TP53 p.Arg379Ser
c.1135C>A · rs749061599 · VCV186762
ClinGen expert panel — TP53 VCEP
Likely Benign for Li-Fraumeni syndrome. Applied ACMG criteria (verbatim):
PM2_Supporting PS4_Supporting BS2 BP4_Moderate
Curation rationale (ClinGen, verbatim)
The NM_000546.6: c.1135C>A variant in TP53 is a missense variant predicted to cause substitution of argine by serine at amino acid 379 (p.Arg379Ser). 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; Internal lab contributor: Invitae). This variant has been reported in 1 proband meeting Revised Chompret criteria and is reported in 1 individual under the age of 40 diagnosed with a HER2+ breast cancer. Based on this evidence, this variant scores 1 total point meeting the TP53 VCEP phenotype scoring criteria of 1-1.5 points. (PS4_Supporting; Internal lab contributors: Invitae, GeneDx). This variant has an allele frequency of 0.000005932 (7/1179994 alleles) in the European (non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). Computational predictor scores (BayesDel = -0.1497; Align GVGD Class C0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing. (BP4_Moderate). In summary, this variant meets the criteria to be classified as Likely Benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2, PS4_Supporting, PM2_Supporting, BS4_Moderate. (Bayesian Points: -4; VCEP specifications version 2.1; 1/16/2025)
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.1669 | likely benign |
|---|---|---|
| REVEL | 0.363 | indeterminate |
| SaProt | LLR -4.76 | tolerated |
| ⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 2.7 | GERP -2.1, phastCons 0.99 |
| Regional constraint | o/e 0.89 | unconstrained · MANE · 6,982 bp · p 0.0085 · regional, not allelic |
| Overall | ||
| CADD | 17.49 | PHRED · no single calibrated threshold — expert panels disagree |
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Remaining individualsnot grpmax-eligible | 0.0016% | 62,504 |
| European (non-Finnish)grpmax | 0.000593% | 168,571 |
Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.
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.Arg379Ser
- Coding
- c.1135C>A
- MANE Select
- NM_000546
- dbSNP
- rs749061599
- Type
- single nucleotide variant
- Location
- chr17:7669656 (GRCh38)
- Gene constraint
- LOEUF 0.449 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 75.83 · 321 PDB
- Residue 379
- a UniProt-annotated variant site (in sporadic cancers; somatic mutation); the 'interaction with carm1' region; an α-helix; the 'disordered' region; the 'basic (repression of dna-binding)' region; the 'interaction with morn3' 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.Arg379His Likely benign ★★★ same residue
- TP53 p.Arg379Leu Likely benign ★★★ same residue
- TP53 p.Arg379= Benign/Likely benign ★★ same residue
- TP53 p.Arg379Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
- TP53 p.Arg379fs Uncertain significance ★ 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-arg379ser (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown