TP53

Chr 17

tumor protein p53

Also known as: BCC7, BMFS5, LFS1, P53, TRP53

NCBI Gene: 7157 ENSG00000141510 UniProt: P04637

The protein is a tumor suppressor that regulates gene expression in response to cellular stress, inducing cell cycle arrest, apoptosis, DNA repair, or metabolic changes. Mutations cause Li-Fraumeni syndrome and predispose to multiple pediatric cancers including adrenocortical carcinoma, osteosarcoma, and choroid plexus papilloma through autosomal dominant inheritance. The pathogenic mechanism involves loss of function of this critical tumor suppressor.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a tumor suppressor protein containing transcriptional activation, DNA binding, and oligomerization domains. The encoded protein responds to diverse cellular stresses to regulate expression of target genes, thereby inducing cell cycle arrest, apoptosis, senescence, DNA repair, or changes in metabolism. Mutations in this gene are associated with a variety of human cancers, including hereditary cancers such as Li-Fraumeni syndrome. Alternative splicing of this gene and the use of alternate promoters result in multiple transcript variants and isoforms. Additional isoforms have also been shown to result from the use of alternate translation initiation codons from identical transcript variants (PMIDs: 12032546, 20937277). [provided by RefSeq, Dec 2016]

GeneReviews ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtEsophageal cancer

UniProtLi-Fraumeni syndrome

UniProtSquamous cell carcinoma of the head and neck

UniProtLung cancer

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · Li-Fraumeni syndrome · 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

6520

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.47

LOEUF

LOF*

Mechanism· G2P

📖

GeneReview available — TP53

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.47LOEUF

pLI 0.532

Z-score 3.26

OE 0.20 (0.10–0.47)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.98Z-score

OE missense 0.82 (0.73–0.92)

192 obs / 234.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.20 (0.10–0.47)

0≤0.351.4

Missense OE?0.82 (0.73–0.92)

0≤0.61.4

Synonymous OE?1.07

0≤1.21.6

LoF obs/exp: 4 / 19.5Missense obs/exp: 192 / 234.3Syn Z: -0.54

Background carrier burden — how many people carry a rare variant somewhere in TP53?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 92

563 rare PASS variants

Rare truncating (LoF)

1 in 1,600

58 rare PASS variants

Rare synonymous (reference)

1 in 200

201 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for TP53. 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 1,600
South Asian	~43k	1 in 120	1 in 540
Remaining (unassigned)	~30k	1 in 96	1 in 4,100
European (Finnish)	~27k	1 in 260	≈ 1 in 27,000
Admixed American	~22k	1 in 100	1 in 1,200
African / African American	~21k	1 in 120	1 in 2,100
East Asian	~20k	1 in 160	1 in 980
Ashkenazi Jewish	~13k	1 in 420	≈ 1 in 4,400
Middle Eastern	~2,884	1 in 190	none seen

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 10 coding exons well covered in gnomAD exomes and genomes.? see exons ↓