Is TP53 p.Arg280Lys (c.839G>A) pathogenic?

TP53 p.Arg280Lys (c.839G>A) is classified Conflicting classifications of pathogenicity in TP53 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-10-14). AlphaMissense: likely pathogenic (0.9936); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with TP53 p.Arg280Lys (c.839G>A)?

TP53 p.Arg280Lys (c.839G>A) is associated with hereditary neoplastic syndrome, head and neck squamous cell carcinoma, Li-Fraumeni syndrome (ClinVar).

How common is TP53 p.Arg280Lys (c.839G>A) in the general population?

TP53 p.Arg280Lys (c.839G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TP53 p.Arg280Lys (c.839G>A)?

AlphaMissense predicts likely pathogenic (score 0.9936) — an in-silico prediction, not a clinical call.

TP53 p.Arg280Lys

c.839G>A · rs121912660 · VCV376657

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9936 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.9936	likely pathogenic · top 8% in TP53
REVEL	0.935	strongly pathogenic-leaning
SaProt	LLR -11.72	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.5, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 6,982 bp · p 0.0085 · regional, not allelic
Overall
CADD	27.0	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

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

Cancer therapy — CIViC

Disease	Therapies	Level	Significance
Cancer	MDM2 Inhibitor AMGMDS3	D	Resistance

Variant & gene context

Gene: TP53
Protein: p.Arg280Lys
Coding: c.839G>A
MANE Select: NM_000546
dbSNP: rs121912660
Type: single nucleotide variant
Location: chr17:7673781 (GRCh38)
Gene constraint: LOEUF 0.449 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.83 · 321 PDB
Residue 280: a DNA-binding region; the 'interaction with axin1' region; a UniProt-annotated variant site (in sporadic cancers; somatic mutation); a UniProt-annotated variant site (in a familial cancer not matching lfs; germline mutation and in sporadic cancers; somatic mutation; no effect on interaction with ccar2); a UniProt-annotated variant site (in a sporadic cancer; somatic mutation); the 'interaction with e4f1' region; the 'interaction with dna' region; an α-helix; the 'interaction with ccar2' region; 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

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: head and neck squamous cell carcinoma Li-Fraumeni syndrome

Similar variants

TP53 p.Arg280Ser Pathogenic/Likely pathogenic ★★ same residue
TP53 p.Arg280Ter Pathogenic/Likely pathogenic ★★ same residue
TP53 p.Arg280Thr Pathogenic/Likely pathogenic ★★ same residue
TP53 p.Arg280Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
TP53 p.Arg280Ile Conflicting classifications of pathogenicity ★ ⚠ same residue
TP53 p.Arg280fs Pathogenic ★★ same residue
TP53 p.Arg280_Arg283delinsHis Likely pathogenic ★ same residue
TP53 p.Arg280del Pathogenic ★ same residue

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-arg280lys (accessed [today's date]).

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