Is TP53 p.Arg249Ser (c.747G>T) pathogenic?

TP53 p.Arg249Ser (c.747G>T) is classified Pathogenic/Likely pathogenic in TP53 (ClinVar, Multiple submitters, 14 submitters; last evaluated 2025-10-11). AlphaMissense: likely pathogenic (0.9995); Absent from gnomAD v4.1; Associated with TP53-related disorder.

What condition is associated with TP53 p.Arg249Ser (c.747G>T)?

TP53 p.Arg249Ser (c.747G>T) is associated with TP53-related disorder, cervical cancer, adrenal cortex carcinoma (ClinVar).

How common is TP53 p.Arg249Ser (c.747G>T) in the general population?

TP53 p.Arg249Ser (c.747G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TP53 p.Arg249Ser (c.747G>T)?

AlphaMissense predicts likely pathogenic (score 0.9995) — an in-silico prediction, not a clinical call.

TP53 p.Arg249Ser

c.747G>T · rs28934571 · VCV12352

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 14 submitters

AlphaMissense

likely pathogenic

0.9995 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

TP53-related disorder

Computational evidence

Protein change
AlphaMissense	0.9995	likely pathogenic ✓ concordant with ClinVar · top 1% in TP53
REVEL	0.769	pathogenic-leaning
SaProt	LLR -13.10	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 -1.4	GERP -4.9
Regional constraint	o/e 0.89	unconstrained · MANE · 6,982 bp · p 0.0085 · regional, not allelic
Overall
CADD	19.25	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

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

Cancer therapy — CIViC

Disease	Therapies	Level	Significance
		D	Dominant Negative
		D	Loss of Function
Cancer	MDM2 Inhibitor AMGMDS3	D	Resistance
		D	Loss of Function
		D	Dominant Negative
		D	Loss of Function

Variant & gene context

Gene: TP53
Protein: p.Arg249Ser
Coding: c.747G>T
MANE Select: NM_000546
dbSNP: rs28934571
Type: single nucleotide variant
Location: chr17:7674216 (GRCh38)
Gene constraint: LOEUF 0.449 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.83 · 321 PDB
Residue 249: a DNA-binding region; the 'interaction with axin1' region; 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 sporadic cancer; somatic mutation; requires 2 nucleotide substitutions); a UniProt-annotated variant site (in sporadic cancers; somatic mutation; does not induce snai1 degradation); 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

TP53-related disorder

Also linked: cervical cancer adrenal cortex carcinoma hepatocellular carcinoma head and neck squamous cell carcinoma hereditary neoplastic syndrome Li-Fraumeni syndrome ovarian neoplasm

Similar variants

TP53 p.Arg249Thr Pathogenic/Likely pathogenic ★★ same residue
TP53 p.Arg249= Benign/Likely benign ★★ same residue
TP53 p.Arg249Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
TP53 p.Arg249Lys Conflicting classifications of pathogenicity ★ ⚠ same residue
TP53 p.Arg249Met Conflicting classifications of pathogenicity ★ ⚠ same residue
TP53 p.Arg249Trp Conflicting classifications of pathogenicity ★ ⚠ same residue
TP53 p.Arg249_Pro250delinsSerSer Uncertain significance ★ same residue
TP53 p.Arg249_Pro250delinsSerThr Conflicting classifications of pathogenicity ★ same residue

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-arg249ser (accessed [today's date]).

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