Is TP53 p.Arg248fs (c.742dup) pathogenic?

TP53 p.Arg248fs (c.742dup) is classified Pathogenic in TP53 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-12). Absent from gnomAD; Associated with Li-Fraumeni syndrome.

What condition is associated with TP53 p.Arg248fs (c.742dup)?

TP53 p.Arg248fs (c.742dup) is associated with Li-Fraumeni syndrome (ClinVar).

How common is TP53 p.Arg248fs (c.742dup) in the general population?

TP53 p.Arg248fs (c.742dup) is absent from gnomAD (gnomAD).

How is Li-Fraumeni syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

TP53 p.Arg248fs

c.742dup · rs2543560402 · VCV2023589

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

Li-Fraumeni syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 7 of 11
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 6	GERP 2.5, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. 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.Arg248fs
Coding: c.742dup
MANE Select: NM_000546
dbSNP: rs2543560402
Type: Duplication
Location: chr17:7674220 (GRCh38)
Gene constraint: LOEUF 0.449 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.83 · 321 PDB
Residue 248: a DNA-binding region; the 'interaction with axin1' region; the 'interaction with the 53bp2 sh3 domain' region; a turn; 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); a UniProt-annotated variant site (in sporadic cancers; somatic mutation); a UniProt-annotated variant site (in lfs; germline mutation and in sporadic cancers; somatic mutation)

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

For Li-Fraumeni syndrome (Orphanet):

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

Similar variants

TP53 p.Arg248Gln Pathogenic ★★★ same residue
TP53 p.Arg248Leu Pathogenic ★★★ same residue
TP53 p.Arg248Trp Pathogenic ★★★ same residue
TP53 p.Arg248Gly Pathogenic/Likely pathogenic ★★ same residue
TP53 p.Arg248Pro Pathogenic/Likely pathogenic ★★ same residue
TP53 p.Ter394LeuextTer? Likely pathogenic ★★★ same condition
TP53 c.375+1dup Pathogenic/Likely pathogenic ★★ same condition
TP53 c.97-1_102dup Pathogenic/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-arg248fs (accessed [today's date]).

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