Is TP53 p.Pro250Arg (c.749C>G) pathogenic?

TP53 p.Pro250Arg (c.749C>G) is classified Uncertain significance in TP53 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-05-05). AlphaMissense: likely pathogenic (0.9472); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with TP53 p.Pro250Arg (c.749C>G)?

TP53 p.Pro250Arg (c.749C>G) is associated with hereditary neoplastic syndrome (ClinVar).

How common is TP53 p.Pro250Arg (c.749C>G) in the general population?

TP53 p.Pro250Arg (c.749C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TP53 p.Pro250Arg (c.749C>G)?

AlphaMissense predicts likely pathogenic (score 0.9472) — an in-silico prediction, not a clinical call.

TP53 p.Pro250Arg

c.749C>G · VCV4865880

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9472 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.9472	likely pathogenic
REVEL	0.963	strongly pathogenic-leaning
SaProt	LLR -12.93	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 12	GERP 2.5, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 6,982 bp · p 0.0085 · regional, not allelic
Overall
CADD	26.4	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.Pro250Arg
Coding: c.749C>G
MANE Select: NM_000546
Type: single nucleotide variant
Location: chr17:7674214 (GRCh38)
Gene constraint: LOEUF 0.449 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.83 · 321 PDB
Residue 250: a DNA-binding region; the 'interaction with axin1' region; a UniProt-annotated variant site (in sporadic cancers; somatic mutation); a UniProt-annotated variant site (in sporadic cancers; somatic mutation; requires 2 nucleotide substitutions); 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)

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

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TP53 p.Pro250Leu Pathogenic/Likely pathogenic ★★ ⚠ same residue
TP53 p.Pro250Ala Uncertain significance ★★ ⚠ same residue
TP53 p.Pro250Ser Uncertain significance ★★ ⚠ same residue
TP53 p.Pro250Thr Uncertain significance ★★ ⚠ same residue
TP53 p.Pro250= 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

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-pro250arg (accessed [today's date]).

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