KCNJ8
protein-codingpotassium inwardly rectifying channel subfamily J member 8, the group of Potassium inwardly rectifying channel subfamily J
Gene summary
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. Defects in this gene may be a cause of J-wave syndromes and sudden infant death syndrome (SIDS). [provided by RefSeq, May 2012]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~10.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0009406
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: Unknown
Disease ID:MONDO:0015263
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0009406
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0015263
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0009406
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0015263
Submitter: ClinGen
**KCNJ8- Brugada syndrome- autosomal dominant** KCNJ8 encodes the inwardly rectifying potassium channel Kir6.1, a subunit of the ATP-sensitive potassium (K-ATP) channel complex with SUR2. It is primarily expressed in cardiac and adipose tissue, with lower expression observed across various other tissues [PMID: 11984590, 9573340, 24339868]. Given its role in regulating potassium influx, variants in KCNJ8 have been proposed to contribute to arrhythmias and sudden cardiac death (SCD) [PMID: 22056721]. Evidence linking KCNJ8 to Brugada syndrome was initially published in 2009 from a case report of a patient with J-point elevation and frequent (>100) unresponsive ventricular fibrillation, who was found to carry a heterozygous p.Ser422Leu variant [PMID: 19120683]. Subsequent studies reported the same p.Ser422Leu variant in additional Brugada or early repolarization cases. A 2010 study identified one Brugada syndrome case and one early repolarization case with the identical missense variant p.Ser422Leu [PMID:20558321]. In 2012, the KCNJ8 p.Ser422Leu variant was found in three patients with Brugada syndrome and one patient with early repolarization syndrome [PMID: 22056721]. Crotti et al. also identified a patient with the same p.Ser422Leu in a cohort of 129 unrelated patients with possible/probable Brugada syndrome [PMID:22840528]. The p.Ser422Leu variant has a population allele frequency of 1.08 x10-3, including an allele frequency of 0.03121 in the Ashkenazi Jewish population. These data suggest that the allele is too common for a condition with complex genetics and reduced penetrance. Previous literature has also similarly raised concerns that the KCNJ8 p.Ser422Leu variant may be too common to be considered causative of Brugada Syndrome, and its inclusion in associated gene lists has been cautioned against [PMID: 29959160, 30821013]. The same p.Ser422Leu variant was also reported in four probands diagnosed with early repolarisation syndrome [PMID: 22056721, 22562657. 19120683, 20558321]. Additional studies have also reported KCNJ8 variants in the context of sudden death, however the allele frequencies are either too high or the variants display comparable functional effects to variants that are common [PMID 21836131]. There is also a case report of a homozygous carrier of the p.Ser422Leu variant who displayed no cardiac phenotype [PMID: 23632791]. The relationship between KCNJ8 and autosomal dominant Brugada syndrome was originally evaluated by the ClinGen Brugada Syndrome Gene Curation Expert Panel in 2017 and was classified as disputed. This gene-disease pair was re-evaluated by the Hereditary Cardiovascular Disorders GCEP on April 8, 2025. Following re-evaluation and the consideration of new evidence, the gene-disease classification remains classified as disputed. This classification was approved by the ClinGen Hereditary Cardiovascular Disorders GCEP on Dec 10, 2025 (in accordance with SOP Version 11).
Inheritance Pattern: AD
Disease ID:MONDO:0009406
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0011001
Submitter: PanelApp Australia
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to KCNJ8 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_004982.4. 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 | 113 | 4 | 117 | |||
| missense | 3 | 140 | 7 | 150 | ||
| nonsense | 2 | 2 | ||||
| start loss | 1 | 1 | ||||
| frameshift | 3 | 3 | ||||
| splice donor/acceptor (+/-2bp) | 2 | 2 | ||||
| Total | 0 | 3 | 148 | 120 | 4 | 275 |
Highest pathogenic variant AF is 6.840497e-7
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_004973.1 | 2 | MANE Select | |
| Ensembl | ENSP00000240662.2 | 2 | MANE Select | |
| Ensembl | ENSP00000440012.1 | 1 | Standard | |
| Ensembl | ENSP00000499300.1 | 2 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- cGMP-PKG signaling pathway - Homo sapiens (human)
- Antiarrhythmic Pathway, Pharmacodynamics
- Disopyramide Action Pathway
- Procainamide (Antiarrhythmic) Action Pathway
- Phenytoin (Antiarrhythmic) Action Pathway
Biological Process
- kidney development
- potassium ion transport
- heart development
- response to lipopolysaccharide
- regulation of ion transmembrane transport
Molecular Function
- inward rectifier potassium channel activity
- ATP binding
- ATP-activated inward rectifier potassium channel activity
- sulfonylurea receptor binding
- voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization
Cellular Component
- mitochondrion
- plasma membrane
- voltage-gated potassium channel complex
- inward rectifying potassium channel
- myofibril
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000240662
- Coding exons
- 2
- Length
- 10627
- Individuals with no LoFs
- 125740
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 8
- Defined
- 125748
- p
- 0.0000318
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 3.45 | 92 | 244 | 0.377 | 0.0000138 | 2804 |
| Missense (PolyPhen) | 28 | 128.85 | 0.21731 | 1576 | ||
| Synonymous | 0.965 | 78 | 89.6 | 0.870 | 0.00000482 | 860 |
| Loss of Function | 2.64 | 3 | 13.5 | 0.223 | 0.00000111 | 129 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000053 | 0.000053 | rare |
| South Asian | 0.000065 | 0.000065 | 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 (By similarity). {ECO:0000250|UniProtKB:Q63664, ECO:0000269|PubMed:28842488}.;
- Disease
- DISEASE: Sudden infant death syndrome (SIDS) [MIM:272120]: SIDS is the sudden death of an infant younger than 1 year that remains unexplained after a thorough case investigation, including performance of a complete autopsy, examination of the death scene, and review of clinical history. Pathophysiologic mechanisms for SIDS may include respiratory dysfunction, cardiac dysrhythmias, cardiorespiratory instability, and inborn errors of metabolism, but definitive pathogenic mechanisms precipitating an infant sudden death remain elusive. {ECO:0000269|PubMed:21836131}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Hypertrichotic osteochondrodysplasia (HTOCD) [MIM:239850]: A rare disorder characterized by congenital hypertrichosis, neonatal macrosomia, a distinct osteochondrodysplasia, and cardiomegaly. The hypertrichosis leads to thick scalp hair, which extends onto the forehead, and a general increase in body hair. In addition, macrocephaly and coarse facial features, including a broad nasal bridge, epicanthal folds, a wide mouth, and full lips, can be suggestive of a storage disorder. About half of affected individuals are macrosomic and edematous at birth, whereas in childhood they usually have a muscular appearance with little subcutaneous fat. Thickened calvarium, narrow thorax, wide ribs, flattened or ovoid vertebral bodies, coxa valga, osteopenia, enlarged medullary canals, and metaphyseal widening of long bones have been reported. Cardiac manifestations such as patent ductus arteriosus, ventricular hypertrophy, pulmonary hypertension, and pericardial effusions are present in approximately 80% of cases. Motor development is usually delayed due to hypotonia. Most patients have a mild speech delay, and a small percentage have learning difficulties or intellectual disability. {ECO:0000269|PubMed:24176758, ECO:0000269|PubMed:24700710, ECO:0000269|PubMed:28842488}. Note=The disease may be caused by mutations affecting distinct genetic loci, including the gene represented in this entry.;
Recessive Scores
- pRec
- 0.210
Intolerance Scores
- LoFtool
- 0.252
- RVIS EVS
- 0.02
- RVIS percentile EVS
- 55.22
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.698
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |