FLAD1

Summary

FLAD1 (flavin adenine dinucleotide synthetase 1, HGNC:24671) is a protein-coding gene on chromosome 1q21.3, encoding Bifunctional FAD diphosphatase/FAD synthase (Q8NFF5). This enzyme has two activities: FAD diphosphatase activity and FAD synthase activity.

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.

Source: NCBI Gene 80308 — RefSeq curated summary.

At a glance

• Gene–disease (curated): myopathy with abnormal lipid metabolism (Definitive, ClinGen)
• GWAS associations: 10
• Clinical variants (ClinVar): 370 total — 18 pathogenic, 10 likely-pathogenic
• Phenotypes (HPO): 17
• Druggable target: yes
• MANE Select transcript: NM_025207

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24671
Approved symbol	FLAD1
Name	flavin adenine dinucleotide synthetase 1
Location	1q21.3
Locus type	gene with protein product
Status	Approved
Aliases	PP591, FAD1
Ensembl gene	ENSG00000160688
Ensembl biotype	protein_coding
OMIM	610595
Entrez	80308

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 8 protein_coding, 5 protein_coding_CDS_not_defined

ENST00000292180, ENST00000295530, ENST00000315144, ENST00000368428, ENST00000368431, ENST00000368432, ENST00000368433, ENST00000477609, ENST00000481758, ENST00000487371, ENST00000489992, ENST00000492620, ENST00000912982

RefSeq mRNA: 4 — MANE Select: NM_025207 NM_001184891, NM_001184892, NM_025207, NM_201398

CCDS: CCDS1078, CCDS1079, CCDS53371, CCDS53372

Canonical transcript exons

ENST00000292180 — 7 exons

Exon	Start	End
ENSE00001215072	154983344	154984066
ENSE00001732786	154988105	154988849
ENSE00003471577	154990159	154990257
ENSE00003496779	154992902	154993111
ENSE00003515723	154989560	154989707
ENSE00003642298	154990339	154990528
ENSE00003673084	154992713	154992786

Expression profiles

Bgee: expression breadth ubiquitous, 260 present calls, max score 93.72.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 14.5402 / max 181.8984, expressed in 1801 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
5547	13.6242	1798
5548	0.9160	516

Top tissues by expression

285 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	93.72	gold quality
granulocyte	CL:0000094	93.61	gold quality
mucosa of transverse colon	UBERON:0004991	92.34	gold quality
hindlimb stylopod muscle	UBERON:0004252	92.15	gold quality
lower esophagus mucosa	UBERON:0035834	92.01	gold quality
skin of leg	UBERON:0001511	91.02	gold quality
skin of abdomen	UBERON:0001416	90.94	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	90.72	gold quality
gastrocnemius	UBERON:0001388	90.59	gold quality
muscle of leg	UBERON:0001383	90.16	gold quality
right lobe of thyroid gland	UBERON:0001119	89.58	gold quality
right lobe of liver	UBERON:0001114	89.56	gold quality
ganglionic eminence	UBERON:0004023	89.25	gold quality
small intestine Peyer’s patch	UBERON:0003454	89.22	gold quality
transverse colon	UBERON:0001157	89.02	gold quality
body of stomach	UBERON:0001161	88.92	gold quality
left lobe of thyroid gland	UBERON:0001120	88.91	gold quality
heart left ventricle	UBERON:0002084	88.90	gold quality
lower esophagus	UBERON:0013473	88.90	gold quality
lower esophagus muscularis layer	UBERON:0035833	88.89	gold quality
spleen	UBERON:0002106	88.77	gold quality
right uterine tube	UBERON:0001302	88.73	gold quality
esophagus mucosa	UBERON:0002469	88.61	gold quality
muscle layer of sigmoid colon	UBERON:0035805	88.52	gold quality
esophagus	UBERON:0001043	88.51	gold quality
zone of skin	UBERON:0000014	88.49	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	88.48	gold quality
cardiac ventricle	UBERON:0002082	88.36	gold quality
ectocervix	UBERON:0012249	88.27	gold quality
metanephros cortex	UBERON:0010533	88.26	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.42

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 7)

• Our data show that a reduction in electron transport proteins, namely FAD synthetase, RFK, CYC1, and SDHB, is seen in patients with ALS. (PMID:19240958)
• Frameshift mutation in the FADS gene is Associated with Multiple Acyl-CoA Dehydrogenase and Combined Respiratory-Chain Deficiency. (PMID:27259049)
• FLAD1-associated multiple acyl-CoA dehydrogenase deficiency identified by newborn screening. (PMID:31392824)
• Mutation of Aspartate 238 in FAD Synthase Isoform 6 Increases the Specific Activity by Weakening the FAD Binding. (PMID:31835305)
• FLAD1 is up-regulated in Gastric Cancer and is a potential prediction of prognosis. (PMID:32714079)
• Retrograde response to mitochondrial dysfunctions associated to LOF variations in FLAD1 exon 2: unraveling the importance of RFVT2. (PMID:36480241)
• Structural insights into the bifunctional enzyme human FAD synthase. (PMID:38688286)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	flad1	ENSDARG00000070390
mus_musculus	Flad1	ENSMUSG00000042642
rattus_norvegicus	Flad1	ENSRNOG00000020642
drosophila_melanogaster	Flad1	FBGN0030431
drosophila_melanogaster	Flad2	FBGN0032522
caenorhabditis_elegans		WBGENE00011271

Protein

Protein identifiers

Bifunctional FAD diphosphatase/FAD synthase — Q8NFF5 (reviewed: Q8NFF5)

All UniProt accessions (4): Q8NFF5, Q5T190, Q5T191, Q5T196

UniProt curated annotations — full annotation on UniProt →

Function. This enzyme has two activities: FAD diphosphatase activity and FAD synthase activity. FAD diphosphatase acts on FAD and NADH to produce FMN and NMNH(2-), respectively. FAD synthase catalyzes the adenylation of flavin mononucleotide (FMN) to form flavin adenine dinucleotide (FAD) coenzyme. In addition to its catalytic activities, the protein also facilitates the delivery of FAD to client apo-flavoproteins. The balance between FAD synthesis and hydrolysis may be regulated by redox-sensing cysteine residues. At a much lower rate, FAD synthase catalyzes the reverse pyrophosphorolytic reaction. FAD synthase can also convert roseoflavin mononucleotide (RoFMN) to roseoflavin adenine dinucleotide (RoFAD); RoFMN is produced by riboflavin kinase when acting on the antibiotic roseoflavin (RoF). FAD synthase cannot convert 8-demethyl-8-amino-riboflavin mononucleotide (AFMN) to 8-demethyl-8-amino-riboflavin adenine dinucleotide (AFAD); AFMN is produced by riboflavin kinase when acting on the antibiotic 8-demethyl-8-amino-riboflavin (AF).

Subunit / interactions. Dimer. Interacts with KDM1A; which promotes KDM1A holoenzyme formation. Interacts with DMGDH; which promotes DMGDH holoenzyme formation.

Subcellular location. Nucleus Mitochondrion matrix Cytoplasm. Cytosol.

Post-translational modifications. May form disulfide bonds.

Disease relevance. Lipid storage myopathy due to flavin adenine dinucleotide synthetase deficiency (LSMFLAD) [MIM:255100] An autosomal recessive, inborn error of metabolism characterized by variable mitochondrial dysfunction. Clinical features range from severe cardiac and respiratory insufficiency with onset in infancy and resulting in early death, to mild muscle weakness with onset in adulthood. Some patients show significant improvement with riboflavin treatment. Analysis of skeletal muscle show multiple mitochondrial respiratory chain deficiency and a lipid storage myopathy in most patients. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. The reducing agent sodium dithionite stimulates FAD synthase activity. The FAD synthase activity is inhibited by GTP and GDP. The FAD synthase activity is also inhibited by the thiol reagents mersalyl, methylmercury, and mercury chloride; mersalyl also inhibits the reverse pyrophosphorylase activity. FAD diphosphatase activity is stimulated by glutathione and mersalyl. FAD diphosphatase activity is inhibited by ADP and ADP-ribose.

Cofactor. The FAD synthase activity requires a divalent metal. Magnesium or cobalt supports the highest FAD synthase activity, it has lower activity with manganese, calcium or zinc. Magnesium is also required for the reverse pyrophosphorolytic reaction. Cobalt does not appear to support the reverse reaction. The FAD diphosphatase activity requires cobalt. Nickel and manganese can substitute with much lower efficiency. Magnesium, calcium and copper cannot substitute. The FAD diphosphatase activity requires potassium. Can also use sodium to a lesser extent.

Pathway. Cofactor biosynthesis; FAD biosynthesis; FAD from FMN: step 1/1.

Similarity. In the N-terminal section; belongs to the MoaB/Mog family. In the C-terminal section; belongs to the PAPS reductase family. FAD1 subfamily.

Isoforms (5)

UniProt ID	Names	Canonical?
Q8NFF5-1	1, FADS1	yes
Q8NFF5-2	2, FADS2
Q8NFF5-3	3
Q8NFF5-4	4
Q8NFF5-5	5

RefSeq proteins (4): NP_001171820, NP_001171821, NP_079483, NP_958800 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001453	MoaB/Mog_dom	Domain
IPR002500	PAPS_reduct_dom	Domain
IPR012183	FLAD1	Family
IPR014729	Rossmann-like_a/b/a_fold	Homologous_superfamily
IPR036425	MoaB/Mog-like_dom_sf	Homologous_superfamily
IPR056596	FLAD1_M	Domain

Pfam: PF00994, PF01507, PF24102

Enzyme classification (BRENDA):

• EC 2.7.7.2 — FAD synthase (BRENDA: 15 organisms, 51 substrates, 37 inhibitors, 124 Km, 60 kcat entries)

Substrate kinetics (BRENDA)

12 substrates with measured Km, best-characterized 12. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
FMN	0.0001–1.5	63
ATP	0.0069–0.121	44
7,8-DIBROMO-FMN	0.0048–0.94	2
7,8-DICHLORO-FMN	0.082–0.12	2
7-CHLORO-FMN	0.0076–0.0086	2
DIPHOSPHATE	0.042–0.114	2
4’-BUTYL-FMN	0.25	1
8-CHLORO-FMN	0.019	1
CTP	0.48	1
FAD	0.0004	1
ISO-FMN	0.015	1
ROSEOFLAVIN MONONUCLEOTIDE	0.116	1

Catalyzed reactions (Rhea), 3 shown:

• FAD + H2O = FMN + AMP + 2 H(+) (RHEA:13889)
• FMN + ATP + H(+) = FAD + diphosphate (RHEA:17237)
• NADH + H2O = reduced beta-nicotinamide D-ribonucleotide + AMP + 2 H(+) (RHEA:48868)

UniProt features (85 total): strand 22, helix 19, binding site 16, splice variant 8, mutagenesis site 5, turn 5, modified residue 4, region of interest 2, sequence variant 2, transit peptide 1, chain 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
8ROM	X-RAY DIFFRACTION	1.69
8RON	X-RAY DIFFRACTION	2.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8NFF5-F1	83.34	0.71

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (16): 436; 487; 487; 489; 492; 505; 540; 547; 547; 549; 402; 404 …

Post-translational modifications (4): 106, 378, 378, 563

Mutagenesis-validated functional residues (5):

Position	Phenotype
338	decreases fad synthase turnover number (kcat) and increases its affinity for atp.
400	decreases fad synthase turnover number (kcat) and increases its affinity for atp.
409	decreases fad synthase turnover number (kcat).
496	decreases fad synthase turnover number (kcat) and increases its affinity for atp.
537	decreases fad diphosphatase activity. decreases fad synthase turnover number (kcat) and increases its affinity for atp.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-196843	Vitamin B2 (riboflavin) metabolism

MSigDB gene sets: 169 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_DN, ELVIDGE_HYPOXIA_DN, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_NUCLEOSIDE_PHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, PATIL_LIVER_CANCER, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, WEI_MYCN_TARGETS_WITH_E_BOX, GARY_CD5_TARGETS_DN, DODD_NASOPHARYNGEAL_CARCINOMA_UP, MULLIGHAN_NPM1_SIGNATURE_3_DN, GRUETZMANN_PANCREATIC_CANCER_UP, chr1q21, CHARAFE_BREAST_CANCER_LUMINAL_VS_MESENCHYMAL_UP, GOCC_MITOCHONDRIAL_MATRIX

GO Biological Process (5): FAD biosynthetic process (GO:0006747), riboflavin metabolic process (GO:0006771), phosphate-containing compound metabolic process (GO:0006796), flavin adenine dinucleotide biosynthetic process (GO:0072388), organophosphate biosynthetic process (GO:0090407)

GO Molecular Function (9): FMN adenylyltransferase activity (GO:0003919), ATP binding (GO:0005524), identical protein binding (GO:0042802), nucleotide binding (GO:0000166), catalytic activity (GO:0003824), protein binding (GO:0005515), transferase activity (GO:0016740), nucleotidyltransferase activity (GO:0016779), FAD diphosphatase activity (GO:0047884)

GO Cellular Component (9): nucleus (GO:0005634), mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), cytosol (GO:0005829), plasma membrane (GO:0005886), sperm midpiece (GO:0097225), sperm principal piece (GO:0097228), sperm end piece (GO:0097229), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Metabolism of water-soluble vitamins and cofactors	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
sperm flagellum	3
intracellular membrane-bounded organelle	2
cytoplasm	2
FAD metabolic process	1
flavin adenine dinucleotide biosynthetic process	1
flavin-containing compound metabolic process	1
metabolic process	1
nucleotide biosynthetic process	1
flavin-containing compound biosynthetic process	1
flavin adenine dinucleotide metabolic process	1
biosynthetic process	1
organophosphate metabolic process	1
adenylyltransferase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
protein binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
molecular_function	1
binding	1
catalytic activity	1
transferase activity, transferring phosphorus-containing groups	1
dinucleotide phosphatase activity	1
mitochondrion	1
intracellular organelle lumen	1
membrane	1
cell periphery	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

2614 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FLAD1	RFK	Q969G6	919
FLAD1	SRCAP	Q6ZRS2	779
FLAD1	G3BP1	Q13283	770
FLAD1	ETFDH	Q16134	765
FLAD1	SLC25A32	Q9H2D1	761
FLAD1	SLC52A1	Q9NWF4	755
FLAD1	ETFB	P38117	718
FLAD1	H2AZ1	P0C0S5	702
FLAD1	SLC52A3	Q9NQ40	669
FLAD1	SLC52A2	Q9HAB3	657
FLAD1	ETFA	P13804	612
FLAD1	SMARCA2	P51531	545
FLAD1	LENEP	Q9Y5L5	524
FLAD1	PCK1	P35558	493
FLAD1	FRMPD1	Q5SYB0	488

IntAct

72 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
FLAD1	SDCBP	psi-mi:“MI:0915”(physical association)	0.670
SDCBP	FLAD1	psi-mi:“MI:0915”(physical association)	0.670
FLAD1	FLAD1	psi-mi:“MI:0915”(physical association)	0.670
FLAD1	TCF4	psi-mi:“MI:0915”(physical association)	0.560
REL	FLAD1	psi-mi:“MI:0915”(physical association)	0.560
FLAD1	REL	psi-mi:“MI:0915”(physical association)	0.560
FLAD1	UBAP2	psi-mi:“MI:0914”(association)	0.560
UBAP2	FLAD1	psi-mi:“MI:0915”(physical association)	0.560
ORF	EIF3F	psi-mi:“MI:0914”(association)	0.560
TRIM23	FLAD1	psi-mi:“MI:0915”(physical association)	0.550
PRTFDC1	FLAD1	psi-mi:“MI:0915”(physical association)	0.550
FLAD1	CDKN1A	psi-mi:“MI:0915”(physical association)	0.550
CDKN1A	FLAD1	psi-mi:“MI:0915”(physical association)	0.550
ZNF689	ZNF593	psi-mi:“MI:0914”(association)	0.530
KLHL14	KCTD21	psi-mi:“MI:0914”(association)	0.530
OTP	FLAD1	psi-mi:“MI:0915”(physical association)	0.400
PDE6H	FLAD1	psi-mi:“MI:0915”(physical association)	0.400
FLAD1	FXR1	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (134): FLAD1 (Two-hybrid), FLAD1 (Two-hybrid), FLAD1 (Two-hybrid), FLAD1 (Two-hybrid), FLAD1 (Affinity Capture-RNA), FLAD1 (Affinity Capture-RNA), FLAD1 (Affinity Capture-MS), FLAD1 (Affinity Capture-MS), FLAD1 (Affinity Capture-MS), FLAD1 (Two-hybrid), FLAD1 (Two-hybrid), FLAD1 (Two-hybrid), FLAD1 (Co-fractionation), FLAD1 (Co-fractionation), PFAS (Co-fractionation)

ESM2 similar proteins: A0A061IR73, A0A7N9VSG0, A7YSY2, D3KCC4, D3ZU57, D4A2B7, O08644, O15197, O19179, O43542, O75064, O95382, P0C0K6, P0C0K7, P51840, P52785, P52824, P54777, Q02846, Q05932, Q13470, Q13608, Q1HG60, Q3ZBE0, Q4KM32, Q5JZY3, Q643R3, Q6MG64, Q6NVG1, Q6ZPS2, Q76MJ5, Q7TNJ2, Q80SX8, Q8BYG9, Q8IZY2, Q8NFF5, Q8R5G7, Q8TDZ2, Q8WWN8, Q91V24

Diamond homologs: B7GG21, O74841, P38913, Q22017, Q5RCH4, Q626I0, Q68EH8, Q6ING7, Q8NFF5, Q8R123, A0M3L5, A0PXD7, A0QY28, A2C089, A3DEA5, A4SGM6, A5F9Y3, A5GDB4, A5N2R5, A6GZI7, A6TNW2, A7HGS8, A7Z4W4, A8AZT4, A8MI49, B0JVG7, B0S3U9, B1I313, B1I8Q2, B2HDA1, B2IM29, B3EHJ0, B3EL42, B3QTC8, B4U0I9, B5E2E1, B7JYM6, B7KFE8, B8I7D0, B8ZNU8

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

370 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	18
Likely pathogenic	10
Uncertain significance	162
Likely benign	138
Benign	14

Top pathogenic / likely-pathogenic (28)

Variant ID	HGVS	Classification
1184538	NM_025207.5(FLAD1):c.797del (p.Glu266fs)	Pathogenic
1921537	NM_025207.5(FLAD1):c.1339C>T (p.Gln447Ter)	Pathogenic
2025475	NM_025207.5(FLAD1):c.796del (p.Glu266fs)	Pathogenic
2064507	NM_025207.5(FLAD1):c.1475del (p.Asp492fs)	Pathogenic
224727	NM_025207.5(FLAD1):c.1484_1486del (p.Ser495del)	Pathogenic
224728	NM_025207.5(FLAD1):c.568_569dup (p.Val191fs)	Pathogenic
224730	NM_025207.5(FLAD1):c.836del (p.Phe279fs)	Pathogenic
224731	NM_025207.5(FLAD1):c.526_537delinsCA (p.Ala176fs)	Pathogenic
224732	NM_025207.5(FLAD1):c.401_404del (p.Phe134fs)	Pathogenic
224733	NM_025207.5(FLAD1):c.324del (p.Arg109fs)	Pathogenic
224734	NM_025207.5(FLAD1):c.498del (p.Ser167fs)	Pathogenic
2799984	NM_025207.5(FLAD1):c.390dup (p.Asn131fs)	Pathogenic
2996191	NM_025207.5(FLAD1):c.811del (p.Leu271fs)	Pathogenic
3008498	NM_025207.5(FLAD1):c.987_988insC (p.Glu330fs)	Pathogenic
3382319	NM_025207.5(FLAD1):c.442C>T (p.Arg148Ter)	Pathogenic
3617508	NM_025207.5(FLAD1):c.1090G>T (p.Glu364Ter)	Pathogenic
3727762	NM_025207.5(FLAD1):c.1375C>T (p.Gln459Ter)	Pathogenic
801554	NM_025207.5(FLAD1):c.745C>T (p.Arg249Ter)	Pathogenic
1185711	NM_025207.5(FLAD1):c.708C>A (p.Cys236Ter)	Likely pathogenic
1936232	NM_025207.5(FLAD1):c.373-3C>G	Likely pathogenic
2124900	NM_025207.5(FLAD1):c.1266-1G>A	Likely pathogenic
2131826	NM_025207.5(FLAD1):c.1117+1G>T	Likely pathogenic
2785834	NM_025207.5(FLAD1):c.1555-1G>C	Likely pathogenic
3600995	NM_025207.5(FLAD1):c.512_528del (p.Thr171fs)	Likely pathogenic
3651086	NM_025207.5(FLAD1):c.1364+1_1364+3del	Likely pathogenic
4537458	NM_025207.5(FLAD1):c.749A>C (p.Asn250Thr)	Likely pathogenic
817013	NM_025207.5(FLAD1):c.1389_1398del (p.Ala463_Glu464insTer)	Likely pathogenic
817479	NM_025207.5(FLAD1):c.1054_1075del (p.Val352fs)	Likely pathogenic

SpliceAI

1046 predictions. Top by Δscore:

Variant	Effect	Δscore
1:154990244:G:GT	donor_gain	1.0000
1:154990255:G:GT	donor_gain	1.0000
1:154990255:GAG:G	donor_gain	1.0000
1:154992557:A:AG	acceptor_gain	1.0000
1:154992558:T:G	acceptor_gain	1.0000
1:154988846:TCAGG:T	donor_loss	0.9900
1:154988847:CAGG:C	donor_loss	0.9900
1:154988848:AGGTA:A	donor_loss	0.9900
1:154988849:GG:G	donor_loss	0.9900
1:154988850:G:C	donor_loss	0.9900
1:154988851:T:G	donor_loss	0.9900
1:154989705:GAG:G	donor_gain	0.9900
1:154990253:AAGAG:A	donor_loss	0.9900
1:154990254:AGAG:A	donor_loss	0.9900
1:154990256:AGGTA:A	donor_loss	0.9900
1:154990257:GG:G	donor_loss	0.9900
1:154990258:G:GA	donor_loss	0.9900
1:154990259:T:A	donor_loss	0.9900
1:154990537:G:GT	donor_gain	0.9900
1:154990537:G:T	donor_gain	0.9900
1:154992562:T:G	acceptor_gain	0.9900
1:154992563:A:AG	acceptor_gain	0.9900
1:154992564:G:GG	acceptor_gain	0.9900
1:154992785:GG:G	donor_gain	0.9900
1:154992786:GG:G	donor_gain	0.9900
1:154992886:A:AG	acceptor_gain	0.9900
1:154992887:C:G	acceptor_gain	0.9900
1:154992894:T:TA	acceptor_gain	0.9900
1:154992898:CCA:C	acceptor_loss	0.9900
1:154992899:CA:C	acceptor_loss	0.9900

AlphaMissense

3751 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:154992716:T:A	W520R	0.997
1:154992716:T:C	W520R	0.997
1:154989665:A:C	D408A	0.996
1:154989665:A:T	D408V	0.996
1:154988117:G:C	D129H	0.994
1:154992734:T:A	W526R	0.994
1:154992734:T:C	W526R	0.994
1:154989649:T:C	F403L	0.993
1:154989651:C:A	F403L	0.993
1:154989651:C:G	F403L	0.993
1:154989663:A:C	K407N	0.993
1:154989663:A:T	K407N	0.993
1:154989664:G:C	D408H	0.993
1:154990439:C:A	R489S	0.993
1:154989665:A:G	D408G	0.992
1:154989666:C:A	D408E	0.992
1:154989666:C:G	D408E	0.992
1:154989674:C:A	A411D	0.992
1:154989686:T:C	L415P	0.992
1:154990235:T:C	F448L	0.992
1:154990237:T:A	F448L	0.992
1:154990237:T:G	F448L	0.992
1:154989650:T:C	F403S	0.991
1:154989662:A:T	K407I	0.991
1:154992736:G:C	W526C	0.990
1:154992736:G:T	W526C	0.990
1:154992769:T:G	C537W	0.990
1:154990496:T:A	W508R	0.989
1:154990496:T:C	W508R	0.989
1:154989661:A:C	K407Q	0.988

dbSNP variants (sampled 300 via entrez): RS1000136839 (1:154985038 T>C), RS1000258368 (1:154985850 C>G,T), RS1000265522 (1:154992210 C>T), RS1000803963 (1:154982223 A>G), RS1001414648 (1:154986489 A>G), RS1001586161 (1:154993096 C>A,G,T), RS1001760827 (1:154986217 T>G), RS1001918307 (1:154991788 G>C,T), RS1002038427 (1:154985451 T>A,C,G), RS1002146504 (1:154985081 A>G), RS1002583534 (1:154984046 G>C,T), RS1004152015 (1:154987975 C>T), RS1004304810 (1:154982786 T>C), RS1004539496 (1:154987565 T>C,G), RS1004591999 (1:154987276 C>A)

Disease associations

OMIM: gene MIM:610595 | disease phenotypes: MIM:255100, MIM:231680

GenCC curated gene-disease

Disease	Classification	Inheritance
myopathy with abnormal lipid metabolism	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
myopathy with abnormal lipid metabolism	Definitive	AR

Mondo (2): myopathy with abnormal lipid metabolism (MONDO:0009703), multiple acyl-CoA dehydrogenase deficiency (MONDO:0009282)

Orphanet (1): Multiple acyl-CoA dehydrogenase deficiency (Orphanet:26791)

HPO phenotypes

17 total (17 of 17 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001290	Generalized hypotonia
HP:0001638	Cardiomyopathy
HP:0001992	Organic aciduria
HP:0002015	Dysphagia
HP:0002093	Respiratory insufficiency
HP:0002650	Scoliosis
HP:0003198	Myopathy
HP:0003236	Elevated circulating creatine kinase concentration
HP:0003546	Exercise intolerance
HP:0003593	Infantile onset
HP:0003701	Proximal muscle weakness
HP:0004755	Supraventricular tachycardia
HP:0008347	Decreased activity of mitochondrial complex IV
HP:0011923	Decreased activity of mitochondrial complex I
HP:0011968	Feeding difficulties
HP:0012548	Fatty replacement of skeletal muscle

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST001942_19	Prostate cancer	2.000000e-08
GCST007294_124	Body fat distribution (trunk fat ratio)	8.000000e-35
GCST007294_3	Body fat distribution (trunk fat ratio)	6.000000e-21
GCST007294_50	Body fat distribution (trunk fat ratio)	1.000000e-15
GCST007295_17	Body fat distribution (leg fat ratio)	3.000000e-13
GCST007295_37	Body fat distribution (leg fat ratio)	7.000000e-17
GCST007295_72	Body fat distribution (leg fat ratio)	1.000000e-28
GCST008103_81	Bipolar disorder	1.000000e-06
GCST010002_367	Refractive error	5.000000e-13
GCST90002403_20	Red blood cell count	6.000000e-21

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004341	body fat distribution
EFO:0004305	erythrocyte count

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C562935	Myopathy with Abnormal Lipid Metabolism (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3879869 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.00	Kd	997.7	nM	CHEMBL3752910
6.00	ED50	997.7	nM	CHEMBL3752910

PubChem BioAssay actives

1 with measured affinity, of 5 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149861: Binding affinity to human FLAD1 incubated for 45 mins by Kinobead based pull down assay	kd	0.9977	uM

CTD chemical–gene interactions

42 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	2
Cyclosporine	increases expression	2
FR900359	affects phosphorylation	1
2,4,6-tribromophenol	decreases expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
bisphenol A	decreases expression	1
decabromobiphenyl ether	decreases expression	1
beta-lapachone	decreases expression	1
cobaltous chloride	decreases expression	1
tetrabromobisphenol A	decreases expression	1
tanshinone	increases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
ICG 001	affects expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Temozolomide	increases expression	1
Sunitinib	increases expression	1
Acrolein	affects cotreatment, increases oxidation, increases abundance	1
Air Pollutants	affects cotreatment, increases abundance, increases oxidation	1
Arsenic	affects cotreatment, increases abundance, increases expression	1
Atrazine	decreases expression	1
Benzo(a)pyrene	increases mutagenesis	1
Diethylstilbestrol	decreases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Estradiol	increases expression	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3879668	Binding	Binding affinity to FAD1 in HEK293T cells at 50 uM incubated for 1 hr by mass spectrometry analysis relative to o-ML349-biotin	Affinity-Based Selectivity Profiling of an In-Class Selective Competitive Inhibitor of Acyl Protein Thioesterase 2. — ACS Med Chem Lett

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B2X6	Abcam HEK293T FLAD1 KO	Transformed cell line	Female

Clinical trials (associated diseases)

3 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT02635269	Not specified	UNKNOWN	Fat and Sugar Metabolism During Exercise in Patients With Metabolic Myopathy
NCT05892692	Not specified	COMPLETED	Nexus of Risk: Sexual Assault, Alcohol Use, and Risky Sex Among College Women
NCT05910151	Not specified	UNKNOWN	Selective Screening of Children for Hereditary Metabolic Diseases by Tandem Mass Spectrometry in Kazakhstan