PSEN1

presenilin 1

4 disorders 2 causative 1 untyped 1 disputed 14q24.2 gene with protein product

HGNC:9508 Monarch NCBI Gene 5663 ENSG00000080815 UniProt P49768 OMIM 104311

Previous symbols: AD3. Aliases: FAD, S182, PS1, PS-1, PSNL1.

Normal function · from ai-gene-review (P49768, commit 79fe13b38970) · AI-generated, not KB evidence

Presenilin-1 is a multi-pass membrane aspartyl protease subunit of the gamma-secretase complex. After endoproteolytic maturation, presenilin-1 N- and C-terminal fragments assemble with nicastrin, APH1, and PEN2 in secretory and endosomal membranes to cleave type I membrane-protein substrates, including APP and Notch receptors. Through this intramembrane protease activity, PSEN1 contributes to amyloid-beta peptide generation, Notch receptor processing, and broader regulated intramembrane proteolysis. Additional evidence links presenilin holoprotein to endoplasmic-reticulum calcium leak/homeostasis and protein-trafficking interactions, but these are secondary to its core gamma-secretase catalytic role.

PSEN1 is the catalytic presenilin subunit of the mature gamma-secretase complex, a multi-pass membrane aspartyl protease that cleaves type I membrane-protein substrates after ectodomain shedding.

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; early endosome membrane; plasma 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 1U	disputed germline	mechanism: PSEN1 Asp333Gly Missense Variant in Cardiomyocytes animal model: Cardiovascular-restricted Psen1 conditional knockout mouse
Early-Onset Autosomal Dominant Alzheimer Disease	causative germline	mechanism: Pathogenic APP, PSEN1, or PSEN2 Germline Variant subtype: PSEN1 scoped to subtype: PSEN1
Hidradenitis Suppurativa	causative	mechanism: Gamma-Secretase Loss of Function subtype: AI3 scoped to subtype: AI3
Alzheimer Disease	untyped Genetic Mutation	mechanism: Amyloid Plaque Formation; Neuronal Endosomal-Lysosomal Acidification Failure 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 1U MONDO:0013371	AD	Disputed 2026-03-04	Dilated Cardiomyopathy 1U disputed

Mechanism modules · computed from kb/

cardiomyopathy_maladaptive_remodeling via Dilated Cardiomyopathy 1U
disabled_macroautophagy via Alzheimer Disease

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