Is TP53 p.Thr284Ser (c.850A>T) pathogenic?

TP53 p.Thr284Ser (c.850A>T) is classified Conflicting classifications of pathogenicity in TP53 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-10-09). AlphaMissense: likely benign (0.2344); Very rare (popmax 0.00271%, nfe); Associated with Li-Fraumeni syndrome.

What condition is associated with TP53 p.Thr284Ser (c.850A>T)?

TP53 p.Thr284Ser (c.850A>T) is associated with Li-Fraumeni syndrome, hereditary neoplastic syndrome (ClinVar).

How common is TP53 p.Thr284Ser (c.850A>T) in the general population?

TP53 p.Thr284Ser (c.850A>T) is very rare (popmax 0.00271%, nfe) (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.Thr284Ser (c.850A>T)?

AlphaMissense predicts likely benign (score 0.2344) — an in-silico prediction, not a clinical call.

TP53 p.Thr284Ser

c.850A>T · rs1204379654 · VCV458571

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.2344 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00271%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Li-Fraumeni syndrome

Computational evidence

Protein change
AlphaMissense	0.2344	likely benign
REVEL	0.495	indeterminate
SaProt	LLR -7.38	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 0.49, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 6,982 bp · p 0.0085 · regional, not allelic
Overall
CADD	22.1	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 0.00271% European (non-Finnish) · 32/1,180,048 alleles

Filtering AF 0.00196% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00168%

Overall 0.00204% 33/1,614,030 alleles · very rare exomes 32/1,461,892 · genomes 1/152,138 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00271%	36,877
Remaining individualsnot grpmax-eligible	0.0016%	62,482

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.Thr284Ser
Coding: c.850A>T
MANE Select: NM_000546
dbSNP: rs1204379654
Type: single nucleotide variant
Location: chr17:7673770 (GRCh38)
Gene constraint: LOEUF 0.449 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.83 · 321 PDB
Residue 284: 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; an α-helix; the 'interaction with ccar2' region; a modified residue (phosphothreonine; by aurkb); 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

Also linked: hereditary neoplastic syndrome

For Li-Fraumeni syndrome (Orphanet):

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

Similar variants

TP53 p.Thr284Ile Likely benign ★★★ same residue
TP53 p.Thr284= Benign/Likely benign ★★ same residue
TP53 p.Thr284Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
TP53 p.Thr284Pro Conflicting classifications of pathogenicity ★ ⚠ same residue
TP53 p.Thr284fs Pathogenic ★ same residue
TP53 p.Thr284_Glu285insAspProIleLeuAlaProLeuProAlaProGlyThr Uncertain significance ★ same residue
TP53 p.Thr284Arg Uncertain significance ★ ⚠ same residue
TP53 c.375+5G>A 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-thr284ser (accessed [today's date]).

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