Is TP53 p.Met384Val (c.1150A>G) pathogenic?

TP53 p.Met384Val (c.1150A>G) is classified Likely benign in TP53 (ClinVar, Expert panel, 9 submitters; last evaluated 2025-01-16). AlphaMissense: likely benign (0.0844); Very rare (popmax 0.00178%, nfe); Associated with Li-Fraumeni syndrome.

What condition is associated with TP53 p.Met384Val (c.1150A>G)?

TP53 p.Met384Val (c.1150A>G) is associated with Li-Fraumeni syndrome, hereditary neoplastic syndrome (ClinVar).

How common is TP53 p.Met384Val (c.1150A>G) in the general population?

TP53 p.Met384Val (c.1150A>G) is very rare (popmax 0.00178%, 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.Met384Val (c.1150A>G)?

AlphaMissense predicts likely benign (score 0.0844) — an in-silico prediction, not a clinical call.

TP53 p.Met384Val

c.1150A>G · rs730882009 · VCV182939

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.0844 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00178%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Li-Fraumeni syndrome

ClinGen expert panel — TP53 VCEP

Likely Benign for Li-Fraumeni syndrome. Applied ACMG criteria (verbatim):

PM2_Supporting BS2_Moderate BP4_Moderate

Curation rationale (ClinGen, verbatim)

The NM_000546.6: c.1150A>G variant in TP53 is a missense variant predicted to cause substitution of methionine by valine at amino acid 384 (p.Met384Val). This variant has been observed in 4-7 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Moderate; Internal lab contributor: Invitae). Computational predictor scores (BayesDel = -0.073; Align GVGD Class C0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing. (BP4_Moderate). This variant has an allele frequency of 0.00001780 (21/1179926 alleles) in the Europen (non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely Benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_Moderate, BP4_Moderate, PM2_Supporting. (Bayesian Points: -3; VCEP specifications version 2.0; 1/16/2025).

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.0844	likely benign
REVEL	0.355	indeterminate
SaProt	LLR -5.13	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP 0.096, phastCons 0.45
Regional constraint	o/e 0.89	unconstrained · MANE · 6,982 bp · p 0.0085 · regional, not allelic
Overall
CADD	15.8	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 0.00178% European (non-Finnish) · 21/1,179,926 alleles

Filtering AF 0.00114% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000971%

Overall 0.00136% 22/1,613,928 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00178%	56,187
Remaining individualsnot grpmax-eligible	0.0016%	62,484

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.Met384Val
Coding: c.1150A>G
MANE Select: NM_000546
dbSNP: rs730882009
Type: single nucleotide variant
Location: chr17:7669641 (GRCh38)
Gene constraint: LOEUF 0.449 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.83 · 321 PDB
Residue 384: the 'interaction with carm1' region; an α-helix; the 'disordered' region; the 'basic (repression of dna-binding)' region; the 'interaction with morn3' 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.Met384Thr Benign ★★★ same residue
TP53 p.Met384Arg Uncertain significance ★ ⚠ same residue
TP53 p.Met384Ile Conflicting classifications of pathogenicity ★ ⚠ same residue
TP53 p.Met384Leu 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-met384val (accessed [today's date]).

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