PSEN2

Chr 1AD

presenilin 2

Also known as: AD3L, AD4, CMD1V, PS2, STM2

NCBI Gene: 5664 ENSG00000143801 UniProt: P49810 OMIM: 600759

This protein functions as the catalytic subunit of the gamma-secretase complex, which cleaves integral membrane proteins including Notch receptors and amyloid precursor protein, and also regulates calcium homeostasis between the endoplasmic reticulum and mitochondria. Mutations cause autosomal dominant Alzheimer disease-4 and dilated cardiomyopathy, typically affecting the nervous system and heart. The gene shows low constraint against loss-of-function mutations (pLI 0.0005), suggesting the pathogenic variants likely act through other mechanisms.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Alzheimer disease-4MIM #606889

Cardiomyopathy, dilated, 1VMIM #613697

UniProtAlzheimer disease 4

Clinical highlights

Gene-disease validity (ClinGen)

dilated cardiomyopathy 1V · ADLimitednot for standalone diagnostic reporting

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.74

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.74LOEUF

pLI 0.001

Z-score 2.44

OE 0.43 (0.26–0.74)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.40Z-score

OE missense 0.93 (0.84–1.03)

254 obs / 272.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.43 (0.26–0.74)

0≤0.351.4

Missense OE?0.93 (0.84–1.03)

0≤0.61.4

Synonymous OE?1.21

0≤1.21.6

LoF obs/exp: 9 / 21.1Missense obs/exp: 254 / 272.8Syn Z: -1.77

ClinVar Variant Classifications

0 submitted variants in ClinVar

ClinVar

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

Franklin by Genoox

AI-powered variant curation and clinical analysis

DECIPHER

Genomic variants and phenotypes in rare disease patients

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

Ovarian CancerFallopian TubePrimary Peritoneal Cancer

Study of Carboplatin and Mirvetuximab Soravtansine in First-Line Treatment of Patients Receiving Neoadjuvant Chemotherapy With Advanced-Stage Ovarian, Fallopian Tube or Primary Peritoneal Cancer

RECRUITING

NCT04606914Phase PHASE2University of Alabama at BirminghamStarted 2021-05-27

mirvetuximab soravtansine (MIRV; IMGN853)

Cerebral Amyloid Aβ Angiopathy

Phenotypic and Molecular Characterisation of Cerebral Amyloid Angiopathy

RECRUITING

NCT06864000University Hospital, RouenStarted 2023-03-31

Alzheimer DiseaseFamilial Alzheimer Disease (FAD)

The Chinese Familial Alzheimer's Network

RECRUITING

NCT03657732Capital Medical UniversityStarted 2005-01-10

Subjective Cognitive Decline (SCD)Subjective Cognitive Complaints (SCCs)Subjective Cognitive Impairment