TP63

Chr 3AD

tumor protein p63

Also known as: AIS, B(p51A), B(p51B), EEC3, KET, LMS, NBP, OFC8

NCBI Gene: 8626 ENSG00000073282 UniProt: Q9H3D4 OMIM: 603273

This gene encodes a member of the p53 family of transcription factors. The functional domains of p53 family proteins include an N-terminal transactivation domain, a central DNA-binding domain and an oligomerization domain. Alternative splicing of this gene and the use of alternative promoters results in multiple transcript variants encoding different isoforms that vary in their functional properties. These isoforms function during skin development and maintenance, adult stem/progenitor cell regulation, heart development and premature aging. Some isoforms have been found to protect the germline by eliminating oocytes or testicular germ cells that have suffered DNA damage. Mutations in this gene are associated with ectodermal dysplasia, and cleft lip/palate syndrome 3 (EEC3); split-hand/foot malformation 4 (SHFM4); ankyloblepharon-ectodermal defects-cleft lip/palate; ADULT syndrome (acro-dermato-ungual-lacrimal-tooth); limb-mammary syndrome; Rap-Hodgkin syndrome (RHS); and orofacial cleft 8. [provided by RefSeq, Aug 2016]

GeneReviews OMIM Research

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.278 OMIM phenotypes

Clinical Summary— TP63

🧬

Gene-Disease Validity (ClinGen)

ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3 · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡

Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

📋

ClinVar Variants

134 unique Pathogenic / Likely Pathogenic· 324 VUS of 841 total submissions

💊

Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

📖

GeneReview available — TP63

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.27LOEUF

pLI 0.997

Z-score 5.08

OE 0.13 (0.07–0.27)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

2.21Z-score

OE missense 0.70 (0.63–0.77)

290 obs / 416.8 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.13 (0.07–0.27)

0≤0.351.4

Missense OE?0.70 (0.63–0.77)

0≤0.61.4

Synonymous OE?1.10

0≤1.21.6

LoF obs/exp: 5 / 39.4Missense obs/exp: 290 / 416.8Syn Z: -0.99

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveTP63-related ADULT syndromeOTHERAD

definitiveTP63-related limb-mammary syndromeOTHERAD

definitiveTP63-related ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndromeLOFAD

definitiveTP63-related Rapp-Hodgkin syndromeDNAD

definitiveTP63-related ectodermal dysplasia Rapp-Hodgkin typeOTHERAD

This gene — mechanism propensity

0.3892th %ile

GOF

0.2696th %ile

LOF

0.82top 5%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · 31% of P/LP variants are LoF · LOEUF 0.27

DN1 literature citation

GOF1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNTaken together, we suggest that not only the dominant negative function of N-truncated p63 but also the effect of cytotoxic molecules may influence the dismal prognosis of ALCL with TP63 rearrangement.1

GOFGain of function mutations of TP63 are known to be responsible for a group of conditions with distal limb and ectodermal involvement, such as ADULT, EEC, LMS, and SHFM4 syndromes.2

LOFImportantly, the mutant TP63 allele leads to nonsense-mediated messenger RNA decay, causing haploinsufficiency.3

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

ClinVar Variant Classifications

841 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic66

Likely Pathogenic68

VUS324

Likely Benign249

Benign81

Conflicting44

Pathogenic

Likely Pathogenic

324

VUS

249

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	29	35	2	0	66
Likely Pathogenic	12	56	0	0	68
VUS	4	258	56	6	324
Likely Benign	3	10	110	126	249
Benign	0	3	73	5	81
Conflicting	—				44
Total	48	362	241	137	832

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

41 pathogenic / likely-pathogenic (of 49) ClinVar copy-number / structural variants overlap TP63 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →