KCNQ3

Chr 8AD

potassium voltage-gated channel subfamily Q member 3

NCBI Gene: 3786 ENSG00000184156 UniProt: O43525

Pore-forming subunit of the voltage-gated potassium (Kv) M-channel which is responsible for the M-current, a key controller of neuronal excitability (PubMed:16319223, PubMed:27564677, PubMed:28793216, PubMed:9872318). M-channel is composed of pore-forming subunits KCNQ2 and KCNQ3 assembled as heterotetramers (PubMed:14534157, PubMed:16319223, PubMed:27564677, PubMed:9872318). The native M-current has a slowly activating and deactivating potassium conductance which plays a critical role in determining the subthreshold electrical excitability of neurons as well as the responsiveness to synaptic inputs (PubMed:14534157, PubMed:16319223, PubMed:28793216). M-channel is selectively permeable in vitro to other cations besides potassium, in decreasing order of affinity K(+) > Rb(+) > Cs(+) > Na(+) (PubMed:28793216). M-channel association with SLC5A3/SMIT1 alters channel ion selectivity, increasing Na(+) and Cs(+) permeation relative to K(+) (PubMed:28793216). Suppressed by activation of M1 muscarinic acetylcholine receptors (PubMed:10713961). KCNQ3 also associates with KCNQ5 to form a functional channel in vitro and may also contribute to the M-current in brain (PubMed:11159685)

Primary Disease Associations & Inheritance

Seizures, benign neonatal, 2MIM #121201

UniProtSeizures, benign familial neonatal 2

591

ClinVar variants

Pathogenic / LP

0.80

pLI score

Active trials

Clinical Summary— KCNQ3

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Gene-Disease Validity (ClinGen)

complex neurodevelopmental disorder · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

3 total gene-disease associations curated

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.80) — some intolerance to loss-of-function variants.

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ClinVar Variants

21 Pathogenic / Likely Pathogenic· 344 VUS of 591 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

0.36LOEUF

pLI 0.801

Z-score 4.74

OE 0.20 (0.12–0.36)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

2.07Z-score

OE missense 0.73 (0.67–0.80)

350 obs / 477.1 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.20 (0.12–0.36)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.73 (0.67–0.80)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.96

0≤1.21.6

LoF obs/exp: 8 / 40.5Missense obs/exp: 350 / 477.1Syn Z: 0.41