

RECRUITING
NCT01793168Sanford HealthStarted 2010-07

External Resources

Links to major genomics databases and tools