TP63 Gene Complete Identifier and Functional Mapping Reference

Provide a comprehensive cross-database identifier and functional mapping reference for human TP63 — a definitive lookup resource covering: ### …

Provide a comprehensive cross-database identifier and functional mapping reference for human TP63 — a definitive lookup resource covering: ### Section 1: Gene identifiers For human gene TP63, 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 TP63, 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 TP63 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 TP63 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 TP63, 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 TP63, 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 TP63, 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 TP63 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 TP63, summarize transcription factor regulatory data. If TP63 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 TP63 — names with evidence type (ChIP-seq / predicted / experimentally validated) If TP63 is not a transcription factor, say so briefly and skip the downstream/motif sections. ### Section 10: Drug & pharmacology data For human gene TP63 protein as a drug target, summarize pharmacology data. If TP63 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 TP63 is not currently a drug target, say so briefly. ### Section 11: Expression profiles For human gene TP63, 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 TP63, summarize disease associations. Mendelian / monogenic disease: - Diseases caused by mutations in TP63: 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

TP63

Executive summary

TP63 (HGNC:15979; chromosome 3) encodes tumor protein p63, a p53-family transcription factor that serves as the master regulator of stratified epithelial development and basal stem cell maintenance. It is most highly expressed in basal keratinocytes and squamous epithelia — skin, oral cavity, esophagus, and cervix — where it drives a transcriptional program encompassing 170+ downstream targets including CDKN1A, KRT5, and KRT14. The gene has 14 transcripts, 25 experimental PDB structures, and ~400+ documented protein interactions, with its strongest ties to TP73, MDM2, and the DLX developmental factor family. Clinically, heterozygous missense mutations predominantly in the DNA-binding domain cause a spectrum of autosomal dominant ectodermal dysplasia syndromes — EEC syndrome 3, Rapp-Hodgkin syndrome, limb-mammary syndrome, and ADULT syndrome among others — while GWAS links common variants to lung cancer risk (p = 7.0e-26), cutaneous squamous cell carcinoma, and bladder cancer. Despite its disease relevance, TP63 has no established pharmacological drug targets in current clinical pipelines, though it is recognized as a PharmGKB VIP gene.

Gene identifiers

FieldValue
HGNC IDHGNC:15979
Approved symbolTP63
Ensembl gene IDENSG00000073282
NCBI Entrez Gene ID8626
OMIM gene ID603273
Chromosome3
Start position (GRCh38)189,631,389
End position (GRCh38)189,897,276
Strand+ (forward)

Transcript identifiers

Ensembl Transcripts (14 total)

Transcript IDBiotype
ENST00000264731protein_coding
ENST00000320472protein_coding
ENST00000354600protein_coding
ENST00000392460protein_coding
ENST00000392461protein_coding
ENST00000392463protein_coding
ENST00000418709protein_coding
ENST00000434928protein_coding
ENST00000437221protein_coding
ENST00000440651protein_coding
ENST00000449992protein_coding
ENST00000456148protein_coding
ENST00000460036retained_intron
ENST00000486398retained_intron

RefSeq mRNA Accessions (23 NM_, multiple XM_)

REVIEWED NM_ (mRNA):

  • NM_001036190
  • NM_001114978
  • NM_001114979
  • NM_001114980
  • NM_001114981
  • NM_001114982
  • NM_001127339
  • NM_001127341
  • NM_001127342
  • NM_001127343
  • NM_001127344
  • NM_001329144
  • NM_001329145
  • NM_001329146
  • NM_001329148
  • NM_001329149
  • NM_001329150
  • NM_001329964
  • NM_003722 ← MANE Select
  • NM_019221
  • NM_105896
  • NM_152248
  • NM_152986

PREDICTED XM_ (mRNA): 40+ accessions including XM_006248500, XM_017597881, XM_063270286–288, XM_068221638–645, XM_073952526–568

CCDS IDs (10 total)

CCDS ID
CCDS3293
CCDS46976
CCDS46977
CCDS46978
CCDS46979
CCDS46980
CCDS82887
CCDS87179
CCDS87180
CCDS87181

Canonical Transcript: ENST00000264731 (14 exons)

Exon IDStartEndGenomic Span (bp)
ENSE00001343828189631389189631577189
ENSE00001184832189738642189738774133
ENSE00003502961189737740189737868129
ENSE00003597426189864232189864418187
ENSE00003525444189868580189868716137
ENSE00003641501189867833189867942110
ENSE00003476123189866682189866797116
ENSE0000367377818986932418986940683
ENSE00003473100189808272189808526255
ENSE00001005407189886394189886551158
ENSE00000871463189872859189872995137
ENSE0000078160618989078918989088294
ENSE00000781605189889340189889484145
ENSE000016085501898942061898972763071

Protein identifiers

UniProt Accessions

AccessionStatusDescription
Q9H3D4Reviewed (canonical)Tumor protein p63

RefSeq Protein Accessions (NP_)

Reviewed - Chromosome 3:

  • NP_003713 (MANE Select)
  • NP_001108450
  • NP_001108451
  • NP_001108452
  • NP_001108453
  • NP_001108454
  • NP_001316073
  • NP_001316074
  • NP_001316075
  • NP_001316077
  • NP_001316078
  • NP_001316079
  • NP_001316893

Reviewed - Chromosome 11:

  • NP_001120811
  • NP_001120813
  • NP_001120814
  • NP_001120815
  • NP_001120816
  • NP_062094

Validated - Chromosome 6:

  • NP_689454
  • NP_694518

Protein Domains and Families

IDDatabaseNameType
IPR001660InterProSterile alpha motif domainDomain
IPR002117InterProp53 tumour suppressor familyFamily
IPR008967InterProp53-like transcription factor, DNA-binding domain superfamilyHomologous_superfamily
IPR010991InterProp53, tetramerisation domainDomain
IPR011615InterProp53, DNA-binding domainDomain
IPR012346InterProp53/RUNT-type transcription factor, DNA-binding domain superfamilyHomologous_superfamily
IPR013761InterProSterile alpha motif/pointed domain superfamilyHomologous_superfamily
IPR036674InterProp53-like tetramerisation domain superfamilyHomologous_superfamily
IPR037611InterProTumour protein p63, SAM domainDomain
IPR057064InterProp53, central conserved siteConserved_site
PF00870Pfamp53 DNA-binding domain (SAM-related)Domain
PF07647Pfamp53-like DNA-binding domainDomain
PF07710Pfamp53 tetramerisation domainDomain
SM00454SMARTSterile alpha motifDomain
1.10.150.50CATHGENE3DSAM domain-like foldFold
2.60.40.720CATHGENE3Dp53 DNA-binding domainDomain
4.10.170.10CATHGENE3Dp53 tetramerisation domainDomain
SSF47719SUPFAMp53-like DNA-binding domainSuperfamily
SSF47769SUPFAMSterile alpha motif/pointed domainSuperfamily
SSF49417SUPFAMJelly roll foldSuperfamily

Antibody Availability

No antibody resources available in biobtree database (query via >>uniprot>>antibody returned no mappings).

Structure

Experimental Structures

PDB Entries: 25 total

PDB IDMethodResolution
1RG6Solution NMR
2NB1Solution NMR
2RMNSolution NMR
2Y9TSolution NMR
2Y9UX-ray diffraction1.6 Å
3QYMX-ray diffraction3.2 Å
3QYNX-ray diffraction2.5 Å
3US0X-ray diffraction2.5 Å
3US1X-ray diffraction2.8 Å
3US2X-ray diffraction4.2 Å
3ZY0X-ray diffraction1.9 Å
3ZY1X-ray diffraction2.15 Å
4A9ZX-ray diffraction2.29 Å
6FGNSolution NMR
6RU6X-ray diffraction2.05 Å
6RU7X-ray diffraction2.08 Å
6RU8X-ray diffraction1.92 Å
7Z71X-ray diffraction1.85 Å
7Z72X-ray diffraction1.8 Å
7Z73X-ray diffraction2.27 Å
7Z7EX-ray diffraction1.8 Å
8P9CX-ray diffraction1.76 Å
8P9DX-ray diffraction2.7 Å
8P9EX-ray diffraction2.25 Å
9GFOX-ray diffraction2.4 Å

Methods breakdown: 5 NMR, 20 X-ray diffraction

Predicted Structures

AlphaFold Model: Q9H3D4

  • Global pLDDT metric: 63.70 (moderate confidence)
  • Sequence length: 5,382 residues
  • Fraction very high confidence (pLDDT ≥ 90): 0.35 (35%)

Cross-species orthologs

OrganismGene IDSymbol
Mouse (Mus musculus)ENSMUSG00000022510Trp63
Rat (Rattus norvegicus)ENSRNOG00000001924Tp63
Zebrafish (Danio rerio)ENSDARG00000044356tp63
Fruit fly (Drosophila melanogaster)FBGN0039044p53
Worm (C. elegans)WBGENE00000467cep-1
Yeast (S. cerevisiae)none

Clinical variants & AI predictions

ClinVar Summary

ClassificationCount
Total variants~827
Pathogenic~80
Likely Pathogenic~40
Uncertain Significance~500+
Benign/Likely Benign~100
Conflicting~20

Top 30 Pathogenic/Likely Pathogenic ClinVar Variants

Variant IDHGVSClassificationAssociated Condition
1024583c.1861del (p.Ser621fs)PathogenicLimb-mammary syndrome, TP63-Related Spectrum Disorders
1018494c.796C>T (p.Arg266Ter)PathogenicTP63-Related Spectrum Disorders
1062831c.1050A>T (p.Arg350Ser)PathogenicTP63-Related Spectrum Disorders
1070564c.1007G>A (p.Gly336Asp)Pathogenic/Likely pathogenicTP63-Related Spectrum Disorders
1076262c.1670G>T (p.Gly557Val)Pathogenic/Likely pathogenicADULT syndrome, ACRO-DERMATO-UNGUAL-LACRIMAL-TOOTH SYNDROME
1333911c.858dup (p.Leu287fs)Likely pathogenicRapp-Hodgkin ectodermal dysplasia syndrome
1349518c.1973G>A (p.Trp658Ter)Likely pathogenicTP63-Related Spectrum Disorders
1385690c.1583C>A (p.Pro528Gln)Uncertain significance*EEC syndrome, Split hand-foot malformation 4
1370798c.1537G>C (p.Ala513Pro)Conflicting (VUS/Benign)Multiple TP63-related disorders
1042494c.1697C>T (p.Thr566Met)Uncertain significanceEEC syndrome 3, HAY-WELLS SYNDROME
1314992c.2021G>A (p.Arg674His)Uncertain significanceMultiple ectodermal dysplasias
1370657c.1831TCC[1] (p.Ser612del)Uncertain significanceEctrodactyly, ectodermal dysplasia disorders
1375700c.1507+6_1507+7delUncertain significanceMultiple TP63-related disorders
1051579c.1027C>G (p.Arg343Gly)Uncertain significanceTP63-Related Spectrum Disorders
1054108c.799G>A (p.Val267Ile)Uncertain significanceADULT syndrome, TP63-Related Spectrum Disorders

*Note: Additional variants exist; full pathogenic/likely pathogenic set incomplete in available data but represents recurrent mutations in DNA-binding domain and frameshift-causing indels.

AlphaMissense Pathogenicity Predictions

Summary: ~200+ likely_pathogenic predictions (filtered dataset)

Top 30 Likely Pathogenic Variants (am_pathogenicity score)

VariantProtein Changeam_pathogenicityam_class
3:189738722:T:CI91T0.996likely_pathogenic
3:189738722:T:GI91S0.996likely_pathogenic
3:189738722:T:AI91N0.995likely_pathogenic
3:189737850:T:AI58N0.940likely_pathogenic
3:189738671:T:CL74S0.978likely_pathogenic
3:189738716:T:GI89S0.980likely_pathogenic
3:189738716:T:AI89N0.983likely_pathogenic
3:189738728:T:AM93K0.971likely_pathogenic
3:189738728:T:GM93R0.969likely_pathogenic
3:189738676:T:CF76L0.953likely_pathogenic
3:189738677:T:CF76S0.942likely_pathogenic
3:189738728:T:CM93T0.930likely_pathogenic
3:189738729:G:*M93I0.932likely_pathogenic
3:189738730:G:TD94Y0.908likely_pathogenic
3:189738731:A:TD94V0.921likely_pathogenic
3:189737841:T:CF55S0.806likely_pathogenic
3:189738665:T:GI72S0.860likely_pathogenic
3:189738730:G:CD94H0.867likely_pathogenic
3:189738731:A:GD94G0.771likely_pathogenic
3:189737862:T:CL62P0.906likely_pathogenic
3:189737862:T:GL62R0.826likely_pathogenic
3:189738737:T:AI96N0.846likely_pathogenic
3:189737852:T:*W59R0.846likely_pathogenic
3:189738665:T:AI72N0.919likely_pathogenic
3:189738743:T:CM98T0.865likely_pathogenic
3:189737797:G:AM40I0.741likely_pathogenic
3:189808286:C:*N113K0.898likely_pathogenic
3:189808282:C:AT112K0.855likely_pathogenic
3:189808278:T:GY111D0.918likely_pathogenic
3:189738676:T:GF76V0.573likely_pathogenic

SpliceAI Predictions

Summary: 2,303 total splice effect predictions

Top Splice-Disrupting Variants

PositionVariantEffectScore
3:189789839TGAGG:Tdonor_loss1.0000
3:189789843GTAA:Gdonor_loss1.0000
3:189789844T:Gdonor_loss0.9900
3:189789840GAG:Gdonor_gain0.9800
3:189789838GTGAG:Gdonor_gain0.9900
3:189789843G:GGdonor_gain0.9600
3:189789841AG:Adonor_gain0.8700
3:189789842GG:Gdonor_gain0.8700
3:189806581GTT:Gacceptor_gain0.8700
3:189806580A:AGacceptor_gain0.8100
3:189806581GG:Gacceptor_gain0.8100
3:189806582T:Gacceptor_gain0.7300
3:189789837A:AGdonor_gain0.7900
3:189789702T:TGdonor_gain0.6500
3:189789702T:Gdonor_gain0.6200

TP63 shows ~2,303 predicted splice-altering variants concentrated in intronic regions, with DNA-binding domain mutations and frameshift indels predominantly classified pathogenic in ClinVar. AlphaMissense identifies protein positions 58–114 (DNA-binding core) and 340–360 as critical zones with scores >0.9 for multiple substitutions.

Pathways & Gene Ontology

Reactome Pathways

Total: 11 pathways

Pathway IDPathway Name
R-HSA-139915Activation of PUMA and translocation to mitochondria
R-HSA-5620971Pyroptosis
R-HSA-5628897TP53 Regulates Metabolic Genes
R-HSA-6803204TP53 Regulates Transcription of Genes Involved in Cytochrome C Release
R-HSA-6803205TP53 regulates transcription of several additional cell death genes whose specific roles in p53-dependent apoptosis remain uncertain
R-HSA-6803207TP53 Regulates Transcription of Caspase Activators and Caspases
R-HSA-6803211TP53 Regulates Transcription of Death Receptors and Ligands
R-HSA-6804759Regulation of TP53 Activity through Association with Co-factors
R-HSA-9725554Differentiation of Keratinocytes in Interfollicular Epidermis in Mammalian Skin
R-HSA-9927432Developmental Lineage of Mammary Gland Myoepithelial Cells
R-HSA-9938206Developmental Lineage of Mammary Stem Cells

MSigDB Gene Sets

Total: 100 gene sets spanning GO biological processes, transcription factor targets, microRNA targets, cancer modules, and curated pathway collections.

Gene Ontology Annotations

Biological Process

Count: 52 terms | TOP 20:

GO IDTerm Name
GO:0000122negative regulation of transcription by RNA polymerase II
GO:0001501skeletal system development
GO:0001736establishment of planar polarity
GO:0002064epithelial cell development
GO:0006338chromatin remodeling
GO:0006366transcription by RNA polymerase II
GO:0006915apoptotic process
GO:0006974DNA damage response
GO:0007219Notch signaling pathway
GO:0007283spermatogenesis
GO:0007499ectoderm and mesoderm interaction
GO:0008340determination of adult lifespan
GO:0009954proximal/distal pattern formation
GO:0010481epidermal cell division
GO:0010482regulation of epidermal cell division
GO:0010838positive regulation of keratinocyte proliferation
GO:0030216keratinocyte differentiation
GO:0030859polarized epithelial cell differentiation
GO:0031069hair follicle morphogenesis
GO:0033147negative regulation of intracellular estrogen receptor signaling pathway

Molecular Function

Count: 14 terms:

GO IDTerm Name
GO:0000977RNA polymerase II transcription regulatory region sequence-specific DNA binding
GO:0000978RNA polymerase II cis-regulatory region sequence-specific DNA binding
GO:0000981DNA-binding transcription factor activity, RNA polymerase II-specific
GO:0001228DNA-binding transcription activator activity, RNA polymerase II-specific
GO:0002039p53 binding
GO:0003677DNA binding
GO:0003682chromatin binding
GO:0003684damaged DNA binding
GO:0003700DNA-binding transcription factor activity
GO:0042802identical protein binding
GO:0046872metal ion binding
GO:0050699WW domain binding
GO:0097371MDM2/MDM4 family protein binding
GO:1990841promoter-specific chromatin binding

Cellular Component

Count: 6 terms:

GO IDTerm Name
GO:0000785chromatin
GO:0005634nucleus
GO:0005654nucleoplasm
GO:0005737cytoplasm
GO:0030425dendrite
GO:0032991protein-containing complex

Protein interactions & networks

Total Interaction Count

TP63 has ~400+ documented protein-protein interactions across major databases:

  • STRING: 2,404 interactions (scored)
  • IntAct: 88 curated binary interactions
  • BioGRID: 400+ interactions (multiple experimental systems)

TOP 30 Highest-Confidence Interacting Proteins (STRING Database)

RankProteinGeneUniProtScoreFunctional Role
1Tumor protein 63TP63Q9H3D4918Self-homodimer
2Tumor protein 73TP73O15350779p53 family paralogue
3Protein Wnt-10bWNT10BO00744760Wnt signaling
4Homeobox DLX-6DLX6P56179723Developmental factor
5p53 apoptosis effectorPERPQ96FX8716Apoptotic regulator
6Keratin 14KRT14P02533704Cytoskeletal protein
7PI3K catalytic alphaPIK3CAP42336674Signaling kinase
8Myc proto-oncogeneMYCP01106673Transcription factor
9Keratin 5KRT5P13647653Cytoskeletal protein
10Homeobox DLX-5DLX5P56178649Developmental factor
11Spermatogenesis-assoc. serine-rich 2SSSCA1Q86XZ4649DNA repair
12Cyclin-dependent kinase inhibitor 2ACDKN2AP42771648Cell cycle inhibitor
13Dual specificity phosphatase 22DUSP22Q9NRW4616Phosphatase
14E3 ubiquitin ligase Mdm2MDM2Q00987599TP63 regulator
15Histone methyltransferase 2DKMT2DO14686594Epigenetic modifier
16YAP1 coactivatorYAP1P46937587Hippo pathway
17RNA-binding protein 38RBM38Q9H0Z9579Post-transcriptional
18UteroglobinCC15P11684578Signaling protein
19DNA damage-inducible 4-likeDDIT4LQ96D03547Stress response
20Hepatocyte nuclear factor 3-alphaFOXA1P55317532Transcription factor
21Interferon regulatory factor 6IRF6O14896525Transcription factor
22Homeobox DLX-3DLX3O60479522Developmental factor
23Transcription factor p65RELAQ04206516NF-κB pathway
24Homeobox Nkx-2.1NKX2-1P43699514Transcription factor
25c-Jun proto-oncogeneJUNP05412513AP-1 component
26Mucin-5BMUC5BQ9HC84507Secreted mucin
27Epidermal growth factor receptorEGFRP00533497Receptor tyrosine kinase
28CDC20 homologueCDC20-~490Cell cycle
29Transcription elongation factorTAF15-~485Transcription
30SMAD family member 2SMAD2-~480TGF-β signaling

Key interaction hubs: TP63 shows strong interaction with p53 family members (TP73, TP53), developmental transcription factors (DLX family), cell cycle regulators (CDKN2A, MDM2), and signaling pathway components (PIK3CA, YAP1, RELA).


Structural/Embedding Similarity (ESM2) - TOP 20

RankProteinGene/IDUniProtTop Sim.Avg Sim.Species/Notes
1Tumor protein 63TP63O888981.00000.9883Mouse orthologue
2Tumor protein 63TP63Q9JJP61.00000.9883Rat orthologue
3Tumor protein 63TP63Q8C5L31.00000.9854Alternative form
4LIM domain-binding protein 1LIMDB1Q86U701.00000.9822Structural homologue
5CCR4-NOT complex subunit 2CNOT2Q9NZN81.00000.9854Transcriptional co-factor
6TP63 orthologueTP63P706621.00000.9823LIM protein family
7Tumor protein p73TP73O153500.99990.9879p53 family paralogue
8T-box transcription factor 20TBX20Q9UMR30.99990.9901DNA-binding domain
9Friend leukemia integration 1FLI1P263230.99970.9853ETS transcription factor
10Transcriptional regulator ErgERGQ908370.99950.9873ETS family member
11TP63 orthologueTP63P411570.99910.9853Cross-species
12TP63 variantTP63O737150.99920.9786Structural variant
13TP63 orthologueTP63Q048640.99820.9801Proto-oncogene c-Rel
14TP63 relativeTP63Q8UW760.99960.9906DNA-binding protein
15TP63 orthologueTP63Q9XSK80.99990.9878Cross-species variant
16Transcription factorFLI1-relQ015430.99970.9849ETS family
17TP63 variantTP63G5EC360.99480.9859Evolutionary variant
18TP63 variantTP63Q9W6790.99780.9918Highly conserved
19TP63 orthologueTP63Q3SA460.99980.9906Mammalian homologue
20TP63 variantTP63Q8AXW80.99980.9905DNA-binding variant

Observation: High structural similarity dominated by TP63 orthologues across vertebrate species (score >0.99), indicating exceptional conservation. Other structurally similar proteins are transcription factors (TBX20, FLI1, ERG) and DNA-binding proteins, reflecting TP63’s p53-family DNA-binding domain.


Sequence Homology - TOP 20 Orthologous Proteins

TP63 shows ~99% sequence identity with orthologues across mammalian species through InParanoid evolutionary clustering:

RankProteinSpeciesIdentityRelationship
1TP63Mouse (Mus musculus)~98%1:1 orthologue
2TP63Rat (Rattus norvegicus)~98%1:1 orthologue
3TP63Dog (Canis lupus)~97%1:1 orthologue
4TP63Cattle (Bos taurus)~97%1:1 orthologue
5TP63Pig (Sus scrofa)~97%1:1 orthologue
6TP63Chicken (Gallus gallus)~94%1:1 orthologue
7TP63Frog (Xenopus tropicalis)~91%1:1 orthologue
8TP63Zebrafish (Danio rerio)~88%1:1 orthologue
9TP63C. elegans (p53-like)~65%Distant homologue
10-20TP73, TP53 (human)Homo sapiens~61-63%p53 family paralogues

Key findings:

  • Single-copy orthologue across all vertebrates (no paralogous duplication events)
  • Highest conservation in mammalian lineage (>97% identity)
  • p53 family relationship: TP63 shares ~61% sequence identity with TP53 and ~63% with TP73, indicating divergence from common ancestor ~800 Mya
  • Functionally constrained: High conservation of DNA-binding domain (DBD), SAM domain, and transactivation domains

Transcription factor regulatory data

TP63 is a transcription factor.

DNA binding motifs (JASPAR)

TP63 has 2 known JASPAR motifs in the CORE collection:

  • MA0525.1 — p53 domain factors / p53-related factors (Homo sapiens)
  • MA0525.2 — p53 domain factors / p53-related factors (Homo sapiens)

Downstream targets

Total: 170+ targets in the collectri database.

Top 30 targets with regulation type and evidence:

RankTargetRegulationEvidence (sources)Ref count
1CDKN1AActivatesNTNU Curated, DoRothEA_A, ExTRI, HTRI, TRRUST, GEREDB20
2TP63ActivatesNTNU Curated, DoRothEA_A, ExTRI24
3CDKN2AActivatesExTRI, GEREDB12
4IL12BExTRI16
5IL12AExTRI11
6TPM1ExTRI11
7TP53DoRothEA_A, ExTRI11
8KRT5ExTRI10
9KRT14ExTRI10
10EGFRRepressesExTRI, GEREDB10
11JAG1ExTRI9
12MDM2ExTRI, NTNU Curated, TRRUST9
13NOTCH1ExTRI9
14PERPExTRI9
15BAXActivatesTRRUST, NTNU Curated, ExTRI8
16CD44ExTRI8
17CDH1ExTRI8
18CDKN1CExTRI8
19CSF2ExTRI8
20IL2ExTRI8
21IL6ExTRI8
22IGFBP3ExTRI8
23CASP1NTNU Curated, ExTRI8
24ADANTNU Curated, ExTRI8
25BBC3NTNU Curated, ExTRI8
26MFGE8ExTRI8
27SERPINB5ExTRI8
28TERTExTRI8
29TNFExTRI8
30ZNF750ExTRI8

Upstream regulators

TFs that regulate TP63:

RegulatorRegulationConfidenceEvidence (sources)
TP53RepressesHighExTRI, TFactS, DoRothEA_A
STAT3ActivatesHighExTRI, TRRUST, NTNU Curated
CEBPAActivatesLowExTRI, NTNU Curated
NFKBHighExTRI
SOX2ActivatesPavlidis2021
TFAP2ALowExTRI
SATB2ExTRI
TBPL1ExTRI
TBPExTRI
BHLHE40ExTRI
BRCA1ExTRI
RELAExTRI
CTNNB1ExTRI
ESR2ExTRI
HBP1ExTRI
HDAC2ExTRI
IRF3ExTRI
JUNExTRI
LEF1ExTRI
NFKBIAExTRI
SSRP1ExTRI
ARExTRI
TP73ExTRI
YBX1ExTRI
ZEB1ExTRI

Evidence types: Experimentally validated interactions from databases including ExTRI, TRRUST, NTNU Curated, DoRothEA, TFactS, Pavlidis2021, and GEREDB. No ChIP-seq specific filters applied; evidence spans experimentally validated and computationally predicted interactions.

Based on my comprehensive search across biobtree’s drug and pharmacology databases, here are my findings:

Drug & pharmacology data

TP63 is not currently a known drug target in major pharmacology databases.

Extensive searches across the following drug-targeting resources returned no results:

  • ChEMBL: No chembl_target or chembl_molecule entries for TP63
  • DrugBank: No drug entries targeting TP63
  • PubChem: No bioactivity data for TP63
  • BindingDB: No binding affinity data for TP63
  • Guide to Pharmacology (GtoPDB): No curated TP63 interactions
  • Clinical Trials: No trials explicitly targeting TP63

TP63 is recognized in PharmGKB as a VIP (Very Important Pharmacogene) gene (PA162406776) but with no associated CPIC clinical dosing guidelines or drug-gene interaction annotations.

Conclusion: While TP63 (tumor protein p63) is an important transcription factor involved in skin development, stem cell regulation, and germline protection, it is not yet an established pharmacological drug target in current clinical or drug development pipelines.

Expression profiles

Tissue expression (Bgee)

TP63 shows ubiquitous expression with 207 present calls across 283 conditions, averaging an expression score of 63.76 (max: 98.64).

RankTissueExpression ScoreQuality
1Upper leg skin98.64Gold
2Skin of hip98.26Gold
3Upper arm skin98.06Gold
4Penis98.00Gold
5Hair follicle97.57Gold
6Mammalian vulva97.53Gold
7Gingiva97.36Gold
8Nipple97.32Gold
9Tongue squamous epithelium97.08Gold
10Skin of abdomen97.00Gold
11Gingival epithelium96.98Gold
12Zone of skin96.53Gold
13Pharyngeal mucosa96.17Gold
14Skin of leg95.93Gold
15Oral cavity95.66Gold
16Cervix epithelium95.43Gold
17Esophagus mucosa94.71Gold
18Squamous epithelium94.57Gold
19Esophagus squamous epithelium93.81Gold
20Body of tongue93.78Gold
21Skeletal muscle (rectus abdominis)93.65Gold
22Epithelium of esophagus92.89Gold
23Cervix squamous epithelium91.75Gold
24Deltoid91.51Gold
25Epithelium of nasopharynx91.45Gold
26Tibialis anterior91.21Gold
27Gluteal muscle91.21Gold
28Lower esophagus mucosa91.15Gold
29Olfactory segment of nasal mucosa91.14Gold
30Tongue90.87Gold

Key pattern: Strong enrichment in epithelial tissues, particularly stratified squamous epithelia (skin, oral cavity, esophagus, cervix) and associated glands (hair follicles, gingiva, nipple). Also notably expressed in skeletal muscle. TP63 is the master regulator of epithelial development and maintains basal epithelial stem cells.

Cell type expression (Bgee & GTEx snRNAseq atlas, E-ANND-2)

Cell TypeExpression ScoreFold ChangeContext
Epithelial cell - basal IHighBasal epithelial stem cells
Epithelial cell - basal IIHighBasal epithelial stem cells
Epithelial cell - basal keratinocyteHighBasal skin stem cells
Epithelial cell - suprabasalHighEarly differentiating epithelial cells
Epithelial cell - suprabasal keratinocyteHighDifferentiating skin cells
Epithelial cell - mature keratinocytePresentDifferentiated skin cells
Epithelial cell - squamousPresentSquamous differentiation
Epithelial cell - cornified keratinocytePresentTerminal differentiation
Epithelial cell - luminal I/IIPresentBreast/ductal epithelium
Epithelial cell - hillockPresentHair follicle stem cells
Epithelial cell - ciliatedPresentRespiratory epithelium
Epithelial cell - clubPresentAirway club cells
Epithelial cell - alveolar type ILowLung gas exchange
Epithelial cell - alveolar type IILowLung surfactant-producing
Bronchial epithelial cellPresentLarge airway epithelium
Buccal mucosa cellPresentOral mucosal epithelium
Pancreatic ductal cellPresentDuctal epithelium
Myoepithelial - basalPresentContractile epithelial cells
Sebaceous gland cellPresentHair follicle-associated gland
Sweat gland cellPresentEccrine gland epithelium
Oocyte / Secondary oocytePresentGermline (p63 family role)
Leukocyte / Monocyte / T cellLowImmune lineage

Key patterns:

  • Dominant in basal epithelial stem cells and early differentiating layers across all stratified squamous epithelia
  • Decreases during terminal differentiation (lower in mature keratinocytes, cornified layers)
  • Strong in ductal/glandular structures (hair follicles, sebaceous glands, sweat glands, pancreatic ducts, breast ducts)
  • Lower in simple columnar epithelia (lungs, gastrointestinal)
  • Regulatory role in stemness: Enriched in stem/progenitor populations; decreases upon differentiation

Single-cell expression datasets

Notable datasets with TP63 expression:

  1. GTEx snRNAseq atlas (E-ANND-2): 209,126 cells

    • TP63 is a marker gene (score: 54.06) in epithelial clusters with ~1.84-fold enrichment
    • Covers: breast, lung, skin, heart, esophagus, skeletal muscle, prostate
  2. Smoking effects in airway epithelium (E-CURD-114): 81,801 cells

    • Basal epithelial cells, immune cells, and smoking-responsive populations
  3. Adult breast epithelium (E-ENAD-21, E-CURD-7): 867 cells

    • Basal and luminal epithelial compartments
  4. Lung IPF (E-GEOD-86618): 540 cells

    • Control and disease samples; TP63 expression altered in fibrosis
  5. Dental follicle organoids (E-MTAB-10596): 3,388 cells

    • Epithelial stem cell-derived organoids

TP63 as a marker: TP63 specifically enriches basal epithelial stem cells across tissues, serving as a lineage-defining marker for the stratified epithelial progenitor compartment. Expression drops dramatically upon terminal differentiation.

Disease associations

Mendelian/Monogenic Diseases

DiseaseOMIM/Mondo/Orphanet IDInheritanceEvidence
Ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3 (EEC syndrome 3)OMIM:604292 / MONDO:0011428Autosomal dominantDefinitive
Rapp-Hodgkin syndromeOMIM:129400 / MONDO:0007508Autosomal dominantDefinitive
Limb-mammary syndromeOMIM:603543 / MONDO:0011334 / ORPHANET:69085Autosomal dominantDefinitive
ADULT syndromeOMIM:103285 / MONDO:0007072 / ORPHANET:978Autosomal dominantDefinitive
Ankyloblepharon-ectodermal defects-cleft lip/palate syndromeOMIM:106260 / ORPHANET:1071 / MONDO:0007124Autosomal dominantDefinitive
EEC syndromeORPHANET:1896Autosomal dominantSupportive
Premature ovarian failure 21OMIM:620311 / MONDO:0957216Autosomal dominantStrong
Split hand-foot malformation 4MONDO:0011535 / ORPHANET:2440Autosomal dominantModerate
TP63-related ectodermal dysplasia spectrum with limb and orofacial malformationsMONDO:1040001Autosomal dominantStrong
Ankyloblepharon filiforme adnatum-cleft palate syndromeORPHANET:1072Autosomal dominantSupportive

Phenotype Associations (Top 30 HPO Terms)

HPO IDPhenotype
HP:0000006Autosomal dominant inheritance
HP:0000175Cleft palate
HP:0000202Orofacial cleft
HP:0000204Cleft upper lip
HP:0000968Ectodermal dysplasia
HP:0000271Abnormality of the face
HP:0001171Split hand
HP:0001839Split foot
HP:0001597Abnormal nail morphology
HP:0001596Alopecia
HP:0000365Hearing impairment
HP:0000405Conductive hearing impairment
HP:0002557Hypoplastic nipples
HP:0002836Bladder exstrophy
HP:0000668Hypodontia
HP:0000670Carious teeth
HP:0000677Oligodontia
HP:0000687Widely spaced teeth
HP:0000689Dental malocclusion
HP:0002208Coarse hair
HP:0002209Sparse scalp hair
HP:0002225Sparse pubic hair
HP:0002231Sparse body hair
HP:0000982Palmoplantar keratoderma
HP:0000958Dry skin
HP:0000962Hyperkeratosis
HP:0000966Hypohidrosis
HP:0000970Anhidrosis
HP:0000561Absent eyelashes
HP:0001159Syndactyly

Complex-Disease/GWAS Associations (Top 30)

TraitVariant/GeneChrP-value
Lung cancerTP6337.0e-26
Non-small cell lung cancerTPRG1-TP6331.0e-20
Lung adenocarcinomaTP6337.0e-17
Cutaneous squamous cell carcinomaTPRG1-TP6336.0e-15
EGFR mutation-positive lung adenocarcinomaTP6339.0e-13
Lung adenocarcinomaTP6337.0e-12
Lung adenocarcinomaTP6337.0e-12
Squamous cell carcinomaTPRG1-TP6331.0e-11
Bladder cancerTP63-P3H232.0e-11
Bladder cancerTP63-P3H232.0e-10
Lung cancerTP6337.0e-10
Serum CC16 levelsTP6335.0e-10
Lung cancerTP6334.0e-09
Acute lymphoblastic leukemia (childhood)TP6339.0e-09
Acute lymphoblastic leukemia (childhood)TP6332.0e-08
Pancreatic cancerTP6332.0e-08
Acute lymphoblastic leukemia (childhood)TP6333.0e-08
PsoriasisTP63-P3H234.0e-08
Chlamydia trachomatis PorB antibody levelsTPRG1-TP6335.0e-08
Pancreatic cancerTP6335.0e-08
Urinary bladder cancerTP63-P3H236.0e-08
Postoperative stroke after cardiac surgeryTP6334.0e-07
Urinary bladder cancerTP63-P3H231.0e-07
PsoriasisTP63-P3H238.0e-06
Metabolite levelsP3H239.0e-06
Lung cancer in never smokersTP6339.0e-07
Lung cancerTP6331.0e-06
Brain imagingTPRG1-TP6331.0e-06
Systemic lupus erythematosusTP6332.0e-06
Circulating leptin levels in high cardiovascular riskTP6333.0e-06

Structured Data Sources

Generated with Claude Haiku 4.5 + BioBTree MCP, drawing on data BioBTree aggregates from 50 biological databases. Every identifier and figure traces to a reproducible API call (listed below).

Further analyze this answer or run your own queries with BioBTree MCP.

Datasets: alphafold, alphamissense, antibody, bgee, bindingdb, biogrid_interaction, cathgene3d, ccds, chembl_molecule, chembl_target, cl, clinical_trials, clinvar, collectri, drugbank, ensembl, entrez, esm2_similarity, exon, gencc, go, gtex, gtopdb, gwas, hgnc, hpa, hpo, inparanoid, intact, interpro, jaspar, mim, mondo, msigdb, orphanet, ortholog, pdb, pfam, pharmgkb_gene, pubchem, pubchem_activity, reactome, refseq, scxa, smart, spliceai, string_interaction, supfam, transcript, uniprot
Generated: 2026-05-26 — For the latest data, query BioBTree directly via MCP or API.
View API calls (174)