Is TP53 p.Pro250Thr (c.748C>A) pathogenic?

TP53 p.Pro250Thr (c.748C>A) is classified Uncertain significance in TP53 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-24). AlphaMissense: likely pathogenic (0.9194); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with TP53 p.Pro250Thr (c.748C>A)?

TP53 p.Pro250Thr (c.748C>A) is associated with hereditary neoplastic syndrome, Li-Fraumeni syndrome (ClinVar).

How common is TP53 p.Pro250Thr (c.748C>A) in the general population?

TP53 p.Pro250Thr (c.748C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TP53 p.Pro250Thr (c.748C>A)?

AlphaMissense predicts likely pathogenic (score 0.9194) — an in-silico prediction, not a clinical call.

TP53 p.Pro250Thr

c.748C>A · rs2151020578 · VCV1759140

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9194 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,613,720)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.9194	likely pathogenic
REVEL	0.949	strongly pathogenic-leaning
SaProt	LLR -10.61	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	25.3	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

No allele count reported in gnomAD v4.1 (AN 1,613,720). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: TP53
Protein: p.Pro250Thr
Coding: c.748C>A
MANE Select: NM_000546
dbSNP: rs2151020578
Type: single nucleotide variant
Location: chr17:7674215 (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

Also linked: Li-Fraumeni syndrome

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.Pro250Arg 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-pro250thr (accessed [today's date]).

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