Is TP53 p.Val274Glu (c.821_822inv) pathogenic?

TP53 p.Val274Glu (c.821822inv) is classified Uncertain significance in TP53 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-16). Associated with Li-Fraumeni syndrome.

What condition is associated with TP53 p.Val274Glu (c.821_822inv)?

TP53 p.Val274Glu (c.821_822inv) is associated with Li-Fraumeni syndrome (ClinVar).

How is Li-Fraumeni syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

TP53 p.Val274Glu

c.821_822inv · VCV1417760

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

Conditions

Li-Fraumeni syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.4	GERP -5.1
Regional constraint	o/e 0.89	unconstrained · MANE · 6,982 bp · p 0.0085 · regional, not allelic

Variant & gene context

Gene: TP53
Protein: p.Val274Glu
Coding: c.821_822inv
MANE Select: NM_000546
Type: Inversion
Location: chr17:7673798 (GRCh38)
Gene constraint: LOEUF 0.449 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.83 · 321 PDB
Residue 274: a DNA-binding region; the 'interaction with axin1' region; a UniProt-annotated variant site (in sporadic cancers; somatic mutation); the 'interaction with e4f1' region; the 'interaction with dna' region; a β-strand; the 'interaction with ccar2' region; the 'interaction with hipk1' region; the 'required for interaction with znf385a' region

Full TP53 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Li-Fraumeni syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Li-Fraumeni syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages
Prevalence: 1-9 / 100 000 (United Kingdom)

Similar variants

TP53 p.Val274= Benign/Likely benign ★★ same residue
TP53 p.Val274fs Pathogenic ★ same residue
TP53 p.Val274Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
TP53 p.Val274Asp Conflicting classifications of pathogenicity ★ ⚠ same residue
TP53 p.Val274Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
TP53 p.Val274Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
TP53 p.Val274Phe Conflicting classifications of pathogenicity ★ ⚠ same residue
TP53 p.Phe109Asn Uncertain significance ★ 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-val274glu (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown