Is FMO3 p.Pro75= (c.225C>T) pathogenic?

FMO3 p.Pro75= (c.225C>T) is classified Conflicting classifications of pathogenicity in FMO3 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-02-01). Ultra-rare (popmax 0.0493%, mid); Associated with trimethylaminuria.

What condition is associated with FMO3 p.Pro75= (c.225C>T)?

FMO3 p.Pro75= (c.225C>T) is associated with trimethylaminuria (ClinVar).

How common is FMO3 p.Pro75= (c.225C>T) in the general population?

FMO3 p.Pro75= (c.225C>T) is ultra-rare (popmax 0.0493%, mid) (gnomAD).

FMO3 p.Pro75=

c.225C>T · rs141235954 · VCV293686

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0493%, mid)

Conditions

trimethylaminuria

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -7.3	GERP -4
Overall
CADD	13.66	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0493% Middle Eastern · 3/6,084 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0104%

Overall 0.0103% 166/1,613,614 alleles · ultra-rare exomes 155/1,461,492 · genomes 11/152,122 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0493%	2,028
European (non-Finnish)	0.0127%	7,865
Remaining individualsnot grpmax-eligible	0.00961%	10,411
Admixed American	0.00834%	11,986
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,598
African / African-American	0.00134%	74,898

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.Pro75=
Coding: c.225C>T
MANE Select: NM_001002294
dbSNP: rs141235954
Type: single nucleotide variant
Location: chr1:171103877 (GRCh38)
Gene constraint: LOEUF 1.314 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.50

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 c.484+2T>G Likely pathogenic ★★ same condition
FMO3 c.828-2A>G Likely pathogenic ★★ same condition
FMO3 p.Arg223Gln Likely pathogenic ★★ same condition
FMO3 p.Arg223Trp Likely pathogenic ★★ same condition
FMO3 p.Arg238Gln Pathogenic/Likely pathogenic ★★ same condition
FMO3 p.Arg238Ter Pathogenic/Likely pathogenic ★★ same condition
FMO3 p.Arg492Trp Pathogenic/Likely pathogenic ★★ same condition
FMO3 p.Arg500Ter Pathogenic/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-pro75 (accessed [today's date]).

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