Is TP53 p.Val272Met (c.814G>A) pathogenic?

TP53 p.Val272Met (c.814G>A) is classified Pathogenic in TP53 (ClinVar, Expert panel, 12 submitters; last evaluated 2022-03-18). AlphaMissense: likely pathogenic (0.9572); Very rare (popmax 0.000169%, nfe); Associated with Li-Fraumeni syndrome 1.

What condition is associated with TP53 p.Val272Met (c.814G>A)?

TP53 p.Val272Met (c.814G>A) is associated with Li-Fraumeni syndrome 1, familial pancreatic carcinoma, hereditary neoplastic syndrome (ClinVar).

How common is TP53 p.Val272Met (c.814G>A) in the general population?

TP53 p.Val272Met (c.814G>A) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about TP53 p.Val272Met (c.814G>A)?

AlphaMissense predicts likely pathogenic (score 0.9572) — an in-silico prediction, not a clinical call.

TP53 p.Val272Met

c.814G>A · rs121912657 · VCV185814

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 12 submitters

AlphaMissense

likely pathogenic

0.9572 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Li-Fraumeni syndrome 1

ClinGen expert panel — TP53 VCEP

Pathogenic for Li-Fraumeni syndrome 1. Applied ACMG criteria (verbatim):

PM6_Strong PS3 PS4_Moderate PM1

Curation rationale (ClinGen, verbatim)

This variant has >10 observations as a somatic hotspot variant in tumors (PM1; cancerhotspots.org v(2)). Transactivation assays show a low functioning allele according to Kato, et al. and there is evidence of a dominant negative effect and loss of function according to Giacomelli, et al. (PS3; PMID: 12826609, 30224644). This variant has been reported in 4 probands meeting Chompret criteria (PS4_Moderate; PMID: 25584008, 23175693, IARC, NIH). There are de novo observations in 2 probands with childhood rhabdomyosarcoma, osteosarcoma, without parental confirmation (PM6_Strong; PMID: IARC, NIH). In summary, TP53 c.814G>A (p.Val272Met) meets criteria to be classified as pathogenic for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PM1, PS3, PS4_Moderate, PM6_Strong.

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.9572	likely pathogenic ✓ concordant with ClinVar
REVEL	0.907	moderately pathogenic-leaning
SaProt	LLR -12.04	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 7.7	GERP 2.5, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 6,982 bp · p 0.0085 · regional, not allelic
Overall
CADD	25.9	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 0.000169% European (non-Finnish) · 2/1,179,950 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,754 alleles · very rare

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.Val272Met
Coding: c.814G>A
MANE Select: NM_000546
dbSNP: rs121912657
Type: single nucleotide variant
Location: chr17:7673806 (GRCh38)
Gene constraint: LOEUF 0.449 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.83 · 321 PDB
Residue 272: a DNA-binding region; the 'interaction with axin1' region; a UniProt-annotated variant site (in a familial cancer not matching lfs; germline mutation and in sporadic cancers; 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 e4f1' 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 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial pancreatic carcinoma hereditary neoplastic syndrome Li-Fraumeni syndrome ovarian neoplasm

Similar variants

TP53 p.Val272Leu Pathogenic/Likely pathogenic ★★ same residue
TP53 p.Val272Ala Uncertain significance ★★ ⚠ same residue
TP53 p.Val272= Benign/Likely benign ★★ same residue
TP53 p.Val272Glu Conflicting classifications of pathogenicity ★ ⚠ same residue
TP53 p.Val272Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
TP53 p.Val272fs Pathogenic ★ same residue
TP53 p.Val272_Arg273insLeu Uncertain significance ★ same residue
TP53 c.375+5G>A 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-val272met (accessed [today's date]).

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