Is FMO3 p.Val58Ile (c.172G>A) pathogenic?

FMO3 p.Val58Ile (c.172G>A) is classified Conflicting classifications of pathogenicity in FMO3 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-28). AlphaMissense: likely benign (0.1598); Rare (popmax 0.352%, eas); Associated with trimethylaminuria.

What condition is associated with FMO3 p.Val58Ile (c.172G>A)?

FMO3 p.Val58Ile (c.172G>A) is associated with trimethylaminuria (ClinVar).

How common is FMO3 p.Val58Ile (c.172G>A) in the general population?

FMO3 p.Val58Ile (c.172G>A) is rare (popmax 0.352%, eas) (gnomAD).

What do computational predictors say about FMO3 p.Val58Ile (c.172G>A)?

AlphaMissense predicts likely benign (score 0.1598) — an in-silico prediction, not a clinical call.

FMO3 p.Val58Ile

c.172G>A · rs144935285 · VCV225365

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1598 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.352%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

trimethylaminuria

Computational evidence

Protein change
AlphaMissense	0.1598	likely benign
REVEL	0.27	benign-leaning
SaProt	LLR -7.41	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.6	GERP 1.8, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 25 kb · p 0.27 · regional, not allelic
Overall
CADD	24.9	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 0.352% East Asian · 158/44,846 alleles

Filtering AF 0.307% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.29%

Overall 0.0137% 221/1,613,894 alleles · rare exomes 186/1,461,688 · genomes 35/152,206 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.352%	284
South Asian	0.0472%	2,118
Remaining individualsnot grpmax-eligible	0.0288%	3,473
Middle Eastern	0.0165%	6,060
European (non-Finnish)	8.48e-05%	1,179,901

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.Val58Ile
Coding: c.172G>A
MANE Select: NM_001002294
dbSNP: rs144935285
Type: single nucleotide variant
Location: chr1:171103824 (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-val58ile (accessed [today's date]).

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