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: 3767 ENSG00000187486 UniProt: Q14654 OMIM: 600937

This protein forms an inward-rectifying potassium channel that associates with the sulfonylurea receptor to regulate insulin secretion in pancreatic beta cells. Mutations cause a spectrum of glucose homeostasis disorders including familial hyperinsulinemic hypoglycemia (autosomal recessive), transient and permanent neonatal diabetes mellitus, and maturity-onset diabetes of the young type 13 (autosomal dominant), with some forms of permanent neonatal diabetes presenting with neurologic features. Disease predominantly results from gain-of-function effects that disrupt normal channel regulation and insulin secretion control.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Diabetes mellitus, transient neonatal 3MIM #610582

Diabetes, permanent neonatal 2, with or without neurologic featuresMIM #618856

Hyperinsulinemic hypoglycemia, familial, 2MIM #601820

ADAR

Maturity-onset diabetes of the young, type 13MIM #616329

Clinical highlights

Gene–disease validity (ClinGen · GenCC)

Definitive · hyperinsulinemic hypoglycemia, familial, 2 · AR · ClinGen 2026
Definitive · monogenic diabetes · AD · ClinGen 2023
Definitive · diabetes mellitus, transient neonatal, 3 · AD · G2P
Definitive · autosomal dominant disease · AD · Natera

+11 more curated pairs

Interpreting a novel variant

Curated mechanisms (Gene2Phenotype) include both loss of function and gain of function. Which applies is variant-dependent — do not assume a null variant is, or isn’t, the pathogenic class without checking the specific variant.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

123

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.21

LOEUF

Multiple*

Mechanism· G2P

📖

GeneReview available — KCNJ11

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

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?

1.65Z-score

OE missense 0.71 (0.63–0.81)

186 obs / 260.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.53 (0.26–1.21)

0≤0.351.4

Missense OE?0.71 (0.63–0.81)

0≤0.61.4

Synonymous OE?0.90

0≤1.21.6

LoF obs/exp: 4 / 7.5Missense obs/exp: 186 / 260.9Syn Z: 0.81

Background carrier burden — how many people carry a rare variant somewhere in KCNJ11?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 190

413 rare PASS variants

Rare truncating (LoF)

1 in 5,700

42 rare PASS variants

Rare synonymous (reference)

1 in 150

216 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for KCNJ11. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 210	1 in 7,300
South Asian	~43k	1 in 190	1 in 7,000
Remaining (unassigned)	~30k	1 in 190	1 in 950
European (Finnish)	~27k	1 in 290	none seen
Admixed American	~22k	1 in 140	none seen
African / African American	~21k	1 in 110	1 in 2,200
East Asian	~20k	1 in 240	1 in 1,700
Ashkenazi Jewish	~13k	1 in 1,200	none seen
Middle Eastern	~2,884	1 in 120	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 1 coding exons well covered in gnomAD exomes and genomes.? see exons ↓