Is TP53 p.Cys124fs (c.371dup) pathogenic?

TP53 p.Cys124fs (c.371dup) is classified Pathogenic in TP53 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-11-18). Very rare (popmax 6.85e-05%); Associated with Li-Fraumeni syndrome 1.

What condition is associated with TP53 p.Cys124fs (c.371dup)?

TP53 p.Cys124fs (c.371dup) is associated with Li-Fraumeni syndrome 1, Li-Fraumeni syndrome, ovarian neoplasm (ClinVar).

How common is TP53 p.Cys124fs (c.371dup) in the general population?

TP53 p.Cys124fs (c.371dup) is very rare (popmax 6.85e-05%) (gnomAD).

TP53 p.Cys124fs

c.371dup · rs1267047192 · VCV634664

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 6.85e-05%)

Conditions

Li-Fraumeni syndrome 1

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 4 of 11
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 8.6	GERP 2.2, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.85e-05%

Overall 6.85e-05% 1/1,459,936 alleles · very rare

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.Cys124fs
Coding: c.371dup
MANE Select: NM_000546
dbSNP: rs1267047192
Type: Duplication
Location: chr17:7675997 (GRCh38)
Gene constraint: LOEUF 0.449 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.83 · 321 PDB
Residue 124: a DNA-binding region; the 'interaction with axin1' region; a β-strand; the 'interaction with ccar2' region; a UniProt-annotated variant site (in a sporadic cancer; somatic mutation); a UniProt-annotated variant site (in sporadic cancers; somatic mutation); the 'interaction with hipk1' region; the 'required for interaction with znf385a' region; the 'required for interaction with fbxo42' region

Full TP53 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Li-Fraumeni syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Li-Fraumeni syndrome ovarian neoplasm

Similar variants

TP53 p.Cys124Ter Pathogenic ★★★ same residue
TP53 p.Cys124Arg Likely pathogenic ★ ⚠ same residue
TP53 p.Cys124= Uncertain significance ★ same residue
TP53 p.Cys124Ser Uncertain significance ★ ⚠ 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
TP53 p.Ala307_Leu308insAlaProArgGluHisTer 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-cys124fs (accessed [today's date]).

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