APP
Chr 21ADamyloid beta precursor protein
Also known as: AAA, ABETA, ABPP, AD1, APPI, CTFgamma, CVAP, PN-II
The APP protein functions as a cell surface receptor involved in neurite growth, neuronal adhesion, axonogenesis, and synaptic formation, and is cleaved by secretases to produce peptides including those that form amyloid plaques. Mutations cause autosomal dominant familial Alzheimer disease and cerebral amyloid angiopathy with various geographic variants (Dutch, Italian, Iowa, Flemish, Arctic). The gene is highly constrained against loss-of-function variants (LOEUF 0.419), reflecting its essential neuronal functions.
Definitive — sufficient evidence for diagnostic panels
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
More LoF-intolerant than ~75% of genes
Mild missense constraint
This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.
Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.
Literature Evidence
Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.
ClinVar Variant Classifications
100 submitted variants in ClinVar
Classification Summary
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 0 | 0 | 4 | 0 | 4 |
Likely Pathogenic | 0 | 0 | 1 | 0 | 1 |
VUS | 1 | 42 | 6 | 3 | 52 |
Likely Benign | 0 | 1 | 12 | 12 | 25 |
Benign | 0 | 0 | 0 | 0 | 0 |
| Total | 1 | 43 | 23 | 15 | 82 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
APP · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
3D Protein StructureAlphaFold
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
Resources, Inspiration, Support and Empowerment (RISE) for Black Pregnant Women
ACTIVE NOT RECRUITINGE-Mindfulness Approaches for Living After Breast Cancer
RECRUITINGCognitive Impairment in Ageing People
RECRUITINGA Phase 2b/3 Clinical Study Evaluating T3D-959 in Mild-to-Moderate Alzheimer's Disease Subjects
NOT YET RECRUITINGPhenotypic and Molecular Characterisation of Cerebral Amyloid Angiopathy
RECRUITINGSEarchiNg biomarkErs Cerebral Amyloid Angiopathy (SENECA)
RECRUITINGA Feasibility Study of Optimal Non-Pharmacological Lifestyle Modifications in People With Type 2 Diabetes
RECRUITINGInvestigating Neurocognitive Disorders Epidemiology
RECRUITINGAlzheimer's Disease Multinuclear Imaging Neuro-Enhanced Resolution (AD-MINER)
RECRUITINGEfficacy of a Prediction Model-based Algorithm to PREVENT Drug-induced Impulse Control Disorders in Parkinson's Disease
NOT YET RECRUITINGEnergy Metabolism Profiles Over Weight-loss and Eating Responses
ACTIVE NOT RECRUITINGAcoramidis Transthyretin Amyloidosis Prevention Trial in the Young (ACT-EARLY) Study in Asymptomatic Carriers of a Pathogenic TTR Variant
RECRUITINGExternal Resources
Links to major genomics databases and tools