APP

amyloid beta precursor protein

6 disorders 3 untyped 2 causative 1 no genetic record 21q21.3 gene with protein product

HGNC:620 Monarch NCBI Gene 351 ENSG00000142192 UniProt P05067 OMIM 104760

Previous symbols: AD1. Aliases: alpha-sAPP.

Normal function · from ai-gene-review (P05067, commit 79fe13b38970) · AI-generated, not KB evidence

Amyloid-beta precursor protein (APP) is a type I transmembrane glycoprotein that undergoes regulated proteolytic processing to generate soluble ectodomains, membrane-tethered C-terminal fragments, amyloid-beta peptides, and the APP intracellular domain. Full-length APP acts at the neuronal cell surface and in secretory/endocytic compartments, where it contributes to cell adhesion, synaptogenesis, neurite outgrowth, axonogenesis, and interactions with extracellular matrix ligands. Alternative splice isoforms differ in inclusion of the Kunitz protease inhibitor domain, giving APP751/770 protease-inhibitor activity that is absent from neuronal APP695. APP and amyloid-beta fragments bind transition metals, especially copper and zinc, linking the ectodomain and cleavage products to metal homeostasis and redox biology. In Alzheimer disease, familial APP variants and APP dosage alter amyloidogenic processing and the production or aggregation of amyloid-beta species.

Full-length APP functions as a cell surface adhesion molecule. APP molecules on neighboring cells engage in trans-dimerization to promote synaptogenesis and cell-cell contact. This is a physiological function of full-length APP at the plasma membrane.

molecular function: cell adhesion mediator activity · directly involved in: cell adhesion · locations: plasma membrane; cell surface

APP regulates axon development through multiple mechanisms. The sAPPalpha ectodomain promotes neurite outgrowth acting as a signaling ligand, while full-length APP interacts with Fe65/Mena to guide axon growth. APP knockout mice show defects in axonogenesis.

molecular function: signaling receptor activator activity · directly involved in: axonogenesis; neuron projection development · locations: plasma membrane; growth cone

APP is highly expressed at synapses and plays physiological roles in synapse formation, maintenance, and plasticity. APP trans-dimerization across the synaptic cleft mediates cell-cell adhesion that contributes to synapse structure. APP knockout models show synaptic deficits.

molecular function: cell adhesion molecule binding · directly involved in: regulation of synapse structure or activity · locations: plasma membrane; neuron projection

APP binds copper and zinc ions via its ectodomain (GFLD/copper-binding domain) and participates in copper homeostasis and reduction of Cu(2+) to Cu(+). This is a direct molecular function of the APP ectodomain.

molecular function: copper ion binding · directly involved in: intracellular copper ion homeostasis · locations: plasma membrane; early endosome

ISOFORM-SPECIFIC: The Kunitz protease inhibitor (KPI) domain in APP751/770 isoforms confers serine protease inhibitor activity (Protease nexin-II function). Absent from the neuronal APP695 isoform.

molecular function: serine-type endopeptidase inhibitor activity · locations: extracellular region; plasma membrane

CLEAVAGE PRODUCT FUNCTION: Abeta peptides (particularly Abeta42) self-assemble into amyloid fibrils via identical protein binding. This is a defining biochemical property of the Abeta cleavage products of APP and is central to Alzheimer disease pathology. Both full-length APP and Abeta cleavage products engage in homodimerization.

molecular function: identical protein binding · directly involved in: amyloid fibril formation · locations: extracellular region; early endosome

APP ectodomain binds heparin and heparan sulfate proteoglycans. This interaction promotes APP dimerization, influences neurite outgrowth, and modulates cell adhesion functions.

molecular function: heparin binding · directly involved in: cell adhesion · locations: plasma membrane; cell surface

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
Cerebral Amyloid Angiopathy	causative	mechanism: Vascular amyloid-beta deposition subtype: Arctic-type; Dutch-type; Flemish-type; Iowa-type; Italian-type; Piedmont-type
Early-Onset Autosomal Dominant Alzheimer Disease	causative germline	mechanism: Increased APP Substrate Dosage; Pathogenic APP, PSEN1, or PSEN2 Germline Variant subtype: APP; APP Duplication scoped to subtype: APP
Alzheimer Disease	untyped Genetic Mutation	mechanism: Amyloid Plaque Formation; Neuronal Endosomal-Lysosomal Acidification Failure; Oligodendrocyte and Myelin Dysfunction scoped to subtype: Early-Onset Alzheimer's Disease
Down_syndrome	untyped Risk Factor
Polycystic Ovary Syndrome	untyped Risk Factor
Inclusion Body Myositis	no genetic record	mechanism: Amyloid-beta and APP Accumulation in Myofibres

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
cerebral amyloid angiopathy, APP-related MONDO:0011583	AD	Definitive 2025-10-22	no dismech entry

Mechanism modules · computed from kb/

amyloidogenesis via Early-Onset Autosomal Dominant Alzheimer Disease
cns_myelin_failure via Alzheimer Disease
disabled_macroautophagy via Alzheimer Disease
focal_axonal_injury_wallerian_degeneration named in the module itself

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