MAPT Gene Complete Identifier and Functional Mapping Reference

Executive summary

MAPT encodes microtubule-associated protein tau, a neuronal cytoskeletal protein that is central to the pathogenesis of Alzheimer’s disease and a broad class of neurodegenerative disorders collectively termed tauopathies. Its highest expression is in cortical brain regions (score 99.52 in cortical plate), consistent with its prominent role in neuronal function. The gene spans chromosome 17q21 and produces at least 52 transcripts, reflecting extraordinary isoform complexity. Pathogenic MAPT variants — predominantly causing frontotemporal dementia with parkinsonism (FTDP-17) — number approximately 30 in ClinVar, and GWAS links the locus to Parkinson’s disease (p = 1×10⁻⁶⁸) and progressive supranuclear palsy (p = 2×10⁻¹²²). Structurally, tau is an intrinsically disordered protein (AlphaFold global pLDDT 49.56, no residues with pLDDT > 90), yet 274 experimental PDB structures capture its disease-relevant filament conformations across multiple tauopathies. Its interaction network (~7,283 documented interactions) is dominated by key phosphorylation kinases CDK5 and GSK3B and major neurodegeneration proteins including APP, APOE, and SNCA.

Gene identifiers

• HGNC ID: HGNC:6893
• Approved symbol: MAPT
• Ensembl gene ID: ENSG00000186868
• NCBI Entrez Gene ID: 4137
• OMIM gene/locus ID: 157140
• Genomic location (GRCh38):
  • Chromosome: 17
  • Start position: 45,894,358 bp
  • End position: 46,028,334 bp
  • Strand: +

Transcript identifiers

Ensembl Transcripts (52 total)

RefSeq mRNA Accessions (57 total)

CCDS IDs (10 total)

MANE Select Transcript: ENST00000262410 (NM_001377265)

Exons (13 total)

Protein identifiers

UniProt accessions

• P10636 (canonical, reviewed) — Microtubule-associated protein tau
• A0A7I2PJZ2 (unreviewed)
• A0A7I2PLE3 (unreviewed)
• A0A7P0T936 (unreviewed)
• I3L2Z2 (unreviewed)

RefSeq protein (NP_ accessions)

NP_001033698, NP_001116538, NP_001116539, NP_001190180, NP_001190181, NP_001263017, NP_001263018, NP_001263019, NP_001263020, NP_001272383, NP_001272384, NP_001272385, NP_001287563, NP_001287564, NP_001287565, NP_001287566, NP_001287567, NP_001287568, NP_001303549, NP_001364194, NP_001364195, NP_001364196, NP_001364197, NP_001369032, NP_001390904, NP_001390905, NP_001390906, NP_001390907, NP_001390908, NP_001390909, NP_001390910, NP_001390911, NP_001390912, NP_001390913, NP_001390916, NP_001390919, NP_001390921, NP_001390923, NP_001390925, NP_001390927, NP_001390928

Protein domains and families

Antibody availability

Limited records in public biobtree antibody databases. However, tau protein (P10636) has extensive cross-references to PDB structures (274 entries) and is well-characterized. Commercial antibody resources available through: Human Protein Atlas (ENSG00000186868), BindingDB (675 entries), and antibody vendor catalogs targeting epitopes across the protein sequence.

Structure

Experimental Structures

PDB Entries: 274 total

By Experimental Method:

Key Structure Types:

• Disease-associated filaments: Paired helical filaments (PHF), straight filaments (SF), and twisted filaments from Alzheimer’s disease, chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and other tauopathies
• Antibody-Tau complexes: Fab fragments in complex with tau peptides (e.g., AT8, PT3, BIIB092, CBTAU series)
• Protein binding complexes: 14-3-3 sigma with phosphorylated tau peptides; tau-microtubule complexes; Fyn kinase interaction
• Tau peptide structures: Individual tau repeat fragments, amyloid-forming VQIVYK segment
• In vitro assembled filaments: Various morphologies under different buffer conditions (PBS, heparin, ions, etc.)

Notable PDB entries: 5O3L, 6HRE (AD PHF); 6TJO, 6TJX (CBD); 7P65 (PSP); 8Q8R, 8Q8S (AD PHF/THF variants); 22JY (highest resolution cryo-EM at 2.2 Å)

Predicted Structures

AlphaFold Model:

• Model ID: P10636
• Global pLDDT: 49.56 (low confidence, consistent with intrinsically disordered protein)
• Fraction with pLDDT > 90: 0.00 (no highly confident regions)
• Protein Length: 758 amino acids (canonical isoform)

Note: Low confidence reflects tau’s nature as an intrinsically disordered protein with limited stable secondary structure in its native state.

Cross-species orthologs

Clinical variants & AI predictions

ClinVar Summary

Top 30 Pathogenic/Likely Pathogenic Clinical Variants

Splice Effect Predictions (SpliceAI)

• Total predictions: ~3,502
• Donor gain events: ~2,800
• Donor loss events: ~400
• Acceptor gain/loss events: ~300

AlphaMissense Pathogenicity Predictions (P10636)

• Total variants assessed: ~700
• Likely pathogenic predictions: ~144
• Pathogenicity range: 0.042–0.997

Pathways & Gene Ontology

Biological Pathways

Reactome (3 pathways):

MSigDB: No gene sets found

Total pathways: 3

Gene Ontology Annotations

Biological Process (51 terms):

Molecular Function (25 terms):

Cellular Component (28 terms):

Protein interactions & networks

Protein-Protein Interactions (STRING, BioGRID, IntAct)

Total interaction count:

• STRING: ~5,558 interactions
• BioGRID: 1,565 interactions
• IntAct: 160 curated interactions
• Combined: ~7,283 interactions documented

TOP 30 highest-confidence STRING interactors (combined score):

Protein Similarity

Structural/Embedding Similarity (ESM2 - top 20 by score):

Sequence Homology (DIAMOND - top 19 by identity %):

Key findings:

• MAPT shows extensive interactions with major neurodegeneration-associated proteins (APP, TARDBP, SNCA, PSEN1/2)
• Key tau phosphorylation kinases (CDK5, GSK3B, FYN) are highly scored interactors
• 14-3-3 proteins (YWHAQ, YWHAZ) are prominent tau-binding partners
• Structural similarity predominantly reflects MAPT orthologs and related microtubule-associated proteins (MAP2, MAP4)
• ESM2 embeddings identify highly similar neurodegenerative disease-associated proteins

Transcription factor regulatory data

MAPT is not a transcription factor. MAPT (microtubule-associated protein tau) is a microtubule-associated protein with 758 amino acids. It does not have known DNA-binding capability and is not classified as a transcription factor. Therefore, downstream targets and DNA-binding motifs are not applicable.

Upstream regulators

The following transcription factors regulate MAPT expression:

Data source: CollecTRI—a curated database of transcriptional regulatory interactions combining literature-derived and computationally predicted TF-gene associations. The interactions listed above represent experimentally validated or literature-supported regulatory relationships, though specific evidence types (e.g., ChIP-seq experiments vs. computational predictions) are not differentiated in the current dataset.

Drug & pharmacology data

MAPT is an established drug target with active development programs in clinical trials, primarily focused on tau-related pathologies in Alzheimer’s disease and frontotemporal dementia.

Targeting molecules

Total count: ~100 molecules in ChEMBL testing against MAPT (CHEMBL1293224)

TOP molecules by highest development phase (Phase 4 = approved):

Note: Most phase 4 compounds are approved for non-tau indications. The primary tau-targeting strategies in clinical development are monoclonal antibodies (anti-amyloid-beta agents that secondarily affect tau pathology).

Clinical trials

24 trials identified in tauopathies, with 20 trials in Alzheimer’s disease specifically:

Phase 3 trials:

• NCT05508789: Donanemab (LY3002813) in early symptomatic AD (TRAILBLAZER-ALZ 5) — RECRUITING

Phase 1-2 tau-targeting trials:

• NCT03538522: NA-831 — COMPLETED
• NCT04445831: Tau-targeted vaccines — COMPLETED
• NCT05318976 & NCT05321498: XPro1595 (TNF-α pathway modulation) — COMPLETED/WITHDRAWN
• NCT02294851: BMS-986168 (tau monoclonal antibody) — COMPLETED
• NCT05344989: APNmAb005 (tau antibody, first-in-human) — RECRUITING

Imaging/biomarker studies:

• NCT02103894: [18F]MNI-777 tau PET — COMPLETED
• NCT02676843: Tau PET with 18F-AV-1451 in MAPT mutation carriers — COMPLETED

Pharmacogenomics

Status: MAPT is a VIP (Very Important Pharmacogene) in PharmGKB but has NO CPIC (Clinical Pharmacogenetics Implementation Consortium) guidelines — no published dosing/response recommendations for MAPT genotypes.

Genetic variants: 601 variants documented in ClinVar, including:

• Pathogenic variants: Associated with frontotemporal dementia (e.g., c.2078C>T p.Pro693Leu, c.2392C>T p.Arg798Trp)
• Functionally relevant: MAPT H1/H2 haplotypes associated with tauopathy risk, but no specific drug-dosing guidelines established

Current evidence: MAPT genetic variants predict tau pathology burden and AD risk but do not yet inform personalized drug selection or dosing for tau-targeting therapies under clinical development.

Expression profiles

Tissue expression (Bgee)

MAPT shows ubiquitous expression (breadth: ubiquitous, average score: 74.48, max: 99.52) with marked enrichment in neural tissues.

Tissue-specific patterns: MAPT demonstrates striking brain-specificity with highest expression in cortical regions (especially frontal and prefrontal cortex, cortical plate at 99.52). Expression remains very high across all major brain structures (cerebrum, cerebellum, basal ganglia, limbic system). Notable secondary expression in skeletal muscle and developing embryonic tissues reflects MAPT’s role in microtubule organization during development and neuronal growth.

Single-cell expression datasets

MAPT is expressed across multiple human single-cell/tissue datasets:

Cell-type-specific patterns: MAPT is enriched in developing neural progenitor cells and differentiating neurons, consistent with its role as a neuronal cytoskeletal protein. Expression peaks in the lateral ganglionic eminence during critical developmental stages (PCW 7–11, corresponding to interneuron migration and specification). Strong expression in iPSC-derived neurons indicates MAPT is a marker of neuronal commitment and maturation. In organoid studies, MAPT expression tracks with neural cell identity and developmental progression.

Expression characteristics

• Developmental profile: High expression during fetal neurogenesis and brain development; maintained in adult neurons
• Neuronal enrichment: Expressed in neural progenitors, neurons, and glial progenitors; lower in non-neural tissues despite ubiquitous classification
• Adult brain regionalization: Highest in cortex, hippocampus, substantia nigra, and other regions implicated in cognition and motor function
• Tauopathy relevance: Widespread brain expression explains MAPT mutation involvement in tauopathies (Frontotemporal dementia, corticobasal degeneration, progressive supranuclear palsy)

Disease associations

Mendelian / Monogenic Diseases

MAPT mutations cause several neurodegenerative tauopathies with autosomal dominant (or recessive) inheritance:

Phenotype Associations (HPO)

Top 30 clinical phenotypes associated with MAPT mutations:

1. HP:0000605 — Supranuclear gaze palsy
2. HP:0000726 — Dementia
3. HP:0001300 — Parkinsonism
4. HP:0002145 — Frontotemporal dementia
5. HP:0002185 — Neurofibrillary tangles
6. HP:0002354 — Memory impairment
7. HP:0000511 — Vertical supranuclear gaze palsy
8. HP:0002063 — Rigidity
9. HP:0002067 — Bradykinesia
10. HP:0006892 — Frontotemporal cerebral atrophy
11. HP:0002141 — Gait imbalance
12. HP:0002172 — Postural instability
13. HP:0001337 — Tremor
14. HP:0001288 — Gait disturbance
15. HP:0001260 — Dysarthria
16. HP:0002015 — Dysphagia
17. HP:0002381 — Aphasia
18. HP:0000727 — Frontal lobe dementia
19. HP:0000738 — Hallucinations
20. HP:0000726 — Dementia
21. HP:0000737 — Irritability
22. HP:0000741 — Apathy
23. HP:0000743 — Frontal release signs
24. HP:0000751 — Personality changes
25. HP:0001268 — Mental deterioration
26. HP:0012444 — Brain atrophy
27. HP:0012671 — Abulia
28. HP:0007164 — Slurred speech
29. HP:0010522 — Dyslexia
30. HP:0011098 — Speech apraxia

Complex Disease / GWAS Associations

Top 30 GWAS-associated traits with MAPT loci (p < 10⁻⁸):

Neurodegenerative / Cognitive (strongest)

1. Parkinson’s disease (p = 1×10⁻⁶⁸, GCST004902)
2. Progressive supranuclear palsy (p = 2×10⁻¹²² to 4×10⁻¹¹³, multiple studies)
3. Corticobasal degeneration (p = 1×10⁻¹², GCST002971)
4. Plasma t-tau levels (p = 1×10⁻¹², GCST004092)
5. General cognitive ability (p = 1×10⁻¹³ to 3×10⁻⁸, multiple studies)
6. Cognitive ability (p = 8×10⁻⁸, GCST005142)
7. Cognitive performance (processing speed) (p = 9×10⁻⁶, GCST008891)
8. Reaction time (p = 1×10⁻¹⁵ to 6×10⁻¹⁵, multiple studies)

Neuroticism / Psychiatric 9. General factor of neuroticism (p = 5×10⁻¹⁵ to 1×10⁻⁹, multiple studies) 10. Alcohol use disorder (consumption score) (p = 2×10⁻¹⁴, GCST012336) 11. Alcohol consumption (drinks per week) (p = 5×10⁻²³, GCST008757) 12. Experiencing mood swings (p = 2×10⁻¹⁰, with WNT3) 13. Feeling hurt (p = 1×10⁻¹¹, with WNT3) 14. Mood instability (p = 7×10⁻²⁰, GCST008357)

Morphometric / Hematologic 15. Red blood cell count (p = 9×10⁻⁶⁶, GCST90002403) 16. Hemoglobin levels (p = 1×10⁻⁶¹, GCST010083) 17. Mean spheric corpuscular volume (p = 2×10⁻⁵³, GCST90002397) 18. Mean reticulocyte volume (p = 5×10⁻²⁸, GCST90002396) 19. Waist-to-hip ratio adjusted for BMI (p = 5×10⁻¹³ to 2×10⁻⁸, multiple studies) 20. A body shape index (p = 5×10⁻¹² to 1×10⁻¹⁰, multiple studies) 21. Waist-hip index (p = 2×10⁻¹² to 2×10⁻⁸, multiple studies) 22. Hip circumference adjusted for BMI (p = 9×10⁻⁹, GCST90020028)

Respiratory / Pulmonary 23. Idiopathic pulmonary fibrosis (p = 6×10⁻⁹ to 3×10⁻¹⁶, MAPT-AS1, GCST009758) 24. Interstitial lung disease (p = 9×10⁻¹⁴, GCST001968)

Cardiovascular 25. Atrial fibrillation (p = 4×10⁻⁹, GCST006061) 26. QRS complex duration (p = 2×10⁻¹⁴, GCST003872)

Metabolic / Other 27. Primary biliary cirrhosis (p = 2×10⁻⁹, GCST005581) 28. Osteoarthrosis (p = 3×10⁻⁸, GCST010771) 29. Male-pattern baldness (p = 1×10⁻²⁶ to 8×10⁻²⁹, multiple studies) 30. Type 1 diabetes (p = 2×10⁻¹⁵, GCST90013445)