Is TP53 p.Pro222= (c.666G>T) pathogenic?

TP53 p.Pro222= (c.666G>T) is classified Benign/Likely benign in TP53 (ClinVar, Multiple submitters, 18 submitters; last evaluated 2026-01-21). Ultra-rare (popmax 0.013%, nfe); Associated with Breast and/or ovarian cancer.

What condition is associated with TP53 p.Pro222= (c.666G>T)?

TP53 p.Pro222= (c.666G>T) is associated with Breast and/or ovarian cancer, hereditary neoplastic syndrome, hereditary breast carcinoma (ClinVar).

How common is TP53 p.Pro222= (c.666G>T) in the general population?

TP53 p.Pro222= (c.666G>T) is ultra-rare (popmax 0.013%, nfe) (gnomAD).

TP53 p.Pro222=

c.666G>T · rs72661118 · VCV132972

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 18 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.013%, nfe)

Conditions

Breast and/or ovarian cancer

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 -9.6	GERP -4.6
Overall
CADD	0.845	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.013% European (non-Finnish) · 153/1,179,906 alleles

Filtering AF 0.0113% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0107%

Overall 0.0102% 164/1,614,028 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.013%	7,712
Remaining individualsnot grpmax-eligible	0.0128%	7,813
African / African-American	0.00267%	37,518
Admixed American	0.00167%	60,016

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.Pro222=
Coding: c.666G>T
MANE Select: NM_000546
dbSNP: rs72661118
Type: single nucleotide variant
Location: chr17:7674865 (GRCh38)
Gene constraint: LOEUF 0.449 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.83 · 321 PDB
Residue 222: a DNA-binding region; the 'interaction with axin1' region; an α-helix; 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); the 'required for interaction with fbxo42' region

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

Disease context

Breast and/or ovarian cancer — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome hereditary breast carcinoma Li-Fraumeni syndrome ovarian neoplasm

Similar variants

TP53 p.Pro222Gln Uncertain significance ★ ⚠ same residue
TP53 p.Pro222Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
TP53 p.Pro222Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
TP53 p.Pro222fs 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-pro222 (accessed [today's date]).

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