TP53 p.Arg158Pro
c.473G>C · rs587782144 · VCV246118
ClinGen expert panel — TP53 VCEP
Pathogenic for Li-Fraumeni syndrome. Applied ACMG criteria (verbatim):
PP3_Moderate PM2_Supporting PS3 PM1 PM5
Curation rationale (ClinGen, verbatim)
The NM_000546.6: c.473G>C variant in TP53 is a missense variant predicted to cause substitution of arginine by proline at amino acid 158 (p.Arg158Pro). This variant received a total of 0.5 points in 1 proband on literature search only (internal data not obtained). (PS4 not met; PMID: 35974385). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PS3; PMIDs: 12826609, 30224644, 29979965). Another missense variant (c.473G>T, p.Arg158Leu) (ClinVar ID: 528248), in the same codon has been classified as pathogenic for Li-Fraumeni syndrome by the ClinGen TP53 VCEP’s specifications. (PM5). This variant has 11 somatic occurrences for the same amino acid change in cancerhotspots.org (v2) sufficient to be defined as a mutational hotspot by the Clingen TP53 VCEP (≥ 10 somatic occurrences, PMID: 30311369) (PM1). Computational predictor scores (BayesDel = 0.575563; 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 Pathogenic for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS3, PP3_moderate, PM1, PM5, PM2_Supporting. (Bayesian Points: 11; VCEP specifications version 2.3)
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.9986 | likely pathogenic ✓ concordant with ClinVar · top 3% in TP53 |
|---|---|---|
| REVEL | 0.916 | moderately pathogenic-leaning |
| SaProt | LLR -18.47 | 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 1.5, phastCons 1 |
| Regional constraint | o/e 0.89 | unconstrained · MANE · 6,982 bp · p 0.0085 · regional, not allelic |
| Overall | ||
| CADD | 24.3 | PHRED · no single calibrated threshold — expert panels disagree |
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.
Variant & gene context
- Gene
- TP53
- Protein
- p.Arg158Pro
- Coding
- c.473G>C
- MANE Select
- NM_000546
- dbSNP
- rs587782144
- Type
- single nucleotide variant
- Location
- chr17:7675139 (GRCh38)
- Gene constraint
- LOEUF 0.449 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 75.83 · 321 PDB
- Residue 158
- a DNA-binding region; the 'interaction with axin1' region; a β-strand; the 'interaction with ccar2' region; a UniProt-annotated variant site (in sporadic cancers; somatic mutation); a UniProt-annotated variant site (in a sporadic cancer; somatic mutation; requires 2 nucleotide substitutions); 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); the 'interaction with hipk1' region; the 'required for interaction with znf385a' region; the 'required for interaction with fbxo42' region
Disease context
Li-Fraumeni syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatmentsAlso linked: head 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.Arg158Leu Pathogenic ★★★ same residue
- TP53 p.Arg158Cys Uncertain significance ★★★ ⚠ same residue
- TP53 p.Arg158Gly Pathogenic ★★ same residue
- TP53 p.Arg158His Pathogenic/Likely pathogenic ★★ same residue
- TP53 p.Arg158= Benign/Likely benign ★★ same residue
- TP53 p.Arg158Ser Pathogenic ★ same residue
- TP53 p.Arg158_Ala159del Pathogenic ★ same residue
- TP53 p.Arg158_Tyr163del Likely pathogenic ★ same residue
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-arg158pro (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown