TP53 p.Arg337Cys
c.1009C>T · rs587782529 · VCV142536
ClinGen expert panel — TP53 VCEP
Pathogenic for Li-Fraumeni syndrome. Applied ACMG criteria (verbatim):
PP4_Moderate PM2_Supporting PM5_Supporting PS2 PS3 PS4 PM1 PP3
Curation rationale (ClinGen, verbatim)
The NM_000546.6(TP53):c.1009C>T variant in TP53 is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 337 (p.Arg337Cys). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual with a strongly LFS-associated cancer and as a de novo occurrence with unconfirmed parental relationships in 1 individual with a moderately LFS-associated cancer totaling 5 phenotype points (PS2; PMID: 18511570, Internal lab contributors). This variant has been reported in 10 unrelated families meeting Revised Chompret; 1 family meeting classic; and reported in 1 individual under the age of 40 diagnosed with a HER2+ breast cancer. Based on this evidence, this variant scores 6.5 total points meeting the TP53 VCEP phenotype scoring criteria of 4-7.5 points. (PS4; PMIDs: 1353190, 9452042; Internal lab contributors). 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 contributors). 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). This variant has 36 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 = 0.316468; Align GVGD = Class C45) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of > 15), evidence that correlates with impact to TP53 via protein change (PP3). Three missense variants (p.Arg337Ser, p.Arg337Pro, p.Arg337Leu) in the same codon have been classified as likely pathogenic for Li-Fraumeni syndrome by the ClinGen TP53 VCEP’s specifications.(PM5_Supporting). 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, PM1, PS4, PP3, PP4_Moderate, PM2_Supporting, PM5_Supporting, PS2. (Bayesian Points: 19; VCEP specifications version 2.3)
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.8021 | likely pathogenic ✓ concordant with ClinVar |
|---|---|---|
| REVEL | 0.715 | pathogenic-leaning |
| SaProt | LLR -10.97 | 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 6.5 | GERP 0.92, phastCons 1 |
| Regional constraint | o/e 0.89 | unconstrained · MANE · 6,982 bp · p 0.0085 · regional, not allelic |
| Overall | ||
| CADD | 22.4 | PHRED · no single calibrated threshold — expert panels disagree |
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
No allele count reported in gnomAD v4.1 (AN 1,613,822). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.
Variant & gene context
- Gene
- TP53
- Protein
- p.Arg337Cys
- Coding
- c.1009C>T
- MANE Select
- NM_000546
- dbSNP
- rs587782529
- Type
- single nucleotide variant
- Location
- chr17:7670700 (GRCh38)
- Gene constraint
- LOEUF 0.449 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 75.83 · 321 PDB
- Residue 337
- a UniProt-annotated variant site (in lfs; germline mutation and in sporadic cancers; somatic mutation; impaired ability to tetramerize and undergo liquid-liquid phase separation); a UniProt-annotated variant site (in sporadic cancers; somatic mutation); a UniProt-annotated variant site (in sporadic cancers; somatic mutation; impaired ability to tetramerize and undergo liquid-liquid phase separation); the 'interaction with carm1' region; an α-helix; the 'interaction with hipk2' region; the 'oligomerization' region; a modified residue (symmetric dimethylarginine; by prmt5); the 'interaction with hipk1' region
Disease context
Li-Fraumeni syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatmentsAlso linked: adrenocortical carcinoma, hereditaryhereditary neoplastic syndromeovarian neoplasm
For Li-Fraumeni syndrome (Orphanet):
- Inheritance
- Autosomal dominant
- Onset
- All ages
- Prevalence
- 1-9 / 100 000 (United Kingdom)
Similar variants
- TP53 p.Arg337Gly Likely pathogenic ★★★ same residue
- TP53 p.Arg337Leu Likely pathogenic ★★★ ⚠ same residue
- TP53 p.Arg337Pro Likely pathogenic ★★★ same residue
- TP53 p.Arg337Ser Likely pathogenic ★★★ same residue
- TP53 p.Arg337= Benign/Likely benign ★★ same residue
- TP53 p.Arg337fs 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-arg337cys (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown