Is TP53 p.Thr125Met (c.374C>T) pathogenic?

TP53 p.Thr125Met (c.374C>T) is classified Conflicting classifications of pathogenicity in TP53 (ClinVar, Conflicting submitters, 21 submitters; last evaluated 2025-11-21). AlphaMissense: likely pathogenic (0.9602); Very rare (popmax 0.00134%, afr); Associated with Li-Fraumeni syndrome 1.

What condition is associated with TP53 p.Thr125Met (c.374C>T)?

TP53 p.Thr125Met (c.374C>T) is associated with Li-Fraumeni syndrome 1, adrenocortical carcinoma, hereditary, familial pancreatic carcinoma (ClinVar).

How common is TP53 p.Thr125Met (c.374C>T) in the general population?

TP53 p.Thr125Met (c.374C>T) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about TP53 p.Thr125Met (c.374C>T)?

AlphaMissense predicts likely pathogenic (score 0.9602) — an in-silico prediction, not a clinical call.

TP53 p.Thr125Met

c.374C>T · rs786201057 · VCV183748

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 21 submitters

AlphaMissense

likely pathogenic

0.9602 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Li-Fraumeni syndrome 1

Computational evidence

Protein change
AlphaMissense	0.9602	likely pathogenic
REVEL	0.925	moderately pathogenic-leaning
SaProt	LLR -11.50	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Pangolin	Δ0.22	loss · gain 0.01 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 12	GERP 2.2, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 6,982 bp · p 0.0085 · regional, not allelic
Overall
CADD	34.0	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

Grpmax group 0.00134% African / African-American · 1/74,868 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,612,144 alleles · very rare exomes 2/1,459,944 · genomes 1/152,200 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,868
European (non-Finnish)	0.000169%	590,019

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.Thr125Met
Coding: c.374C>T
MANE Select: NM_000546
dbSNP: rs786201057
Type: single nucleotide variant
Location: chr17:7675995 (GRCh38)
Gene constraint: LOEUF 0.449 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.83 · 321 PDB
Residue 125: 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); 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

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

Also linked: adrenocortical carcinoma, hereditary familial pancreatic carcinoma hereditary neoplastic syndrome Li-Fraumeni syndrome

Similar variants

TP53 p.Thr125= Pathogenic/Likely pathogenic ★★ same residue
TP53 p.Thr125Arg Pathogenic/Likely pathogenic ★★ same residue
TP53 p.Thr125Lys Pathogenic ★★ same residue
TP53 p.Thr125Ala Uncertain significance ★★ ⚠ same residue
TP53 p.Thr125Pro Conflicting classifications of pathogenicity ★ ⚠ same residue
TP53 p.Thr125fs Pathogenic ★ same residue
TP53 c.375+5G>A Likely pathogenic ★★★ same condition
TP53 c.919+1G>A 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-thr125met (accessed [today's date]).

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