KCNG4

Chr 16

potassium voltage-gated channel modifier subfamily G member 4

Also known as: KV6.3, KV6.4

NCBI Gene: 93107 ENSG00000168418 UniProt: Q8TDN1 OMIM: 607603

The KCNG4 protein functions as a regulatory subunit that modulates voltage-gated potassium channels by altering their activation, deactivation, and inactivation kinetics when coassembled with other channel subunits like KCNB1. Mutations in KCNG4 cause autosomal dominant spinocerebellar ataxia type 18, characterized by progressive cerebellar dysfunction. The gene shows autosomal dominant inheritance and has relatively low constraint to loss-of-function variation.

OMIM ResearchSummary from RefSeq, UniProt

Voltage-gated potassium (Kv) channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. This gene encodes a member of the potassium channel, voltage-gated, subfamily G. This member functions as a modulatory subunit. The gene has strong expression in brain. Multiple alternatively spliced variants have been found in normal and cancerous tissues. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.89

Clinical Summary— KCNG4

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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

122 VUS of 133 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?

1.89LOEUF

pLI 0.000

Z-score -1.49

OE 1.43 (1.00–1.89)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-1.66Z-score

OE missense 1.25 (1.16–1.35)

434 obs / 347.2 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.43 (1.00–1.89)

0≤0.351.4

Missense OE?1.25 (1.16–1.35)

0≤0.61.4

Synonymous OE?1.26

0≤1.21.6

LoF obs/exp: 20 / 14.0Missense obs/exp: 434 / 347.2Syn Z: -2.60

This gene — mechanism propensity

0.73top 25%

GOF

0.86top 5%

LOF

0.2872th %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

133 submitted variants in ClinVar

ClinVar

Classification Summary

VUS122

Likely Benign5

Benign5

122

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	122	0	122
Likely Benign	5	0	5
Benign	2	3	5
Total	129	3	132

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

View in ClinVar →

44 pathogenic / likely-pathogenic (of 71) ClinVar copy-number / structural variants overlap KCNG4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →