Is TP53 p.Pro72Arg (c.215C>G) pathogenic?

TP53 p.Pro72Arg (c.215C>G) is classified Benign in TP53 (ClinVar, Expert panel, 34 submitters; last evaluated 2025-12-05). AlphaMissense: likely benign (0.0724); Common (popmax 74.8%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with Li-Fraumeni syndrome.

What condition is associated with TP53 p.Pro72Arg (c.215C>G)?

TP53 p.Pro72Arg (c.215C>G) is associated with Li-Fraumeni syndrome, bone osteosarcoma, hereditary breast ovarian cancer syndrome (ClinVar).

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.Pro72Arg (c.215C>G)?

AlphaMissense predicts likely benign (score 0.0724) — an in-silico prediction, not a clinical call.

TP53 p.Pro72Arg

Q: How common is TP53 p.Pro72Arg (c.215C>G) in the general population?

TP53 p.Pro72Arg (c.215C>G) is common (popmax 74.8%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.215C>G · rs1042522 · VCV12351

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 34 submitters

AlphaMissense

likely benign

0.0724 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 74.8%, nfe) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Li-Fraumeni syndrome

Computational evidence

Protein change
AlphaMissense	0.0724	likely benign
REVEL	0.368	indeterminate
SaProt	LLR -9.11	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.5	GERP 1.1, phastCons 0.015
Regional constraint	o/e 0.89	unconstrained · MANE · 6,982 bp · p 0.0085 · regional, not allelic
Overall
CADD	12.91	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

Grpmax group 74.8% European (non-Finnish) · 882,123/1,179,968 alleles

Filtering AF 74.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 74.6%

Overall 70.8% 1,142,226/1,613,582 alleles · common

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	74.8%	1
Finnishnot grpmax-eligible	73.3%	1
Ashkenazi Jewishnot grpmax-eligible	71.9%	1
Admixed American	71.1%	1
Remaining individualsnot grpmax-eligible	69.4%	1
Amishnot grpmax-eligible	67%	1
Middle Eastern	60.6%	2
East Asian	60.1%	2
South Asian	50.7%	2
African / African-American	38.2%	3

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.

Cancer therapy — CIViC

Disease	Level	Significance
Lung Carcinoma	B	Poor Outcome
Cervical Cancer	B	Poor Outcome
Oligodendroglioma	B	Poor Outcome

Variant & gene context

Gene: TP53
Protein: p.Pro72Arg
Coding: c.215C>G
MANE Select: NM_000546
dbSNP: rs1042522
Type: single nucleotide variant
Location: chr17:7676154 (GRCh38)
Gene constraint: LOEUF 0.449 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.83 · 321 PDB
Residue 72: a UniProt-annotated variant site (in sporadic cancers; somatic mutation; requires 2 nucleotide substitutions); a UniProt-annotated variant site (in sporadic cancers; somatic mutation); a UniProt-annotated variant site (in a sporadic cancer; somatic mutation); a UniProt-annotated variant site (in); the 'interaction with ccar2' region; the 'interaction with hrmt1l2' region; the 'disordered' region; the 'interaction with wwox' 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: bone osteosarcoma hereditary breast ovarian cancer syndrome exocrine pancreatic carcinoma colorectal cancer hepatocellular carcinoma adrenocortical carcinoma, hereditary choroid plexus papilloma basal cell carcinoma, susceptibility to, 7 hereditary neoplastic syndrome nasopharyngeal carcinoma hereditary breast carcinoma acute myeloid leukemia glioma susceptibility 1 bone marrow failure syndrome 5

For Li-Fraumeni syndrome (Orphanet):

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

Similar variants

TP53 p.Pro72Ala Likely benign ★★★ same residue
TP53 p.Pro72His Benign ★★★ ⚠ same residue
TP53 p.Pro72Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
TP53 p.Pro72Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
TP53 p.Pro72Cys Uncertain significance ★★★ same residue
TP53 p.Pro72Ser Uncertain significance ★★ same residue
TP53 p.Pro72fs Pathogenic ★ same residue
TP53 p.Pro72_Val73delinsArgMet Conflicting classifications of pathogenicity ★ same residue

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-pro72arg (accessed [today's date]).

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