Is TP53 p.Lys351Arg (c.1052A>G) pathogenic?

TP53 p.Lys351Arg (c.1052A>G) is classified Uncertain significance in TP53 (ClinVar, Single submitter, 1 submitter; last evaluated 2017-06-10). AlphaMissense: likely benign (0.0909); Very rare (popmax 6.2e-05%); Associated with Li-Fraumeni syndrome.

What condition is associated with TP53 p.Lys351Arg (c.1052A>G)?

TP53 p.Lys351Arg (c.1052A>G) is associated with Li-Fraumeni syndrome (ClinVar).

How common is TP53 p.Lys351Arg (c.1052A>G) in the general population?

TP53 p.Lys351Arg (c.1052A>G) is very rare (popmax 6.2e-05%) (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.Lys351Arg (c.1052A>G)?

AlphaMissense predicts likely benign (score 0.0909) — an in-silico prediction, not a clinical call.

TP53 p.Lys351Arg

c.1052A>G · rs1555524396 · VCV458513

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0909 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.2e-05%)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Li-Fraumeni syndrome

Computational evidence

Protein change
AlphaMissense	0.0909	likely benign
REVEL	0.367	indeterminate
SaProt	LLR -4.80	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 0.98	GERP -1.2, phastCons 0.98
Regional constraint	o/e 0.89	unconstrained · MANE · 6,982 bp · p 0.0085 · regional, not allelic
Overall
CADD	20.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.2e-05%

Overall 6.2e-05% 1/1,614,116 alleles · very rare exomes 1/1,461,812 · genomes 0/152,304 · joint denominator

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.Lys351Arg
Coding: c.1052A>G
MANE Select: NM_000546
dbSNP: rs1555524396
Type: single nucleotide variant
Location: chr17:7670657 (GRCh38)
Gene constraint: LOEUF 0.449 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.83 · 321 PDB
Residue 351: the 'interaction with carm1' region; the 'interaction with hipk2' region; the 'oligomerization' region; the 'disordered' region; a cross-link site; the 'interaction with hipk1' 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.Lys351Asn Uncertain significance ★★ ⚠ same residue
TP53 p.Lys351Glu Uncertain significance ★★ ⚠ same residue
TP53 p.Lys351fs Likely pathogenic ★ same residue
TP53 p.Lys351Ter 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
TP53 p.Ala138Pro Likely 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-lys351arg (accessed [today's date]).

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