GSAP
protein-codinggamma-secretase activating protein
Gene summary
Accumulation of neurotoxic amyloid-beta is a major hallmark of Alzheimer disease (AD; MIM 104300). Formation of amyloid-beta is catalyzed by gamma-secretase (see PSEN1; MIM 104311), a protease with numerous substrates. PION, or GSAP, selectively increases amyloid-beta production through a mechanism involving its interaction with both gamma-secretase and its substrate, the amyloid-beta precursor protein (APP; MIM 104760) C-terminal fragment (APP-CTF) (He et al., 2010 [PubMed 20811458]).[supplied by OMIM, Nov 2010]
- PION
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~105.6 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 GSAP variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_017439.4. 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 | 1 | 1 | ||||
| missense | 104 | 13 | 1 | 118 | ||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 7 | 7 | ||||
| Total | 0 | 0 | 112 | 13 | 1 | 126 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_059135.2 | 31 | MANE Select | |
| Ensembl | ENSP00000257626.7 | 31 | MANE Select | |
| RefSeq | NP_001337825.1 | 30 | Standard | |
| RefSeq | NP_001337826.1 | 30 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Biological Process
- regulation of proteolysis
- positive regulation of amyloid-beta formation
Molecular Function
- amyloid-beta binding
- protein binding
Cellular Component
- trans-Golgi network
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000257626
- Coding exons
- 31
- Length
- 105650
- Individuals with no LoFs
- 125647
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 101
- Defined
- 125748
- p
- 0.000402
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.528 | 389 | 419 | 0.927 | 0.0000208 | 5601 |
| Missense (PolyPhen) | 72 | 92.056 | 0.78213 | 1344 | ||
| Synonymous | 0.957 | 142 | 157 | 0.903 | 0.00000842 | 1507 |
| Loss of Function | 1.54 | 42 | 54.3 | 0.774 | 0.00000247 | 713 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00020 | 0.00018 | rare |
| Latino/Admixed American | 0.00030 | 0.00029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00044 | 0.00044 | rare |
| Finnish | 0.00019 | 0.00018 | rare |
| European (Non-Finnish) | 0.00057 | 0.00055 | rare |
| South Asian | 0.00034 | 0.00033 | rare |
| Other | 0.00050 | 0.00049 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Regulator of gamma-secretase activity, which specifically activates the production of amyloid-beta protein (amyloid-beta protein 40 and amyloid-beta protein 42), without affecting the cleavage of other gamma-secretase targets such has Notch. The gamma-secretase complex is an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (amyloid-beta precursor protein). Specifically promotes the gamma-cleavage of APP CTF-alpha (also named APP-CTF) by the gamma-secretase complex to generate amyloid- beta, while it reduces the epsilon-cleavage of APP CTF-alpha, leading to a low production of AICD. {ECO:0000269|PubMed:20811458}.;
Intolerance Scores
- RVIS EVS
- 0.27
- RVIS percentile EVS
- 70.64
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |