KCNJ5
protein-codingpotassium inwardly rectifying channel subfamily J member 5, the group of Potassium inwardly rectifying channel subfamily J
Gene summary
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]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~29.8 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0013359
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0008222
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0013359
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0013279
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0013279
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0002442
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0013359
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0013359
Submitter: ClinGen
KCNJ5 was first reported in relation to autosomal dominant familial hyperaldosteronism in 2011 (Choi et al., PMID: 21311022). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found clear differences in molecular mechanisms and phenotypic variability. Therefore, the following disease entities have been split into multiple disease entities: hyperaldosteronism, familial, type III (OMIM: 613677) and long QT syndrome 13 (OMIM: 613485). The split curation for long QT syndrome 13 has been completed separately. 8 variants (all missense) that have been reported in at least 8 probands in 7 publications (PMID: 21311022, 22203740, 22308486, 22628607, 24420545, 24574546, 27403928) are included in this curation. The mutations are all located near the pore/selectivity filter of the potassium channel. The mechanism of pathogenicity appears to be gain-of-function, with increased sodium conductance associated with loss of channel permeability, which leads to increased levels of aldosterone. This gene-disease relationship is also supported by experimental evidence (somatic mutations in humans, biochemical functional evidence, and expression-level evidence; PMID: 21311022, 24037882; & GTEx expression data). The somatic mutations were counted in experimental evidence since they were not inherited and resemble a functional model in humans. GTEx expression-level evidence indicates very high expression in the adrenal gland. In summary, there is definitive evidence supporting the relationship between KCNJ5 and autosomal dominant familial hyperaldosteronism. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Tubulopathy GCEP on the meeting date 1/15/2026 (SOP Version 11).
Inheritance Pattern: AD
Disease ID:MONDO:0013359
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0002442
Submitter: ClinGen
KCNJ5 encodes an inward rectifying potassium channel. The gene is located within a 16 million base pair region (11q23.3-24.3) identified by linkage analysis in a large Chinese family with LQTS (PMID 20560207). The Gly387Arg variant identified in this family, however, is now recognized to be present in 1/200 individuals of East Asian descent, making it very unlikely to be a rare cause of a rare disease. Because there is very little other data supporting the association of KCNJ5 with LQTS, the level of evidence for this gene-disease association was classified as disputed. Note: All LQTS genes were curated by 3 separate blinded teams. The evidence and scores reached by these 3 teams were reviewed by the LQTS Clinical Domain Expert Panel. For a detailed discussion of this group's work and the separate scores of the 3 teams please see "Adler et al. An International, Multicentered, Evidence-Based Reappraisal of Genes Reported to Cause Congenital Long QT Syndrome. Circulation 2020;141(6):418-428. doi: 10.1161/CIRCULATIONAHA.119.043132”
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular; Endocrine
Intervention: Cardiovascular; Endocrine
Rationale: In Long QT syndrome, preventive measures and medical management may be helpful to help decrease morbidity; sudden death in infancy has been reported; In Hyperaldosteronism, familial, hypertension and aldosteronism are not reversed by administration of exogenous glucocorticoids and patients require adrenalectomy
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to KCNJ5 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000890.5. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 4 | 152 | 156 | |||
| missense | 5 | 3 | 228 | 32 | 1 | 269 |
| nonsense | 7 | 2 | 9 | |||
| start loss | 0 | |||||
| frameshift | 9 | 9 | ||||
| splice donor/acceptor (+/-2bp) | 1 | 1 | ||||
| Total | 5 | 3 | 249 | 186 | 1 | 444 |
Highest pathogenic variant AF is 0.000004800643
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000881.3 | 2 | MANE Select | |
| Ensembl | ENSP00000433295.1 | 2 | MANE Select | |
| RefSeq | NP_001341098.1 | 2 | Standard | |
| Ensembl | ENSP00000339960.4 | 2 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Aldosterone synthesis and secretion - Homo sapiens (human)
- Oxytocin signaling pathway - Homo sapiens (human)
- Retrograde endocannabinoid signaling - Homo sapiens (human)
- Serotonergic synapse - Homo sapiens (human)
- Dopaminergic synapse - Homo sapiens (human)
Biological Process
- potassium ion transport
- regulation of ion transmembrane transport
- regulation of heart rate by cardiac conduction
- membrane repolarization during atrial cardiac muscle cell action potential
- membrane repolarization during ventricular cardiac muscle cell action potential
Molecular Function
- inward rectifier potassium channel activity
- protein binding
- G-protein activated inward rectifier potassium channel activity
- voltage-gated potassium channel activity involved in atrial cardiac muscle cell action potential repolarization
- voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization
Cellular Component
- plasma membrane
- voltage-gated potassium channel complex
- external side of plasma membrane
- T-tubule
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000529694
- Coding exons
- 2
- Length
- 29680
- Individuals with no LoFs
- 125727
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 21
- Defined
- 125748
- p
- 0.0000835
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.33 | 190 | 249 | 0.763 | 0.0000162 | 2777 |
| Missense (PolyPhen) | 92 | 124.85 | 0.73686 | 1338 | ||
| Synonymous | -0.388 | 104 | 99.1 | 1.05 | 0.00000663 | 828 |
| Loss of Function | 1.23 | 7 | 11.5 | 0.608 | 6.93e-7 | 125 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0.00014 | 0.00014 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00011 | 0.00011 | rare |
| Finnish | 0.000093 | 0.000092 | rare |
| European (Non-Finnish) | 0.000062 | 0.000062 | rare |
| South Asian | 0.00013 | 0.00013 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: This potassium channel is controlled by G proteins. Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it. Their voltage dependence is regulated by the concentration of extracellular potassium; as external potassium is raised, the voltage range of the channel opening shifts to more positive voltages. The inward rectification is mainly due to the blockage of outward current by internal magnesium. Can be blocked by external barium. {ECO:0000269|PubMed:22315453, ECO:0000269|PubMed:22628607, ECO:0000269|PubMed:24037882, ECO:0000269|PubMed:27099398, ECO:0000269|PubMed:27293068}.;
- Disease
- DISEASE: Hyperaldosteronism, familial, 3 (HALD3) [MIM:613677]: A form of hyperaldosteronism characterized by hypertension secondary to massive adrenal mineralocorticoid production. HALD3 patients present with childhood hypertension, elevated aldosteronism levels, and high levels of the hybrid steroids 18-oxocortisol and 18-hydroxycortisol. Hypertension and aldosteronism are not reversed by administration of exogenous glucocorticoids and patients require adrenalectomy to control hypertension. {ECO:0000269|PubMed:21311022, ECO:0000269|PubMed:22203740, ECO:0000269|PubMed:22275527, ECO:0000269|PubMed:22308486, ECO:0000269|PubMed:22315453, ECO:0000269|PubMed:22628607, ECO:0000269|PubMed:22848660, ECO:0000269|PubMed:24037882, ECO:0000269|PubMed:27099398}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=Somatic mutations in KCNJ5 have been found in aldosterone-producing adrenal adenomas and can be responsible for aldosteronism associated with cell autonomous proliferation. APAs are typically solitary, well circumscribed tumors diagnosed between ages 30 and 70. They come to medical attention due to new or worsening hypertension, often with hypokalemia. The precise role of KCNJ5 mutations in APA is under debate. They produce increased sodium conductance and cell depolarization, which in adrenal glomerulosa cells produces calcium entry, the signal for aldosterone production and cell proliferation. However, they may not be causative of APA development but may be a consequence of tumorigenesis, playing only a contributory role toward aldosterone overproduction and tumor growth (PubMed:22275527). Somatic mutations in KCNJ5 have not been found in non-aldosterone secreting adrenal adenomas suggesting that they are specifically associated with APA (PubMed:22275527 and PubMed:22848660). {ECO:0000269|PubMed:21311022, ECO:0000269|PubMed:22203740, ECO:0000269|PubMed:22275527, ECO:0000269|PubMed:22848660}.; DISEASE: Note=Mutations in KCNJ5 are involved in the pathogenesis of hypertension without primary aldosteronism but with increased aldosterone response to ACTH stimulation. {ECO:0000269|PubMed:27293068}.;
Recessive Scores
- pRec
- 0.167
Intolerance Scores
- LoFtool
- 0.101
- RVIS EVS
- -0.53
- RVIS percentile EVS
- 20.7
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.372
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |