PSEN2
protein-codingpresenilin 2, the group of Peptidase family A22
Gene summary
Alzheimer's disease (AD) patients with an inherited form of the disease carry mutations in the presenilin proteins (PSEN1 or PSEN2) or the amyloid precursor protein (APP). These disease-linked mutations result in increased production of the longer form of amyloid-beta (main component of amyloid deposits found in AD brains). Presenilins are postulated to regulate APP processing through their effects on gamma-secretase, an enzyme that cleaves APP. Also, it is thought that the presenilins are involved in the cleavage of the Notch receptor such that, they either directly regulate gamma-secretase activity, or themselves act are protease enzymes. Two alternatively spliced transcript variants encoding different isoforms of PSEN2 have been identified. [provided by RefSeq, Jul 2008]
- AD4
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~57.5 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0015140
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0011743
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0016333
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0011743
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0013373
Submitter: ClinGen
PSEN2 was originally evaluated for DCM by the ClinGen DCM GCEP on December 13, 2019. Evidence of the association of this gene with DCM was re-evaluated using SOP v10 on October 4, 2024. The overall genetic evidence points decreased over time. With these updates at the time of recuration, the clinical validity classification did not change and remains Limited. A summary of the information contributing to the classification of this gene at the time of re-evaluation is summarized herein. PSEN2 was first reported in relation to autosomal dominant dilated cardiomyopathy in 2006 (Li et al. PMID: 17186461). Human genetic evidence supporting this gene-disease relationship includes case level data. Two missense variants have been reported in 4 probands in two studies (Li et al. PMID: 17186461, Gianni et al. PMID: 20194882). While Li et al. demonstrated limited segregation and functional evidence for the missense variant identified in their study, both of the reported missense variants have subsequently been found at a frequency higher than would be expected for a monogenic, pathogenic effect in population reference data sets. No new human genetic evidence has emerged since the last curation. This gene-disease relationship is supported by expression studies (Mohuczy et al. PMID: 12468103, Gupta et al. PMID: 20443895). No new experimental evidence was identified in this re-curation. In summary, there is a lack of new supporting evidence in the period since the previous curation. There is limited evidence to support this gene-disease relationship. More evidence is needed to support the relationship of PSEN2 with AD DCM. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on May 30th, 2025 (SOP Version 10)
Inheritance Pattern: AD
Disease ID:MONDO:0015470
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular; Neurologic; Obstetric
Intervention: Cardiovascular; Obstetric
Rationale: Preventive measures and medical management may be helpful to help decrease morbidity; Precautions/surveillance may be beneficial prior to/during pregnancy
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to PSEN2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000447.3. 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 | 5 | 85 | 1 | 91 | ||
| missense | 6 | 5 | 139 | 19 | 169 | |
| nonsense | 3 | 3 | ||||
| start loss | 1 | 1 | ||||
| frameshift | 1 | 5 | 6 | |||
| splice donor/acceptor (+/-2bp) | 2 | 4 | 6 | |||
| Total | 7 | 7 | 157 | 104 | 1 | 276 |
Highest pathogenic variant AF is 0.000019208463
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000438.2 | 10 | MANE Select | |
| Ensembl | ENSP00000355747.3 | 10 | MANE Select | |
| RefSeq | NP_001424466.1 | 10 | Standard | |
| RefSeq | NP_036618.2 | 10 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| psen2 | Danio rerio | Structure: neuron Quality: increased amount abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Neurotrophin signaling pathway - Homo sapiens (human)
- Alzheimer,s disease - Homo sapiens (human)
- Notch signaling pathway - Homo sapiens (human)
- NOTCH-Core
- Alzheimers Disease
Biological Process
- response to hypoxia
- membrane protein ectodomain proteolysis
- calcium ion transport
- Notch receptor processing
- protein processing
Molecular Function
- endopeptidase activity
- aspartic-type endopeptidase activity
- protein binding
- aspartic endopeptidase activity, intramembrane cleaving
Cellular Component
- Golgi membrane
- kinetochore
- nucleus
- nuclear inner membrane
- endoplasmic reticulum
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000366783
- Coding exons
- 10
- Length
- 25922
- Individuals with no LoFs
- 125721
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 27
- Defined
- 125748
- p
- 0.000107
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.404 | 254 | 273 | 0.931 | 0.0000168 | 2913 |
| Missense (PolyPhen) | 88 | 106.14 | 0.82908 | 1218 | ||
| Synonymous | -1.77 | 145 | 120 | 1.21 | 0.00000866 | 904 |
| Loss of Function | 2.44 | 9 | 21.1 | 0.426 | 9.11e-7 | 255 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.00012 | 0.00012 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00014 | 0.00014 | rare |
| South Asian | 0.00023 | 0.00023 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Probable catalytic subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (amyloid-beta precursor protein). Requires the other members of the gamma-secretase complex to have a protease activity. May play a role in intracellular signaling and gene expression or in linking chromatin to the nuclear membrane. May function in the cytoplasmic partitioning of proteins. {ECO:0000269|PubMed:10497236, ECO:0000269|PubMed:10652302}.;
- Disease
- DISEASE: Alzheimer disease 4 (AD4) [MIM:606889]: A familial early- onset form of Alzheimer disease. Alzheimer disease is a neurodegenerative disorder characterized by progressive dementia, loss of cognitive abilities, and deposition of fibrillar amyloid proteins as intraneuronal neurofibrillary tangles, extracellular amyloid plaques and vascular amyloid deposits. The major constituents of these plaques are neurotoxic amyloid-beta protein 40 and amyloid-beta protein 42, that are produced by the proteolysis of the transmembrane APP protein. The cytotoxic C- terminal fragments (CTFs) and the caspase-cleaved products, such as C31, are also implicated in neuronal death. {ECO:0000269|PubMed:10631141, ECO:0000269|PubMed:10732806, ECO:0000269|PubMed:22503161, ECO:0000269|PubMed:7638622, ECO:0000269|PubMed:7651536, ECO:0000269|PubMed:9384602}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Cardiomyopathy, dilated 1V (CMD1V) [MIM:613697]: A disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death. {ECO:0000269|PubMed:17186461}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.664
Intolerance Scores
- LoFtool
- 0.0232
- RVIS EVS
- -1.02
- RVIS percentile EVS
- 8.04
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.761
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |