PDK4
protein-codingpyruvate dehydrogenase kinase 4
Gene summary
This gene is a member of the PDK/BCKDK protein kinase family and encodes a mitochondrial protein with a histidine kinase domain. This protein is located in the matrix of the mitrochondria and inhibits the pyruvate dehydrogenase complex by phosphorylating one of its subunits, thereby contributing to the regulation of glucose metabolism. Expression of this gene is regulated by glucocorticoids, retinoic acid and insulin. [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~13.0 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
No GenCC data available for this gene.
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to PDK4 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_002612.4. 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 | 3 | 3 | ||||
| missense | 57 | 1 | 1 | 59 | ||
| nonsense | 2 | 2 | ||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 2 | 2 | ||||
| Total | 0 | 0 | 64 | 1 | 1 | 66 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_002603.1 | 11 | MANE Select | |
| Ensembl | ENSP00000005178.5 | 11 | MANE Select | |
| Ensembl | ENSP00000556108.1 | 11 | Standard | |
| Ensembl | ENSP00000556109.1 | 11 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Estrogen Receptor Pathway
- Nuclear Receptors Meta-Pathway
- Amino Acid metabolism
- Signal Transduction
- Regulation of pyruvate dehydrogenase (PDH) complex
Biological Process
- glucose metabolic process
- protein phosphorylation
- regulation of pH
- insulin receptor signaling pathway
- cellular response to starvation
Molecular Function
- protein kinase activity
- pyruvate dehydrogenase (acetyl-transferring) kinase activity
- ATP binding
Cellular Component
- mitochondrion
- mitochondrial matrix
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000005178
- Coding exons
- 11
- Length
- 12993
- Individuals with no LoFs
- 125666
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 82
- Defined
- 125748
- p
- 0.000326
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.351 | 208 | 223 | 0.934 | 0.0000112 | 2677 |
| Missense (PolyPhen) | 97 | 102.38 | 0.94747 | 1176 | ||
| Synonymous | -1.27 | 92 | 77.8 | 1.18 | 0.00000367 | 781 |
| Loss of Function | 0.677 | 19 | 22.5 | 0.846 | 0.00000117 | 273 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00056 | 0.00055 | rare |
| Latino/Admixed American | 0.00015 | 0.00014 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00044 | 0.00038 | rare |
| Finnish | 0.00019 | 0.00018 | rare |
| European (Non-Finnish) | 0.00039 | 0.00039 | rare |
| South Asian | 0.00033 | 0.00033 | rare |
| Other | 0.00050 | 0.00049 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Kinase that plays a key role in regulation of glucose and fatty acid metabolism and homeostasis via phosphorylation of the pyruvate dehydrogenase subunits PDHA1 and PDHA2. This inhibits pyruvate dehydrogenase activity, and thereby regulates metabolite flux through the tricarboxylic acid cycle, down-regulates aerobic respiration and inhibits the formation of acetyl-coenzyme A from pyruvate. Inhibition of pyruvate dehydrogenase decreases glucose utilization and increases fat metabolism in response to prolonged fasting and starvation. Plays an important role in maintaining normal blood glucose levels under starvation, and is involved in the insulin signaling cascade. Via its regulation of pyruvate dehydrogenase activity, plays an important role in maintaining normal blood pH and in preventing the accumulation of ketone bodies under starvation. In the fed state, mediates cellular responses to glucose levels and to a high-fat diet. Regulates both fatty acid oxidation and de novo fatty acid biosynthesis. Plays a role in the generation of reactive oxygen species. Protects detached epithelial cells against anoikis. Plays a role in cell proliferation via its role in regulating carbohydrate and fatty acid metabolism. {ECO:0000269|PubMed:15955060, ECO:0000269|PubMed:18658136, ECO:0000269|PubMed:21816445, ECO:0000269|PubMed:21852536}.;
Recessive Scores
- pRec
- 0.354
Intolerance Scores
- LoFtool
- 0.801
- RVIS EVS
- 0.04
- RVIS percentile EVS
- 56.92
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.961
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |