TP53 p.Val10Ile
c.28G>A · rs535274413 · VCV127806
ClinGen expert panel — TP53 VCEP
Benign for Li-Fraumeni syndrome. Applied ACMG criteria (verbatim):
PM2_Supporting BS2 BS3 BP4_moderate
Curation rationale (ClinGen, verbatim)
The NM_000546.6: c.28G>A variant in TP53 is a missense variant predicted to cause substitution of Valine by Isoleucine at amino acid 10 (p.Val10Ile). 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 contributors: SCV000184102.7). This variant has an allele frequency of .000021066 (34/1613962 alleles) across gnomAD v4.1.0 (after removing low AB alleles likely to represent CHIP contamination and recalculating total allele frequency) which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = -0.0961; 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 Benign for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2, PM2_Supporting, BS3, BP4_moderate. (Bayesian Points: -9; VCEP specifications version 2.0; 7/24/2024).
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.0604 | likely benign |
|---|---|---|
| REVEL | 0.474 | indeterminate |
| SaProt | LLR -7.76 | 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 -1.4 | GERP -4.6 |
| Regional constraint | o/e 0.89 | unconstrained · MANE · 6,982 bp · p 0.0085 · regional, not allelic |
| Overall | ||
| CADD | 5.256 | 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 |
|---|---|---|
| African / African-Americangrpmax | 0.008% | 12,499 |
| South Asian | 0.00769% | 13,012 |
| Admixed American | 0.005% | 19,987 |
| Remaining individualsnot grpmax-eligible | 0.0032% | 31,252 |
| European (non-Finnish) | 0.00144% | 69,413 |
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.Val10Ile
- Coding
- c.28G>A
- MANE Select
- NM_000546
- dbSNP
- rs535274413
- Type
- single nucleotide variant
- Location
- chr17:7676567 (GRCh38)
- Gene constraint
- LOEUF 0.449 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 75.83 · 321 PDB
- Residue 10
- a turn; the 'interaction with ccar2' region; the 'interaction with hrmt1l2' region; the 'transcription activation (acidic)' region; a UniProt-annotated variant site (in a sporadic cancer; somatic mutation)
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.Val10Leu Likely benign ★★★ same residue
- TP53 p.Val10= Benign/Likely benign ★★ same residue
- TP53 p.Val10Asp Uncertain significance ★ ⚠ same residue
- TP53 p.Val10Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
- TP53 p.Val10Phe 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-val10ile (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown