Is TP53 p.Val225Phe (c.673G>T) pathogenic?

TP53 p.Val225Phe (c.673G>T) is classified Uncertain significance in TP53 (ClinVar, Single submitter, 2 submitters; last evaluated 2024-11-13). AlphaMissense: ambiguous (0.4754); Very rare (popmax 0.00223%, eas); Associated with Li-Fraumeni syndrome.

What condition is associated with TP53 p.Val225Phe (c.673G>T)?

TP53 p.Val225Phe (c.673G>T) is associated with Li-Fraumeni syndrome (ClinVar).

How common is TP53 p.Val225Phe (c.673G>T) in the general population?

TP53 p.Val225Phe (c.673G>T) is very rare (popmax 0.00223%, eas) (gnomAD).

How is Li-Fraumeni syndrome inherited?

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

What do computational predictors say about TP53 p.Val225Phe (c.673G>T)?

AlphaMissense predicts ambiguous (score 0.4754) — an in-silico prediction, not a clinical call.

TP53 p.Val225Phe

c.673G>T · rs746504075 · VCV2122381

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4754 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Li-Fraumeni syndrome

Computational evidence

Protein change
AlphaMissense	0.4754	ambiguous
REVEL	0.704	pathogenic-leaning
SaProt	LLR -9.47	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	GERP 0.67, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 6,982 bp · p 0.0085 · regional, not allelic
Overall
CADD	26.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,812 alleles

Overall 6.23e-05% 1/1,605,012 alleles · very rare exomes 1/1,453,278 · genomes 0/151,734 · joint denominator

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.Val225Phe
Coding: c.673G>T
MANE Select: NM_000546
dbSNP: rs746504075
Type: single nucleotide variant
Location: chr17:7674290 (GRCh38)
Gene constraint: LOEUF 0.449 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.83 · 321 PDB
Residue 225: a DNA-binding region; the 'interaction with axin1' region; a turn; the 'interaction with ccar2' region; the 'interaction with hipk1' region; the 'required for interaction with znf385a' region; a UniProt-annotated variant site (in sporadic cancers; somatic mutation); a UniProt-annotated variant site (in a sporadic cancer; somatic mutation); the 'required for interaction with fbxo42' 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.Val225Asp Conflicting classifications of pathogenicity ★ ⚠ same residue
TP53 p.Val225Ile Conflicting classifications of pathogenicity ★ ⚠ same residue
TP53 p.Val225= Likely benign ★ 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
TP53 p.Ala138Pro Likely pathogenic ★★★ same condition
TP53 p.Ala138Val 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-val225phe (accessed [today's date]).

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