KCNQ1

Chr 11ADAR

potassium voltage-gated channel subfamily Q member 1

NCBI Gene: 3784ENSG00000053918UniProt: P51787

Pore-forming subunit of the voltage-gated potassium (Kv) channel involved in the regulation of cardiomyocyte excitability and important in normal development and functions of myocardium, inner ear, stomach and colon (PubMed:10646604, PubMed:25441029). Associates with KCNE beta subunits that modulates current kinetics (PubMed:10646604, PubMed:11101505, PubMed:19687231, PubMed:8900283, PubMed:9108097, PubMed:9312006). Induces a voltage-dependent current by rapidly activating and slowly deactivating potassium-selective outward current (PubMed:10646604, PubMed:11101505, PubMed:25441029, PubMed:8900283, PubMed:9108097, PubMed:9312006). Also promotes a delayed voltage activated potassium current showing outward rectification characteristic (By similarity). During beta-adrenergic receptor stimulation, participates in cardiac repolarization by associating with KCNE1 to form the I(Ks) cardiac potassium current that increases the amplitude and slows down the activation kinetics of outward potassium current I(Ks) (By similarity) (PubMed:10646604, PubMed:11101505, PubMed:8900283, PubMed:9108097, PubMed:9312006). Muscarinic agonist oxotremorine-M strongly suppresses KCNQ1/KCNE1 current (PubMed:10713961). When associated with KCNE3, forms the potassium channel that is important for cyclic AMP-stimulated intestinal secretion of chloride ions (PubMed:10646604). This interaction with KCNE3 is reduced by 17beta-estradiol, resulting in the reduction of currents (By similarity). During conditions of increased substrate load, maintains the driving force for proximal tubular and intestinal sodium ions absorption, gastric acid secretion, and cAMP-induced jejunal chloride ions secretion (By similarity). Allows the provision of potassium ions to the luminal membrane of the secretory canaliculus in the resting state as well as during stimulated acid secretion (By similarity). When associated with KCNE2, forms a heterooligomer complex leading to currents with an apparently instantaneous activation, a rapid deactivation process and a linear current-voltage relationship and decreases the amplitude of the outward current (PubMed:11101505). When associated with KCNE4, inhibits voltage-gated potassium channel activity (PubMed:19687231). When associated with KCNE5, this complex only conducts current upon strong and continued depolarization (PubMed:12324418). Also forms a heterotetramer with KCNQ5; has a voltage-gated potassium channel activity (PubMed:24855057). Binds with phosphatidylinositol 4,5-bisphosphate (PubMed:25037568). KCNQ1-KCNE2 channel associates with Na(+)-coupled myo-inositol symporter in the apical membrane of choroid plexus epithelium and regulates the myo-inositol gradient between blood and cerebrospinal fluid with an impact on neuron excitability (By similarity)

Primary Disease Associations & Inheritance

{Long QT syndrome 1, acquired, susceptibility to}MIM #192500
AD
Atrial fibrillation, familial, 3MIM #607554
AD
Jervell and Lange-Nielsen syndromeMIM #220400
AR
Long QT syndrome 1MIM #192500
AD
Short QT syndrome 2MIM #609621
AD
UniProtType 2 diabetes mellitus
591
ClinVar variants
61
Pathogenic / LP
0.00
pLI score
2
Active trials
Clinical Summary— KCNQ1
🧬
Gene-Disease Validity (ClinGen)
Jervell and Lange-Nielsen syndrome · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

4 total gene-disease associations curated

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
61 Pathogenic / Likely Pathogenic· 181 VUS of 591 total submissions
💊
Clinical Trials
2 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
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.
0.81LOEUF
pLI 0.000
Z-score 2.37
OE 0.54 (0.37–0.81)
Tolerant

Typical tolerance to LoF variation

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.
1.83Z-score
OE missense 0.74 (0.67–0.82)
295 obs / 397.8 exp
Tolerant

Mild missense constraint

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.0.54 (0.37–0.81)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.74 (0.67–0.82)
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.1.17
0≤1.21.6
LoF obs/exp: 17 / 31.3Missense obs/exp: 295 / 397.8Syn Z: -1.73

ClinVar Variant Classifications

591 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic33
Likely Pathogenic28
VUS181
Likely Benign266
Benign78
Conflicting5
33
Pathogenic
28
Likely Pathogenic
181
VUS
266
Likely Benign
78
Benign
5
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
21
4
8
0
33
Likely Pathogenic
11
10
7
0
28
VUS
4
146
30
1
181
Likely Benign
1
3
176
86
266
Benign
0
2
75
1
78
Conflicting
—5
Total3716529688591

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

View in ClinVar →

Protein Context — Lollipop Plot

KCNQ1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

KCNQ1-related long QT syndrome

definitive
ARLoss Of FunctionAltered Gene Product Structure, Decreased Gene Product Level
Cardiac
G2P ↗
splice acceptor variantsplice donor variantframeshift variantstop gainedmissense variantinframe deletioninframe insertionstop gained NMD triggeringframeshift variant NMD triggering

KCNQ1-related long QT syndrome

definitive
ADLoss Of FunctionAltered Gene Product Structure, Decreased Gene Product Level
Cardiac
G2P ↗
splice acceptor variantsplice donor variantframeshift variantstop gainedmissense variantinframe deletioninframe insertionstop gained NMD triggeringframeshift variant NMD triggering

KCNQ1-related hypertrophic cardiomyopathy

disputed
ADUndeterminedUncertain
Cardiac
G2P ↗

KCNQ1-related short QT syndrome

strong
ADGain Of FunctionAltered Gene Product Structure
Cardiac
G2P ↗
missense variant

KCNQ1-related Jervell and Lange-Nielsen syndrome

definitive
ARLoss Of FunctionAbsent Gene Product, Altered Gene Product Structure
Dev. DisordersCardiacEar
G2P ↗
splice acceptor variantsplice donor variantframeshift variantstop gainedmissense variantstop gained NMD triggeringframeshift variant NMD triggering

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

{Long QT syndrome 1, acquired, susceptibility to}

MIM #192500

Molecular basis of disorder known

Autosomal dominant

Atrial fibrillation, familial, 3

MIM #607554

Molecular basis of disorder known

Autosomal dominant

Jervell and Lange-Nielsen syndrome

MIM #220400

Molecular basis of disorder known

Autosomal recessive

Long QT syndrome 1

MIM #192500

Molecular basis of disorder known

Autosomal dominant

Short QT syndrome 2

MIM #609621

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — KCNQ1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls.
Walsh R et al.·Genet Med
2021Cohort
Spectrum and prevalence of mutations from the first 2,500 consecutive unrelated patients referred for the FAMILION long QT syndrome genetic test.
Kapplinger JD et al.·Heart Rhythm
2009Cohort
Early-Onset Atrial Fibrillation and the Prevalence of Rare Variants in Cardiomyopathy and Arrhythmia Genes.
Yoneda ZT et al.·JAMA Cardiol
2021
An International, Multicentered, Evidence-Based Reappraisal of Genes Reported to Cause Congenital Long QT Syndrome.
Adler A et al.·Circulation
2020
Genetic testing for long-QT syndrome: distinguishing pathogenic mutations from benign variants.
Kapa S et al.·Circulation
2009
Structural and non-coding variants increase the diagnostic yield of clinical whole genome sequencing for rare diseases.
Pagnamenta AT et al.·Genome Med
2023
From Genotype to Phenotype.
Mackley M et al.·Circ Genom Precis Med
2018Review
Phylogenetic and physicochemical analyses enhance the classification of rare nonsynonymous single nucleotide variants in type 1 and 2 long-QT syndrome.
Giudicessi JR et al.·Circ Cardiovasc Genet
2012
Asymmetry of parental origin in long QT syndrome: preferential maternal transmission of KCNQ1 variants linked to channel dysfunction.
Itoh H et al.·Eur J Hum Genet
2016
Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing.
Tester DJ et al.·Heart Rhythm
2005Cohort
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Characterization of an induced pluripotent stem cell line from a long QT syndrome type 1 patient possessing the KCNQ1 c.691C > T (p.Arg231Cys) variant.
Choi J et al.·Stem Cell Res
2026
Generation of pluripotent stem cell line (IPWi001-A) and a corresponding CRISPR/Cas9 modified isogenic rescue control (IPWi001-A-1) from a patient with arrhythmia-induced cardiomyopathy harboring a KCNQ1 truncating mutation.
Anders M et al.·Stem Cell Res
2026
A mechanistic understanding of how KCNE1 tunes KCNQ1 channel pharmacology.
Judah Y et al.·Structure
2026
Integrated analysis and functional validation reveal KCNQ1 tumor suppressor targeting by dahuang Zhechong Pills via cuproptosis modulation in colorectal cancer.
Wang P et al.·Comput Biol Chem
2026Functional
High-throughput screening identifies a trafficking corrector for long QT syndrome-associated KCNQ1 variants.
Moster KRC et al.·JCI Insight
2026
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
PreDiabetes

Pharmacogenetics of the Response to GLP-1 in Mexican-Americans With Prediabetes

RECRUITING
NCT05119179Phase PHASE4The University of Texas Health Science Center, HoustonStarted 2021-11-22
Semaglutide
Type 2 Diabetes MellitusSusceptibility, Genetic

Association of Gene Polymorphism With Susceptibility to T2DM and the Therapeutic Responses to Exenatide in Chinese Patients With T2DM

RECRUITING
NCT06256419Phase NAThe Affiliated Hospital of Xuzhou Medical UniversityStarted 2024-01-01
GLP-1 receptor agonistresponders group and nonresponders group

External Resources

Links to major genomics databases and tools