FLAD1

Chr 1AR

flavin adenine dinucleotide synthetase 1

Also known as: FAD1, FADS, LSMFLAD, PP591

NCBI Gene: 80308 ENSG00000160688 UniProt: Q8NFF5 OMIM: 610595

The enzyme catalyzes the adenylation of flavin mononucleotide (FMN) to form flavin adenine dinucleotide (FAD), an essential coenzyme for cellular metabolism, and also has FAD diphosphatase activity that breaks down FAD back to FMN. Mutations cause lipid storage myopathy due to flavin adenine dinucleotide synthetase deficiency, inherited in an autosomal recessive pattern. The gene is highly constrained against loss-of-function variants, indicating its critical importance for normal cellular function.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes the enzyme that catalyzes adenylation of flavin mononucleotide (FMN) to form flavin adenine dinucleotide (FAD) coenzyme. Alternatively spliced transcript variants encoding distinct isoforms have been observed. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Lipid storage myopathy due to flavin adenine dinucleotide synthetase deficiencyMIM #255100

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · myopathy with abnormal lipid metabolism · AR · ClinGen 2020

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.59

LOEUF

LOF

Mechanism· G2P

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.59LOEUF

pLI 0.009

Z-score 3.07

OE 0.33 (0.19–0.59)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.58Z-score

OE missense 0.91 (0.83–1.00)

306 obs / 336.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.33 (0.19–0.59)

0≤0.351.4

Missense OE?0.91 (0.83–1.00)

0≤0.61.4

Synonymous OE?0.81

0≤1.21.6

LoF obs/exp: 8 / 24.4Missense obs/exp: 306 / 336.0Syn Z: 1.72

Background carrier burden — how many people carry a rare variant somewhere in FLAD1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 65

799 rare PASS variants

Rare truncating (LoF)

1 in 770

143 rare PASS variants

Rare synonymous (reference)

1 in 250

303 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for FLAD1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 85	1 in 910
South Asian	~43k	1 in 91	1 in 500
Remaining (unassigned)	~30k	1 in 49	1 in 410
European (Finnish)	~27k	1 in 270	1 in 920
Admixed American	~22k	1 in 51	1 in 560
African / African American	~21k	1 in 73	1 in 250
East Asian	~20k	1 in 87	1 in 710
Ashkenazi Jewish	~13k	1 in 1,600	1 in 2,500
Middle Eastern	~2,884	1 in 63	≈ 1 in 960

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 6 of 7 coding exons well covered in gnomAD exomes; exon 3 marginal. Genomes: all 7.? see exons ↓