Is TP53 p.Pro72Thr (c.214C>A) pathogenic?

TP53 p.Pro72Thr (c.214C>A) is classified Conflicting classifications of pathogenicity in TP53 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-10-03). AlphaMissense: likely benign (0.0613); Very rare (popmax 0.000254%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with TP53 p.Pro72Thr (c.214C>A)?

TP53 p.Pro72Thr (c.214C>A) is associated with hereditary neoplastic syndrome, Li-Fraumeni syndrome (ClinVar).

How common is TP53 p.Pro72Thr (c.214C>A) in the general population?

TP53 p.Pro72Thr (c.214C>A) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about TP53 p.Pro72Thr (c.214C>A)?

AlphaMissense predicts likely benign (score 0.0613) — an in-silico prediction, not a clinical call.

TP53 p.Pro72Thr

c.214C>A · rs587782769 · VCV232750

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0613 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0613	likely benign
REVEL	0.273	benign-leaning
SaProt	LLR -8.23	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
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	3.417	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 0.000254% European (non-Finnish) · 3/1,179,974 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000248% 4/1,613,668 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,464
European (non-Finnish)grpmax	0.000254%	393,324

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro72Thr
Coding: c.214C>A
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

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Li-Fraumeni syndrome

Similar variants

TP53 p.Pro72Ala Likely benign ★★★ same residue
TP53 p.Pro72Arg Benign ★★★ same residue
TP53 p.Pro72His Benign ★★★ ⚠ same residue
TP53 p.Pro72Leu 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-pro72thr (accessed [today's date]).

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