KCNG3

Chr 2

potassium voltage-gated channel modifier subfamily G member 3

Also known as: KV10.1, KV6.3

NCBI Gene: 170850 ENSG00000171126 OMIM: 606767

KCNG3 encodes a voltage-gated potassium channel gamma subunit that regulates neuronal excitability by modulating the kinetics and voltage-dependence of heterotetrameric potassium channels when coassembled with other subunits like KCNB1. Mutations in KCNG3 cause autosomal recessive spinocerebellar ataxia type 22, which presents with progressive cerebellar dysfunction. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.638), suggesting some tolerance to loss of function.

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 is a gamma subunit functioning as a modulatory molecule. Alternative splicing results in two transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.64

Clinical Summary— KCNG3

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.25) despite low pLI — interpret in context.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.64LOEUF

pLI 0.272

Z-score 2.43

OE 0.25 (0.11–0.64)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

2.32Z-score

OE missense 0.58 (0.50–0.67)

138 obs / 239.1 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.25 (0.11–0.64)

0≤0.351.4

Missense OE?0.58 (0.50–0.67)

0≤0.61.4

Synonymous OE?1.37

0≤1.21.6

LoF obs/exp: 3 / 12.2Missense obs/exp: 138 / 239.1Syn Z: -2.88

This gene — mechanism propensity

0.76top 25%

GOF

0.84top 5%

LOF

0.2871th %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.