Is TP53 p.Lys321= (c.963A>G) pathogenic?

TP53 p.Lys321= (c.963A>G) is classified Benign/Likely benign in TP53 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-04-04). Absent from gnomAD v4.1; Associated with Li-Fraumeni syndrome 1.

What condition is associated with TP53 p.Lys321= (c.963A>G)?

TP53 p.Lys321= (c.963A>G) is associated with Li-Fraumeni syndrome 1, hereditary neoplastic syndrome, Li-Fraumeni syndrome (ClinVar).

How common is TP53 p.Lys321= (c.963A>G) in the general population?

TP53 p.Lys321= (c.963A>G) is absent from gnomAD v4.1 (gnomAD).

TP53 p.Lys321=

c.963A>G · rs2151011521 · VCV2837534

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Li-Fraumeni syndrome 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.126	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.72	GERP -4.1, phastCons 0.01
Overall
CADD	5.205	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TP53
Protein: p.Lys321=
Coding: c.963A>G
MANE Select: NM_000546
dbSNP: rs2151011521
Type: single nucleotide variant
Location: chr17:7673565 (GRCh38)
Gene constraint: LOEUF 0.449 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.83 · 321 PDB
Residue 321: a UniProt-annotated variant site (in kidney cancer; germline mutation); a UniProt-annotated variant site (in a sporadic cancer; somatic mutation); the 'disordered' region; the 'interaction with carm1' region; the 'interaction with hipk2' region; a modified residue (n6-acetyllysine); the 'interaction with hipk1' region

Full TP53 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Li-Fraumeni syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome Li-Fraumeni syndrome

Similar variants

TP53 p.Lys321Ter Pathogenic ★ same residue
TP53 p.Lys321Thr Uncertain significance ★ ⚠ same residue
TP53 p.Lys321del Uncertain significance ★★ same residue
TP53 p.Lys321fs 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-lys321 (accessed [today's date]).

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