PSEN2
Chr 1presenilin 2
Also known as: AD3L, AD4, CMD1V, PS2, STM2
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]
Limited evidence — not for standalone diagnostic reporting
Some data sources returned errors (1)
omim: Error: OMIM fetch failed: 429
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Typical tolerance to LoF variation
Mild missense constraint
This gene — mechanism propensity
This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). The Badonyi & Marsh model scores dominant-negative highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports gain-of-function. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.
Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.
Literature Evidence
Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.
References
ClinVar Variant Classifications
368 submitted variants in ClinVar
Classification Summary
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 1 | 6 | 1 | 0 | 8 |
Likely Pathogenic | 2 | 1 | 0 | 0 | 3 |
VUS | 8 | 131 | 23 | 3 | 165 |
Likely Benign | 0 | 10 | 39 | 75 | 124 |
Benign | 0 | 0 | 28 | 4 | 32 |
Conflicting | — | 21 | |||
| Total | 11 | 148 | 91 | 82 | 353 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →32 pathogenic / likely-pathogenic (of 40) ClinVar copy-number / structural variants overlap PSEN2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →
Protein Context — Lollipop Plot
PSEN2 · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
Safety and Efficacy of Mutation-targeted Precision Genetic Therapy for Ataxia-Telangiectasia (A-T)
RECRUITINGStudy of Carboplatin and Mirvetuximab Soravtansine in First-Line Treatment of Patients Receiving Neoadjuvant Chemotherapy With Advanced-Stage Ovarian, Fallopian Tube or Primary Peritoneal Cancer
RECRUITINGThe Chinese Familial Alzheimer's Network
RECRUITINGPhenotypic and Molecular Characterisation of Cerebral Amyloid Angiopathy
RECRUITINGLow Dose Tamoxifen With or Without Omega-3 Fatty Acids for Breast Cancer Risk Reduction
RECRUITINGAn Innovative Method in SAliva Samples for the Early Differential Diagnosis of High-impact NeuroDegenerative Diseases Through Raman Spectroscopy
ENROLLING BY INVITATIONChina Cognition and Aging Study
RECRUITINGThe Signature of Alzheimer's Disease in Subjective Cognitive Decline
RECRUITINGExternal Resources
Links to major genomics databases and tools