Is FMO3 p.Pro153fs (c.458_459del) pathogenic?

FMO3 p.Pro153fs (c.458459del) is classified Pathogenic in FMO3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-01). Very rare (popmax 0.00446%, eas); Associated with trimethylaminuria.

What condition is associated with FMO3 p.Pro153fs (c.458_459del)?

FMO3 p.Pro153fs (c.458_459del) is associated with trimethylaminuria (ClinVar).

How common is FMO3 p.Pro153fs (c.458_459del) in the general population?

FMO3 p.Pro153fs (c.458_459del) is very rare (popmax 0.00446%, eas) (gnomAD).

FMO3 p.Pro153fs

c.458_459del · VCV3573961

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Conditions

trimethylaminuria

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 4 of 9
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.89	GERP -4

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,858 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000277%

Overall 0.000124% 2/1,613,984 alleles · very rare exomes 2/1,461,698 · genomes 0/152,286 · joint denominator

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: FMO3
Protein: p.Pro153fs
Coding: c.458_459del
MANE Select: NM_001002294
Type: Deletion
Location: chr1:171107810 (GRCh38)
Gene constraint: LOEUF 1.314 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.50
Residue 153: a UniProt-annotated variant site (in tmau; 90% reduction in catalytic efficiency toward trimethylamine and benzydamine; 34% reduction in catalytic efficiency toward methyl p-tolyl sulfide; nearly no effect on affinity for these substrates)

Full FMO3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

trimethylaminuria — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

FMO3 p.Pro153Leu Pathogenic/Likely pathogenic ★★ same residue
FMO3 p.Arg131fs Pathogenic/Likely pathogenic ★★ same condition
FMO3 p.Asn80fs Pathogenic/Likely pathogenic ★★ same condition
FMO3 p.Phe242fs Pathogenic/Likely pathogenic ★★ same condition
FMO3 p.Pro380fs Pathogenic/Likely pathogenic ★★ same condition
FMO3 p.Val187fs Pathogenic/Likely pathogenic ★★ same condition
FMO3 p.Asn227fs Likely pathogenic ★ same condition
FMO3 p.Lys416fs 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/fmo3-p-pro153fs (accessed [today's date]).

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