Is TP53 p.Lys321Ter (c.961A>T) pathogenic?

TP53 p.Lys321Ter (c.961A>T) is classified Pathogenic in TP53 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-10). Very rare (popmax 8.47e-05%, nfe); Associated with Li-Fraumeni syndrome.

What condition is associated with TP53 p.Lys321Ter (c.961A>T)?

TP53 p.Lys321Ter (c.961A>T) is associated with Li-Fraumeni syndrome (ClinVar).

How common is TP53 p.Lys321Ter (c.961A>T) in the general population?

TP53 p.Lys321Ter (c.961A>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

How is Li-Fraumeni syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

TP53 p.Lys321Ter

c.961A>T · rs2073154382 · VCV842397

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

Li-Fraumeni syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 9 of 11
REVEL	0.369	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.2	GERP 2.1, phastCons 1
Overall
CADD	38.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,038 alleles

Overall 6.2e-05% 1/1,614,166 alleles · very rare exomes 1/1,461,884 · genomes 0/152,282 · 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.Lys321Ter
Coding: c.961A>T
MANE Select: NM_000546
dbSNP: rs2073154382
Type: single nucleotide variant
Location: chr17:7673567 (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 — 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.Lys321= Benign/Likely benign ★★ same residue
TP53 p.Lys321del Uncertain significance ★★ same residue
TP53 p.Lys321fs Pathogenic ★ same residue
TP53 p.Lys321Thr Uncertain significance ★ ⚠ 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-lys321ter (accessed [today's date]).

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