KCNG1

Chr 20

potassium voltage-gated channel modifier subfamily G member 1

Also known as: K13, KCNG, KV6.1, kH2

NCBI Gene: 3755 ENSG00000026559 UniProt: Q9UIX4 OMIM: 603788

This gene encodes a regulatory alpha-subunit of voltage-gated potassium channels that modulates channel gating kinetics when coassembled with KCNB1 or KCNB2, but does not form functional channels independently. Mutations in KCNG1 cause autosomal recessive spinocerebellar ataxia type 13, a neurodegenerative disorder affecting coordination and movement. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.753), and inheritance follows an autosomal recessive pattern.

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 gene is abundantly expressed in skeletal muscle. Multiple alternatively spliced transcript variants have been found in normal and cancerous tissues. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.75

Clinical Summary— KCNG1

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Population Constraint (gnomAD)

Low constraint (pLI 0.03) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

38 VUS of 40 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Missense constrained — critical functional residues

LoF Constraint?

0.75LOEUF

pLI 0.026

Z-score 2.22

OE 0.36 (0.19–0.75)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

4.28Z-score

OE missense 0.38 (0.33–0.43)

141 obs / 374.0 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.36 (0.19–0.75)

0≤0.351.4

Missense OE?0.38 (0.33–0.43)

0≤0.61.4

Synonymous OE?0.84

0≤1.21.6

LoF obs/exp: 5 / 14.0Missense obs/exp: 141 / 374.0Syn Z: 1.72

This gene — mechanism propensity

0.80top 10%

GOF

0.87top 5%

LOF

0.2091th %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

40 submitted variants in ClinVar

ClinVar

Classification Summary

VUS38

Likely Benign1

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	38	38
Likely Benign	1	1
Benign	0	0
Total	39	39

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

View in ClinVar →

13 pathogenic / likely-pathogenic (of 15) ClinVar copy-number / structural variants overlap KCNG1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →