TP53 p.Arg282Leu
c.845G>T · rs730882008 · VCV182938
ClinGen expert panel — TP53 VCEP
Uncertain Significance for Li-Fraumeni syndrome. Applied ACMG criteria (verbatim):
PP3_Moderate PM2_Supporting PM1 BS2_Moderate BS3
Curation rationale (ClinGen, verbatim)
The NM_000546.6: c.845G>T variant in TP53 is a missense variant predicted to cause substitution of arginine by leucine at amino acid 282 (p.Arg282Leu). This variant has an allele frequency of 0.000003098 (5/1613954 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting and has a subpopulation allele frequency of <0.00004 in all non-bottleneck populations with 2 or more alleles present (PM2_Supporting). 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; PMIDs: 28975465, 34906214). 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 contributor). 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 = 0.3605; Align GVGD = Class 65) 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). This variant resides within a codon (NM_00546.4: 175, 245, 248, 249, 273, 282) of TP53 that is defined as a mutational hotspot by the ClinGen TP53 VCEP (PM1; PMID: 8023157). In summary this variant meets the criteria to be classified as a variant of unknown significance for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PM2_Supporting, BS2_Moderate, PP3_Moderate, PM1, BS3. (Bayesian Points: -1; VCEP specifications version 2.3)
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.9405 | likely pathogenic |
|---|---|---|
| REVEL | 0.898 | moderately pathogenic-leaning |
| SaProt | LLR -12.95 | damaging |
| ⇒ AlphaMissense, REVEL and SaProt all call this damaging. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 6 | GERP 2.5, phastCons 1 |
| Regional constraint | o/e 0.89 | unconstrained · MANE · 6,982 bp · p 0.0085 · regional, not allelic |
| Overall | ||
| CADD | 26.5 | PHRED · no single calibrated threshold — expert panels disagree |
ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| East Asiangrpmax | 0.00223% | 44,858 |
| European (non-Finnish) | 0.000339% | 295,008 |
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 |
|---|---|---|---|
| Stomach Carcinoma | EAP Protocol | C | Sensitivity/Response |
Variant & gene context
- Gene
- TP53
- Protein
- p.Arg282Leu
- Coding
- c.845G>T
- MANE Select
- NM_000546
- dbSNP
- rs730882008
- Type
- single nucleotide variant
- Location
- chr17:7673775 (GRCh38)
- Gene constraint
- LOEUF 0.449 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 75.83 · 321 PDB
- Residue 282
- a DNA-binding region; the 'interaction with axin1' region; a UniProt-annotated variant site (in sporadic cancers; somatic mutation); the 'interaction with e4f1' region; a UniProt-annotated variant site (in lfs; germline mutation and in sporadic cancers; somatic mutation); a UniProt-annotated variant site (in a sporadic cancer; somatic mutation); a UniProt-annotated variant site (in a familial cancer not matching lfs; germline mutation and in sporadic cancers; somatic mutation); a UniProt-annotated variant site (in lfs; germline mutation and in sporadic cancers; somatic mutation; does not induce snai1 degradation); the 'disordered' region; an α-helix; the 'interaction with ccar2' region; the 'interaction with hipk1' region; the 'required for interaction with znf385a' region
Disease context
Li-Fraumeni syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatmentsAlso linked: adrenocortical carcinoma, hereditaryhereditary neoplastic syndrome
For Li-Fraumeni syndrome (Orphanet):
- Inheritance
- Autosomal dominant
- Onset
- All ages
- Prevalence
- 1-9 / 100 000 (United Kingdom)
Similar variants
- TP53 p.Arg282Gly Pathogenic ★★ same residue
- TP53 p.Arg282Pro Pathogenic/Likely pathogenic ★★ same residue
- TP53 p.Arg282Trp Pathogenic/Likely pathogenic ★★ same residue
- TP53 p.Arg282= Likely benign ★★ same residue
- TP53 p.Arg282Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
- TP53 p.Arg282fs Pathogenic ★★ same residue
- TP53 p.Arg282_Arg283insThr 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-arg282leu (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown