TP53 p.Arg110His
c.329G>A · rs11540654 · VCV127808
ClinGen expert panel — TP53 VCEP
Likely Benign for Li-Fraumeni syndrome. Applied ACMG criteria (verbatim):
BS2_Moderate BP4 BS3_Supporting
Curation rationale (ClinGen, verbatim)
The NM_000546.6: c.329G>A variant in TP53 is a missense variant predicted to cause substitution of arginine by histidine at amino acid 110 (p.Arg110His). This variant has been observed in 4-7 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_Moderate; Internal lab contributors). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00007119 (84/1,180,010 alleles) in the European (non-Finnish) population (PM2, BS1, and BA1 are not met). 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 = 0.0728; Align GVGD Class 0) are below the recommended thresholds (BayesDel < 0.16 and > -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). In summary, this variant meets the criteria to be classified as Likely Benign for Li Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_Moderate, BS3_Supporting, BP4. (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 | 0.0631 | likely benign |
|---|---|---|
| REVEL | 0.592 | indeterminate |
| SaProt | LLR -9.62 | 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 -4.1 | GERP -4.4 |
| Regional constraint | o/e 0.89 | unconstrained · MANE · 6,982 bp · p 0.0085 · regional, not allelic |
| Overall | ||
| CADD | 17.14 | 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 |
|---|---|---|
| East Asiangrpmax | 0.00891% | 11,218 |
| Admixed American | 0.00833% | 12,003 |
| Remaining individualsnot grpmax-eligible | 0.00802% | 12,470 |
| European (non-Finnish) | 0.00712% | 14,048 |
| African / African-American | 0.00267% | 37,491 |
| Finnishnot grpmax-eligible | 0.00156% | 64,034 |
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.Arg110His
- Coding
- c.329G>A
- MANE Select
- NM_000546
- dbSNP
- rs11540654
- Type
- single nucleotide variant
- Location
- chr17:7676040 (GRCh38)
- Gene constraint
- LOEUF 0.449 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 75.83 · 321 PDB
- Residue 110
- a DNA-binding region; a β-strand; the 'interaction with ccar2' region; a UniProt-annotated variant site (in sporadic cancers; somatic mutation); a UniProt-annotated variant site (in a sporadic cancer; somatic mutation); a UniProt-annotated variant site (in a familial cancer not matching lfs; germline mutation and in sporadic cancers; somatic mutation; does not induce snai1 degradation); the 'interaction with wwox' region; the 'interaction with hipk1' region; the 'required for interaction with znf385a' region
Disease context
Li-Fraumeni syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatmentsAlso linked: breast cancerhereditary neoplastic syndrome
For Li-Fraumeni syndrome (Orphanet):
- Inheritance
- Autosomal dominant
- Onset
- All ages
- Prevalence
- 1-9 / 100 000 (United Kingdom)
Similar variants
- TP53 p.Arg110Gly Likely pathogenic ★★★ ⚠ same residue
- TP53 p.Arg110Leu Pathogenic ★★★ ⚠ same residue
- TP53 p.Arg110Pro Pathogenic ★★★ same residue
- TP53 p.Arg110Cys Uncertain significance ★★★ ⚠ same residue
- TP53 p.Arg110Ser Uncertain significance ★★ ⚠ same residue
- TP53 p.Arg110= Benign/Likely benign ★★ same residue
- TP53 p.Arg110_Phe113del Likely pathogenic ★★ same residue
- TP53 p.Arg110fs Pathogenic ★★ same residue
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-arg110his (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown