Is TP53 p.Pro4= (c.12G>T) pathogenic?

TP53 p.Pro4= (c.12G>T) is classified Benign/Likely benign in TP53 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-03-31). Very rare (popmax 0.00167%, amr); Associated with hereditary neoplastic syndrome.

What condition is associated with TP53 p.Pro4= (c.12G>T)?

TP53 p.Pro4= (c.12G>T) is associated with hereditary neoplastic syndrome, Li-Fraumeni syndrome (ClinVar).

How common is TP53 p.Pro4= (c.12G>T) in the general population?

TP53 p.Pro4= (c.12G>T) is very rare (popmax 0.00167%, amr) (gnomAD).

TP53 p.Pro4=

c.12G>T · rs876658274 · VCV1080351

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -14	GERP -4.2
Overall
CADD	0.061	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/59,968 alleles

Overall 6.84e-05% 1/1,461,774 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.Pro4=
Coding: c.12G>T
MANE Select: NM_000546
dbSNP: rs876658274
Type: single nucleotide variant
Location: chr17:7676583 (GRCh38)
Gene constraint: LOEUF 0.449 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.83 · 321 PDB
Residue 4: an α-helix; the 'interaction with ccar2' region; the 'interaction with hrmt1l2' region; the 'transcription activation (acidic)' 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.Pro4Leu Likely benign ★★★ same residue
TP53 p.Pro4Ala Uncertain significance ★ ⚠ same residue
TP53 p.Pro4Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
TP53 p.Pro4Ser Uncertain significance ★ ⚠ same residue
TP53 p.Pro4Gln Likely benign ★ 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

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-pro4 (accessed [today's date]).

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