Is TP53 p.Ser303Arg (c.909C>G) pathogenic?

TP53 p.Ser303Arg (c.909C>G) is classified Conflicting classifications of pathogenicity in TP53 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-01-08). AlphaMissense: ambiguous (0.3755); Very rare (popmax 0.00167%, amr); Associated with hereditary neoplastic syndrome.

What condition is associated with TP53 p.Ser303Arg (c.909C>G)?

TP53 p.Ser303Arg (c.909C>G) is associated with hereditary neoplastic syndrome, Li-Fraumeni syndrome (ClinVar).

How common is TP53 p.Ser303Arg (c.909C>G) in the general population?

TP53 p.Ser303Arg (c.909C>G) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about TP53 p.Ser303Arg (c.909C>G)?

AlphaMissense predicts ambiguous (score 0.3755) — an in-silico prediction, not a clinical call.

TP53 p.Ser303Arg

c.909C>G · rs1412434159 · VCV1024359

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3755 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.3755	ambiguous
REVEL	0.565	indeterminate
SaProt	LLR -7.45	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP -3.3, phastCons 0.29
Regional constraint	o/e 0.89	unconstrained · MANE · 6,982 bp · p 0.0085 · regional, not allelic
Overall
CADD	16.56	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 0.00167% Admixed American · 1/60,016 alleles

Overall 6.2e-05% 1/1,614,146 alleles · very rare exomes 1/1,461,892 · genomes 0/152,254 · joint denominator

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.Ser303Arg
Coding: c.909C>G
MANE Select: NM_000546
dbSNP: rs1412434159
Type: single nucleotide variant
Location: chr17:7673711 (GRCh38)
Gene constraint: LOEUF 0.449 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.83 · 321 PDB
Residue 303: a UniProt-annotated variant site (in sporadic cancers; somatic mutation); the 'disordered' region; the 'interaction with carm1' region; the 'interaction with ccar2' region; the 'interaction with hipk1' region

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.Ser303Gly Likely benign ★★★ same residue
TP53 p.Ser303Asn Conflicting classifications of pathogenicity ★ ⚠ same residue
TP53 p.Ser303= Likely benign ★ same residue
TP53 p.Ser303fs Pathogenic ★ 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
TP53 p.Ala138Pro 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-ser303arg (accessed [today's date]).

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