KCNJ5

Chr 11AD

potassium inwardly rectifying channel subfamily J member 5

Also known as: CIR, GIRK4, KATP1, KIR3.4, LQT13

NCBI Gene: 3762 ENSG00000120457 UniProt: P48544 OMIM: 600734

This gene encodes an inward-rectifier potassium channel subunit that preferentially allows potassium influx and is regulated by G-proteins and extracellular potassium concentrations. Mutations cause autosomal dominant familial hyperaldosteronism type III and long QT syndrome 13, affecting adrenal hormone regulation and cardiac electrophysiology. The gene shows low constraint to loss-of-function variants (pLI 0.0003), suggesting that complete protein loss may be tolerated.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes an integral membrane protein which belongs to one of seven subfamilies of inward-rectifier potassium channel proteins called potassium channel subfamily J. The encoded protein is a subunit of the potassium channel which is homotetrameric. It is controlled by G-proteins and has a greater tendency to allow potassium to flow into a cell rather than out of a cell. Naturally occurring mutations in this gene are associated with aldosterone-producing adenomas. [provided by RefSeq, Aug 2017]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Hyperaldosteronism, familial, type IIIMIM #613677

Long QT syndrome 13MIM #613485

Clinical highlights

Gene–disease validity (ClinGen)

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.14

LOEUF

Multiple*

Mechanism· predicted

📖

GeneReview available — KCNJ5

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?

1.14LOEUF

pLI 0.000

Z-score 1.23

OE 0.61 (0.34–1.14)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

1.33Z-score

OE missense 0.76 (0.68–0.86)

190 obs / 249.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.61 (0.34–1.14)

0≤0.351.4

Missense OE?0.76 (0.68–0.86)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 7 / 11.5Missense obs/exp: 190 / 249.0Syn Z: -0.39

Background carrier burden — how many people carry a rare variant somewhere in KCNJ5?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 180

482 rare PASS variants

Rare truncating (LoF)

1 in 4,700

45 rare PASS variants

Rare synonymous (reference)

1 in 180

221 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for KCNJ5. 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 240	1 in 4,500
South Asian	~43k	1 in 120	1 in 5,400
Remaining (unassigned)	~30k	1 in 140	≈ 1 in 10,000
European (Finnish)	~27k	1 in 760	≈ 1 in 13,000
Admixed American	~22k	1 in 130	≈ 1 in 5,600
African / African American	~21k	1 in 150	≈ 1 in 6,400
East Asian	~20k	1 in 200	≈ 1 in 4,000
Ashkenazi Jewish	~13k	1 in 410	none seen
Middle Eastern	~2,884	1 in 180	≈ 1 in 2,900

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 2 coding exons well covered in gnomAD exomes and genomes.? see exons ↓