PROX1
protein-codingprospero homeobox 1, the group of PROS class homeoboxes
Gene summary
The protein encoded by this gene is a member of the homeobox transcription factor family. Members of this family contain a homeobox domain that consists of a 60-amino acid helix-turn-helix structure that binds DNA and RNA. The protein encoded by this gene is conserved across vertebrates and may play an essential role during development. Altered levels of this protein have been reported in cancers of different organs, such as colon, brain, blood, breast, pancreas, liver and esophagus. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2012]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~58.3 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0005453
Submitter: ClinGen
*PROX1* was first reported in relation to autosomal dominant congenital heart disease in 2009 (Gill Harinder K et al., PMID: 19471316). One unique 4- Mb de novo inversion that has been reported in one proband with CHD in one publication is included in this curation (PMID: 19471316). This gene-disease relationship is supported by expression evidence and an animal model. (PMID:19091769, 19471316). In summary, the evidence supporting the relationship between *PROX1* and congenital heart disease has been disputed, and no valid evidence remains to support the claim. More evidence is needed to either support or entirely refute the role *PROX1* plays in this disease. This classification was approved by the ClinGen Congenital Heart Disease GCEP on the meeting date August 12th, 2024 (SOP Version 10).
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to PROX1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001270616.2. 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 | 6 | 1 | 7 | |||
| missense | 64 | 1 | 65 | |||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 0 | 0 | 64 | 7 | 1 | 72 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001257545.1 | 4 | MANE Select | |
| Ensembl | ENSP00000355925.4 | 4 | MANE Select | |
| RefSeq | NP_002754.2 | 4 | Standard | |
| Ensembl | ENSP00000400694.1 | 4 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| prox1a | Danio rerio | Structure: vascular lymphangioblast Quality: decreased amount abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- PTF1A related regulatory pathway
- EMT transition in Colorectal Cancer
Biological Process
- negative regulation of transcription by RNA polymerase II
- cell fate determination
- kidney development
- liver development
- positive regulation of endothelial cell proliferation
Molecular Function
- RNA polymerase II proximal promoter sequence-specific DNA binding
- DNA-binding transcription factor activity, RNA polymerase II-specific
- DNA-binding transcription repressor activity, RNA polymerase II-specific
- DNA binding
- DNA-binding transcription factor activity
Cellular Component
- nucleus
- cytoplasm
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000366958
- Coding exons
- 4
- Length
- 58072
- Individuals with no LoFs
- 125708
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 1
- Defined
- 125709
- p
- 0.00000398
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 3.52 | 233 | 441 | 0.528 | 0.0000258 | 4890 |
| Missense (PolyPhen) | 73 | 186.27 | 0.3919 | 2048 | ||
| Synonymous | 0.931 | 163 | 179 | 0.911 | 0.0000113 | 1430 |
| Loss of Function | 4.59 | 2 | 28.4 | 0.0703 | 0.00000179 | 297 |
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) | 0.0000088 | 0.0000088 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Transcription factor involved in developmental processes such as cell fate determination, gene transcriptional regulation and progenitor cell regulation in a number of organs. Plays a critical role in embryonic development and functions as a key regulatory protein in neurogenesis and the development of the heart, eye lens, liver, pancreas and the lymphatic system. Involved in the regulation of the circadian rhythm. Represses: transcription of the retinoid-related orphan receptor RORG, transcriptional activator activity of RORA and RORG and the expression of RORA/G-target genes including core clock components: ARNTL/BMAL1, NPAS2 and CRY1 and metabolic genes: AVPR1A and ELOVL3. {ECO:0000269|PubMed:23723244, ECO:0000303|PubMed:22733308}.;
Recessive Scores
- pRec
- 0.142
Intolerance Scores
- LoFtool
- 0.0397
- RVIS EVS
- -0.67
- RVIS percentile EVS
- 15.62
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.536
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |