KCNC4

Chr 1

potassium voltage-gated channel subfamily C member 4

Also known as: C1orf30, HKSHIIIC, KSHIIIC, KV3.4

NCBI Gene: 3749 ENSG00000116396 UniProt: Q03721 OMIM: 176265

The protein is a voltage-gated potassium channel that opens in response to membrane voltage changes and displays rapid activation and inactivation kinetics, which is important for neuronal excitability. Mutations cause progressive sensorineural hearing loss and cerebellar ataxia, inherited in an autosomal dominant pattern. This gene is not highly constrained against loss-of-function variants, and a GeneReviews entry is available for detailed clinical guidance.

GeneReviews OMIM ResearchSummary from RefSeq, UniProt

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 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. It generates atypical voltage-dependent transient current that may be important for neuronal excitability. Multiple transcript variants have been found for this gene. [provided by RefSeq, Jul 2010]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.73

Clinical Summary— KCNC4

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

97 VUS of 118 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — KCNC4

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.73LOEUF

pLI 0.004

Z-score 2.40

OE 0.39 (0.22–0.73)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

2.06Z-score

OE missense 0.72 (0.65–0.79)

302 obs / 421.1 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.39 (0.22–0.73)

0≤0.351.4

Missense OE?0.72 (0.65–0.79)

0≤0.61.4

Synonymous OE?1.03

0≤1.21.6

LoF obs/exp: 7 / 18.0Missense obs/exp: 302 / 421.1Syn Z: -0.36

This gene — mechanism propensity

0.81top 10%

GOF

0.88top 5%

LOF

0.2679th %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

118 submitted variants in ClinVar

ClinVar

Classification Summary

VUS97

Likely Benign9

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	1	96	0	97
Likely Benign	0	7	2	9
Benign	0	0	0	0
Total	1	103	2	106

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

View in ClinVar →

16 pathogenic / likely-pathogenic (of 19) ClinVar copy-number / structural variants overlap KCNC4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →