TP53 p.Arg181Cys
c.541C>T · rs587782596 · VCV142624
ClinGen expert panel — TP53 VCEP
Likely Pathogenic for Li-Fraumeni syndrome. Applied ACMG criteria (verbatim):
PP4_Moderate PP3_Moderate PM2_Supporting PS4 PM1_Supporting PP1 BS2
Curation rationale (ClinGen, verbatim)
The NM_000546.6: c.541C>T variant in TP53 is a missense variant predicted to cause substitution of Arginine by Cysteine at amino acid 181 (p.Arg181Cys). This variant has been reported in 10 unrelated families meeting Revised Chompret criteria and reported in 1 individuals under the age of 40 diagnosed with a HER2+ breast cancer. Based on this evidence, this variant scores 5.5 total points meeting the TP53 VCEP phenotype scoring criteria of 4-7.5 points. (PS4; PMIDs: 1581912, 27866339, 28486781, 27501770, Internal contributors). The variant has been reported to segregate with LFS-associated cancers in 3-4 meioses in 2 families (PP1; PMID:28486781, Clinvar SCV000186999.12). At least two individuals with this variant were found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID: 34906512, Internal lab contributor). This variant has been observed in at least 8 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; ClinVarSCV000186999.12, Internal lab contributor). This variant has an allele frequency of 0.000001859 (3/1614080 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). In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation and retained growth suppression activity suggesting that this variant does not impact protein function; however, all assays did not agree (BS3_Supporting not met; PMIDs: 12826609, 30224644, 29979965, 39774325). This variant has 9 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 (2-9 somatic occurrences, PMID: 30311369) (PM1_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2, PS4, PP3_Moderate, PP4_Moderate, PP1, PM1_Supporting, PM2_Supporting. (Bayesian Points: 7; VCEP specifications version 2.3)
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.7821 | likely pathogenic ✓ concordant with ClinVar |
|---|---|---|
| REVEL | 0.891 | moderately pathogenic-leaning |
| SaProt | LLR -8.94 | tolerated |
| ⇒ AlphaMissense and REVEL call this damaging; SaProt does not. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 9.9 | GERP 2.5, phastCons 1 |
| Regional constraint | o/e 0.89 | unconstrained · MANE · 6,982 bp · p 0.0085 · regional, not allelic |
| Overall | ||
| CADD | 26.1 | 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.Arg181Cys
- Coding
- c.541C>T
- MANE Select
- NM_000546
- dbSNP
- rs587782596
- Type
- single nucleotide variant
- Location
- chr17:7675071 (GRCh38)
- Gene constraint
- LOEUF 0.449 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 75.83 · 321 PDB
- Residue 181
- a DNA-binding region; the 'interaction with axin1' region; a β-strand; the 'interaction with ccar2' region; 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); a UniProt-annotated variant site (in a familial cancer not matching lfs; germline mutation and in sporadic cancers; 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: adrenocortical carcinoma, hereditaryhereditary neoplastic syndromehereditary breast carcinoma
For Li-Fraumeni syndrome (Orphanet):
- Inheritance
- Autosomal dominant
- Onset
- All ages
- Prevalence
- 1-9 / 100 000 (United Kingdom)
Similar variants
- TP53 p.Arg181Ser Uncertain significance ★★★ ⚠ same residue
- TP53 p.Arg181His Pathogenic/Likely pathogenic ★★ ⚠ same residue
- TP53 p.Arg181Pro Pathogenic/Likely pathogenic ★★ same residue
- TP53 p.Arg181= Benign/Likely benign ★★ same residue
- TP53 p.Arg181Leu Conflicting classifications of pathogenicity ★ ⚠ 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-arg181cys (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown