TP53 p.Pro219Leu
c.656C>T · rs1420675064 · VCV826488
ClinGen expert panel — TP53 VCEP
Uncertain Significance for Li-Fraumeni syndrome. Applied ACMG criteria (verbatim):
PP3_Moderate PM2_Supporting
Curation rationale (ClinGen, verbatim)
The NM_000546.6: c.656C>T variant in TP53 is a missense variant predicted to cause substitution of proline by leucine at amino acid 219 (p.Pro219Leu). Although this variant has been observed in germline cases, to our knowledge, this variant has not been reported in individuals meeting classical LFS or Chompret criteria (PS4 not met; Internal lab contributors). This variant has an allele frequency of 6.195e-7 (1/1614106 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting and has no more than one allele per non-bottleneck subpopulation (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed conflicting results with respect to transactivation, growth suppression activity, and/or tetramer formation (PS3/BS3 not met; PMIDs: 12826609, 39774325, 29979965, 30224644). Computational predictor scores (BayesDel = 0.585695; Align GVGD = Class C65) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of 65), evidence that correlates with impact to TP53 via protein change (PP3_Moderate). In summary, this variant meets the criteria to be classified as variant of uncertain signficance for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PM2_Supporting, PP3_Moderate. (Bayesian Points: 3; VCEP specifications version 2.4)
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.4909 | ambiguous |
|---|---|---|
| REVEL | 0.947 | strongly pathogenic-leaning |
| SaProt | LLR -12.58 | damaging |
| ⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call. | ||
| Splicing | ||
| SpliceAI | <0.2 | all four deltas below 0.2 · G>C here scores Δ0.31 · evaluated, not missing |
| Constraint at this position | ||
| Conservation | phyloP 12 | GERP 2.3, phastCons 1 |
| Regional constraint | o/e 0.89 | unconstrained · MANE · 6,982 bp · p 0.0085 · regional, not allelic |
| Overall | ||
| CADD | 28.3 | PHRED · no single calibrated threshold — expert panels disagree |
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
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.Pro219Leu
- Coding
- c.656C>T
- MANE Select
- NM_000546
- dbSNP
- rs1420675064
- Type
- single nucleotide variant
- Location
- chr17:7674875 (GRCh38)
- Gene constraint
- LOEUF 0.449 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 75.83 · 321 PDB
- Residue 219
- a DNA-binding region; the 'interaction with axin1' region; a β-strand; the 'interaction with ccar2' region; the 'interaction with hipk1' region; the 'required for interaction with znf385a' region; a UniProt-annotated variant site (in a sporadic cancer; somatic mutation; requires 2 nucleotide substitutions); a UniProt-annotated variant site (in a sporadic cancer; somatic mutation); a UniProt-annotated variant site (in sporadic cancers; somatic mutation); a UniProt-annotated variant site (in a familial cancer not matching lfs; germline mutation and in sporadic cancers; somatic mutation); the 'required for interaction with fbxo42' region
Disease context
Li-Fraumeni syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatmentsAlso linked: hereditary neoplastic syndrome
For Li-Fraumeni syndrome (Orphanet):
- Inheritance
- Autosomal dominant
- Onset
- All ages
- Prevalence
- 1-9 / 100 000 (United Kingdom)
Similar variants
- TP53 p.Pro219= Benign/Likely benign ★★ same residue
- TP53 p.Pro219Ala Uncertain significance ★ ⚠ same residue
- TP53 p.Pro219Arg Uncertain significance ★ ⚠ same residue
- TP53 p.Pro219Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
- TP53 p.Pro219Thr Uncertain significance ★ ⚠ same residue
- TP53 p.Pro219fs Pathogenic ★ same residue
- TP53 c.375+5G>A Likely pathogenic ★★★ same condition
- TP53 c.919+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-pro219leu (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown