APP
protein-codingamyloid beta precursor protein, the group of Receptor ligands
Gene summary
This gene encodes a cell surface receptor and transmembrane precursor protein that is cleaved by secretases to form a number of peptides. Some of these peptides are secreted and can bind to the acetyltransferase complex APBB1/TIP60 to promote transcriptional activation, while others form the protein basis of the amyloid plaques found in the brains of patients with Alzheimer disease. In addition, two of the peptides are antimicrobial peptides, having been shown to have bacteriocidal and antifungal activities. Mutations in this gene have been implicated in autosomal dominant Alzheimer disease and cerebroarterial amyloidosis (cerebral amyloid angiopathy). Multiple transcript variants encoding several different isoforms have been found for this gene. [provided by RefSeq, Aug 2014]
- AD1
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~290.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0007088
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0015140
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0017949
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0011583
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0017948
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0017945
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0015033
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0007088
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0011583
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0011583
Submitter: ClinGen
*APP* was first reported in relation to autosomal dominant cerebral amyloid angiopathy in 1990 (Levy *et al.* PMID: 2111584) and to autosomal dominant early-onset Alzheimer’s disease in 1991 (Goate *et al.* PMID: 1671712). Affected individuals may present with progressive cognitive decline, cerebral vascular amyloidosis with white matter changes, and stroke with or without hemorrhage. Disease-causing *APP* variants lead to Alzheimer’s disease or cerebral amyloid angiopathy with autosomal dominant inheritance (PMIDs: 28003277, 31011484), although rare cases of homozygous *APP* variants in affected individuals have been reported (PMIDs: 20842367, 25948718). The molecular mechanism of disease is reported to be dominant negative, as genetic variations, particularly those near the C-terminal region of *APP*, result in aberrant processing of the protein product (PMIDs: 19286555, 22727994, 28003277). Disease-causing variants in the APP gene elicit a spectrum of neurodegenerative and neurovascular phenotypes resulting from an abnormal clearance of amyloid peptides, either by overproduction and decreased clearance of amyloid peptides, with deposition of amyloid in plaques and blood vessel walls (PMIDs: 28003277, 31011484). Variants in *APP*, have been reported in individuals with the following disease entities: Alzheimer’s disease and cerebral amyloid angiopathy. Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found no significant difference in molecular mechanism and inheritance pattern and found considerable interfamilial and intrafamilial variability of neurodegenerative and neurovascular phenotypes. Therefore, Cerebral amyloid angiopathy, APP-related (MONDO:0011583) and Early-onset autosomal dominant Alzheimer disease (MONDO:0015140) have been lumped into one disease entity, termed *APP*-related brain and vascular amyloidosis. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Twenty-two variants (20 missense, 1 in-frame deletion, and 1 whole gene triplication) that have been reported in 21 probands in 19 publications (PMIDs: 1302033, 2111584, 7986173, 9328472, 11063718, 11528419, 15365148, 15776278, 16178030, 18437002, 20010303, 20697050, 22702962, 23931937, 26803359, 27858710, 30090657, 34532568, 38130827) and one ClinVar submission (ClinVar ID: SCV002102396.3) are included in this curation. Variants in this gene segregated with disease in thirty-six additional family members (PMIDs: 1302033, 7986173). Of note, the A673T missense variant has been reported to confer protection against Alzheimer’s disease and was not included in this curation (PMID: 37120095). Intragenic *APP* copy number variants (two duplications and one triplication) have also been reported in individuals affected by Alzheimer’s disease (PMIDs: 16921174, 34532568). Only the *APP* triplication reported by Grangeon L. *et al.* 2021 was included in this curation as the exact genomic breakpoints of the *APP* duplications reported by Sleegers K. *et al.* 2006 are unknown. Moreover, copy number variants involving *APP* and other genes have been reported in individuals affected by Alzheimer’s disease and cerebral amyloid angiopathy. However, these multigenic variations are outside the scope of this curation and are not included as evidence (PMIDs: 16369530, 37170141). Of note, the ClinGen Dosage Sensitivity Working Group previously determined there is sufficient evidence for triplosensitivity in *APP*. This gene-disease relationship is supported by animal models, expression studies, or *in vitro* functional assay. Bulk tissue gene expression data from the GTEx Portal indicates *APP* is highly expressed in the brain (PMID: 23715323, dbGaP Accession phs000424.v10.p2). Pathogenic variants surrounding and within the amyloid sequence of *APP* have been shown to significantly impact the levels of total Aβ, Aβ40, and Aβ42 secreted by affected individuals as well as in transfected HEK293 cell models (PMID: 11528419, 27858710, 29112196). Shafaati *et al.* reported increased accumulation of 27-hydroxycholesterol in postmortem brain tissues of Alzheimer’s disease patients with pathogenic variants in *APP* as compared to those of controls (PMID: 21335619). In addition, various strains of transgenic mice with *APP* variants recapitulated the cerebral amyloid angiopathy phenotype observed in human patients (PMID: 8810256, 10570203, 15311282, 19026746). More evidence is available in the literature, but the maximum score for genetic evidence and/or experimental evidence (12 pts.) has been reached. In summary, there is definitive evidence to support the relationship between *APP* and autosomal dominant Alzheimer’s disease and autosomal dominant cerebral amyloid angiopathy both of which to be lumped into one disease entity, termed *APP*-related brain and vascular amyloidosis. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Neurovascular GCEP on October 22, 2025 (SOP Version 11).
Inheritance Pattern: AD
Disease ID:MONDO:0017947
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0017946
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular; Neurologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to APP variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000484.4. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 18 | 115 | 4 | 137 | ||
| missense | 18 | 13 | 204 | 38 | 3 | 276 |
| nonsense | 2 | 2 | ||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 4 | 4 | ||||
| Total | 18 | 13 | 228 | 153 | 7 | 419 |
Highest pathogenic variant AF is 0.000052671956
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000475.1 | 18 | MANE Select | |
| Ensembl | ENSP00000284981.4 | 18 | MANE Select | |
| RefSeq | NP_001129488.1 | 17 | Standard | |
| RefSeq | NP_001129601.1 | 15 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| appb | Danio rerio | Structure: secondary motor neuron Quality: decreased process quality abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Serotonergic synapse - Homo sapiens (human)
- Alzheimer,s disease - Homo sapiens (human)
- Alzheimers Disease
- Endoderm Differentiation
- Apoptosis-related network due to altered Notch3 in ovarian cancer
Biological Process
- positive regulation of protein phosphorylation
- suckling behavior
- astrocyte activation involved in immune response
- platelet degranulation
- mRNA polyadenylation
Molecular Function
- DNA binding
- serine-type endopeptidase inhibitor activity
- signaling receptor binding
- protein binding
- heparin binding
Cellular Component
- extracellular region
- extracellular space
- nuclear envelope lumen
- cytoplasm
- endosome
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000346798
- Coding exons
- 18
- Length
- 290586
- Individuals with no LoFs
- 125719
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 29
- Defined
- 125748
- p
- 0.000115
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.39 | 369 | 452 | 0.816 | 0.0000282 | 5100 |
| Missense (PolyPhen) | 125 | 169.34 | 0.73815 | 1828 | ||
| Synonymous | -0.700 | 183 | 171 | 1.07 | 0.0000121 | 1428 |
| Loss of Function | 4.68 | 12 | 46.4 | 0.259 | 0.00000280 | 491 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00018 | 0.00018 | rare |
| Latino/Admixed American | 0.000058 | 0.000058 | rare |
| Ashkenazi Jewish | 0.000099 | 0.000099 | rare |
| East Asian | 0.00027 | 0.00027 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00013 | 0.00013 | rare |
| South Asian | 0.000065 | 0.000065 | rare |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Functions as a cell surface receptor and performs physiological functions on the surface of neurons relevant to neurite growth, neuronal adhesion and axonogenesis. Interaction between APP molecules on neighboring cells promotes synaptogenesis (PubMed:25122912). Involved in cell mobility and transcription regulation through protein-protein interactions. Can promote transcription activation through binding to APBB1-KAT5 and inhibits Notch signaling through interaction with Numb. Couples to apoptosis-inducing pathways such as those mediated by G(O) and JIP. Inhibits G(o) alpha ATPase activity (By similarity). Acts as a kinesin I membrane receptor, mediating the axonal transport of beta-secretase and presenilin 1. Involved in copper homeostasis/oxidative stress through copper ion reduction. In vitro, copper-metallated APP induces neuronal death directly or is potentiated through Cu(2+)-mediated low-density lipoprotein oxidation. Can regulate neurite outgrowth through binding to components of the extracellular matrix such as heparin and collagen I and IV. The splice isoforms that contain the BPTI domain possess protease inhibitor activity. Induces a AGER- dependent pathway that involves activation of p38 MAPK, resulting in internalization of amyloid-beta peptide and leading to mitochondrial dysfunction in cultured cortical neurons. Provides Cu(2+) ions for GPC1 which are required for release of nitric oxide (NO) and subsequent degradation of the heparan sulfate chains on GPC1. {ECO:0000250, ECO:0000269|PubMed:25122912}.; FUNCTION: Appicans elicit adhesion of neural cells to the extracellular matrix and may regulate neurite outgrowth in the brain. {ECO:0000250}.; FUNCTION: N-APP binds TNFRSF21 triggering caspase activation and degeneration of both neuronal cell bodies (via caspase-3) and axons (via caspase-6).;
- Disease
- DISEASE: Alzheimer disease 1 (AD1) [MIM:104300]: A familial early- onset form of Alzheimer disease. It can be associated with cerebral amyloid angiopathy. Alzheimer disease is a neurodegenerative disorder characterized by progressive dementia, loss of cognitive abilities, and deposition of fibrillar amyloid proteins as intraneuronal neurofibrillary tangles, extracellular amyloid plaques and vascular amyloid deposits. The major constituents of these plaques are neurotoxic amyloid-beta protein 40 and amyloid-beta protein 42, that are produced by the proteolysis of the transmembrane APP protein. The cytotoxic C- terminal fragments (CTFs) and the caspase-cleaved products, such as C31, are also implicated in neuronal death. {ECO:0000269|PubMed:10097173, ECO:0000269|PubMed:10631141, ECO:0000269|PubMed:10665499, ECO:0000269|PubMed:10867787, ECO:0000269|PubMed:11063718, ECO:0000269|PubMed:11311152, ECO:0000269|PubMed:11528419, ECO:0000269|PubMed:12034808, ECO:0000269|PubMed:1302033, ECO:0000269|PubMed:1303239, ECO:0000269|PubMed:1303275, ECO:0000269|PubMed:1415269, ECO:0000269|PubMed:15201367, ECO:0000269|PubMed:15365148, ECO:0000269|PubMed:15668448, ECO:0000269|PubMed:1671712, ECO:0000269|PubMed:1678058, ECO:0000269|PubMed:1908231, ECO:0000269|PubMed:1925564, ECO:0000269|PubMed:1944558, ECO:0000269|PubMed:8267572, ECO:0000269|PubMed:8290042, ECO:0000269|PubMed:8476439, ECO:0000269|PubMed:8577393, ECO:0000269|PubMed:9328472, ECO:0000269|PubMed:9754958}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Cerebral amyloid angiopathy, APP-related (CAA-APP) [MIM:605714]: A hereditary localized amyloidosis due to amyloid- beta A4 peptide(s) deposition in the cerebral vessels. The principal clinical characteristics are recurrent cerebral and cerebellar hemorrhages, recurrent strokes, cerebral ischemia, cerebral infarction, and progressive mental deterioration. Patients develop cerebral hemorrhage because of the severe cerebral amyloid angiopathy. Parenchymal amyloid deposits are rare and largely in the form of pre-amyloid lesions or diffuse plaque- like structures. They are Congo red negative and lack the dense amyloid cores commonly present in Alzheimer disease. Some affected individuals manifest progressive aphasic dementia, leukoencephalopathy, and occipital calcifications. {ECO:0000269|PubMed:11409420, ECO:0000269|PubMed:12654973, ECO:0000269|PubMed:16178030, ECO:0000269|PubMed:20697050, ECO:0000269|PubMed:2111584}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.557
Intolerance Scores
- LoFtool
- 0.00427
- RVIS EVS
- -0.98
- RVIS percentile EVS
- 8.8
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.929
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |