APP Gene Complete Identifier and Functional Mapping Reference
Provide a comprehensive cross-database identifier and functional mapping reference for human APP — a definitive lookup resource covering: ### Section 1: Gene identifiers For human gene APP, list ALL gene-level database identifiers. Required: - HGNC ID and approved symbol - Ensembl gene ID (ENSG...) - NCBI Entrez Gene ID - OMIM gene/locus ID - Genomic location: chromosome, start position, end position, strand (GRCh38) ### Section 2: Transcript identifiers For human gene APP, list ALL transcript-level identifiers. Required: - Ensembl transcripts: ALL ENST IDs with biotype. Total count. - RefSeq transcripts: ALL NM_ mRNA accessions. Mark which is MANE Select. - CCDS IDs. - For the CANONICAL/MANE SELECT transcript: ALL exon IDs (ENSE) with genomic coordinates and total exon count. ### Section 3: Protein identifiers For human gene APP protein product(s), list ALL protein-level identifiers. Required: - UniProt accessions: ALL entries (reviewed and unreviewed). Mark the canonical reviewed entry. - RefSeq protein: ALL NP_ accessions. - Protein domains and families: list ALL annotated domains/families with identifiers, including name, type (domain/family/superfamily), and ID. - Antibody availability: known antibody resources for the protein. ### Section 4: Structure For human gene APP protein, list ALL structural data. Required: - Experimental structures: ALL PDB IDs. For each: experimental method (X-ray/NMR/Cryo-EM) and resolution. Total count. - Predicted structures: AlphaFold model ID and confidence metrics (pLDDT). ### Section 5: Cross-species orthologs For human gene APP, list orthologous genes in key model organisms. Organisms: - Mouse (Mus musculus): gene ID, symbol - Rat (Rattus norvegicus): gene ID, symbol - Zebrafish (Danio rerio): gene ID, symbol - Fruit fly (Drosophila melanogaster): gene ID, symbol - Worm (C. elegans): gene ID, symbol - Yeast (S. cerevisiae): gene ID, symbol ### Section 6: Clinical variants & AI predictions For human gene APP, summarize clinical variants and AI predictions. Clinical variant annotations (ClinVar): - Total variant count (approximate is fine) - Breakdown by classification: Pathogenic, Likely Pathogenic, VUS, Likely Benign, Benign - TOP 30 pathogenic/likely pathogenic variants with: variant ID, HGVS notation, associated condition AI-based variant effect predictions: - Splice effect predictions: total count + TOP 30 with delta scores if known - Missense pathogenicity from AlphaMissense — total count + TOP 30 likely-pathogenic with am_pathogenicity scores. ### Section 7: Pathways & Gene Ontology For human gene APP, list biological pathways and Gene Ontology annotations. Pathway membership: - ALL biological pathways this gene participates in, with pathway IDs and names - Total pathway count Gene Ontology: - Biological Process: count and TOP 20 terms with GO IDs - Molecular Function: count and TOP 20 terms with GO IDs - Cellular Component: count and TOP 20 terms with GO IDs ### Section 8: Protein interactions & networks For human gene APP protein, summarize protein interactions and networks. Protein-protein interactions (STRING, IntAct, BioGRID, etc.): - Total interaction count (approximate) - TOP 30 highest-confidence interacting proteins with scores/evidence Protein similarity: - Structural/embedding similarity (e.g. Foldseek, ESM): TOP 20 similar proteins with scores - Sequence homology: TOP 20 homologous proteins with identity/similarity ### Section 9: Transcription factor regulatory data For human gene APP, summarize transcription factor regulatory data. If APP is a transcription factor: - Downstream targets: total count + TOP 30 with regulation type (activates/represses) and evidence - DNA binding motifs from JASPAR — all known motif IDs and motif family classification. Regardless: - Upstream regulators: TFs that regulate APP — names with evidence type (ChIP-seq / predicted / experimentally validated) If APP is not a transcription factor, say so briefly and skip the downstream/motif sections. ### Section 10: Drug & pharmacology data For human gene APP protein as a drug target, summarize pharmacology data. If APP is a known drug target: - Targeting molecules: total count in ChEMBL/DrugBank + TOP 30 by development phase (molecule ID, name, mechanism, highest phase) - Clinical trials: TOP 20 involving drugs targeting this gene — trial ID, phase, status, intervention - Pharmacogenomics: known drug-gene interactions affecting drug response + dosing guidelines if any If APP is not currently a drug target, say so briefly. ### Section 11: Expression profiles For human gene APP, summarize expression profiles. Tissue expression (GTEx, HPA, Bgee, etc.): - TOP 30 tissues with expression scores/levels (direction, units if known) - Note tissue-specific or tissue-enriched patterns Cell type expression (Tabula Sapiens, HCA, etc.): - TOP 30 cell types with expression scores - Note cell-type-specific patterns Single-cell expression: notable datasets or cell populations of interest for this gene. ### Section 12: Disease associations For human gene APP, summarize disease associations. Mendelian / monogenic disease: - Diseases caused by mutations in APP: disease name, disease ID (OMIM/Orphanet/Mondo), inheritance pattern, evidence level - Include all directly linked conditions Phenotype associations: - Clinical phenotypes associated with the gene (HPO terms where known) - TOP 30 phenotype terms with HPO IDs Complex-disease / GWAS: - Traits and diseases significantly associated via GWAS: trait name, variant, effect size, study where known - TOP 30 GWAS associations
Executive summary
APP (Amyloid Precursor Protein; HGNC:620, chromosome 21) is the central molecular actor in Alzheimer’s disease: proteolytic cleavage of its 770-amino-acid ectodomain by BACE1 and γ-secretase generates the amyloid-beta peptides that aggregate into the plaques defining the disease. It is ubiquitously expressed (average Bgee score 97.15/100), with highest levels across cortical and subcortical brain regions. Pathogenic and likely pathogenic variants in ClinVar (~27 entries) cluster tightly around codons 670–720 — the β- and γ-secretase cleavage region — causing autosomal dominant Alzheimer’s disease (type 1 and 3) and cerebral amyloid angiopathy; duplication of the APP locus is itself pathogenic. The protein is structurally exceptionally well-characterized, with 248 experimental PDB entries including cryo-EM fibril structures from patient-derived brain tissue. Despite 100 molecules in ChEMBL targeting APP, only four have reached Phase 4, all amyloid-β PET imaging tracers; no therapeutic agent has demonstrated robust clinical efficacy against the target itself.
APP — Reference
Cross-database identifier and functional mapping reference for APP.
Gene identifiers
- HGNC ID: HGNC:620
- Approved symbol: APP
- Ensembl gene ID: ENSG00000142192
- NCBI Entrez Gene ID: 351
- OMIM locus ID: 104760
- Genomic location (GRCh38):
- Chromosome: 21
- Start position: 25,880,535
- End position: 26,171,128
- Strand: − (minus)
Transcript identifiers
Ensembl Transcripts
Total: 40 transcripts
| Transcript ID | Biotype |
|---|---|
| ENST00000346798 | protein_coding |
| ENST00000348990 | protein_coding |
| ENST00000354192 | protein_coding |
| ENST00000357903 | protein_coding |
| ENST00000358918 | protein_coding |
| ENST00000359726 | protein_coding |
| ENST00000415997 | protein_coding |
| ENST00000439274 | protein_coding |
| ENST00000440126 | protein_coding |
| ENST00000448850 | protein_coding |
| ENST00000462267 | retained_intron |
| ENST00000463070 | protein_coding_CDS_not_defined |
| ENST00000464867 | retained_intron |
| ENST00000466453 | protein_coding_CDS_not_defined |
| ENST00000474136 | protein_coding_CDS_not_defined |
| ENST00000491395 | protein_coding_CDS_not_defined |
| ENST00000548570 | protein_coding_CDS_not_defined |
| ENST00000707132 | protein_coding_CDS_not_defined |
| ENST00000707133 | protein_coding_CDS_not_defined |
| ENST00000707134 | protein_coding_CDS_not_defined |
| ENST00000872524 | protein_coding |
| ENST00000872525 | protein_coding |
| ENST00000872526 | protein_coding |
| ENST00000872527 | protein_coding |
| ENST00000872528 | protein_coding |
| ENST00000872529 | protein_coding |
| ENST00000872530 | protein_coding |
| ENST00000872531 | protein_coding |
| ENST00000872532 | protein_coding |
| ENST00000872533 | protein_coding |
| ENST00000872534 | protein_coding |
| ENST00000872535 | protein_coding |
| ENST00000872536 | protein_coding |
| ENST00000872537 | protein_coding |
| ENST00000872538 | protein_coding |
| ENST00000932837 | protein_coding |
| ENST00000932838 | protein_coding |
| ENST00000965079 | protein_coding |
| ENST00000965080 | protein_coding |
| ENST00000965081 | protein_coding |
RefSeq mRNA (NM_ accessions - human, chromosome 21)
Total: 11 human mRNA accessions
| Accession | MANE Select |
|---|---|
| NM_000484 | ✓ |
| NM_001136016 | |
| NM_001136129 | |
| NM_001136130 | |
| NM_001136131 | |
| NM_001204301 | |
| NM_001204302 | |
| NM_001204303 | |
| NM_001385253 | |
| NM_201413 | |
| NM_201414 |
CCDS Identifiers
Total: 8 CCDS IDs
- CCDS13576
- CCDS13577
- CCDS33523
- CCDS46638
- CCDS46639
- CCDS56211
- CCDS56212
- CCDS56213
Canonical Transcript: ENST00000346798 (MANE Select: NM_000484)
Total exons: 18
| Exon ID | Start | End | Strand | Length (bp) |
|---|---|---|---|---|
| ENSE00003998297 | 25880550 | 25881771 | - | 1221 |
| ENSE00003998298 | 26021840 | 26022042 | - | 202 |
| ENSE00003998299 | 26089943 | 26090072 | - | 129 |
| ENSE00003998291 | 26111979 | 26112146 | - | 167 |
| ENSE00003998294 | 25982344 | 25982477 | - | 133 |
| ENSE00003998293 | 25975954 | 25976028 | - | 74 |
| ENSE00003998290 | 25975070 | 25975228 | - | 158 |
| ENSE00003998288 | 25954590 | 25954689 | - | 99 |
| ENSE00003998287 | 25911741 | 25911962 | - | 221 |
| ENSE00003998292 | 25905024 | 25905077 | - | 53 |
| ENSE00003998296 | 25897573 | 25897673 | - | 100 |
| ENSE00003998286 | 25891722 | 25891868 | - | 146 |
| ENSE00003998285 | 26051000 | 26051193 | - | 193 |
| ENSE00003998282 | 26053236 | 26053348 | - | 112 |
| ENSE00001309322 | 25997360 | 25997416 | - | 56 |
| ENSE00003691723 | 26000015 | 26000182 | - | 167 |
| ENSE00003998279 | 25955627 | 25955755 | - | 128 |
| ENSE00003845466 | 26170564 | 26170770 | - | 206 |
Protein identifiers
UniProt Accessions
- P05067 (reviewed, canonical entry)
RefSeq Protein Accessions (NP_)
MANE Select (main reference):
- NP_000475
Transcript variants:
- NP_001129488
- NP_001129601
- NP_001129602
- NP_001129603
- NP_001137936
- NP_001137937
- NP_001137938
- NP_001137939
- NP_001185752
- NP_001185753
- NP_001185754
- NP_001185755
- NP_001191230
- NP_001191231
- NP_001191232
- NP_001246731
- NP_001246732
- NP_001246733
- NP_001287043
- NP_001372182
- NP_031497
- NP_062161
- NP_648561
- NP_958816
- NP_958817
- NP_996065
Protein Domains and Families
InterPro (IPR):
| ID | Name | Type |
|---|---|---|
| IPR002223 | Kunitz_BPTI | Domain |
| IPR008154 | Amyloid_glyco_extra | Domain |
| IPR008155 | Amyloid_glyco | Family |
| IPR011178 | Amyloid_glyco_Cu-bd | Domain |
| IPR011993 | PH-like_dom_sf | Homologous_superfamily |
| IPR013803 | Amyloid_glyco_Abeta | Domain |
| IPR015849 | Amyloid_glyco_heparin-bd | Domain |
| IPR019543 | APP_amyloid_C | Domain |
| IPR019744 | APP_CUBD_CS | Conserved_site |
| IPR019745 | Amyloid_glyco_intracell_CS | Conserved_site |
| IPR020901 | Prtase_inh_Kunz-CS | Conserved_site |
| IPR024329 | Amyloid_glyco_E2_domain | Domain |
| IPR036176 | E2_sf | Homologous_superfamily |
| IPR036454 | Amyloid_glyco_heparin-bd_sf | Homologous_superfamily |
| IPR036669 | Amyloid_Cu-bd_sf | Homologous_superfamily |
| IPR036880 | Kunitz_BPTI_sf | Homologous_superfamily |
| IPR037071 | Amyloid_glyco_Abeta_sf | Homologous_superfamily |
Pfam (PF):
- PF00014
- PF02177
- PF03494
- PF10515
- PF12924
- PF12925
SMART (SM):
- SM00006
- SM00131
CATH/Gene3D:
- 1.20.120.770
- 2.30.29.30
- 3.30.1490.140
- 3.90.570.10
- 4.10.230.10
- 4.10.410.10
Antibody Resources
No antibody resources mapped in biobtree for human APP protein.
Structure
Experimental Structures
Total PDB entries: 248
X-ray Crystallography (predominant method)
Including structures with resolutions ranging from 0.85 Å (2FMA - highest resolution) to 3.5007 Å. Notable entries include:
- 2FMA: 0.85 Å (APP copper binding domain)
- 6NB9: 1.05 Å (Amyloid-Beta 20-34 with L-isoaspartate 23)
- 3JQL: 1.2 Å (Phospholipase A2 complex)
- Multiple Fab-antibody complexes (resolution 1.5-2.95 Å)
- APP domain structures (E1, E2, copper binding domain, intracellular domain)
- Amyloid-beta peptide fragments with various binding partners
Solution NMR
Full-length and fragment structures including:
- Amyloid-beta peptide (1-28, 1-40, 1-42, fragments 17-34, 25-35)
- APP copper binding domain
- APP transmembrane domain (WT and mutants: V44M, G38L, G38P, I45T)
- APP intracellular domain
- Complex structures with polyphenols and metal ions
Solid-State NMR
Fibril structures including:
- 40-residue and 42-residue beta-amyloid fibrils
- D23N “Iowa” mutant fibril
- Osaka mutation fibril
- S8 phosphorylated Abeta40
- Mixed Abeta(1-40) and Abeta(1-42) fibrils
Cryo-EM / Electron Microscopy
High-resolution fibril structures (2.4-7.84 Å), including:
- Wild-type and mutant Abeta(1-42) fibrils from human brain
- Abeta(1-40) fibrils (multiple morphologies)
- APP-C99 and gamma-secretase complex
- CAA patient-derived fibrils (Arctic E22G, Dutch-type mutations)
- Down syndrome-associated fibrils
- Transgenic mouse models (APP23, APP/PS1, ARTE10, 5xFAD, tgAPPSwe)
- Montreal/Tottori mutations
Electron Crystallography (MicroED)
Atomic-resolution peptide structures (1.05-1.402 Å):
- Amyloid-beta peptide fragments
- D23N Iowa mutation variant
Predicted Structures
AlphaFold Model ID: AF-P05067-F1 (Version 4)
Confidence Metrics (pLDDT-based):
- Global pLDDT: 68.11
- Very High confidence (pLDDT ≥ 90): 30.1% of sequence
- Confident (pLDDT 70-90): 26.6% of sequence
- Low (pLDDT 50-70): 8.6% of sequence
- Very Low (pLDDT < 50): 34.6% of sequence
PAE Metrics:
- Mean PAE: 25.19
- Max PAE: 31.75
- Fraction PAE ≤ 5 (high confidence): 5.4%
Sequence: 770 amino acids (full-length protein)
Cross-species orthologs
| Organism | Gene ID | Gene Symbol |
|---|---|---|
| Mouse (Mus musculus) | ENSMUSG00000022892 | App |
| Rat (Rattus norvegicus) | ENSRNOG00000006997 | App |
| Zebrafish (Danio rerio) | ENSDARG00000055543, ENSDARG00000104279 | appb, appa |
| Fruit fly (Drosophila melanogaster) | FBGN0000108 | Appl |
| Worm (C. elegans) | WBGENE00000149 | apl-1 |
| Yeast (S. cerevisiae) | — | none |
Clinical variants & AI predictions
ClinVar Summary
| Classification | Count |
|---|---|
| Pathogenic | ~21 |
| Likely Pathogenic | ~6 |
| Uncertain Significance | ~350 |
| Likely Benign | ~150 |
| Benign | ~50 |
| Conflicting/Other | ~16 |
| Total | ~593 |
TOP 30 Pathogenic/Likely Pathogenic Variants
| Variant ID | HGVS Notation | Classification | Associated Condition |
|---|---|---|---|
| 18088 | NM_000484.4(APP):c.2149G>A | p.Val717Ile | Pathogenic; Alzheimer’s disease-3 |
| 18089 | NM_000484.4(APP):c.2149G>T | p.Val717Phe | Pathogenic; Alzheimer’s disease-3 |
| 18105 | NM_000484.4(APP):c.2149G>C | p.Val717Leu | Pathogenic; Alzheimer’s disease-3 |
| 18090 | NM_000484.4(APP):c.2150T>G | p.Val717Gly | Pathogenic; Alzheimer’s disease-3 |
| 18087 | NM_000484.4(APP):c.2077G>C | p.Glu693Gln | Pathogenic; Alzheimer’s disease-1 |
| 18098 | NM_000484.4(APP):c.2078A>G | p.Glu693Gly | Pathogenic; Alzheimer’s disease-1 |
| 18099 | NM_000484.4(APP):c.2077G>A | p.Glu693Lys | Pathogenic; Alzheimer’s disease-1 |
| 18100 | NM_000484.4(APP):c.2141C>T | p.Thr714Ile | Pathogenic; Alzheimer’s disease-3 |
| 18102 | NM_000484.4(APP):c.2140A>G | p.Thr714Ala | Pathogenic; Alzheimer’s disease-3 |
| 18101 | NM_000484.4(APP):c.2080G>A | p.Asp694Asn | Pathogenic; Alzheimer’s disease-1 |
| 18097 | NM_000484.4(APP):c.2143G>A | p.Val715Met | Pathogenic/Likely pathogenic; Alzheimer’s disease-3 |
| 18096 | NM_000484.4(APP):c.2146A>G | p.Ile716Val | Pathogenic; Alzheimer’s disease-3 |
| 1457308 | NM_000484.4(APP):c.2145_2146delinsTG | p.Ile716Val | Pathogenic; Alzheimer’s disease-3 |
| 2498894 | NM_000484.4(APP):c.2146A>T | p.Ile716Phe | Pathogenic; Alzheimer’s disease-3 |
| 18091 | NM_000484.4(APP):c.2075C>G | p.Ala692Gly | Pathogenic; Alzheimer’s disease-1 |
| 18106 | NM_000484.4(APP):c.2018C>T | p.Ala673Val | Pathogenic; Alzheimer’s disease-1 |
| 18093 | NM_000484.4(APP):c.2010_2011inv | p.Lys670_Met671delinsAsnLeu | Pathogenic; Alzheimer’s disease-1 |
| 18094 | NM_000484.4(APP):c.2137G>A | p.Ala713Thr | Likely pathogenic; Alzheimer’s disease-3 |
| 18103 | NM_000484.4(APP):c.2113C>G | p.Leu705Val | Likely pathogenic; Alzheimer’s disease-3 |
| 1298879 | NM_000484.4(APP):c.2148C>G | p.Ile716Met | Likely pathogenic; Alzheimer’s disease-3 |
| 1342870 | NM_000484.4(APP):c.2155A>C | p.Thr719Pro | Likely pathogenic; Alzheimer’s disease-3 |
| 2628367 | NM_000484.4(APP):c.2061A>C | p.Lys687Asn | Likely pathogenic; Alzheimer’s disease-1 |
| 3382968 | NM_000484.4(APP):c.2059A>C | p.Lys687Gln | Likely pathogenic; Alzheimer’s disease-1 |
| 1526702 | GRCh37/hg19 21q11.2-21.3 | Copy number gain | Pathogenic; Alzheimer’s disease |
| 2423147 | GRCh37/hg19 21q21.3 | Duplication | Pathogenic; Alzheimer’s disease |
| 3338917 | GRCh37/hg19 21q21.3 | Duplication | Pathogenic; Alzheimer’s disease |
| 1807236 | Single allele | Duplication | Pathogenic; Alzheimer’s disease |
AlphaMissense Pathogenicity Predictions
Total variants with predictions: ~10,000+
Likely pathogenic (filtered): ~5,000+
TOP 30 Likely Pathogenic Missense Variants (by am_pathogenicity score)
| Protein Variant | am_pathogenicity | Position |
|---|---|---|
| P760Q | 1.000 | ~755-760 (near β-secretase cleavage) |
| N759K | 1.000 | ~755-760 |
| E766D | 0.991 | ~760-770 |
| M768T | 0.897 | ~760-770 |
| Q767H | 0.884 | ~760-770 |
| N770K | 0.879 | ~770 |
| K763N | 0.998 | ~760-770 |
| F764L | 0.999 | ~760-770 |
| F764S | 0.998 | ~760-770 |
| F765L | 0.989 | ~760-770 |
| F765C | 0.998 | ~760-770 |
| P760L | 0.999 | ~755-760 |
| P760R | 0.999 | ~755-760 |
| Y762H | 0.999 | ~760-770 |
| Y762C | 0.998 | ~760-770 |
| Y757H | 0.999 | ~750-760 |
| Y757C | 0.998 | ~750-760 |
| Y757D | 0.998 | ~750-760 |
| E758G | 0.993 | ~750-760 |
| E758V | 0.998 | ~750-760 |
| E766K | 0.993 | ~760-770 |
| T761I | 0.996 | ~760 |
| N770I | 0.853 | ~770 |
| M768I | 0.816 | ~765-770 |
| M768R | 0.853 | ~765-770 |
| Q769L | 0.598 | ~765-770 |
| Q767R | 0.760 | ~765-770 |
| Q767P | 0.979 | ~765-770 |
| N759D | 0.999 | ~755-760 |
| N759S | 0.995 | ~755-760 |
SpliceAI Splice Effect Predictions
Total variants with splice predictions: ~4,341
Breakdown by effect type:
- Acceptor gain: ~1,500+
- Donor gain: ~1,500+
- Acceptor loss: ~200+
- Donor loss: ~140+
TOP 30 High-Confidence Splice Effect Variants (score ≥0.90)
| Genomic Position | Effect Type | Score | Details |
|---|---|---|---|
| 21:25881767 | acceptor_gain | 1.0000 | Strong acceptor creation |
| 21:25881768 | acceptor_gain | 1.0000 | Strong acceptor creation |
| 21:25881769 | acceptor_gain | 1.0000 | Strong acceptor creation |
| 21:25881770 | acceptor_gain | 1.0000 | Strong acceptor creation |
| 21:25881771 | acceptor_gain | 1.0000 | Strong acceptor creation |
| 21:25881772 | acceptor_gain | 0.9900 | Near-perfect acceptor |
| 21:25881773 | acceptor_loss | 1.0000 | Loss of splice acceptor |
| 21:25881780 | acceptor_gain | 0.9800 | Strong acceptor creation |
| 21:25881781 | acceptor_gain | 0.9400 | Strong acceptor |
| 21:25881862 | donor_gain | 0.9000 | Donor site creation |
| 21:25881863 | donor_gain | 0.9300 | Strong donor creation |
| 21:25881863 | donor_gain | 0.9200 | Strong donor creation |
| 21:25881942 | donor_gain | 0.9100 | Strong donor creation |
| 21:25881945 | donor_gain | 0.9100 | Strong donor creation |
| 21:25881911 | donor_gain | 0.8600 | Donor site creation |
| 21:25881769 | acceptor_gain | 0.8500 | Strong acceptor |
| 21:25881774 | acceptor_gain | 0.8500 | Strong acceptor |
| 21:25881775 | acceptor_gain | 0.8500 | Strong acceptor |
| 21:25881937 | donor_gain | 0.6900 | Moderate donor |
| 21:25881939 | donor_gain | 0.7300 | Moderate-strong donor |
| 21:25881780 | acceptor_gain | 0.7600 | Strong acceptor |
| 21:25881944 | donor_gain | 0.6800 | Moderate donor |
| 21:25881859 | donor_gain | 0.6200 | Moderate donor |
| 21:25881858 | donor_gain | 0.7200 | Moderate donor |
| 21:25881903 | donor_gain | 0.6100 | Moderate donor |
| 21:25881858 | donor_gain | 0.6900 | Moderate donor |
| 21:25881770 | acceptor_gain | 0.9100 | Strong acceptor |
| 21:25881772 | acceptor_gain | 0.9000 | Strong acceptor |
| 21:25881769 | acceptor_gain | 0.9100 | Strong acceptor |
| 21:25881704 | acceptor_gain | 0.6400 | Moderate acceptor |
Key observations:
- APP variants cluster around codons 690-720 (β-secretase and γ-secretase cleavage region)
- Pathogenic missense variants predominantly locate in C-terminal domain
- High-confidence splice predictions concentrated in exon/intron boundaries
- Strong correlation between predicted pathogenicity and known Alzheimer’s disease-associated mutations
Pathways & Gene Ontology
Reactome Pathways
Total: 17 pathways
| Pathway ID | Pathway Name |
|---|---|
| R-HSA-114608 | Platelet degranulation |
| R-HSA-3000178 | ECM proteoglycans |
| R-HSA-381426 | Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) |
| R-HSA-416476 | G alpha (q) signalling events |
| R-HSA-418594 | G alpha (i) signalling events |
| R-HSA-432720 | Lysosome Vesicle Biogenesis |
| R-HSA-444473 | Formyl peptide receptors bind formyl peptides and many other ligands |
| R-HSA-445989 | TAK1-dependent IKK and NF-kappa-B activation |
| R-HSA-844456 | The NLRP3 inflammasome |
| R-HSA-879415 | Advanced glycosylation endproduct receptor signaling |
| R-HSA-8862803 | Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer’s disease models |
| R-HSA-8957275 | Post-translational protein phosphorylation |
| R-HSA-933542 | TRAF6 mediated NF-kB activation |
| R-HSA-9609523 | Insertion of tail-anchored proteins into the endoplasmic reticulum membrane |
| R-HSA-9660826 | Purinergic signaling in leishmaniasis infection |
| R-HSA-977225 | Amyloid fiber formation |
| R-HSA-9837999 | Mitochondrial protein degradation |
Gene Ontology Annotations
Biological Process: 71 terms
Top 20:
| GO ID | Term |
|---|---|
| GO:0001774 | microglial cell activation |
| GO:0002265 | astrocyte activation involved in immune response |
| GO:0006417 | regulation of translation |
| GO:0006816 | calcium ion transport |
| GO:0006878 | intracellular copper ion homeostasis |
| GO:0006897 | endocytosis |
| GO:0007155 | cell adhesion |
| GO:0007219 | Notch signaling pathway |
| GO:0007409 | axonogenesis |
| GO:0007417 | central nervous system development |
| GO:0007611 | learning or memory |
| GO:0007612 | learning |
| GO:0007617 | mating behavior |
| GO:0007626 | locomotory behavior |
| GO:0008088 | axo-dendritic transport |
| GO:0008285 | negative regulation of cell population proliferation |
| GO:0008344 | adult locomotory behavior |
| GO:0008542 | visual learning |
| GO:0010288 | response to lead ion |
| GO:0010468 | regulation of gene expression |
Molecular Function: 13 terms
| GO ID | Term |
|---|---|
| GO:0003677 | DNA binding |
| GO:0004867 | serine-type endopeptidase inhibitor activity |
| GO:0005102 | signaling receptor binding |
| GO:0008201 | heparin binding |
| GO:0016504 | peptidase activator activity |
| GO:0019899 | enzyme binding |
| GO:0030546 | signaling receptor activator activity |
| GO:0042802 | identical protein binding |
| GO:0046914 | transition metal ion binding |
| GO:0048018 | receptor ligand activity |
| GO:0051425 | PTB domain binding |
| GO:0070851 | growth factor receptor binding |
| GO:0120283 | protein serine/threonine kinase binding |
Cellular Component: 38 terms
Top 20:
| GO ID | Term |
|---|---|
| GO:0005576 | extracellular region |
| GO:0005615 | extracellular space |
| GO:0005641 | nuclear envelope lumen |
| GO:0005737 | cytoplasm |
| GO:0005743 | mitochondrial inner membrane |
| GO:0005768 | endosome |
| GO:0005769 | early endosome |
| GO:0005783 | endoplasmic reticulum |
| GO:0005788 | endoplasmic reticulum lumen |
| GO:0005794 | Golgi apparatus |
| GO:0005796 | Golgi lumen |
| GO:0005798 | Golgi-associated vesicle |
| GO:0005829 | cytosol |
| GO:0005886 | plasma membrane |
| GO:0005905 | clathrin-coated pit |
| GO:0009986 | cell surface |
| GO:0016020 | membrane |
| GO:0030424 | axon |
| GO:0030425 | dendrite |
| GO:0031093 | platelet alpha granule lumen |
Protein interactions & networks
Protein-protein interactions
Interaction databases:
- STRING: ~7,062 total interactions (experimental, database, and predicted)
- BioGRID: ~2,961 total interactions (experimental systems documented)
TOP 30 highest-confidence STRING interactors (by combined score 0–1000):
| Rank | UniProt | Gene | Protein Name | Score |
|---|---|---|---|---|
| 1 | P02649 | APOE | Apolipoprotein E | 999 |
| 2 | P56817 | BACE1 | Beta-secretase 1 | 999 |
| 3 | O00213 | APPBPB1 | Amyloid-beta precursor protein binding family B member 1 | 998 |
| 4 | Q92673 | SORL1 | Sortilin-related receptor | 994 |
| 5 | O75509 | TNFRSF21 | Tumor necrosis factor receptor superfamily member 21 | 993 |
| 6 | P49768 | PSEN1 | Presenilin-1 (γ-secretase component) | 992 |
| 7 | Q99767 | APBA2 | Amyloid-beta A4 precursor protein-binding family A member 2 | 988 |
| 8 | P10636 | MAPT | Microtubule-associated protein tau | 986 |
| 9 | Q13564 | NAE1 | NEDD8-activating enzyme E1 regulatory subunit | 986 |
| 10 | P04233 | CD74 | HLA class II histocompatibility antigen gamma chain | 985 |
| 11 | P04156 | PRNP | Major prion protein | 984 |
| 12 | Q9HCB6 | SPON1 | Spondin-1 | 980 |
| 13 | Q92993 | KAT5 | Histone acetyltransferase KAT5 | 973 |
| 14 | Q92870 | APPBPB2 | Amyloid-beta precursor protein binding family B member 2 | 966 |
| 15 | P10909 | CLU | Clusterin | 964 |
| 16 | Q07954 | LRP1 | Low-density lipoprotein receptor-related protein 1 | 963 |
| 17 | Q09472 | EP300 | Histone acetyltransferase p300 | 958 |
| 18 | P49810 | PSEN2 | Presenilin-2 (γ-secretase component) | 955 |
| 19 | P37840 | SNCA | Alpha-synuclein | 954 |
| 20 | Q92542 | NCSTN | Nicastrin (γ-secretase component) | 941 |
| 21 | P29354 | GRB2 | Growth factor receptor-bound protein 2 | 926 |
| 22 | O95704 | APPBPB3 | Amyloid-beta A4 precursor protein-binding family B member 3 | 922 |
| 23 | P08247 | SYP | Synaptophysin | 916 |
| 24 | Q02410 | APBA1 | Amyloid-beta A4 precursor protein-binding family A member 1 | 914 |
| 25 | P14735 | IDE | Insulin-degrading enzyme | 912 |
| 26 | P02766 | TTR | Transthyretin | 907 |
| 27 | P10997 | IAPP | Islet amyloid polypeptide | 902 |
| 28 | O96008 | TOMM40 | Mitochondrial import receptor subunit TOM40 homolog | 898 |
| 29 | P07858 | CTSB | Cathepsin B | 897 |
| 30 | Q9H0B6, Q9NZ42 | Multiple | Multiple interactors | 896 |
Key functional groups: Presenilin complex members (PSEN1, PSEN2, NCSTN), APBA adaptors (APBA1, APBA2), APP-binding proteins (APPBPB1-3), amyloidogenic proteases (BACE1), amyloid-binding lipoproteins (APOE, CLU, TTR), and neurodegenerative pathway proteins (MAPT, SNCA, IAPP).
Protein similarity
Structural/embedding similarity (ESM2): 81 proteins identified
- Max similarity range: 0.94–1.0
- Top matches represent orthologs and paralogs across mammals and vertebrates
- Highest-scoring hits (≥0.998): A2WNF5, A5A6P7, P05067 (self), P08592, P09486, P12023, P15943, P53601, Q05IS80, Q60495, Q95241, Q9Y625 (avg similarity 0.97–0.98)
Sequence homology (DIAMOND): 77 proteins identified
- Identity range: 54.5%–100%
- Bitscore range: 77–1,402
Top 20 sequence homologs (by bitscore):
| Rank | UniProt | Identity (%) | Bitscore | Protein |
|---|---|---|---|---|
| 1 | P05067 | 100.0 | 1402 | APP (human, self-reference) |
| 2 | Q5IS80 | 100.0 | 1402 | APP ortholog |
| 3 | P12023 | 99.0 | 1399 | APP paralog |
| 4 | P53601 | 100.0 | 1397 | APP ortholog |
| 5 | P08592 | 99.0 | 1395 | APP-related protein |
| 6 | P79307 | 100.0 | 1367 | APP variant |
| 7 | Q60495 | 100.0 | 1365 | APP ortholog (mouse) |
| 8 | Q95241 | 100.0 | 1353 | APP ortholog |
| 9 | P15943 | 91.4 | 1276 | APP-related protein |
| 10 | Q06481 | 91.4 | 1277 | APP homolog |
| 11 | P15989 | 65.3 | 3273 | Distant homolog (high-complexity match) |
| 12 | Q03157 | 88.1 | 1056 | Conserved APP domain |
| 13 | Q06335 | 87.6 | 1203 | APP-family protein |
| 14 | P49223 | 54.5 | 77.4 | Minimal identity match |
| 15 | O43278 | 76.3 | 842 | Kunitz-type protease inhibitor 1 |
| 16 | O43291 | 70.6 | 361 | Kunitz-type protease inhibitor 2 |
| 17 | P02760 | 84.6 | 580 | Protein AMBP |
| 18 | Q07456 | 88.3 | 643 | APP-domain protein |
| 19 | Q2UY09 | 86.7 | 819 | Conserved homolog |
| 20 | Q2UY11 | 86.6 | 825 | Conserved homolog |
Top 20 matches predominantly span: APP orthologs across vertebrates (96–100% identity), APP-related family proteins, and proteins sharing Kunitz protease-inhibitor domains characteristic of APP.
Transcription factor regulatory data
APP (amyloid beta precursor protein) is not a transcription factor. It is a protein-coding gene (locus group: protein-coding gene) and does not encode a DNA-binding transcription factor. Therefore, no downstream targets or JASPAR DNA binding motifs are applicable.
Upstream regulators
APP is regulated by the following transcription factors:
High-confidence regulators:
| Transcription Factor | Regulation | Evidence Type |
|---|---|---|
| CTCF | Activation | Curated (TRRUST, TFactS, SIGNOR, NTNU Curated, DoRothEA) |
| SMAD2 | Activation | Experimentally validated (ExTRI, NTNU Curated) |
| PURA | Unknown | Experimentally validated (ExTRI) |
| ETS2 | Unknown | Curated/Experimentally validated (TRRUST, GEREDB, ExTRI) |
| MYC | Unknown | Predicted/Curated (DoRothEA, HTRI) |
| AP1 | Unknown | Curated/Experimentally validated (ExTRI, HTRI, TRRUST, DoRothEA) |
Low-confidence regulators (19 additional): AHR (Low), ESR2 (Low), ESR1 (Low), EGR1 (Low), BSX (Low), CTNNB1 (Repression, Low), AR (Low), CEBPG (Low), CNOT4 (Low), SP3 (Low), STAT1 (Unknown), RARA (Repression), PPARG (Repression)
Total: 19 upstream transcription factor regulators identified from COLLECTRI database (NTNU Curated, ExTRI, TRRUST, GEREDB, DoRothEA, TFactS, SIGNOR sources).
Drug & pharmacology data
APP (Amyloid-beta Precursor Protein) is a validated drug target with 100 targeting molecules in ChEMBL.
Targeting Molecules Summary
- Total count: 100 molecules in ChEMBL targeting APP (P05067)
- By development phase: Phase 4 (4), Phase 3 (6), Phase 2 (4), Phase 0-1 (~86)
TOP 30 Molecules by Development Phase
Phase 4 (Approved/Published):
- CHEMBL1774461 — FLORBETAPIR F 18 | Amyloid-β PET imaging tracer | 44 clinical trials
- CHEMBL1908919 — FLORBETAPIR | Amyloid-β imaging agent (parent molecule) | 8 clinical trials
- CHEMBL191083 — METHYLENE BLUE CATION | Multi-target (APP stabilization, tauopathy) | 76 clinical trials
- CHEMBL2042122 — FLUTEMETAMOL F 18 | Amyloid-β PET imaging agent | 2 clinical trials
Phase 3 (Clinical Development): 5. CHEMBL140 — CURCUMIN | Multi-target antioxidant; amyloid aggregation inhibitor | 204 clinical trials 6. CHEMBL145 — CAFFEIC ACID | Polyphenol; antioxidant mechanism | 3 clinical trials 7. CHEMBL149082 — TRAMIPROSATE | Amyloid-β aggregation inhibitor (homotaurine) | 3 clinical trials 8. CHEMBL165 — RESVERATROL | Sirtuins/NAD+ pathway activator; antioxidant | 14 clinical trials 9. CHEMBL2048308 — FLUTAFURANOL | Amyloid-β PET imaging agent | No clinical trials 10. CHEMBL151 — LUTEOLIN | Flavonoid; multi-target antioxidant | 8 clinical trials
Phase 2 (Clinical Development): 11. CHEMBL1368322 — PARAROSANILINE | Dye compound; unclear mechanism 12. CHEMBL150 — KAEMPFEROL | Flavonoid; antioxidant | Included in curcumin trials 13. CHEMBL207456 — PITTSBURGH COMPOUND B | Amyloid-β PET imaging tracer | Research phase 14. CHEMBL2364601 — AFTOBETIN | Phenolic compound | No trial data
Remaining Phase 0-1 molecules (16-100): 86 compounds in preclinical/early research stages, including natural products (resveratrol derivatives, polyphenols), synthetic small molecules, and imaging agents.
Clinical Trials
Top APP-targeting drugs with documented clinical trial activity:
- CURCUMIN: 204 trials across multiple indications including Alzheimer’s disease, cognitive decline, neuroinflammation
- METHYLENE BLUE: 76 trials; primary focus on cognitive/neurodegenerative conditions
- FLORBETAPIR F 18: 44 trials; all diagnostic (PET imaging for amyloid pathology assessment)
- RESVERATROL: 14 trials; aging, cardiovascular, metabolic indications
- TRAMIPROSATE: 3 completed Phase 3 trials for mild-to-moderate Alzheimer’s disease (failed primary endpoints; discontinued development)
Pharmacogenomics
No known pharmacogenomics data or APP-gene dosing interactions documented in current databases. APP targeting drugs show no established genetic variants affecting drug response. Dosing is standard across populations with no APP genotype-guided adjustments in clinical practice.
Expression profiles
Tissue Expression (Bgee)
APP demonstrates ubiquitous expression across human tissues (expression breadth: ubiquitous, average score: 97.15/100). The following table shows the top 30 tissues and anatomical regions with expression scores from Bgee:
| Rank | Tissue/Region | Expression Score | Quality |
|---|---|---|---|
| 1 | Prefrontal cortex | 99.79 | Gold |
| 2 | Renal medulla | 99.69 | Gold |
| 3 | Brodmann area 9 | 99.69 | Gold |
| 4 | Medial globus pallidus | 99.66 | Gold |
| 5 | Stromal cell of endometrium | 99.65 | Gold |
| 6 | Tendon of biceps brachii | 99.64 | Gold |
| 7 | Cortical plate | 99.61 | Gold |
| 8 | Globus pallidus | 99.58 | Gold |
| 9 | Primary visual cortex | 99.58 | Gold |
| 10 | Islet of Langerhans | 99.56 | Gold |
| 11 | C1 segment of cervical spinal cord | 99.56 | Gold |
| 12 | Choroid plexus epithelium | 99.55 | Gold |
| 13 | Metanephros cortex | 99.55 | Gold |
| 14 | Occipital lobe | 99.53 | Gold |
| 15 | Dorsolateral prefrontal cortex | 99.51 | Gold |
| 16 | Nucleus accumbens | 99.47 | Gold |
| 17 | Brodmann area 23 | 99.46 | Gold |
| 18 | Colonic epithelium | 99.46 | Gold |
| 19 | Frontal cortex | 99.45 | Gold |
| 20 | Putamen | 99.45 | Gold |
| 21 | Ventral tegmental area | 99.45 | Gold |
| 22 | Gall bladder | 99.45 | Gold |
| 23 | Caudate nucleus | 99.44 | Gold |
| 24 | Spinal cord | 99.44 | Gold |
| 25 | Hypothalamus | 99.43 | Gold |
| 26 | Endothelial cell | 99.42 | Gold |
| 27 | Inferior vagus X ganglion | 99.41 | Gold |
| 28 | Neocortex | 99.41 | Gold |
| 29 | Corpus callosum | 99.41 | Gold |
| 30 | Amygdala | 99.40 | Gold |
Key patterns: Strong enrichment in brain regions (prefrontal cortex, Brodmann areas, basal ganglia, neocortex), particularly in cortical and subcortical structures consistent with APP’s role in Alzheimer’s disease. Significant expression also detected in kidney, endothelium, and gastrointestinal tissues.
Single-Cell Expression Datasets (Single Cell Expression Atlas)
APP is detected across 38 independent single-cell experiments spanning diverse tissues and disease states. Notable datasets include:
| Dataset ID | Description | Tissue/Context | Cell Count |
|---|---|---|---|
| E-CURD-114 | Cellular specificity of smoking effects | Human airway epithelium | 81,801 |
| E-HCAD-15 | Profibrotic roles in disease | Pulmonary fibrosis tissue | 372,319 |
| E-HCAD-9 | Intrahepatic immune landscape | Human liver | 79,612 |
| E-MTAB-9543 | GI tract atlas across space/time | Gastrointestinal tract | 319,479 |
| E-MTAB-10287 | Endometrial and uterine tissue | Endometrium/uterus | 340,047 |
| E-MTAB-8142 | Skin cell types | Breast skin | 809,675 |
| E-GEOD-180759 | Immune response in CNS disease | MS brain lesions | 421,220 |
| E-MTAB-10042 | Hematopoietic development | Fetal bone marrow | 21,485 |
| E-GEOD-135922 | Retinal and choroidal cells | Retina/choroid | 55,571 |
| E-GEOD-137537 | Retinal cell atlas | Retina | 12,881 |
| E-GEOD-139324 | Immune landscape | Head and neck cancer | 204,315 |
| E-MTAB-6701 | Fetal-maternal interface | First trimester placenta | 135,071 |
| E-GEOD-131882 | Kidney in diabetes | Diabetic kidney | 43,748 |
Key cell-type contexts: APP is broadly expressed across epithelial cells, endothelial cells, immune cells (macrophages, microglia), and neural cells across healthy and disease states. Particularly abundant in datasets from neuroinflammatory contexts (MS, CNS disease) and developmental tissues (fetal bone marrow, placenta).
Disease associations
Mendelian / Monogenic Diseases
| Disease Name | Disease ID | Inheritance | Evidence Level |
|---|---|---|---|
| Alzheimer disease type 1 | OMIM:104300 / MONDO:0007088 | Autosomal dominant | Strong |
| Cerebral amyloid angiopathy, APP-related | OMIM:605714 / MONDO:0011583 | Autosomal dominant | Strong |
| Early-onset autosomal dominant Alzheimer disease | Orphanet:1020 / MONDO:0015140 | Autosomal dominant | Supportive |
| ABeta amyloidosis, Dutch type | Orphanet:100006 / MONDO:0015033 | Autosomal dominant | Supportive |
| ABeta amyloidosis, Iowa type | Orphanet:324708 / MONDO:0017946 | Autosomal dominant | Supportive |
| ABeta amyloidosis, Italian type | Orphanet:324713 / MONDO:0017947 | Autosomal dominant | Supportive |
| ABetaA21G amyloidosis | Orphanet:324718 / MONDO:0017948 | Autosomal dominant | Supportive |
| ABeta amyloidosis, Arctic type | Orphanet:324723 / MONDO:0017949 | Autosomal dominant | Supportive |
| ABetaL34V amyloidosis | Orphanet:324703 | Autosomal dominant | Supportive |
| Hereditary cerebral amyloid angiopathy | Orphanet:85458 | Autosomal dominant | Supportive |
| Familial focal epilepsy with variable foci | Orphanet:98820 / MONDO:0020310 | Autosomal dominant | Supportive |
Phenotype Associations (Top 30 HPO Terms)
| HPO ID | Phenotype |
|---|---|
| HP:0000006 | Autosomal dominant inheritance |
| HP:0001250 | Seizure |
| HP:0002511 | Alzheimer disease |
| HP:0000726 | Dementia |
| HP:0002354 | Memory impairment |
| HP:0001268 | Mental deterioration |
| HP:0000708 | Atypical behavior |
| HP:0000734 | Disinhibition |
| HP:0000738 | Hallucinations |
| HP:0001289 | Confusion |
| HP:0002381 | Aphasia |
| HP:0011970 | Cerebral amyloid angiopathy |
| HP:0001342 | Cerebral hemorrhage |
| HP:0004968 | Recurrent cerebral hemorrhage |
| HP:0011695 | Cerebellar hemorrhage |
| HP:0001297 | Stroke |
| HP:0002637 | Cerebral ischemia |
| HP:0002120 | Cerebral cortical atrophy |
| HP:0002185 | Neurofibrillary tangles |
| HP:0003791 | Deposits immunoreactive to beta-amyloid protein |
| HP:0001300 | Parkinsonism |
| HP:0001251 | Ataxia |
| HP:0001336 | Myoclonus |
| HP:0002015 | Dysphagia |
| HP:0000657 | Oculomotor apraxia |
| HP:0000504 | Abnormality of vision |
| HP:0002076 | Migraine |
| HP:0001259 | Coma |
| HP:0001263 | Global developmental delay |
| HP:0012759 | Neurodevelopmental abnormality |
Complex Disease / GWAS Associations (Top 7)
| Trait/Disease | Effect Size (p-value) | Associated Gene | Chromosome |
|---|---|---|---|
| Alzheimer’s disease | 1.0 × 10⁻¹¹ | APP | 21 |
| Cerebrospinal fluid α-synuclein levels | 2.0 × 10⁻⁷ | GABPA - APP | 21 |
| Glaucoma (primary open-angle) | 3.0 × 10⁻⁷ | GABPA - APP | 21 |
| Glaucoma (primary open-angle) | 7.0 × 10⁻⁶ | GABPA - APP | 21 |
| Longitudinal change in brain amyloid plaque burden | 3.0 × 10⁻⁶ | JAM2 | 21 |
| Spatial processing | 2.0 × 10⁻⁶ | APP | 21 |
| HDL cholesterol levels in HIV infection | 8.0 × 10⁻⁶ | — | — |