PDK1
protein-codingpyruvate dehydrogenase kinase 1
Gene summary
Pyruvate dehydrogenase (PDH) is a mitochondrial multienzyme complex that catalyzes the oxidative decarboxylation of pyruvate and is one of the major enzymes responsible for the regulation of homeostasis of carbohydrate fuels in mammals. The enzymatic activity is regulated by a phosphorylation/dephosphorylation cycle. Phosphorylation of PDH by a specific pyruvate dehydrogenase kinase (PDK) results in inactivation. Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jun 2013]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~53.3 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 PDK1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_002610.5. 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 | 2 | 1 | 3 | |||
| missense | 56 | 1 | 57 | |||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 0 | 0 | 58 | 2 | 0 | 60 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_002601.1 | 11 | MANE Select | |
| Ensembl | ENSP00000282077.3 | 11 | MANE Select | |
| RefSeq | NP_001265478.1 | 12 | Standard | |
| Ensembl | ENSP00000376352.2 | 12 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Central carbon metabolism in cancer - Homo sapiens (human)
- HIF-1 signaling pathway - Homo sapiens (human)
- Axon guidance - Homo sapiens (human)
- Celecoxib Pathway, Pharmacodynamics
- Fc Epsilon Receptor I Signaling in Mast Cells
Biological Process
- glucose metabolic process
- protein phosphorylation
- cell population proliferation
- intrinsic apoptotic signaling pathway in response to oxidative stress
- regulation of acetyl-CoA biosynthetic process from pyruvate
Molecular Function
- protein kinase activity
- pyruvate dehydrogenase (acetyl-transferring) kinase activity
- protein binding
- ATP binding
Cellular Component
- nucleus
- nucleolus
- mitochondrion
- mitochondrial matrix
- mitochondrial pyruvate dehydrogenase complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000282077
- Coding exons
- 11
- Length
- 69723
- Individuals with no LoFs
- 125671
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 77
- Defined
- 125748
- p
- 0.000306
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.15 | 185 | 234 | 0.789 | 0.0000126 | 2833 |
| Missense (PolyPhen) | 69 | 92.034 | 0.74972 | 1102 | ||
| Synonymous | 0.473 | 78 | 83.5 | 0.934 | 0.00000458 | 838 |
| Loss of Function | 2.26 | 12 | 24.0 | 0.501 | 0.00000132 | 279 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00012 | 0.00012 | rare |
| Latino/Admixed American | 0.000088 | 0.000087 | rare |
| Ashkenazi Jewish | 0.000099 | 0.000099 | rare |
| East Asian | 0.0016 | 0.0016 | notable |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.00028 | 0.00028 | rare |
| South Asian | 0.00023 | 0.00023 | rare |
| Other | 0.00016 | 0.00016 | 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. Plays an important role in cellular responses to hypoxia and is important for cell proliferation under hypoxia. Protects cells against apoptosis in response to hypoxia and oxidative stress. {ECO:0000269|PubMed:17683942, ECO:0000269|PubMed:18541534, ECO:0000269|PubMed:22195962, ECO:0000269|PubMed:7499431}.;
Recessive Scores
- pRec
- 0.0828
Intolerance Scores
- LoFtool
- 0.798
- RVIS EVS
- -0.31
- RVIS percentile EVS
- 31.93
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.120
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |