APP (Amyloid-beta precursor protein) variants and mutations

APP (also known as Amyloid-beta precursor protein) is a human protein-coding gene encoding an amyloid-beta precursor protein. Its processing produces multiple fragments involved in neuronal biology, including amyloid-beta peptides generated by beta- and gamma-secretase cleavage. Increased amyloidogenic processing, pathogenic variants, or increased gene dosage can cause autosomal dominant Alzheimer disease or cerebral amyloid angiopathy. This analysis covers 1,078 APP variants and mutations. Of these, 3.1% have pathogenic or likely pathogenic clinical classifications, 76% have computational variant effect predictions from REVEL and MutPred, and 65% have population-specific frequency data. Disease context includes Alzheimer disease, Alzheimer disease type 1, and cerebral amyloid angiopathy, APP-related. Example APP variants include P3H, L5F, and L5V.

Variant analysis overview

Gene: APP
Protein: Amyloid-beta precursor protein
UniProt accession: P05067
Organism: Homo sapiens
Variants analyzed: 1078
Variant scope: all variants
Completed: 2026-08-10

Variant and mutation evidence

Variant composition: 882 unspecified-consequence records; 97 synonymous variants; 78 missense variants; 8 in-frame deletions; 6 splice-region variants; 2 stop-gained variants; 3 frameshift variants; 2 in-frame insertions
Clinical classifications: 33 pathogenic or likely pathogenic; 55 benign or likely benign; 214 uncertain-significance; 1 conflicting; 154 other clinical labels.
Computational signals: 159 REVEL high-risk; 12 MutPred high-risk.
Variant classes: 945 missense; 97 synonymous; 35 truncating or splice.
Prediction scores: 819 variants have prediction scores (76% of the analyzed set).

Clinical, disease, and population context

Clinical evidence: 15 records have expert-only or criteria-backed evidence.
Clinical annotations: 458 variants have clinical annotations.
Population evidence: 779 variants have population-frequency evidence.
Disease context: 25 disease associations are represented. Top associations: Alzheimer disease, Alzheimer disease type 1, cerebral amyloid angiopathy, APP-related, Hereditary cerebral hemorrhage with amyloidosis, ABeta amyloidosis, dutch type, ABeta amyloidosis, Italian type, ABeta amyloidosis, Iowa type, ABeta amyloidosis, Arctic type, ABetaA21G amyloidosis, AD1, a patient with late onset Alzheimer disease.

Protein structure and variant hotspots

Protein features: 1 transmembrane segments; 3 domains; 15 binding sites; 21 post-translational modification sites.
Ancestry evidence: 702 variants have ancestry-specific frequency data.
Structural context: 496 variants have structural context.
PTM context: 34 variants overlap post-translational modification sites.
3D hotspots: 1 hotspot clusters were identified. Clusters at residues 41-120 (intolerant, 27 variants).
Allosteric analysis: 19 functional sites were identified.
gnomAD gene constraint: pLI 1.00 (highly intolerant of loss-of-function variation); LOEUF 0.31; missense Z-score 2.22.

Data sources

Evidence in this analysis draws on EBI Proteins Variation, UniProt, gnomAD v4, EuropePMC, 3D Hotspot Analysis, Interaction Network Analysis, Protein Data Bank, AlphaFold DB, gnomAD constraint, Open Targets, ClinGen, LitVar.

Notable APP variants

Examples include P3H, L5F, L5V, A6V, L7V, L8F, A11S, A11T. Listed records include available protein-change notation, database identifiers, clinical classifications, computational predictions, population evidence, experimental measurements, and disease context.

APP analysis run — APP (1,078 variants) — completed 2026-08-10