Is TP53 p.Pro219Arg (c.656C>G) pathogenic?

TP53 p.Pro219Arg (c.656C>G) is classified Uncertain significance in TP53 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-06-08). AlphaMissense: likely pathogenic (0.6961); Absent from gnomAD v4.1; Associated with Li-Fraumeni syndrome.

What condition is associated with TP53 p.Pro219Arg (c.656C>G)?

TP53 p.Pro219Arg (c.656C>G) is associated with Li-Fraumeni syndrome (ClinVar).

How common is TP53 p.Pro219Arg (c.656C>G) in the general population?

TP53 p.Pro219Arg (c.656C>G) is absent from gnomAD v4.1 (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.Pro219Arg (c.656C>G)?

AlphaMissense predicts likely pathogenic (score 0.6961) — an in-silico prediction, not a clinical call.

TP53 p.Pro219Arg

c.656C>G · rs1420675064 · VCV953426

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6961 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Li-Fraumeni syndrome

Computational evidence

Protein change
AlphaMissense	0.6961	likely pathogenic
REVEL	0.966	strongly pathogenic-leaning
SaProt	LLR -12.62	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.31	donor gain · deltas
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 6,982 bp · p 0.0085 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

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.Pro219Arg
Coding: c.656C>G
MANE Select: NM_000546
dbSNP: rs1420675064
Type: single nucleotide variant
Location: chr17:7674875 (GRCh38)
Gene constraint: LOEUF 0.449 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.83 · 321 PDB
Residue 219: a DNA-binding region; the 'interaction with axin1' region; a β-strand; the 'interaction with ccar2' region; the 'interaction with hipk1' region; the 'required for interaction with znf385a' region; a UniProt-annotated variant site (in a sporadic cancer; somatic mutation; requires 2 nucleotide substitutions); a UniProt-annotated variant site (in a sporadic cancer; somatic mutation); a UniProt-annotated variant site (in sporadic cancers; somatic mutation); a UniProt-annotated variant site (in a familial cancer not matching lfs; germline mutation and in sporadic cancers; 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.Pro219Leu Uncertain significance ★★★ ⚠ same residue
TP53 p.Pro219= Benign/Likely benign ★★ same residue
TP53 p.Pro219Ala Uncertain significance ★ ⚠ same residue
TP53 p.Pro219Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
TP53 p.Pro219Thr Uncertain significance ★ ⚠ same residue
TP53 p.Pro219fs Pathogenic ★ same residue
TP53 c.375+5G>A Likely pathogenic ★★★ same condition
TP53 c.919+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-pro219arg (accessed [today's date]).

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