PSEN2

presenilin 2

3 disorders 1 untyped 1 unknown 1 causative 1q42.13 gene with protein product

HGNC:9509 Monarch NCBI Gene 5664 ENSG00000143801 UniProt P49810 OMIM 600759

Previous symbols: AD4. Aliases: AD3L, STM2, PS2, PS-2, E5-1.

Normal function · from ai-gene-review (P49810, commit 79fe13b38970) · AI-generated, not KB evidence

Presenilin-2 is a multi-pass membrane aspartyl protease subunit of gamma-secretase complexes. After endoproteolytic maturation, PSEN2 N- and C-terminal fragments assemble with nicastrin, APH1, and PEN2 to cleave type I membrane-protein substrates, including APP-derived C-terminal fragments and Notch receptor substrates. PSEN2-containing complexes are distinguished from PSEN1 complexes by stronger late endosome/lysosome enrichment mediated by an AP-1-dependent N-terminal sorting motif, which shapes substrate access and intracellular amyloid-beta generation. Additional evidence links PSEN2 to endoplasmic-reticulum/mitochondrial calcium coupling and membrane-contact site biology, but these activities are secondary to its gamma-secretase catalytic role.

PSEN2 is a catalytic presenilin isoform in mature gamma-secretase complexes. It cleaves membrane-protein substrates including APP-derived C-terminal fragments and Notch receptor substrates, with PSEN2 complexes showing prominent late endosome/lysosome enrichment that shapes substrate specificity and intracellular amyloid-beta generation.

molecular function: aspartic endopeptidase activity, intramembrane cleaving · directly involved in: membrane protein ectodomain proteolysis; amyloid precursor protein catabolic process; amyloid-beta formation; Notch receptor processing; Notch signaling pathway · locations: endoplasmic reticulum membrane; Golgi membrane; late endosome membrane; lysosomal membrane · in complex: gamma-secretase complex

In the knowledge base · computed from kb/ at build time

Disorders

Relationship is the entry's genetic[].relationship_type. untyped means the entry has a genetic record for the gene but does not type it; its free-text association is shown instead.

Disorder	Relationship	Where the gene appears
Dilated Cardiomyopathy 1V	unknown germline	mechanism: PSEN2 Ser130Leu Missense Variant in Cardiomyocytes animal model: Presenilin-2 knockout mouse (cardiac phenotype)
Early-Onset Autosomal Dominant Alzheimer Disease	causative germline	mechanism: Pathogenic APP, PSEN1, or PSEN2 Germline Variant subtype: PSEN2 scoped to subtype: PSEN2
Alzheimer Disease	untyped Genetic Mutation	mechanism: Amyloid Plaque Formation scoped to subtype: Early-Onset Alzheimer's Disease

ClinGen gene–disease validity · snapshot 2026-10-03 · matched to entries by MONDO

An entry matches when ClinGen's MONDO disease is the entry's own disease term, a subtype term, or an exact-match mapping. An amber status marks an entry ClinGen supports the gene for (Definitive, Strong or Moderate) whose own record does not type it. A Limited, Disputed or Refuted tier on such an entry is not a gap.

ClinGen disease	MOI	Classification	dismech entry
dilated cardiomyopathy 1V MONDO:0013373	AD	Limited 2026-03-04	Dilated Cardiomyopathy 1V unknown

Mechanism modules · computed from kb/

cardiomyopathy_maladaptive_remodeling via Dilated Cardiomyopathy 1V

Identity from HGNC (snapshot 2026-10-01). Page layers are described in the gene pages documentation.