Is TP53 p.Pro191Arg (c.572C>G) pathogenic?

TP53 p.Pro191Arg (c.572C>G) is classified Likely benign in TP53 (ClinVar, Expert panel, 13 submitters; last evaluated 2025-01-16). AlphaMissense: ambiguous (0.5246); Very rare (popmax 0.005%, amr); Associated with Li-Fraumeni syndrome.

What condition is associated with TP53 p.Pro191Arg (c.572C>G)?

TP53 p.Pro191Arg (c.572C>G) is associated with Li-Fraumeni syndrome, hereditary neoplastic syndrome (ClinVar).

How common is TP53 p.Pro191Arg (c.572C>G) in the general population?

TP53 p.Pro191Arg (c.572C>G) is very rare (popmax 0.005%, amr) (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.Pro191Arg (c.572C>G)?

AlphaMissense predicts ambiguous (score 0.5246) — an in-silico prediction, not a clinical call.

TP53 p.Pro191Arg

c.572C>G · rs587778718 · VCV127816

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 13 submitters

AlphaMissense

ambiguous

0.5246 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Conditions

Li-Fraumeni syndrome

ClinGen expert panel — TP53 VCEP

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

BS3 BP4

Curation rationale (ClinGen, verbatim)

The NM_000546.6: c.572C>G variant in TP53 is a missense variant predicted to cause substitution of proline by arginine at amino acid 191 (p.Pro191Arg). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00005 (3/59996 alleles) in the Admixed American population (PM2, BS1, and BA1 are not met). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function(BS3; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = 0.0942; Align GVGD Class 35) 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). 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: BS3, BP4. (Bayesian Points: -5; VCEP specifications version 2.2; 1/16/2025)

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

Computational evidence

Protein change
AlphaMissense	0.5246	ambiguous
REVEL	0.617	indeterminate
SaProt	LLR -9.13	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 6,982 bp · p 0.0085 · regional, not allelic
Overall
CADD	24.7	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 0.005% Admixed American · 3/59,996 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000372% 6/1,614,068 alleles · very rare exomes 5/1,461,892 · genomes 1/152,176 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	19,999
European (non-Finnish)	0.000254%	393,349

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.Pro191Arg
Coding: c.572C>G
MANE Select: NM_000546
dbSNP: rs587778718
Type: single nucleotide variant
Location: chr17:7674959 (GRCh38)
Gene constraint: LOEUF 0.449 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.83 · 321 PDB
Residue 191: a DNA-binding region; the 'interaction with axin1' region; the 'interaction with ccar2' region; a UniProt-annotated variant site (in sporadic cancers; somatic mutation); the 'interaction with hipk1' region; the 'required for interaction with znf385a' region; the 'required for interaction with fbxo42' 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: hereditary neoplastic syndrome

For Li-Fraumeni syndrome (Orphanet):

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

Similar variants

TP53 p.Pro191His Uncertain significance ★★ ⚠ same residue
TP53 p.Pro191Leu Uncertain significance ★ ⚠ same residue
TP53 p.Pro191Ser Uncertain significance ★ ⚠ same residue
TP53 p.Pro191= Likely benign ★ same residue
TP53 p.Pro191del Pathogenic/Likely 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

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-pro191arg (accessed [today's date]).

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