Is TP53 p.Pro47Ser (c.139C>T) pathogenic?

TP53 p.Pro47Ser (c.139C>T) is classified Benign in TP53 (ClinVar, Expert panel, 27 submitters; last evaluated 2024-08-05). AlphaMissense: likely benign (0.0695); Low-frequency (popmax 1.64%, afr); Associated with Li-Fraumeni syndrome.

What condition is associated with TP53 p.Pro47Ser (c.139C>T)?

TP53 p.Pro47Ser (c.139C>T) is associated with Li-Fraumeni syndrome, bone osteosarcoma, hereditary breast ovarian cancer syndrome (ClinVar).

How common is TP53 p.Pro47Ser (c.139C>T) in the general population?

TP53 p.Pro47Ser (c.139C>T) is low-frequency (popmax 1.64%, afr) (gnomAD).

How is Li-Fraumeni syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about TP53 p.Pro47Ser (c.139C>T)?

AlphaMissense predicts likely benign (score 0.0695) — an in-silico prediction, not a clinical call.

TP53 p.Pro47Ser

c.139C>T · rs1800371 · VCV43588

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 27 submitters

AlphaMissense

likely benign

0.0695 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.64%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Li-Fraumeni syndrome

ClinGen expert panel — TP53 VCEP

Benign for Li-Fraumeni syndrome. Applied ACMG criteria (verbatim):

BS2 BS3 BP4 BA1

Curation rationale (ClinGen, verbatim)

The NM_000546.6: c.139C>T variant in TP53 is a missense variant predicted to cause substitution of Proline by Serine at amino acid 47 (p.Pro47Ser). The filtering allele frequency of the c.139C>T variant in the TP53 gene is 0.01560 for African/African American population by gnomAD v4.1.0, which is higher than the ClinGen TP53 VCEP threshold (≥0.001) for BA1, and therefore meets this criterion (BA1). In summary, this variant meets the criteria to be classified as benign for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BA1 (Bayesian Points: N/A; VCEP specifications version 2.0; 7/24/2024).

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.0695	likely benign
REVEL	0.32	indeterminate
SaProt	LLR -6.28	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -4.9	GERP -3.8
Regional constraint	o/e 0.89	unconstrained · MANE · 6,982 bp · p 0.0085 · regional, not allelic
Overall
CADD	0.021	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.64% African / African-American · 1,227/74,990 alleles

Filtering AF 1.56% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.53%

Overall 0.087% 1,404/1,614,080 alleles · low-frequency exomes 706/1,461,882 · genomes 698/152,198 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.64%	61
Remaining individualsnot grpmax-eligible	0.128%	781
Admixed American	0.123%	811
Middle Eastern	0.0495%	2,019
South Asian	0.00878%	11,386
European (non-Finnish)	0.00102%	98,334

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Cancer therapy — CIViC

Disease	Therapies	Level	Significance
Cancer	Cisplatin	E	Resistance

Variant & gene context

Gene: TP53
Protein: p.Pro47Ser
Coding: c.139C>T
MANE Select: NM_000546
dbSNP: rs1800371
Type: single nucleotide variant
Location: chr17:7676230 (GRCh38)
Gene constraint: LOEUF 0.449 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.83 · 321 PDB
Residue 47: a UniProt-annotated variant site (in sporadic cancers; somatic mutation); a UniProt-annotated variant site (in); an α-helix; the 'interaction with ccar2' region; the 'interaction with hrmt1l2' region

Full TP53 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Li-Fraumeni syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: bone osteosarcoma hereditary breast ovarian cancer syndrome exocrine pancreatic carcinoma colorectal cancer breast cancer hepatocellular carcinoma adrenocortical carcinoma, hereditary choroid plexus papilloma basal cell carcinoma, susceptibility to, 7 hereditary neoplastic syndrome nasopharyngeal carcinoma hereditary breast carcinoma glioma susceptibility 1 bone marrow failure syndrome 5

For Li-Fraumeni syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages
Prevalence: 1-9 / 100 000 (United Kingdom)

Similar variants

TP53 p.Pro47Ala Uncertain significance ★★ ⚠ same residue
TP53 p.Pro47Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
TP53 p.Pro47Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
TP53 p.Pro47= Likely benign ★ same residue
TP53 p.Pro47fs Pathogenic ★★ same residue
TP53 c.375+5G>A Likely pathogenic ★★★ same condition
TP53 c.919+1G>A Pathogenic ★★★ same condition
TP53 c.97-1G>A Pathogenic ★★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/tp53-p-pro47ser (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown