Is FMO3 p.Lys416fs (c.1246_1247del) pathogenic?

FMO3 p.Lys416fs (c.12461247del) is classified Likely pathogenic in FMO3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-23). Very rare (popmax 0.000173%, nfe); Associated with trimethylaminuria.

What condition is associated with FMO3 p.Lys416fs (c.1246_1247del)?

FMO3 p.Lys416fs (c.1246_1247del) is associated with trimethylaminuria (ClinVar).

How common is FMO3 p.Lys416fs (c.1246_1247del) in the general population?

FMO3 p.Lys416fs (c.1246_1247del) is very rare (popmax 0.000173%, nfe) (gnomAD).

FMO3 p.Lys416fs

c.1246_1247del · VCV3574037

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000173%, nfe)

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	escapes	premature termination codon within the last 50 nt of the penultimate exon (8 of 9, 13 nt from its 3' end) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.02	GERP -0.25

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000173% European (non-Finnish) · 2/1,158,248 alleles

Filtering AF 2.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000126% 2/1,589,440 alleles · very rare exomes 2/1,437,144 · genomes 0/152,296 · 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.Lys416fs
Coding: c.1246_1247del
MANE Select: NM_001002294
Type: Deletion
Location: chr1:171116267 (GRCh38)
Gene constraint: LOEUF 1.314 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.50
Residue 416: a UniProt-annotated variant site (2-fold decrease in affinity for trimethylamine; 3-fold decrease in catalytic efficiency toward methimazole; 3-fold increase in catalytic efficiency toward sulindac; 30% increase in catalytic efficiency toward ethylenethiourea)

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.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.Pro153fs Pathogenic ★ same condition
FMO3 p.Glu65fs 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-lys416fs (accessed [today's date]).

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