TP53 p.His193Pro
c.578A>C · rs786201838 · VCV376612
ClinGen expert panel — TP53 VCEP
Pathogenic for Li-Fraumeni syndrome. Applied ACMG criteria (verbatim):
PP3_Moderate PM2_Supporting PS2 PS3 PM1_Supporting PP4
Curation rationale (ClinGen, verbatim)
The NM_000546.6: c.578A>C variant in TP53 is a missense variant predicted to cause substitution of histidine by proline at amino acid 193 (p.His193Pro). In vitro assays performed in yeast and human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PMIDs: 12826609, 30224644, 29979965) (PS3). Computational predictor scores (BayesDel = 0.5922; Align GVGD = Class C65) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of 65), evidence that correlates with impact to TP53 via protein change (PP3_Moderate). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual with a strongly-associated LFS-associated cancer totaling 4 phenotype points (PS2; PMID: 19556618). At least one individual with this variant was found to have a variant allele fraction of 25-35%, which is a significant predictor of variant pathogenicity (PP4, PMID: 34906512, Internal lab contributor: SCV002651939.1). This variant has an allele frequency of 6.196e-7 (1/1614048 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). This variant has 8 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 Pathogenic for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS3, PP3_Moderate, PS2, PP4, PM2_Supporting, PM1_Supporting. (Bayesian Points: 13; VCEP specifications version 2.0; 7/24/2024)
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.9975 | likely pathogenic ✓ concordant with ClinVar · top 4% in TP53 |
|---|---|---|
| REVEL | 0.87 | moderately pathogenic-leaning |
| SaProt | LLR -15.55 | 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 7.9 | GERP 2.3, phastCons 1 |
| Regional constraint | o/e 0.89 | unconstrained · MANE · 6,982 bp · p 0.0085 · regional, not allelic |
| Overall | ||
| CADD | 26.8 | 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.His193Pro
- Coding
- c.578A>C
- MANE Select
- NM_000546
- dbSNP
- rs786201838
- Type
- single nucleotide variant
- Location
- chr17:7674953 (GRCh38)
- Gene constraint
- LOEUF 0.449 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 75.83 · 321 PDB
- Residue 193
- a DNA-binding region; the 'interaction with axin1' region; the 'interaction with ccar2' region; a UniProt-annotated variant site (in a sporadic cancer; somatic mutation); a UniProt-annotated variant site (in sporadic cancers; somatic mutation); a UniProt-annotated variant site (in 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: 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.His193Arg Pathogenic/Likely pathogenic ★★ same residue
- TP53 p.His193Asn Pathogenic/Likely pathogenic ★★ same residue
- TP53 p.His193Tyr Pathogenic/Likely pathogenic ★★ same residue
- TP53 p.His193Asp Conflicting classifications of pathogenicity ★ ⚠ same residue
- TP53 p.His193Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
- TP53 p.His193Leu Conflicting classifications of pathogenicity ★ ⚠ 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-his193pro (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown