FMO4

Chr 1

flavin containing dimethylaniline monoxygenase 4

Also known as: FMO2

NCBI Gene: 2329 ENSG00000076258 UniProt: P31512 OMIM: 136131

FMO4 encodes flavin-containing monooxygenase 4, an NADPH-dependent enzyme that catalyzes the oxidative metabolism of xenobiotics including drugs and pesticides. This gene has extremely low constraint against loss-of-function variants (pLI ~0, LOEUF 1.18), and no human diseases have been definitively associated with FMO4 mutations to date. The related gene FMO3 causes trimethylaminuria (fish odor syndrome) through impaired metabolism of trimethylamine, but FMO4's specific role in human disease remains unclear.

OMIM ResearchSummary from RefSeq, UniProt

Metabolic N-oxidation of diet-derived amino-trimethylamine (TMA) is mediated by flavin-containing monooxygenase and is subject to an inherited FMO3 polymorphism in man. This results in a small subpopulation with reduced TMA N-oxidation capacity and causes fish odor syndrome (Trimethylaminuria). Three forms of the enzyme are encoded by genes clustered in the 1q23-q25 region. Flavin-containing monooxygenases are NADPH-dependent flavoenzymes that catalyzes the oxidation of soft nucleophilic heteroatom centers in drugs, pesticides, and xenobiotics. [provided by RefSeq, Jan 2015]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.18

Clinical Summary— FMO4

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

73 VUS of 92 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.18LOEUF

pLI 0.000

Z-score 0.92

OE 0.79 (0.55–1.18)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.44Z-score

OE missense 0.93 (0.84–1.03)

276 obs / 297.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.79 (0.55–1.18)

0≤0.351.4

Missense OE?0.93 (0.84–1.03)

0≤0.61.4

Synonymous OE?0.98

0≤1.21.6

LoF obs/exp: 18 / 22.7Missense obs/exp: 276 / 297.2Syn Z: 0.17

This gene — mechanism propensity

0.7131th %ile

GOF

0.72top 25%

LOF

0.2581th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

92 submitted variants in ClinVar

ClinVar

Classification Summary

VUS73

Likely Benign4

Benign3

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	72	1	0	73
Likely Benign	4	0	0	4
Benign	1	0	2	3
Total	77	1	2	80

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

26 pathogenic / likely-pathogenic (of 32) ClinVar copy-number / structural variants overlap FMO4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →