Is FMO3 p.Arg417His (c.1250G>A) pathogenic?

FMO3 p.Arg417His (c.1250G>A) is classified Conflicting classifications of pathogenicity in FMO3 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-01-31). AlphaMissense: likely benign (0.0912); Ultra-rare (popmax 0.0944%, afr); Associated with trimethylaminuria.

What condition is associated with FMO3 p.Arg417His (c.1250G>A)?

FMO3 p.Arg417His (c.1250G>A) is associated with trimethylaminuria (ClinVar).

How common is FMO3 p.Arg417His (c.1250G>A) in the general population?

FMO3 p.Arg417His (c.1250G>A) is ultra-rare (popmax 0.0944%, afr) (gnomAD).

What do computational predictors say about FMO3 p.Arg417His (c.1250G>A)?

AlphaMissense predicts likely benign (score 0.0912) — an in-silico prediction, not a clinical call.

FMO3 p.Arg417His

c.1250G>A · rs200985584 · VCV875898

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0912 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0944%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

trimethylaminuria

Computational evidence

Protein change
AlphaMissense	0.0912	likely benign
REVEL	0.044	moderately benign-leaning
SaProt	LLR -10.60	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.66	GERP -1
Regional constraint	o/e 1.04	unconstrained · MANE · 25 kb · p 0.27 · regional, not allelic
Overall
CADD	11.81	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 0.0944% African / African-American · 70/74,136 alleles

Filtering AF 0.0766% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0701%

Overall 0.0118% 186/1,570,762 alleles · ultra-rare exomes 132/1,418,480 · genomes 54/152,282 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0944%	1,059
Middle Eastern	0.0338%	2,960
Admixed American	0.0251%	3,988
South Asian	0.0133%	7,498
Remaining individualsnot grpmax-eligible	0.0082%	12,194
European (non-Finnish)	0.00683%	14,632
Finnishnot grpmax-eligible	0.00626%	15,982

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.Arg417His
Coding: c.1250G>A
MANE Select: NM_001002294
dbSNP: rs200985584
Type: single nucleotide variant
Location: chr1:171116274 (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 p.Arg417Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
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

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-arg417his (accessed [today's date]).

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