Is TP53 p.Glu224= (c.672G>A) pathogenic?

TP53 p.Glu224= (c.672G>A) is classified Pathogenic/Likely pathogenic in TP53 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-10-28). Absent from gnomAD v4.1; Associated with Li-Fraumeni syndrome 1.

What condition is associated with TP53 p.Glu224= (c.672G>A)?

TP53 p.Glu224= (c.672G>A) is associated with Li-Fraumeni syndrome 1, hereditary neoplastic syndrome, Li-Fraumeni syndrome (ClinVar).

How common is TP53 p.Glu224= (c.672G>A) in the general population?

TP53 p.Glu224= (c.672G>A) is absent from gnomAD v4.1 (gnomAD).

TP53 p.Glu224=

c.672G>A · rs267605076 · VCV80709

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Li-Fraumeni syndrome 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.90	donor loss · deltas
Pangolin	Δ0.78	loss · gain 0.50 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.7	GERP 1.3, phastCons 1
Overall
CADD	24.7	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TP53
Protein: p.Glu224=
Coding: c.672G>A
MANE Select: NM_000546
dbSNP: rs267605076
Type: single nucleotide variant
Location: chr17:7674859 (GRCh38)
Gene constraint: LOEUF 0.449 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.83 · 321 PDB
Residue 224: a DNA-binding region; the 'interaction with axin1' region; an α-helix; 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 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome Li-Fraumeni syndrome

Similar variants

TP53 p.Glu224Ala Uncertain significance ★★ ⚠ same residue
TP53 p.Glu224Gly Uncertain significance ★★ ⚠ same residue
TP53 p.Glu224Lys Uncertain significance ★★ ⚠ same residue
TP53 p.Glu224Asp Uncertain significance ★ ⚠ same residue
TP53 p.Glu224fs Pathogenic ★ 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-glu224 (accessed [today's date]).

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