APP
amyloid beta precursor protein, the group of Receptor ligands
Basic information
Region (hg38): 21:25880534-26171128
Previous symbols: [ "AD1" ]
Links
Phenotypes
GenCC
Source:
- Alzheimer disease type 1 (Strong), mode of inheritance: AD
- cerebral amyloid angiopathy, APP-related (Strong), mode of inheritance: AD
- early-onset autosomal dominant Alzheimer disease (Supportive), mode of inheritance: AD
- ABeta amyloidosis, dutch type (Supportive), mode of inheritance: AD
- ABetaL34V amyloidosis (Supportive), mode of inheritance: AD
- ABeta amyloidosis, Iowa type (Supportive), mode of inheritance: AD
- ABeta amyloidosis, Italian type (Supportive), mode of inheritance: AD
- ABetaA21G amyloidosis (Supportive), mode of inheritance: AD
- ABeta amyloidosis, Arctic type (Supportive), mode of inheritance: AD
- cerebral amyloid angiopathy, APP-related (Strong), mode of inheritance: AD
- Alzheimer disease type 1 (Strong), mode of inheritance: AD
Clinical Genomic Database
Source:
| Condition | Inheritance | Intervention Categories | Intervention/Rationale | Manifestation Categories | References |
|---|---|---|---|---|---|
| Alzheimer disease, familial; Cerebral amyloid angiopathy | AD | General | 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 | Cardiovascular; Neurologic | 2111584; 1679289; 1944558; 1671712; 1925564; 1678058; 1303275; 1303239; 1415269; 1520398; 1302033; 1642228; 8290042; 8154870; 9328472; 9754958; 10097173; 10441572; 11063718; 10821838; 11409420; 11528419; 12034808; 15365148; 15668448; 16033913; 16505331; 16369530; 16685645; 17325276; 18413473; 19047566; 19286555; 19225789; 22491860; 22702962; 22801501; 22815225; 23102935 |
ClinVar
This is a list of variants' phenotypes submitted to
- Alzheimer disease (298 variants)
- not provided (138 variants)
- not specified (19 variants)
- Alzheimer disease type 1 (12 variants)
- Inborn genetic diseases (12 variants)
- APP-related condition (8 variants)
- Alzheimer disease type 1;Cerebral amyloid angiopathy, APP-related (5 variants)
- Cerebral amyloid angiopathy, APP-related;Alzheimer disease type 1 (5 variants)
- Cerebral amyloid angiopathy, APP-related (5 variants)
- Primary degenerative dementia of the Alzheimer type, presenile onset (2 variants)
- Early-onset autosomal dominant Alzheimer disease (2 variants)
- Vascular dementia (1 variants)
- ABeta amyloidosis, Iowa type (1 variants)
- Alzheimer disease, protection against (1 variants)
- ABeta amyloidosis, dutch type (1 variants)
- See cases (1 variants)
- APP POLYMORPHISM (1 variants)
- Hereditary cerebral hemorrhage with amyloidosis (1 variants)
- Early-onset dementia of unclear type (1 variants)
Variants pathogenicity by type
Statistics on ClinVar variants can assist in determining whether a specific variant type in the APP gene is commonly pathogenic or not.
In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.
Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.
| Variant type | Pathogenic | Likely pathogenic | VUS | Likely benign | Benign | Sum |
|---|---|---|---|---|---|---|
| synonymous | 66 | 83 | ||||
| missense | 12 | 117 | 13 | 151 | ||
| nonsense | 0 | |||||
| start loss | 1 | |||||
| frameshift | 0 | |||||
| inframe indel | 8 | |||||
| splice donor/acceptor (+/-2bp) | 1 | |||||
| splice region ? | 14 | 7 | 2 | 23 | ||
| non coding ? | 22 | 48 | 63 | 133 | ||
| Total | 12 | 5 | 156 | 128 | 76 |
Variants in APP
This is a list of pathogenic ClinVar variants found in the APP region.
You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.
| Position | Type | Phenotype | Significance | ClinVar |
|---|---|---|---|---|
| 21-25880545-A-C | Early-onset autosomal dominant Alzheimer disease | Likely benign (Jun 14, 2016) | ||
| 21-25880655-A-C | Alzheimer disease | Uncertain significance (Jan 12, 2018) | ||
| 21-25880703-C-T | Alzheimer disease | Benign (Jan 12, 2018) | ||
| 21-25880756-C-T | Alzheimer disease | Benign (Jan 12, 2018) | ||
| 21-25880757-G-C | Alzheimer disease | Benign (Jan 13, 2018) | ||
| 21-25880860-G-A | Alzheimer disease | Uncertain significance (Mar 16, 2018) | ||
| 21-25880932-A-G | Alzheimer disease | Likely benign (Jan 13, 2018) | ||
| 21-25880935-C-T | Alzheimer disease | Uncertain significance (Jan 13, 2018) | ||
| 21-25880946-G-A | Alzheimer disease | Benign (Jan 12, 2018) | ||
| 21-25881007-G-A | Alzheimer disease | Likely benign (Jan 13, 2018) | ||
| 21-25881046-T-C | Alzheimer disease | Likely benign (Jan 12, 2018) | ||
| 21-25881080-G-T | Alzheimer disease | Likely benign (Apr 27, 2017) | ||
| 21-25881149-A-G | Alzheimer disease | Uncertain significance (Jan 13, 2018) | ||
| 21-25881181-T-C | Alzheimer disease | Uncertain significance (Jan 12, 2018) | ||
| 21-25881216-T-C | Alzheimer disease | Uncertain significance (Apr 27, 2017) | ||
| 21-25881298-T-C | Alzheimer disease | Likely benign (Jan 13, 2018) | ||
| 21-25881314-A-C | Alzheimer disease | Uncertain significance (Jan 12, 2018) | ||
| 21-25881315-T-C | Alzheimer disease | Uncertain significance (Apr 27, 2017) | ||
| 21-25881381-G-A | Alzheimer disease | Uncertain significance (Jan 13, 2018) | ||
| 21-25881476-T-G | Alzheimer disease | Uncertain significance (Jan 12, 2018) | ||
| 21-25881573-G-T | Alzheimer disease | Uncertain significance (Jan 12, 2018) | ||
| 21-25881652-G-A | Uncertain significance (Jun 01, 2016) | |||
| 21-25881663-C-T | Alzheimer disease | Uncertain significance (Jan 12, 2018) | ||
| 21-25881664-G-A | Uncertain significance (Apr 26, 2022) | |||
| 21-25881668-G-A | Uncertain significance (Sep 17, 2020) |
GnomAD
Source:
| Gene | Type | Bio Type | Transcript | Coding Exons | Length |
|---|---|---|---|---|---|
| APP | protein_coding | protein_coding | ENST00000346798 | 18 | 290586 |
| pLI Probability LOF Intolerant | pRec Probability LOF Recessive | Individuals with no LOFs | Individuals with Homozygous LOFs | Individuals with Heterozygous LOFs | Defined | p |
|---|---|---|---|---|---|---|
| 0.0465 | 0.953 | 125719 | 0 | 29 | 125748 | 0.000115 |
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible in Transcript | |
|---|---|---|---|---|---|---|
| Missense | 1.39 | 369 | 452 | 0.816 | 0.0000282 | 5100 |
| Missense in 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 |
LoF frequencies by population
| Ethnicity | Sum of pLOFs | p |
|---|---|---|
| African & African-American | 0.000242 | 0.000242 |
| Ashkenazi Jewish | 0.0000994 | 0.0000992 |
| East Asian | 0.000272 | 0.000272 |
| Finnish | 0.00 | 0.00 |
| European (Non-Finnish) | 0.000132 | 0.000132 |
| Middle Eastern | 0.000272 | 0.000272 |
| South Asian | 0.0000653 | 0.0000653 |
| Other | 0.000163 | 0.000163 |
dbNSFP
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.;
- Pathway
- 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;Copper homeostasis;TGF-beta Signaling Pathway;Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer,s disease models;Signaling by GPCR;Lysosome Vesicle Biogenesis;Clathrin derived vesicle budding;Toll Like Receptor 7/8 (TLR7/8) Cascade;Notch;trans-Golgi Network Vesicle Budding;Signal Transduction;Signaling by Interleukins;Vesicle-mediated transport;generation of amyloid b-peptide by ps1;platelet amyloid precursor protein pathway;Membrane Trafficking;Post-translational protein phosphorylation;Cytokine Signaling in Immune system;Toll Like Receptor 9 (TLR9) Cascade;MyD88 cascade initiated on plasma membrane;Toll Like Receptor 10 (TLR10) Cascade;Toll Like Receptor 3 (TLR3) Cascade;Toll Like Receptor 5 (TLR5) Cascade;ZBP1(DAI) mediated induction of type I IFNs;Toll-Like Receptors Cascades;Post-translational protein modification;TRAF6 mediated NF-kB activation;DDX58/IFIH1-mediated induction of interferon-alpha/beta;DEx/H-box helicases activate type I IFN and inflammatory cytokines production ;Metabolism of proteins;Interleukin-1 signaling;Innate Immune System;Immune System;Fibroblast growth factor-1;Formyl peptide receptors bind formyl peptides and many other ligands;Peptide ligand-binding receptors;Amyloid fiber formation;Class A/1 (Rhodopsin-like receptors);GPCR ligand binding;Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs);RIP-mediated NFkB activation via ZBP1;Platelet degranulation ;Response to elevated platelet cytosolic Ca2+;Platelet activation, signaling and aggregation;TAK1 activates NFkB by phosphorylation and activation of IKKs complex;EGFR1;TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation;Hemostasis;MyD88 dependent cascade initiated on endosome;G alpha (i) signalling events;Advanced glycosylation endproduct receptor signaling;Cytosolic sensors of pathogen-associated DNA ;TRIF(TICAM1)-mediated TLR4 signaling ;MyD88-independent TLR4 cascade ;Toll Like Receptor 4 (TLR4) Cascade;G alpha (q) signalling events;GPCR downstream signalling;MyD88:Mal cascade initiated on plasma membrane;Toll Like Receptor TLR1:TLR2 Cascade;Toll Like Receptor TLR6:TLR2 Cascade;Toll Like Receptor 2 (TLR2) Cascade;Caspase Cascade in Apoptosis;Glypican 1 network;p75(NTR)-mediated signaling;Interleukin-1 family signaling
(Consensus)
Recessive Scores
- pRec
- 0.557
Intolerance Scores
- loftool
- 0.00427
- rvis_EVS
- -0.98
- rvis_percentile_EVS
- 8.8
Haploinsufficiency Scores
- pHI
- 0.959
- hipred
- Y
- hipred_score
- 0.718
- ghis
- 0.606
Essentials
- essential_gene_CRISPR
- N
- essential_gene_CRISPR2
- N
- essential_gene_gene_trap
- N
- gene_indispensability_pred
- E
- gene_indispensability_score
- 0.929
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |
Mouse Genome Informatics
- Gene name
- App
- Phenotype
- hematopoietic system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); normal phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); reproductive system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); immune system phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); growth/size/body region phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); homeostasis/metabolism phenotype; cellular phenotype; muscle phenotype;
Zebrafish Information Network
- Gene name
- appb
- Affected structure
- secondary motor neuron
- Phenotype tag
- abnormal
- Phenotype quality
- decreased process quality
Gene ontology
- Biological process
- positive regulation of protein phosphorylation;suckling behavior;astrocyte activation involved in immune response;platelet degranulation;mRNA polyadenylation;regulation of translation;protein phosphorylation;cellular copper ion homeostasis;endocytosis;response to oxidative stress;cell adhesion;regulation of epidermal growth factor-activated receptor activity;G protein-coupled receptor signaling pathway;Notch signaling pathway;axonogenesis;learning or memory;learning;mating behavior;locomotory behavior;axo-dendritic transport;cholesterol metabolic process;negative regulation of cell population proliferation;adult locomotory behavior;visual learning;cellular process;response to lead ion;regulation of gene expression;positive regulation of gene expression;negative regulation of gene expression;positive regulation of peptidyl-threonine phosphorylation;negative regulation of endopeptidase activity;positive regulation of peptidase activity;positive regulation of G2/M transition of mitotic cell cycle;microglia development;axon midline choice point recognition;neuron remodeling;dendrite development;regulation of Wnt signaling pathway;extracellular matrix organization;forebrain development;neuron projection development;positive regulation of protein binding;tumor necrosis factor production;positive regulation of peptidyl-serine phosphorylation;ionotropic glutamate receptor signaling pathway;regulation of multicellular organism growth;positive regulation of phosphorylation;post-translational protein modification;cellular protein metabolic process;innate immune response;negative regulation of neuron differentiation;positive regulation of mitotic cell cycle;positive regulation of transcription by RNA polymerase II;positive regulation of JNK cascade;astrocyte activation;regulation of long-term neuronal synaptic plasticity;collateral sprouting in absence of injury;regulation of peptidyl-tyrosine phosphorylation;regulation of synapse structure or activity;synapse organization;neuromuscular process controlling balance;cognition;positive regulation of DNA-binding transcription factor activity;positive regulation of NF-kappaB transcription factor activity;synaptic growth at neuromuscular junction;positive regulation of protein metabolic process;neuron apoptotic process;smooth endoplasmic reticulum calcium ion homeostasis;positive regulation of astrocyte activation;positive regulation of ERK1 and ERK2 cascade;cellular response to copper ion;cellular response to manganese ion;cellular response to cAMP;cellular response to norepinephrine stimulus;modulation of age-related behavioral decline;modulation of excitatory postsynaptic potential;regulation of spontaneous synaptic transmission;negative regulation of long-term synaptic potentiation;positive regulation of long-term synaptic potentiation;positive regulation of NIK/NF-kappaB signaling;positive regulation of amyloid-beta formation;positive regulation of microglial cell activation;cellular response to amyloid-beta;negative regulation of low-density lipoprotein receptor activity;regulation of presynapse assembly;positive regulation of amyloid fibril formation;amyloid fibril formation;cellular response to nerve growth factor stimulus;neuron projection maintenance;positive regulation of signaling receptor activity;regulation of NMDA receptor activity;positive regulation of T cell migration
- Cellular component
- extracellular region;extracellular space;nuclear envelope lumen;cytoplasm;endosome;early endosome;endoplasmic reticulum lumen;smooth endoplasmic reticulum;rough endoplasmic reticulum;Golgi apparatus;Golgi lumen;Golgi-associated vesicle;cytosol;plasma membrane;integral component of plasma membrane;clathrin-coated pit;cell-cell junction;cell surface;integral component of membrane;COPII-coated ER to Golgi transport vesicle;axon;platelet alpha granule lumen;neuromuscular junction;endosome lumen;trans-Golgi network membrane;ciliary rootlet;dendritic spine;dendritic shaft;perikaryon;receptor complex;main axon;membrane raft;apical part of cell;synapse;perinuclear region of cytoplasm;presynaptic active zone;spindle midzone;recycling endosome;extracellular exosome;astrocyte projection;growth cone lamellipodium;growth cone filopodium
- Molecular function
- DNA binding;serine-type endopeptidase inhibitor activity;signaling receptor binding;protein binding;heparin binding;peptidase activator activity;enzyme binding;receptor activator activity;identical protein binding;transition metal ion binding;PTB domain binding;growth factor receptor binding