PPARGC1A
protein-codingPPARG coactivator 1 alpha, the group of RNA binding motif containing
Gene summary
The protein encoded by this gene is a transcriptional coactivator that regulates the genes involved in energy metabolism. This protein interacts with PPARgamma, which permits the interaction of this protein with multiple transcription factors. This protein can interact with, and regulate the activities of, cAMP response element binding protein (CREB) and nuclear respiratory factors (NRFs). It provides a direct link between external physiological stimuli and the regulation of mitochondrial biogenesis, and is a major factor that regulates muscle fiber type determination. This protein may be also involved in controlling blood pressure, regulating cellular cholesterol homoeostasis, and the development of obesity. [provided by RefSeq, Jul 2008]
- PPARGC1
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~149.0 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 PPARGC1A variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_013261.5. 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 | 9 | 3 | 12 | |||
| missense | 111 | 2 | 3 | 116 | ||
| nonsense | 2 | 2 | ||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 1 | 1 | ||||
| Total | 0 | 0 | 114 | 11 | 6 | 131 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_037393.1 | 13 | MANE Select | |
| Ensembl | ENSP00000264867.2 | 13 | MANE Select | |
| RefSeq | NP_001317680.1 | 13 | Standard | |
| RefSeq | NP_001317681.1 | 13 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| ppargc1a | Danio rerio | Structure: muscle Quality: morphology abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Adipocytokine signaling pathway - Homo sapiens (human)
- Insulin resistance - Homo sapiens (human)
- Huntington,s disease - Homo sapiens (human)
- AMPK signaling pathway - Homo sapiens (human)
- Thermogenesis - Homo sapiens (human)
Biological Process
- response to reactive oxygen species
- autophagy of mitochondrion
- temperature homeostasis
- cellular glucose homeostasis
- negative regulation of protein phosphorylation
Molecular Function
- DNA binding
- transcription coregulator activity
- transcription coactivator activity
- RNA binding
- protein binding
Cellular Component
- nucleus
- nucleoplasm
- nuclear euchromatin
- PML body
- cytosolic ribosome
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000264867
- Coding exons
- 13
- Length
- 149049
- Individuals with no LoFs
- 125720
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 11
- Defined
- 125731
- p
- 0.0000437
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.00 | 385 | 444 | 0.866 | 0.0000247 | 5226 |
| Missense (PolyPhen) | 97 | 126.79 | 0.76502 | 1584 | ||
| Synonymous | -0.186 | 169 | 166 | 1.02 | 0.00000935 | 1511 |
| Loss of Function | 5.08 | 5 | 39.4 | 0.127 | 0.00000200 | 481 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000058 | 0.000058 | rare |
| Ashkenazi Jewish | 0.00010 | 0.000099 | rare |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000072 | 0.000070 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Transcriptional coactivator for steroid receptors and nuclear receptors. Greatly increases the transcriptional activity of PPARG and thyroid hormone receptor on the uncoupling protein promoter. Can regulate key mitochondrial genes that contribute to the program of adaptive thermogenesis. Plays an essential role in metabolic reprogramming in response to dietary availability through coordination of the expression of a wide array of genes involved in glucose and fatty acid metabolism. Induces the expression of PERM1 in the skeletal muscle in an ESRRA-dependent manner. Also involved in the integration of the circadian rhythms and energy metabolism. Required for oscillatory expression of clock genes, such as ARNTL/BMAL1 and NR1D1, through the coactivation of RORA and RORC, and metabolic genes, such as PDK4 and PEPCK. {ECO:0000269|PubMed:10713165, ECO:0000269|PubMed:20005308, ECO:0000269|PubMed:21376232, ECO:0000269|PubMed:23836911}.;
Recessive Scores
- pRec
- 0.840
Intolerance Scores
- LoFtool
- 0.0500
- RVIS EVS
- -0.11
- RVIS percentile EVS
- 45.57
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 1.00
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | High |
| Cancer | Medium | Medium | Medium |