TP63

Chr 3

tumor protein p63

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

NCBI Gene: 8626 ENSG00000073282 UniProt: Q9H3D4

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 Research

GeneReviews ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtAcro-dermato-ungual-lacrimal-tooth syndrome

UniProtAnkyloblepharon-ectodermal defects-cleft lip/palate

UniProtEctrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3

UniProtSplit-hand/foot malformation 4

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3 · AD · ClinGen 2024

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

172

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.27

LOEUF· LoF intol.

Multiple*

Mechanism· G2P

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GeneReview available — TP63

Authoritative clinical overview · Recommended first read

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Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

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

Background carrier burden — how many people carry a rare variant somewhere in TP63?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 75

818 rare PASS variants

Rare truncating (LoF)

1 in 1,300

45 rare PASS variants

Rare synonymous (reference)

1 in 100

406 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for TP63. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 100	1 in 1,000
South Asian	~43k	1 in 72	1 in 1,700
Remaining (unassigned)	~30k	1 in 79	1 in 3,000
European (Finnish)	~27k	1 in 130	1 in 3,000
Admixed American	~22k	1 in 81	1 in 3,300
African / African American	~21k	1 in 62	≈ 1 in 10,000
East Asian	~20k	1 in 71	1 in 810
Ashkenazi Jewish	~13k	1 in 220	none seen
Middle Eastern	~2,884	1 in 94	≈ 1 in 1,400

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 14 coding exons well covered in gnomAD exomes and genomes.? see exons ↓