Is TP53 p.Arg342Pro (c.1025G>C) pathogenic?

TP53 p.Arg342Pro (c.1025G>C) is classified Pathogenic in TP53 (ClinVar, Expert panel, 12 submitters; last evaluated 2024-09-06). AlphaMissense: likely pathogenic (0.9836); Absent from gnomAD v4.1; Associated with Li-Fraumeni syndrome.

What condition is associated with TP53 p.Arg342Pro (c.1025G>C)?

TP53 p.Arg342Pro (c.1025G>C) is associated with Li-Fraumeni syndrome, hereditary neoplastic syndrome, ovarian neoplasm (ClinVar).

How common is TP53 p.Arg342Pro (c.1025G>C) in the general population?

TP53 p.Arg342Pro (c.1025G>C) 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.Arg342Pro (c.1025G>C)?

AlphaMissense predicts likely pathogenic (score 0.9836) — an in-silico prediction, not a clinical call.

TP53 p.Arg342Pro

c.1025G>C · rs375338359 · VCV215996

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 12 submitters

AlphaMissense

likely pathogenic

0.9836 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Li-Fraumeni syndrome

ClinGen expert panel — TP53 VCEP

Pathogenic for Li-Fraumeni syndrome. Applied ACMG criteria (verbatim):

PP1_Strong PM2_Supporting PS3 PM1_Supporting PS4_Moderate PP3

Curation rationale (ClinGen, verbatim)

The NM_000546.6: c.1025G>C variant in TP53 is a missense variant predicted to cause substitution of arginine by proline at amino acid 342 (p.Arg342Pro). This variant has been reported in 3 unrelated families meeting Classic criteria. Based on this evidence, this variant scores 3 total points meeting the TP53 VCEP phenotype scoring criteria of 2-3.5 points. (PS4_Moderate; PMIDs 25981898, 25226867, 19714490). The variant has been reported to segregate with LFS-associated cancers in ≥ 7 meioses from 3 families (PP1_Strong; PMIDs 25981898, 25226867, 19714490). In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation, loss of growth suppression activity, and impaired tetramer formation indicating that this variant impacts protein function (PS3; PMIDs: 12826609, 30224644, 16007150). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). Computational predictor scores (BayesDel = 0.24; Align GVGD = Class C35) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of > 15), evidence that correlates with impact to TP53 via protein change (PP3). This variant has 8 somatic occurrences for the same amino acid change in cancerhotspots.org (v2) sufficient to be defined as a mutational hotspot by the Clingen TP53 VCEP (2-9 somatic occurrences, PMID: 30311369) (PM1_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS4_Moderate, PP1_Strong, PS3, PM2_Supporting, PP3, PM1_Supporting. (Bayesian Points: 13; VCEP specifications version 2.0; 9/6/2024)

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.9836	likely pathogenic ✓ concordant with ClinVar
REVEL	0.65	pathogenic-leaning
SaProt	LLR -14.13	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 -0.34	GERP -2.5
Regional constraint	o/e 0.89	unconstrained · MANE · 6,982 bp · p 0.0085 · regional, not allelic
Overall
CADD	20.2	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.

Variant & gene context

Gene: TP53
Protein: p.Arg342Pro
Coding: c.1025G>C
MANE Select: NM_000546
dbSNP: rs375338359
Type: single nucleotide variant
Location: chr17:7670684 (GRCh38)
Gene constraint: LOEUF 0.449 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.83 · 321 PDB
Residue 342: a UniProt-annotated variant site (in a sporadic cancer; somatic mutation); a UniProt-annotated variant site (in sporadic cancers; somatic mutation); the 'interaction with carm1' region; an α-helix; the 'interaction with hipk2' region; the 'oligomerization' region; the 'interaction with hipk1' 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

Also linked: hereditary neoplastic syndrome ovarian neoplasm

For Li-Fraumeni syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages
Prevalence: 1-9 / 100 000 (United Kingdom)

Similar variants

TP53 p.Arg342Gln Likely benign ★★★ same residue
TP53 p.Arg342Ter Pathogenic ★★ same residue
TP53 p.Arg342Gly Uncertain significance ★★ same residue
TP53 p.Arg342= Benign/Likely benign ★★ same residue
TP53 p.Arg342Leu Uncertain significance ★ ⚠ same residue
TP53 p.Arg342fs Pathogenic/Likely pathogenic ★★ same residue
TP53 p.Arg342_Glu343insTer Pathogenic same residue
TP53 c.375+5G>A 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-arg342pro (accessed [today's date]).

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