Is TP53 p.Pro72Ala (c.214C>G) pathogenic?

TP53 p.Pro72Ala (c.214C>G) is classified Likely benign in TP53 (ClinVar, Expert panel, 12 submitters; last evaluated 2025-02-06). AlphaMissense: likely benign (0.0481); Ultra-rare (popmax 0.0134%, eas); Associated with Li-Fraumeni syndrome.

What condition is associated with TP53 p.Pro72Ala (c.214C>G)?

TP53 p.Pro72Ala (c.214C>G) is associated with Li-Fraumeni syndrome, bone osteosarcoma, colorectal cancer (ClinVar).

How common is TP53 p.Pro72Ala (c.214C>G) in the general population?

TP53 p.Pro72Ala (c.214C>G) is ultra-rare (popmax 0.0134%, eas) (gnomAD).

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.Pro72Ala (c.214C>G)?

AlphaMissense predicts likely benign (score 0.0481) — an in-silico prediction, not a clinical call.

TP53 p.Pro72Ala

c.214C>G · rs587782769 · VCV142854

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 12 submitters

AlphaMissense

likely benign

0.0481 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Li-Fraumeni syndrome

ClinGen expert panel — TP53 VCEP

Likely Benign for Li-Fraumeni syndrome. Applied ACMG criteria (verbatim):

BS2_Moderate BP4_Moderate

Curation rationale (ClinGen, verbatim)

The NM_000546.6: c.214C>G variant in TP53 is a missense variant predicted to cause substitution of proline by alanine at amino acid 72 (p.Pro72Ala). This is a polymorphic residue (alternate nomenclature: p.Arg72). This variant received a total of 0.5 points in one individual. (PS4 not met; Internal lab contributors). This variant has been observed in 4-7 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Moderate; Internal lab contributor). In vitro assays performed in yeast and/or human cell lines showed conflicting results with respect to transactivation, growth suppression activity, and/or tetramer formation (PS3/BS3 not met; PMIDs: 12826609, 30224644). Computational predictor scores (BayesDel = -0.215412; Align GVGD Class C0) are below the recommended thresholds (BayesDel < 0.16 and > -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing (BP4_Moderate). In summary, this variant meets the criteria to be classified as Likely Benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_Moderate, BP4_Moderate. (Bayesian Points: -4; VCEP specifications version 2.2; 2/6/2025)

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.0481	likely benign
REVEL	0.319	indeterminate
SaProt	LLR -6.75	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 -0.19	GERP -2.2
Regional constraint	o/e 0.89	unconstrained · MANE · 6,982 bp · p 0.0085 · regional, not allelic
Overall
CADD	0.332	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 0.0134% East Asian · 6/44,892 alleles

Filtering AF 0.00579% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00394%

Overall 0.000682% 11/1,613,666 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0134%	7,482
South Asian	0.0011%	91,068
European (non-Finnish)	0.000339%	294,993

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.Pro72Ala
Coding: c.214C>G
MANE Select: NM_000546
dbSNP: rs587782769
Type: single nucleotide variant
Location: chr17:7676155 (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 colorectal cancer hepatocellular carcinoma adrenocortical carcinoma, hereditary choroid plexus papilloma basal cell carcinoma, susceptibility to, 7 familial pancreatic carcinoma hereditary neoplastic syndrome nasopharyngeal carcinoma hereditary breast carcinoma 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.Pro72Arg 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-pro72ala (accessed [today's date]).

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