TP53 p.Pro82Leu
c.245C>T · rs534447939 · VCV182946
ClinGen expert panel — TP53 VCEP
Likely Benign for Li-Fraumeni syndrome. Applied ACMG criteria (verbatim):
PM2_Supporting BS2_moderate BS3 BP4
Curation rationale (ClinGen, verbatim)
The NM_000546.6: c.245C>T variant in TP53 is a missense variant predicted to cause substitution of proline by leucine at amino acid 82 (p.Pro82Leu). This variant has been observed in 4-7 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Moderate; Internal Lab Contributors: SCV000215716.6). This variant has an allele frequency of 0.00003335 (5/59976 alleles) in the Admixed American population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = 0.0708; Align GVGD Class C0) are below the recommended thresholds (BayesDel < 0.16 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predictor score of [0.01] predicts that the variant has no impact on splicing (score threshold <0.210) (BP4). In summary, this variant meets the criteria to be classified as Likely Benign for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_moderate, PM2_Supporting BS3, BP4, (Bayesian Points: -6; VCEP specifications version 2.0; 7/24/2024).
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.0705 | likely benign |
|---|---|---|
| REVEL | 0.57 | indeterminate |
| SaProt | LLR -10.65 | damaging |
| ⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP -0.78 | GERP -2.8 |
| Regional constraint | o/e 0.89 | unconstrained · MANE · 6,982 bp · p 0.0085 · regional, not allelic |
| Overall | ||
| CADD | 12.89 | PHRED · no single calibrated threshold — expert panels disagree |
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Ashkenazi Jewishnot grpmax-eligible | 0.00338% | 29,600 |
| Admixed Americangrpmax | 0.00333% | 29,988 |
| South Asian | 0.0033% | 30,341 |
| African / African-American | 0.00267% | 37,497 |
| Remaining individualsnot grpmax-eligible | 0.0016% | 62,420 |
| European (non-Finnish) | 0.000763% | 131,072 |
Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.
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.
Variant & gene context
- Gene
- TP53
- Protein
- p.Pro82Leu
- Coding
- c.245C>T
- MANE Select
- NM_000546
- dbSNP
- rs534447939
- Type
- single nucleotide variant
- Location
- chr17:7676124 (GRCh38)
- Gene constraint
- LOEUF 0.449 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 75.83 · 321 PDB
- Residue 82
- a UniProt-annotated variant site (in lfs; germline mutation and in sporadic cancers; somatic mutation); a UniProt-annotated variant site (in sporadic cancers; somatic mutation); the 'interaction with ccar2' region; the 'interaction with hrmt1l2' region; the 'disordered' region; the 'interaction with wwox' region
Disease context
Li-Fraumeni syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatmentsAlso linked: breast cancerhead and neck squamous cell carcinomahereditary neoplastic syndrome
For Li-Fraumeni syndrome (Orphanet):
- Inheritance
- Autosomal dominant
- Onset
- All ages
- Prevalence
- 1-9 / 100 000 (United Kingdom)
Similar variants
- TP53 p.Pro82= Benign/Likely benign ★★ same residue
- TP53 p.Pro82Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
- TP53 p.Pro82Arg Uncertain significance ★ ⚠ same residue
- TP53 p.Pro82Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
- TP53 p.Pro82Thr Likely benign ★ ⚠ same residue
- TP53 p.Pro82fs Pathogenic ★ same residue
- TP53 p.Pro82_Ala83insThrPro Uncertain significance ★ same residue
- TP53 c.375+5G>A Likely 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-pro82leu (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown