Is TP53 p.Lys291Arg (c.872A>G) pathogenic?

TP53 p.Lys291Arg (c.872A>G) is classified Uncertain significance in TP53 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-22). AlphaMissense: likely benign (0.0741); Very rare (popmax 0.00223%, eas); Associated with Li-Fraumeni syndrome.

What condition is associated with TP53 p.Lys291Arg (c.872A>G)?

TP53 p.Lys291Arg (c.872A>G) is associated with Li-Fraumeni syndrome (ClinVar).

How common is TP53 p.Lys291Arg (c.872A>G) in the general population?

TP53 p.Lys291Arg (c.872A>G) is very rare (popmax 0.00223%, 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.Lys291Arg (c.872A>G)?

AlphaMissense predicts likely benign (score 0.0741) — an in-silico prediction, not a clinical call.

TP53 p.Lys291Arg

c.872A>G · VCV4710305

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0741 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Li-Fraumeni syndrome

Computational evidence

Protein change
AlphaMissense	0.0741	likely benign
REVEL	0.694	pathogenic-leaning
SaProt	LLR -4.76	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6.2	GERP 1.5, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 6,982 bp · p 0.0085 · regional, not allelic
Overall
CADD	22.0	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 0.00223% East Asian · 1/44,852 alleles

Overall 0.000124% 2/1,614,008 alleles · very rare exomes 1/1,461,892 · genomes 1/152,116 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,852
South Asian	0.0011%	91,092

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.Lys291Arg
Coding: c.872A>G
MANE Select: NM_000546
Type: single nucleotide variant
Location: chr17:7673748 (GRCh38)
Gene constraint: LOEUF 0.449 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.83 · 321 PDB
Residue 291: a DNA-binding region; the 'interaction with axin1' region; the 'interaction with e4f1' region; a UniProt-annotated variant site (in sporadic cancers; somatic mutation); the 'disordered' region; the 'interaction with ccar2' region; a cross-link site; the 'interaction with hipk1' region; the 'required for interaction with znf385a' 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

For Li-Fraumeni syndrome (Orphanet):

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

Similar variants

TP53 p.Lys291Asn Conflicting classifications of pathogenicity ★ ⚠ same residue
TP53 p.Lys291Gln Uncertain significance ★ ⚠ same residue
TP53 p.Lys291Glu Conflicting classifications of pathogenicity ★ same residue
TP53 p.Lys291= Likely benign ★ same residue
TP53 p.Lys291fs 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-lys291arg (accessed [today's date]).

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