Is TP53 p.Met133Ile (c.399G>A) pathogenic?

TP53 p.Met133Ile (c.399G>A) is classified Conflicting classifications of pathogenicity in TP53 (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2025-08-02). AlphaMissense: likely pathogenic (0.5785); Very rare (popmax 0.004%, afr); Associated with adrenocortical carcinoma, hereditary.

What condition is associated with TP53 p.Met133Ile (c.399G>A)?

TP53 p.Met133Ile (c.399G>A) is associated with adrenocortical carcinoma, hereditary, hereditary neoplastic syndrome, Li-Fraumeni syndrome (ClinVar).

How common is TP53 p.Met133Ile (c.399G>A) in the general population?

TP53 p.Met133Ile (c.399G>A) is very rare (popmax 0.004%, afr) (gnomAD).

How is Adrenocortical carcinoma inherited?

Typically Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about TP53 p.Met133Ile (c.399G>A)?

AlphaMissense predicts likely pathogenic (score 0.5785) — an in-silico prediction, not a clinical call.

TP53 p.Met133Ile

c.399G>A · rs1064795139 · VCV421437

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely pathogenic

0.5785 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

adrenocortical carcinoma, hereditary

Computational evidence

Protein change
AlphaMissense	0.5785	likely pathogenic
REVEL	0.479	indeterminate
SaProt	LLR -4.26	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.4	GERP -4.9
Regional constraint	o/e 0.89	unconstrained · MANE · 6,982 bp · p 0.0085 · regional, not allelic
Overall
CADD	17.59	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 0.004% African / African-American · 3/75,034 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000494%

Overall 0.000248% 4/1,614,074 alleles · very rare exomes 4/1,461,814 · genomes 0/152,260 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.004%	25,011
Remaining individualsnot grpmax-eligible	0.0016%	62,504

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.Met133Ile
Coding: c.399G>A
MANE Select: NM_000546
dbSNP: rs1064795139
Type: single nucleotide variant
Location: chr17:7675213 (GRCh38)
Gene constraint: LOEUF 0.449 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.83 · 321 PDB
Residue 133: a DNA-binding region; the 'interaction with axin1' region; a β-strand; the 'interaction with ccar2' region; a UniProt-annotated variant site (in a sporadic cancer; somatic mutation); a UniProt-annotated variant site (in sporadic cancers; somatic mutation); a UniProt-annotated variant site (in lfs; germline mutation and in sporadic cancers; somatic mutation); the 'interaction with hipk1' region; the 'required for interaction with znf385a' region; the 'required for interaction with fbxo42' region

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

Disease context

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

Also linked: hereditary neoplastic syndrome Li-Fraumeni syndrome

For Adrenocortical carcinoma (Orphanet):

Inheritance: Not applicable
Onset: Childhood
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

TP53 p.Met133Thr Pathogenic ★★ ⚠ same residue
TP53 p.Met133Lys Uncertain significance ★ ⚠ same residue
TP53 p.Met133Val Uncertain significance ★ ⚠ same residue
TP53 p.Met133Arg 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-met133ile (accessed [today's date]).

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