KCNG2

Chr 18

potassium voltage-gated channel modifier subfamily G member 2

Also known as: KCNF2, KV6.2

NCBI Gene: 26251 ENSG00000178342 UniProt: Q9UJ96 OMIM: 605696

The protein is a regulatory gamma subunit of voltage-gated potassium channels that modulates channel kinetics and voltage-dependent activation when coassembled with other subunits like KCNB1, contributing to cellular excitability regulation including cardiac action potential repolarization. Mutations in KCNG2 cause autosomal dominant epileptic encephalopathy with onset typically in early childhood. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.67), suggesting some intolerance to complete protein loss.

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 of the voltage-gated potassium channel. The delayed-rectifier type channels containing this subunit may contribute to cardiac action potential repolarization. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.67

Clinical Summary— KCNG2

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.60) — some intolerance to loss-of-function variants.

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ClinVar Variants

83 VUS of 89 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.67LOEUF

pLI 0.602

Z-score 2.13

OE 0.14 (0.05–0.67)

Moderately constrained

Typical tolerance to LoF variation

Missense Constraint?

1.75Z-score

OE missense 0.70 (0.62–0.79)

185 obs / 265.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.14 (0.05–0.67)

0≤0.351.4

Missense OE?0.70 (0.62–0.79)

0≤0.61.4

Synonymous OE?1.06

0≤1.21.6

LoF obs/exp: 1 / 7.1Missense obs/exp: 185 / 265.0Syn Z: -0.53

This gene — mechanism propensity

0.7133th %ile

GOF

0.89top 5%

LOF

0.3259th %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

89 submitted variants in ClinVar

ClinVar

Classification Summary

VUS83

Likely Benign4

VUS

Likely 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	83	0	83
Likely Benign	2	2	4
Benign	0	0	0
Total	85	2	87

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

View in ClinVar →

165 pathogenic / likely-pathogenic (of 194) ClinVar copy-number / structural variants overlap KCNG2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →