TP53 p.Val157Ile
c.469G>A · rs121912654 · VCV185404
ClinGen expert panel — TP53 VCEP
Likely Benign for Li-Fraumeni syndrome. Applied ACMG criteria (verbatim):
BS2_Supporting BP4_Moderate BS3_Supporting
Curation rationale (ClinGen, verbatim)
The NM_000546.6:c.469G>A variant in TP53 is a missense variant predicted to cause substitution of valine by isoleucine at amino acid 157 (p.Val157Ile). This variant has been observed in at least 2 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_Supporting; Internal Contributors: Invitae, Ambry). In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3_Supporting; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = -0.057; 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_supporting, BS3_supporting, BP4_Moderate. (Bayesian Points: -4; VCEP specifications version 2.0, 1/16/2025).
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.1052 | likely benign |
|---|---|---|
| REVEL | 0.425 | indeterminate |
| SaProt | LLR -7.46 | tolerated |
| ⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 1.8 | GERP -0.67, phastCons 0.98 |
| Regional constraint | o/e 0.89 | unconstrained · MANE · 6,982 bp · p 0.0085 · regional, not allelic |
| Overall | ||
| CADD | 14.05 | 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 |
|---|---|---|
| Middle Easterngrpmax | 0.0165% | 6,062 |
| Admixed American | 0.00667% | 15,001 |
| Remaining individualsnot grpmax-eligible | 0.0048% | 20,835 |
| Finnishnot grpmax-eligible | 0.00312% | 32,008 |
| East Asian | 0.00223% | 44,876 |
| African / African-American | 0.00133% | 75,036 |
| South Asian | 0.0011% | 91,082 |
| European (non-Finnish) | 0.000763% | 131,115 |
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.Val157Ile
- Coding
- c.469G>A
- MANE Select
- NM_000546
- dbSNP
- rs121912654
- Type
- single nucleotide variant
- Location
- chr17:7675143 (GRCh38)
- Gene constraint
- LOEUF 0.449 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 75.83 · 321 PDB
- Residue 157
- 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); 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: 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.Val157Phe Pathogenic/Likely pathogenic ★★ same residue
- TP53 p.Val157= Conflicting classifications of pathogenicity ★ same residue
- TP53 p.Val157Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
- TP53 p.Val157Asp Conflicting classifications of pathogenicity ★ ⚠ same residue
- TP53 p.Val157Leu Uncertain significance ★ ⚠ same residue
- TP53 p.Val157_Arg158dup Uncertain significance ★ same residue
- TP53 p.Val157del 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-val157ile (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown