KCNJ11

Chr 11ADAR

potassium inwardly rectifying channel subfamily J member 11

Also known as: BIR, HHF2, IKATP, KIR6.2, MODY13, PHHI, PNDM2, TNDM3

NCBI Gene: 3767ENSG00000187486UniProt: Q14654

Potassium channels are present in most mammalian cells, where they participate in a wide range of physiologic responses. The protein encoded by this gene is an integral membrane protein and inward-rectifier type potassium channel. The encoded protein, which has a greater tendency to allow potassium to flow into a cell rather than out of a cell, is controlled by G-proteins and is found associated with the sulfonylurea receptor SUR. Mutations in this gene are a cause of familial persistent hyperinsulinemic hypoglycemia of infancy (PHHI), an autosomal recessive disorder characterized by unregulated insulin secretion. Defects in this gene may also contribute to autosomal dominant non-insulin-dependent diabetes mellitus type II (NIDDM), transient neonatal diabetes mellitus type 3 (TNDM3), and permanent neonatal diabetes mellitus (PNDM). Multiple alternatively spliced transcript variants that encode different protein isoforms have been described for this gene. [provided by RefSeq, Oct 2009]

Primary Disease Associations & Inheritance

Diabetes mellitus, transient neonatal 3MIM #610582
AD
Diabetes, permanent neonatal 2, with or without neurologic featuresMIM #618856
AD
Hyperinsulinemic hypoglycemia, familial, 2MIM #601820
ADAR
Maturity-onset diabetes of the young, type 13MIM #616329
AD
562
ClinVar variants
82
Pathogenic / LP
0.01
pLI score
2
Active trials
Clinical Summary— KCNJ11
🧬
Gene-Disease Validity (ClinGen)
monogenic diabetes · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.01) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
82 Pathogenic / Likely Pathogenic· 254 VUS of 562 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.
1.21LOEUF
pLI 0.011
Z-score 1.20
OE 0.53 (0.26–1.21)
Tolerant

Highly tolerant — LoF variants common in population

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.
1.65Z-score
OE missense 0.71 (0.63–0.81)
186 obs / 260.9 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.0.53 (0.26–1.21)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.71 (0.63–0.81)
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.0.90
0≤1.21.6
LoF obs/exp: 4 / 7.5Missense obs/exp: 186 / 260.9Syn Z: 0.81

ClinVar Variant Classifications

562 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic36
Likely Pathogenic46
VUS254
Likely Benign105
Benign10
Conflicting111
36
Pathogenic
46
Likely Pathogenic
254
VUS
105
Likely Benign
10
Benign
111
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
7
13
16
0
36
Likely Pathogenic
12
30
4
0
46
VUS
5
186
54
9
254
Likely Benign
0
6
2
97
105
Benign
0
7
2
1
10
Conflicting
—111
Total2424278107562

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

View in ClinVar →

Protein Context — Lollipop Plot

KCNJ11 · protein map & ClinVar variants

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

Gene2Phenotype Curations

KCNJ11-related familial hyperinsulinism

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

KCNJ11-related diabetes mellitus, transient neonatal

definitive
ADGain Of FunctionAltered Gene Product Structure
Dev. Disorders
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Diabetes mellitus, transient neonatal 3

MIM #610582

Molecular basis of disorder known

Autosomal dominant

Diabetes, permanent neonatal 2, with or without neurologic features

MIM #618856

Molecular basis of disorder known

Autosomal dominant

Hyperinsulinemic hypoglycemia, familial, 2

MIM #601820

Molecular basis of disorder known

Autosomal dominantAutosomal recessive

Maturity-onset diabetes of the young, type 13

MIM #616329

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — KCNJ11
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Update of variants identified in the pancreatic β-cell K(ATP) channel genes KCNJ11 and ABCC8 in individuals with congenital hyperinsulinism and diabetes.
De Franco E et al.·Hum Mutat
2020Review
Genotype and phenotype correlations in 417 children with congenital hyperinsulinism.
Snider KE et al.·J Clin Endocrinol Metab
2013
Pathogenic variants in actionable MODY genes are associated with type 2 diabetes.
Bonnefond A et al.·Nat Metab
2020
Congenital Hyperinsulinism: Diagnosis and Treatment Update.
Demirbilek H et al.·J Clin Res Pediatr Endocrinol
2017Review
Exploring antidiabetic drug targets as potential disease-modifying agents in osteoarthritis.
Fu K et al.·EBioMedicine
2024
Clinical and molecular characterisation of 300 patients with congenital hyperinsulinism.
Kapoor RR et al.·Eur J Endocrinol
2013Cohort
Congenital hyperinsulinism: recent updates on molecular mechanisms, diagnosis and management.
Giri D et al.·J Pediatr Endocrinol Metab
2021Review
Statistical evidence for high-penetrance MODY-causing genes in a large population-based cohort.
Billings LK et al.·Endocrinol Diabetes Metab
2022Cohort
Congenital hyperinsulinism.
Hussain K·Semin Fetal Neonatal Med
2005Review
Genotype-histotype-phenotype correlations in hyperinsulinemic hypoglycemia.
Larsen AR et al.·Histol Histopathol
2024Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Morbid ObesityBariatric SurgeryTelerehabilitation

Exercise to Fight Obesity

RECRUITING
NCT06934681Phase NAInstituto de Investigacion Sanitaria La FeStarted 2025-05-19
Usual Care GroupControlled exercise with telerehabilitation
Neurodevelopmental DisordersIntellectual DisabilityDevelopment Delay

Impact of Sulphonylureas on Neurodevelopmental Outcomes in KCNJ11-related Intermediate Developmental Delay, Epilepsy and Neonatal Diabetes (iDEND) Syndrome

RECRUITING
NCT05751525Royal Devon and Exeter NHS Foundation TrustStarted 2016-07-01
Sulfonylurea

External Resources

Links to major genomics databases and tools