FTO

Summary

FTO (FTO alpha-ketoglutarate dependent dioxygenase, HGNC:24678) is a protein-coding gene on chromosome 16q12.2, encoding Alpha-ketoglutarate-dependent dioxygenase FTO (Q9C0B1). RNA demethylase that mediates oxidative demethylation of different RNA species, such as mRNAs, tRNAs and snRNAs, and acts as a regulator of fat mass, adipogenesis and energy homeostasis.

This gene is a nuclear protein of the AlkB related non-haem iron and 2-oxoglutarate-dependent oxygenase superfamily but the exact physiological function of this gene is not known. Other non-heme iron enzymes function to reverse alkylated DNA and RNA damage by oxidative demethylation. Studies in mice and humans indicate a role in nervous and cardiovascular systems and a strong association with body mass index, obesity risk, and type 2 diabetes.

Source: NCBI Gene 79068 — RefSeq curated summary.

At a glance

• Gene–disease (curated): lethal polymalformative syndrome, Boissel type (Strong, GenCC)
• GWAS associations: 338
• Clinical variants (ClinVar): 291 total — 4 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 36
• Druggable target: yes — 18 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001080432

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24678
Approved symbol	FTO
Name	FTO alpha-ketoglutarate dependent dioxygenase
Location	16q12.2
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1752, MGC5149, ALKBH9, IFEX9
Ensembl gene	ENSG00000140718
Ensembl biotype	protein_coding
OMIM	610966
Entrez	79068

Gene structure

Transcript identifiers

Ensembl transcripts: 25 — 15 protein_coding, 5 nonsense_mediated_decay, 5 protein_coding_CDS_not_defined

ENST00000268349, ENST00000431610, ENST00000460382, ENST00000463855, ENST00000464071, ENST00000471389, ENST00000472835, ENST00000563011, ENST00000570395, ENST00000612285, ENST00000635892, ENST00000636030, ENST00000636091, ENST00000636218, ENST00000636491, ENST00000636992, ENST00000637001, ENST00000637049, ENST00000637062, ENST00000637562, ENST00000637845, ENST00000637969, ENST00000918264, ENST00000918265, ENST00000918266

RefSeq mRNA: 12 — MANE Select: NM_001080432 NM_001080432, NM_001363891, NM_001363894, NM_001363896, NM_001363897, NM_001363898, NM_001363899, NM_001363900, NM_001363901, NM_001363903, NM_001363905, NM_001363988

CCDS: CCDS32448

Canonical transcript exons

ENST00000471389 — 9 exons

Exon	Start	End
ENSE00001319762	53825864	53826491
ENSE00001946879	54111762	54121941
ENSE00003480244	53844155	53844298
ENSE00003492841	53933985	53934109
ENSE00003499057	53810140	53810217
ENSE00003523757	53873786	53873865
ENSE00003575733	53879844	53879987
ENSE00003604517	53888832	53888951
ENSE00003793523	53704156	53704229

Expression profiles

Bgee: expression breadth ubiquitous, 294 present calls, max score 97.74.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 40.4805 / max 746.3879, expressed in 1811 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
154099	40.2686	1811
154101	0.1271	15
154106	0.0780	15
154102	0.0069	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	97.74	gold quality
bronchial epithelial cell	CL:0002328	97.66	gold quality
Brodmann (1909) area 10	UBERON:0013541	97.48	gold quality
epithelium of bronchus	UBERON:0002031	97.21	gold quality
middle frontal gyrus	UBERON:0002702	97.07	gold quality
frontal pole	UBERON:0002795	97.00	gold quality
bronchus	UBERON:0002185	96.98	gold quality
substantia nigra pars compacta	UBERON:0001965	96.89	gold quality
prefrontal cortex	UBERON:0000451	96.77	gold quality
corpus callosum	UBERON:0002336	96.77	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	96.74	gold quality
mammary duct	UBERON:0001765	96.68	gold quality
inferior olivary complex	UBERON:0002127	96.60	gold quality
Brodmann (1909) area 46	UBERON:0006483	96.57	gold quality
lateral nuclear group of thalamus	UBERON:0002736	96.50	gold quality
postcentral gyrus	UBERON:0002581	96.46	gold quality
entorhinal cortex	UBERON:0002728	96.43	gold quality
middle temporal gyrus	UBERON:0002771	96.33	gold quality
epithelium of mammary gland	UBERON:0003244	96.32	gold quality
ganglionic eminence	UBERON:0004023	96.28	gold quality
paraflocculus	UBERON:0005351	96.27	gold quality
islet of Langerhans	UBERON:0000006	96.26	gold quality
superior frontal gyrus	UBERON:0002661	96.26	gold quality
orbitofrontal cortex	UBERON:0004167	96.26	gold quality
substantia nigra pars reticulata	UBERON:0001966	96.23	gold quality
parietal lobe	UBERON:0001872	96.22	gold quality
calcaneal tendon	UBERON:0003701	96.09	gold quality
lateral globus pallidus	UBERON:0002476	96.05	gold quality
smooth muscle tissue	UBERON:0001135	96.03	gold quality
olfactory bulb	UBERON:0002264	96.02	silver quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CEBPA, CEBPB, CUX1, FOXA2, STAT3, USF1

miRNA regulators (miRDB)

121 targeting FTO, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4775	99.98	75.00	6394
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-6857-5P	99.87	65.32	985
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-383-3P	99.85	65.84	1359
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-130B-5P	99.83	68.50	1888
HSA-MIR-548AZ-3P	99.82	70.56	3549

Literature-anchored findings (GeneRIF, showing 40)

• A genome-wide search for type 2 diabetes-susceptibility genes identified a common variant in the FTO gene that predisposes to diabetes through an effect on body mass index (PMID:17434869)
• Association with obesity in adult and childre. Interestingly, this association receives clear confirmation under a Transmission Disequilibrium Test design which is robust to population stratification. (PMID:17496892)
• FTO-meediaated weight gain does not predispose individuals to type 1 diabetes as it does for type 2 diabetes. (PMID:17657473)
• common genetic variants in the FTO gene are associated with substantial changes in BMI, hip circumference, and body weight (PMID:17658951)
• Variation in the FTO gene locus is associated with cerebrocortical insulin resistance in humans. (PMID:17917711)
• Our study of the FTO polymorphisms has generated no evidence to support the thrifty genotype hypothesis for Oceanic populations (PMID:17928949)
• Variation in FTO is associated with type 2 diabetes when not adjusted for body mass index and with an overall increase in body fat mass. (PMID:17942823)
• Data do not support that the FTO common variants are major contributors of obesity or type 2 diabetes in a Chinese Han population. (PMID:17959933)
• Amino acid conservation of FTO protein suggests that it is a member of the non-heme dioxygenase superfamily. (PMID:17996046)
• Subcutaneous adipose tissue biopsies were taken for fat cell metabolism studies and FTO genotype analysis (PMID:18048838)
• SNP rs1421085 has a MAF of 0.41 and rs9939609 of 0.40 in our control population and the calculated ORs are 1.31 and 1.28, respectively (PMID:18055244)
• common variability in FTO is associated with increased obesity risk or resistance and may in part account for differences between closely related individuals (PMID:18218107)
• BMI increases associated with FTO genotypes begin in youth and are maintained throughout adulthood (PMID:18239580)
• This study suggests that FTO may have an important role for gender specific development of severe obesity and insulin resistance in children. (PMID:18249188)
• Expression of adipose tissue FTO mRNA is fat depot-specific and negatively correlates with measures of obesity. (PMID:18251005)
• a role of the common rs9939609 SNP in FTO gene in the early stages of fat accretion in humans and disclose novel associations between this SNP and both serum visfatin and abdominal fat mass in neonates. (PMID:18252780)
• Discuss Fto/Ftm gene expression regulation via CUTL1. (PMID:18256137)
• revuew of genomic analyses of FTO in adipocytes and obesity-related genetic variation (PMID:18281390)
• Genetic variation at the FTO locus contributes to the etiology of obesity, insulin resistance, and increased plasma leptin levels. (PMID:18316358)
• variants in the FTO gene confer a similar magnitude of risk of obesity to children as to their adult counterparts and appear to have a global impact (PMID:18335027)
• Neither our parental comparisons nor the use of FTO genotype as an instrumental variable, suggest that greater maternal BMI during offspring development has a marked effect on offspring fat mass at age 9-11 y. (PMID:18336062)
• FTO rs9939609 SNP was associated with an increased risk for metabolic syndrome in a multi-ethnic sample. (PMID:18339204)
• FTO genotype is associated with metabolic traits to an extent entirely consistent with its effect on body mass index. (PMID:18346983)
• Increased BMI in morbid obesity is associated with a combination of FTO and INSIG2 SNPs. (PMID:18347269)
• 15 SNPs, including rs9939609 and rs1121980, in a linkage disequilibrium (LD) block of approximately 50 kb demonstrated significant associations with obesity (PMID:18379722)
• FTO is a common obesity susceptibility gene in Filipinos, with an effect size similar to that seen in samples of European origin. (PMID:18426866)
• The AA-genotype of FTO rs9939609 had higher resting energy expenditure in the age-adjusted model, but the association was eliminated when adjusting for fat mass and lean body mass. (PMID:18445669)
• The predominant effect of FTO variants on polycystic ovary syndrome susceptibility is probably mediated through adiposity (PMID:18478198)
• Genetic variation in the FTO gene is strongly associated with obesity and BMI in the Chinese population. (PMID:18487448)
• During lifestyle intervention, there was also no influence of the FTO polymorphism on changes in body weight or fat distribution. (PMID:18535549)
• FTO genotype probably affects obesity via effects on food intake rather than energy expenditure. (PMID:18551109)
• Two SNPs in the FTO gene (rs1421085 and rs17817449) were genotyped using the TaqMan method in a Korean population (n = 1,733). The two SNPs were then used for an association study with BMI through statistical analyses. (PMID:18551112)
• FTO is a strong influential gene in polycystic ovary syndrome and correlated to various components of MetS including obesity, IFG, glucose intolerance and insulin resistance. (PMID:18572014)
• The commonest known risk allele for obesity is likely to exert at least some of its effects by influencing appetite. (PMID:18583465)
• FTO SNPs revealed a significant association with type 2 diabetes (PMID:18598350)
• Data show that FTO single nucleotide polymorphisms are associated with obesity in the Chinese and Malay populations in Singapore. (PMID:18599522)
• There is an association of FTO gene variants with obesity, including parameters of visceral (abdominal) obesity, in the adult general population from Spain. (PMID:18616701)
• Data show that the association between FTO SNP rs9939609 and obesity risk may decline at older age. The variant affects circulating adiponectin and leptin levels through the changes in BMI. (PMID:18647953)
• Fatness induced by FTO rs9939609 in early childhood is sustained until early adulthood, where further weight gain may occur. FTO rs9939609 may, however, also be associated with linear growth and LBM mainly through the effect on fat mass (PMID:18663371)
• Study show that polymorphisms in FTO were associated with type 2 diabetes risk in the studied population. (PMID:18694974)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	fto	ENSDARG00000044216
mus_musculus	Fto	ENSMUSG00000055932
rattus_norvegicus	Fto	ENSRNOG00000011728

Protein

Protein identifiers

Alpha-ketoglutarate-dependent dioxygenase FTO — Q9C0B1 (reviewed: Q9C0B1)

Alternative names: Fat mass and obesity-associated protein, U6 small nuclear RNA (2’-O-methyladenosine-N(6)-)-demethylase FTO, U6 small nuclear RNA N(6)-methyladenosine-demethylase FTO, mRNA (2’-O-methyladenosine-N(6)-)-demethylase FTO, mRNA N(6)-methyladenosine demethylase FTO, tRNA N1-methyl adenine demethylase FTO

All UniProt accessions (14): Q9C0B1, A0A1B0GTC3, A0A1B0GTC5, A0A1B0GTI3, A0A1B0GTY1, A0A1B0GTY5, A0A1B0GTZ8, A0A1B0GU26, A0A1B0GUC3, A0A1B0GUY7, A0A1B0GV98, A0A1B0GVH5, F8WCB8, X6R3I0

UniProt curated annotations — full annotation on UniProt →

Function. RNA demethylase that mediates oxidative demethylation of different RNA species, such as mRNAs, tRNAs and snRNAs, and acts as a regulator of fat mass, adipogenesis and energy homeostasis. Specifically demethylates N(6)-methyladenosine (m6A) RNA, the most prevalent internal modification of messenger RNA (mRNA) in higher eukaryotes. M6A demethylation by FTO affects mRNA expression and stability. Also able to demethylate m6A in U6 small nuclear RNA (snRNA). Mediates demethylation of N(6),2’-O-dimethyladenosine cap (m6A(m)), by demethylating the N(6)-methyladenosine at the second transcribed position of mRNAs and U6 snRNA. Demethylation of m6A(m) in the 5’-cap by FTO affects mRNA stability by promoting susceptibility to decapping. Also acts as a tRNA demethylase by removing N(1)-methyladenine from various tRNAs. Has no activity towards 1-methylguanine. Has no detectable activity towards double-stranded DNA. Also able to repair alkylated DNA and RNA by oxidative demethylation: demethylates single-stranded RNA containing 3-methyluracil, single-stranded DNA containing 3-methylthymine and has low demethylase activity towards single-stranded DNA containing 1-methyladenine or 3-methylcytosine. Ability to repair alkylated DNA and RNA is however unsure in vivo. Involved in the regulation of fat mass, adipogenesis and body weight, thereby contributing to the regulation of body size and body fat accumulation. Involved in the regulation of thermogenesis and the control of adipocyte differentiation into brown or white fat cells. Regulates activity of the dopaminergic midbrain circuitry via its ability to demethylate m6A in mRNAs. Plays an oncogenic role in a number of acute myeloid leukemias by enhancing leukemic oncogene-mediated cell transformation: acts by mediating m6A demethylation of target transcripts such as MYC, CEBPA, ASB2 and RARA, leading to promote their expression.

Subunit / interactions. Monomer. May also exist as homodimer.

Subcellular location. Nucleus. Nucleus speckle. Cytoplasm.

Tissue specificity. Ubiquitously expressed, with relatively high expression in adrenal glands and brain; especially in hypothalamus and pituitary. Highly expressed in highly expressed in acute myeloid leukemias (AML) with t(11;11)(q23;23) with KMT2A/MLL1 rearrangements, t(15;17)(q21;q21)/PML-RARA, FLT3-ITD, and/or NPM1 mutations.

Disease relevance. Growth retardation, developmental delay, and facial dysmorphism (GDFD) [MIM:612938] A severe polymalformation syndrome characterized by postnatal growth retardation, microcephaly, severe psychomotor delay, functional brain deficits and characteristic facial dysmorphism. In some patients, structural brain malformations, cardiac defects, genital anomalies, and cleft palate are observed. Early death occurs by the age of 3 years. The disease is caused by variants affecting the gene represented in this entry. Obesity (OBESITY) [MIM:601665] A condition characterized by an increase of body weight beyond the limitation of skeletal and physical requirements, as the result of excessive accumulation of body fat. Disease susceptibility is associated with variants affecting the gene represented in this entry. It is unclear whether variations associated with obesity directly affect FTO function or alter the expression of adjacent genes such as IRX3, rather than FTO itself. A pathogenic intronic FTO variation (rs1421085) disrupts an evolutionarily conserved motif for ARID5B binding. Loss of ARID5B binding results in overexpression of two genes distal to FTO, IRX3 and IRX5. IRX3 and IRX5 overexpression shifts pre-adipocytes differentiation from brown to white fat cells, resulting in increased lipid storage and loss of mitochondrial thermogenesis.

Activity regulation. Activated by ascorbate. Inhibited by N-oxalylglycine, fumarate and succinate. RNA N(6)-methyladenosine demethylase activity is inhibited by fluorescein derivatives. RNA N(6)-methyladenosine demethylase activity is selectively inhibited by meclofenamic acid; inhibition is specific to FTO and meclofenamic acid does not inhibit ALKBH5. Specifically inhibited by R-2-hydroxyglutarate (R-2HG), an oncometabolite that also exerts a broad antileukemic activity. Inhibition by R-2HG leads to increased level of N(6)-methyladenosine-containing transcripts, leading to down-regulate expression of MYC and CEBPA transcripts.

Cofactor. Binds 1 Fe(2+) ion per subunit.

Domain organisation. The 3D-structure of the Fe2OG dioxygenase domain is similar to that of the Fe2OG dioxygenase domain found in the bacterial DNA repair dioxygenase alkB and its mammalian orthologs, but sequence similarity is very low. As a consequence, the domain is not detected by protein signature databases.

Polymorphism. Genetic variations at the FTO locus define the body mass index quantitative trait locus 14 (BMIQ14) [MIM:612460]. Variance in body mass index is a susceptibility factor for obesity.

Similarity. Belongs to the fto family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q9C0B1-1	1	yes
Q9C0B1-2	2
Q9C0B1-3	3
Q9C0B1-4	4

RefSeq proteins (12): NP_001073901, NP_001350820, NP_001350823, NP_001350825, NP_001350826, NP_001350827, NP_001350828, NP_001350829, NP_001350830, NP_001350832, NP_001350834, NP_001350917 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR024366	FTO_C	Domain
IPR024367	FTO_cat_dom	Domain
IPR032868	FTO	Family
IPR037151	AlkB-like_sf	Homologous_superfamily
IPR038413	FTO_C_sf	Homologous_superfamily

Pfam: PF12933, PF12934

Enzyme classification (BRENDA):

• EC 1.14.11.53 — mRNA N6-methyladenine demethylase (BRENDA: 6 organisms, 33 substrates, 22 inhibitors, 11 Km, 10 kcat entries)

Substrate kinetics (BRENDA)

9 substrates with measured Km, best-characterized 9. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
N3-METHYLTHYMINE IN SINGLE-STRANDED DNA	0.0009–0.0019	2
N3-METHYLURACIL IN SINGLE-STRANDED MRNA	0.0021–0.0085	2
2-OXOGLUTARATE	0.0025	1
5’-UACACUCGAUCUGG(M6A)CUAAAGCUGCUC-3’-BIOTIN	0.0002	1
CCCC(M6A)CCCCCCCCC	2.583	1
GA(M6A)CA	2.251	1
GCGG(M6A)CUCCAGAUG	1.755	1
GG(M6A)CU	2.334	1
N6-METHYLADENINE IN MRNA	0.0017	1

Catalyzed reactions (Rhea), 5 shown:

• an N(6)-methyladenosine in mRNA + 2-oxoglutarate + O2 = an adenosine in mRNA + formaldehyde + succinate + CO2 (RHEA:49520)
• an N(1)-methyladenosine in tRNA + 2-oxoglutarate + O2 = an adenosine in tRNA + formaldehyde + succinate + CO2 (RHEA:54576)
• a 5’-end (N(7)-methyl 5’-triphosphoguanosine)-(N(6),2’-O-dimethyladenosine) in mRNA + 2-oxoglutarate + O2 = a 5’-end (N(7)-methyl 5’-triphosphoguanosine)-(2’-O-methyladenosine) in mRNA + formaldehyde + succinate + CO2 (RHEA:57896)
• N(6)-methyladenosine in U6 snRNA + 2-oxoglutarate + O2 = adenosine in U6 snRNA + formaldehyde + succinate + CO2 (RHEA:57900)
• a 5’-end (N(7)-methyl 5’-triphosphoguanosine)-(N(6),2’-O-dimethyladenosine) in U6 snRNA + 2-oxoglutarate + O2 = a 5’-end (N(7)-methyl 5’-triphosphoguanosine)-(2’-O-methyladenosine) in U6 snRNA + formaldehyde + succinate + CO2 (RHEA:57904)

UniProt features (71 total): strand 21, helix 15, binding site 11, mutagenesis site 6, splice variant 5, sequence variant 5, region of interest 2, modified residue 2, turn 2, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

28 structures.

PDB	Method	Resolution (Å)
4IE5	X-RAY DIFFRACTION	1.95
5DAB	X-RAY DIFFRACTION	2.1
8IT9	X-RAY DIFFRACTION	2.14
4ZS2	X-RAY DIFFRACTION	2.16
4QKN	X-RAY DIFFRACTION	2.2
5F8P	X-RAY DIFFRACTION	2.2
6AKW	X-RAY DIFFRACTION	2.2
7WCV	X-RAY DIFFRACTION	2.3
9VG4	X-RAY DIFFRACTION	2.3
7CKK	X-RAY DIFFRACTION	2.35
4QHO	X-RAY DIFFRACTION	2.37
4ZS3	X-RAY DIFFRACTION	2.45
4IDZ	X-RAY DIFFRACTION	2.46
3LFM	X-RAY DIFFRACTION	2.5
4IE6	X-RAY DIFFRACTION	2.5
4IE4	X-RAY DIFFRACTION	2.5
4IE0	X-RAY DIFFRACTION	2.53
7E8Z	X-RAY DIFFRACTION	2.55
4IE7	X-RAY DIFFRACTION	2.6
9KNI	X-RAY DIFFRACTION	2.63
4CXY	X-RAY DIFFRACTION	2.65
4CXX	X-RAY DIFFRACTION	2.76
6AEJ	X-RAY DIFFRACTION	2.8
6AK4	X-RAY DIFFRACTION	2.8
9KNH	X-RAY DIFFRACTION	2.9
9OHS	X-RAY DIFFRACTION	3.07
4CXW	X-RAY DIFFRACTION	3.1
5ZMD	X-RAY DIFFRACTION	3.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9C0B1-F1	91.33	0.80

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 (11): 307; 316–318; 320; 322; 96; 108; 205; 231–234; 231; 233; 295

Post-translational modifications (2): 4, 216

Mutagenesis-validated functional residues (6):

Position	Phenotype
96	almost abolishes enzyme activity.
108	abolishes enzyme activity.
114	perturbs interaction between n-terminal and c-terminal domains and strongly reduces enzyme activity.
231–233	abolishes ability to demethylate n(6)-methyladenosine rnas (m6a) rnas.
234	abolishes enzyme activity. abolishes ability to demethylate n(6)-methyladenosine rnas (m6a) rnas; when associated with q
392	perturbs interaction between n-terminal and c-terminal domains and strongly reduces enzyme activity.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-73943	Reversal of alkylation damage by DNA dioxygenases

MSigDB gene sets: 0 (showing top):

GO Biological Process (11): temperature homeostasis (GO:0001659), DNA alkylation repair (GO:0006307), regulation of lipid storage (GO:0010883), snRNA processing (GO:0016180), regulation of multicellular organism growth (GO:0040014), RNA repair (GO:0042245), regulation of respiratory system process (GO:0044065), adipose tissue development (GO:0060612), mRNA destabilization (GO:0061157), regulation of white fat cell proliferation (GO:0070350), regulation of brown fat cell differentiation (GO:0090335)

GO Molecular Function (11): ferrous iron binding (GO:0008198), transferase activity (GO:0016740), oxidative RNA demethylase activity (GO:0035515), broad specificity oxidative DNA demethylase activity (GO:0035516), mRNA N6-methyladenosine dioxygenase activity (GO:1990931), tRNA demethylase activity (GO:1990984), protein binding (GO:0005515), oxidoreductase activity (GO:0016491), 2-oxoglutarate-dependent dioxygenase activity (GO:0016706), metal ion binding (GO:0046872), dioxygenase activity (GO:0051213)

GO Cellular Component (5): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), nuclear speck (GO:0016607)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
DNA Damage Reversal	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
catalytic activity	2
2-oxoglutarate-dependent dioxygenase activity	2
oxidative RNA demethylase activity	2
multicellular organismal-level homeostasis	1
DNA repair	1
lipid storage	1
regulation of cellular process	1
RNA processing	1
snRNA metabolic process	1
multicellular organism growth	1
regulation of developmental growth	1
regulation of multicellular organismal process	1
RNA metabolic process	1
respiratory system process	1
regulation of respiratory gaseous exchange	1
regulation of system process	1
animal organ development	1
connective tissue development	1
negative regulation of gene expression	1
regulation of mRNA stability	1
RNA destabilization	1
positive regulation of mRNA catabolic process	1
white fat cell proliferation	1
regulation of fat cell proliferation	1
regulation of fat cell differentiation	1
brown fat cell differentiation	1
iron ion binding	1
demethylase activity	1
catalytic activity, acting on RNA	1
DNA demethylase activity	1
catalytic activity, acting on a tRNA	1
binding	1
oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen	1
dioxygenase activity	1
cation binding	1
oxidoreductase activity	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

2334 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FTO	ALKBH5	Q6P6C2	969
FTO	ALKBH1	Q13686	959
FTO	MC4R	P32245	945
FTO	METTL14	Q9HCE5	939
FTO	WTAP	Q15007	914
FTO	IGF2BP2	Q9Y6M1	914
FTO	TMEM18	Q96B42	905
FTO	METTL3	Q86U44	900
FTO	YTHDF1	Q9BYJ9	897
FTO	YTHDF2	Q9Y5A9	890
FTO	YTHDC1	Q96MU7	886
FTO	YTHDF3	Q7Z739	881
FTO	GNPDA2	Q8TDQ7	880
FTO	VIRMA	Q69YN4	880
FTO	CDKAL1	Q5VV42	868

IntAct

59 interactions, top by confidence:

A	B	Type	Score
GPX7	GAK	psi-mi:“MI:0914”(association)	0.640
GNG8	GNB5	psi-mi:“MI:0914”(association)	0.640
ZNF576	ZBED1	psi-mi:“MI:0914”(association)	0.640
OR5F1	UBA6	psi-mi:“MI:0914”(association)	0.530
FSD1	UBFD1	psi-mi:“MI:0914”(association)	0.530
DIRAS2	UNC13B	psi-mi:“MI:0914”(association)	0.530
ALX3	CRTAP	psi-mi:“MI:0914”(association)	0.530
ZMAT3	ACTA2	psi-mi:“MI:0914”(association)	0.530
GNG2	GNB5	psi-mi:“MI:0914”(association)	0.530
SLC2A5	LPGAT1	psi-mi:“MI:0914”(association)	0.530
MPHOSPH6	ZFC3H1	psi-mi:“MI:0914”(association)	0.530
PRNP	CARNS1	psi-mi:“MI:0914”(association)	0.350
PRNP	WDR91	psi-mi:“MI:0914”(association)	0.350
SDC1	ARVCF	psi-mi:“MI:0914”(association)	0.350
FGB	NME2	psi-mi:“MI:0914”(association)	0.350
TYW3	KIF2A	psi-mi:“MI:0914”(association)	0.350
ZNF232	ZNF197	psi-mi:“MI:0914”(association)	0.350
NFYA	NME2P1	psi-mi:“MI:0914”(association)	0.350
MPZL1	ALDH1A2	psi-mi:“MI:0914”(association)	0.350
SLX4	SMAP	psi-mi:“MI:0914”(association)	0.350
GABARAPL2		psi-mi:“MI:0914”(association)	0.350
SPANXN4	UBA6	psi-mi:“MI:0914”(association)	0.350
C19orf25	NBAS	psi-mi:“MI:0914”(association)	0.350
GNG8	POTEF	psi-mi:“MI:0914”(association)	0.350

BioGRID (103): FTO (Affinity Capture-MS), FTO (Proximity Label-MS), FTO (Affinity Capture-MS), FTO (Affinity Capture-MS), FTO (Affinity Capture-MS), FTO (Affinity Capture-MS), FTO (Affinity Capture-MS), FTO (Affinity Capture-MS), FTO (Affinity Capture-MS), FTO (Affinity Capture-MS), FTO (Affinity Capture-MS), FTO (Affinity Capture-MS), FTO (Affinity Capture-MS), FTO (Affinity Capture-MS), FTO (Affinity Capture-MS)

ESM2 similar proteins: A2A9C3, A2RRP1, A4FUC0, F1PLN3, O75153, O76024, O88480, P03271, P03272, P03273, P12539, P12540, P48752, P56695, P82649, P82650, P82918, P82924, P83565, Q1T765, Q1XHY1, Q32LL9, Q5EA18, Q5R7X0, Q5SW19, Q5T011, Q5TM62, Q5U2W4, Q5ZI69, Q5ZKP2, Q6AXT0, Q6AXZ5, Q6DIK0, Q6GLY5, Q6NUV0, Q767K8, Q80UJ7, Q8BGW1, Q8QZV7, Q8VE18

Diamond homologs: F1PLN3, Q2A121, Q5R7X0, Q68F54, Q8BGW1, Q9C0B1

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
CEBPA	“up-regulates quantity by expression”	FTO	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	2
Uncertain significance	166
Likely benign	68
Benign	33

Top pathogenic / likely-pathogenic (6)

Variant ID	HGVS	Classification
208336	NM_001080432.3(FTO):c.956C>T (p.Ser319Phe)	Pathogenic
2426110	NC_000016.9:g.(?53635988)(55539614_?)del	Pathogenic
4279296	GRCh37/hg19 16q12.2(chr16:53707345-53771635)x1	Pathogenic
686175	GRCh37/hg19 16q12.2(chr16:53789151-54049153)x1	Pathogenic
1055	NM_001080432.3(FTO):c.947G>A (p.Arg316Gln)	Likely pathogenic
3065660	NM_001080432.3(FTO):c.124-1G>A	Likely pathogenic

SpliceAI

5700 predictions. Top by Δscore:

Variant	Effect	Δscore
16:53810134:A:AG	acceptor_gain	1.0000
16:53810135:A:G	acceptor_gain	1.0000
16:53810137:CA:C	acceptor_loss	1.0000
16:53810138:A:AG	acceptor_gain	1.0000
16:53810138:A:C	acceptor_loss	1.0000
16:53810139:G:GA	acceptor_gain	1.0000
16:53810139:GA:G	acceptor_gain	1.0000
16:53810139:GAA:G	acceptor_gain	1.0000
16:53810139:GAAA:G	acceptor_gain	1.0000
16:53810139:GAAAC:G	acceptor_gain	1.0000
16:53810214:GCAG:G	donor_gain	1.0000
16:53810215:CAG:C	donor_loss	1.0000
16:53810216:AG:A	donor_loss	1.0000
16:53810217:GGTA:G	donor_loss	1.0000
16:53825862:A:AG	acceptor_gain	1.0000
16:53825863:G:GG	acceptor_gain	1.0000
16:53844151:GCA:G	acceptor_loss	1.0000
16:53844152:CA:C	acceptor_loss	1.0000
16:53844153:A:AG	acceptor_gain	1.0000
16:53844153:AGG:A	acceptor_loss	1.0000
16:53844154:G:GA	acceptor_gain	1.0000
16:53844278:G:GT	donor_gain	1.0000
16:53873769:T:A	acceptor_gain	1.0000
16:53873780:CTGTA:C	acceptor_loss	1.0000
16:53873781:TGTAG:T	acceptor_loss	1.0000
16:53873782:GTAG:G	acceptor_loss	1.0000
16:53873783:TAGA:T	acceptor_loss	1.0000
16:53873784:A:AT	acceptor_loss	1.0000
16:53873784:AGAT:A	acceptor_gain	1.0000
16:53873785:GAT:G	acceptor_gain	1.0000

AlphaMissense

3335 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:53826428:T:A	W230R	1.000
16:53826428:T:C	W230R	1.000
16:53826430:G:C	W230C	1.000
16:53826430:G:T	W230C	1.000
16:53826355:T:A	N205K	0.999
16:53826355:T:G	N205K	0.999
16:53826429:G:C	W230S	0.999
16:53826431:C:G	H231D	0.999
16:53844211:T:A	W270R	0.999
16:53844211:T:C	W270R	0.999
16:53844226:A:G	K275E	0.999
16:53844228:G:C	K275N	0.999
16:53844228:G:T	K275N	0.999
16:53844235:T:A	W278R	0.999
16:53844235:T:C	W278R	0.999
16:53844237:G:C	W278C	0.999
16:53844237:G:T	W278C	0.999
16:53844254:G:A	G284D	0.999
16:53873814:T:G	C308W	0.999
16:53873816:T:A	V309D	0.999
16:53873842:A:C	S318R	0.999
16:53873844:T:A	S318R	0.999
16:53873844:T:G	S318R	0.999
16:53810206:T:C	F38L	0.998
16:53810208:C:A	F38L	0.998
16:53810208:C:G	F38L	0.998
16:53844218:T:A	V272D	0.998
16:53844221:G:A	G273D	0.998
16:53844257:T:C	L285S	0.998
16:53873803:C:G	H305D	0.998

dbSNP variants (sampled 300 via entrez): RS1000004866 (16:53702021 T>C), RS1000015611 (16:53768525 GC>G), RS1000021640 (16:53911105 T>C), RS1000029007 (16:54016002 G>T), RS1000034301 (16:53869989 A>G), RS1000036692 (16:53797388 C>T), RS1000042063 (16:53713589 C>A), RS1000066793 (16:53883359 C>T), RS1000067379 (16:53970349 G>A), RS1000071412 (16:53928082 G>A), RS1000085288 (16:54011046 G>A), RS1000101262 (16:53893049 G>T), RS1000119526 (16:53958587 A>C,T), RS1000129519 (16:53964473 A>G), RS1000129859 (16:53884471 T>C)

Disease associations

OMIM: gene MIM:610966 | disease phenotypes: MIM:612938, MIM:156000, MIM:213300, MIM:249000

GenCC curated gene-disease

Disease	Classification	Inheritance
lethal polymalformative syndrome, Boissel type	Strong	Autosomal recessive

Mondo (4): lethal polymalformative syndrome, Boissel type (MONDO:0013050), Meniere disease (MONDO:0007972), Joubert syndrome (MONDO:0018772), Meckel syndrome (MONDO:0018921)

Orphanet (4): Lethal polymalformative syndrome, Boissel type (Orphanet:210144), Isolated Joubert syndrome (Orphanet:475), Meckel syndrome (Orphanet:564), NON RARE IN EUROPE: Menière disease (Orphanet:45360)

HPO phenotypes

36 total (30 of 36 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000175	Cleft palate
HP:0000193	Bifid uvula
HP:0000233	Thin vermilion border
HP:0000238	Hydrocephalus
HP:0000278	Retrognathia
HP:0000280	Coarse facial features
HP:0000407	Sensorineural hearing impairment
HP:0000463	Anteverted nares
HP:0000470	Short neck
HP:0000965	Cutis marmorata
HP:0001156	Brachydactyly
HP:0001250	Seizure
HP:0001276	Hypertonia
HP:0001305	Dandy-Walker malformation
HP:0001339	Lissencephaly
HP:0001508	Failure to thrive
HP:0001511	Intrauterine growth retardation
HP:0001513	Obesity
HP:0001537	Umbilical hernia
HP:0001612	Weak cry
HP:0001629	Ventricular septal defect
HP:0001639	Hypertrophic cardiomyopathy
HP:0001643	Patent ductus arteriosus
HP:0001800	Hypoplastic toenails
HP:0002678	Skull asymmetry
HP:0003577	Congenital onset
HP:0003819	Death in childhood
HP:0005484	Secondary microcephaly

GWAS associations

338 associations (top):

Study	Trait	p-value
GCST000022_1	Body mass index	3.000000e-35
GCST000024_4	Type 2 diabetes	1.000000e-12
GCST000025_9	Type 2 diabetes	7.000000e-14
GCST000047_5	Type 2 diabetes	2.000000e-07
GCST000060_1	Obesity-related traits	3.000000e-08
GCST000060_2	Obesity-related traits	9.000000e-07
GCST000060_3	Obesity-related traits	9.000000e-07
GCST000129_1	Obesity (early onset extreme)	1.000000e-07
GCST000167_15	Type 2 diabetes	7.000000e-06
GCST000185_1	Body mass index	4.000000e-08
GCST000277_3	Type 2 diabetes	2.000000e-17
GCST000296_3	Body mass index	4.000000e-13
GCST000296_5	Body mass index	1.000000e-47
GCST000298_5	Body mass index	4.000000e-51
GCST000299_7	Weight	5.000000e-36
GCST000299_8	Weight	6.000000e-14
GCST000317_2	Obesity	1.000000e-28
GCST000317_3	Obesity	7.000000e-18
GCST000317_4	Obesity	5.000000e-13
GCST000381_5	Biomedical quantitative traits	2.000000e-07
GCST000426_6	Obesity (extreme)	6.000000e-12
GCST000427_7	Waist circumference	5.000000e-19
GCST000663_2	Obesity (early onset extreme)	5.000000e-19
GCST000712_13	Type 2 diabetes	3.000000e-08
GCST000830_24	Body mass index	5.000000e-120
GCST000850_1	Body mass in chronic obstructive pulmonary disease	4.000000e-08
GCST000880_10	Menarche (age at onset)	3.000000e-08
GCST001046_1	Obesity	1.000000e-07
GCST001057_10	Obesity	2.000000e-12
GCST001128_3	Adiposity	3.000000e-26

EFO canonical traits (63, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0004343	waist-hip ratio
EFO:0004338	body weight
EFO:0004703	age at menarche
EFO:0000195	metabolic syndrome
EFO:0004696	sex hormone-binding globulin measurement
EFO:0003939	energy intake
EFO:0004530	triglyceride measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0005851	height-adjusted body mass index
EFO:0007119	Sasang constitutional medicine type
EFO:0007123	So-Eum
EFO:0005937	longitudinal BMI measurement
EFO:0005000	leptin measurement
EFO:0007800	body fat percentage
EFO:0004458	C-reactive protein measurement
EFO:0004318	smoking behavior
EFO:0008002	physical activity measurement
EFO:0004995	lean body mass
EFO:0006941	grip strength measurement
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0004329	alcohol drinking
EFO:0006340	mean arterial pressure
EFO:0005763	pulse pressure measurement
EFO:0006336	diastolic blood pressure
EFO:0006527	smoking status measurement
EFO:0006335	systolic blood pressure
EFO:0009270	heel bone mineral density
EFO:0004653	response to TNF antagonist

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008575	Meniere Disease	C09.218.568.217.500
C567856	Growth Retardation, Developmental Delay, Coarse Facies, And Early Death (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2331065 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

18 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 678,992 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1057	FLUORESCEIN	4	329,940
CHEMBL1591	DEMECLOCYCLINE	4	20,295
CHEMBL2338329	ROXADUSTAT	4	1,063
CHEMBL509	MECLOFENAMIC ACID	4	45,809
CHEMBL945	AMILORIDE	4	63,705
CHEMBL95	TACRINE	4	35,360
CHEMBL953	ENTACAPONE	4	16,791
CHEMBL3989553	NAFAMOSTAT MESYLATE	3	390
CHEMBL41286	DIACEREIN	3	5,090
CHEMBL428676	AMONAFIDE	3	8,237
CHEMBL50	QUERCETIN	3	74,559
CHEMBL1370446	METIZOLINE	2	443
CHEMBL151	LUTEOLIN	2	23,523
CHEMBL239800	FENOBAM ANHYDROUS	2	2,850
CHEMBL31574	FISETIN	2	7,745
CHEMBL43482	MITONAFIDE	2	8,660
CHEMBL8260	BAICALEIN	2	8,592
CHEMBL150	KAEMPFEROL	1	25,940

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

PharmGKB clinical annotations

7 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs12595985	Toxicity	3	atenolol	Hypertension
rs16952570	Toxicity	3	mercaptopurine	Crohn Disease;Irritable Bowel Syndrome;Leukopenia;Neutropenia;Ulcerative Colitis
rs16952570	Toxicity	3	azathioprine	Crohn Disease;Irritable Bowel Syndrome;Leukopenia;Neutropenia;Ulcerative Colitis
rs79206939	Toxicity	3	azathioprine;mercaptopurine	Irritable Bowel Syndrome;Leukopenia
rs9937709	Toxicity	3	ethanol	Alcohol abuse
rs9939609	Efficacy	3	interferon alfa-2a;recombinant;interferon alfa-2b;recombinant;ribavirin	Chronic hepatitis C virus infection;HIV infectious disease
rs9940629	Toxicity	3	atenolol	Hypertension

PharmGKB variants

16 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1121980	FTO		0.00	0
rs1421085	FTO		0.00	0
rs4784333	FTO		0.00	0
rs6499640	FTO		0.00	0
rs8050136	FTO		0.00	0
rs9930506	FTO		0.00	0
rs9939609	FTO	3	2.00	1	interferon alfa-2a;recombinant;interferon alfa-2b;recombinant;ribavirin
rs9940629	FTO	3	1.50	1	atenolol
rs12595985	FTO	3	1.50	1	atenolol
rs79206939	FTO	3	3.75	1	azathioprine;mercaptopurine
rs16952570	FTO	3	4.00	2	azathioprine;mercaptopurine
rs17817449	FTO		0.00	0
rs9937709	FTO	3	1.50	1	ethanol
rs11075995	FTO		0.00	0
rs12596638	FTO		0.00	0
rs1125338	FTO		0.00	0

ChEMBL bioactivities

246 potent at pChembl≥5 of 342 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.55	Kd	28	nM	CHEMBL5196484
7.50	IC50	31.4	nM	CHEMBL6170540
7.22	IC50	60	nM	CHEMBL4572939
7.16	IC50	70	nM	CHEMBL5195767
7.10	IC50	80	nM	CHEMBL5219846
7.06	IC50	87	nM	CHEMBL5196484
6.96	IC50	110	nM	CHEMBL5200892
6.92	IC50	120	nM	CHEMBL5410889
6.80	IC50	160	nM	CHEMBL5207866
6.75	IC50	180	nM	CHEMBL6177289
6.70	IC50	200	nM	CHEMBL5174419
6.57	IC50	270	nM	CHEMBL5194680
6.57	IC50	270	nM	CHEMBL6169482
6.50	IC50	320	nM	CHEMBL6174327
6.48	IC50	330	nM	CHEMBL5220094
6.47	Kd	340	nM	CHEMBL5219846
6.47	IC50	340	nM	CHEMBL465179
6.46	IC50	350	nM	CHEMBL5204291
6.46	IC50	350	nM	CHEMBL5207797
6.42	IC50	380	nM	CHEMBL6177637
6.40	IC50	400	nM	CHEMBL4532629
6.40	IC50	400	nM	CHEMBL4572939
6.40	IC50	400	nM	CHEMBL5596599
6.37	IC50	430	nM	CHEMBL5219336
6.36	IC50	440	nM	CHEMBL5203668
6.35	IC50	450	nM	CHEMBL6170540
6.34	IC50	460	nM	CHEMBL6142158
6.31	IC50	490	nM	CHEMBL5275957
6.30	IC50	500	nM	CHEMBL4563561
6.30	IC50	500	nM	CHEMBL4461072
6.26	IC50	550	nM	CHEMBL6171910
6.24	IC50	570	nM	CHEMBL5183243
6.23	IC50	590	nM	CHEMBL6167443
6.22	IC50	600	nM	CHEMBL5176527
6.19	IC50	640	nM	CHEMBL1253979
6.17	IC50	670	nM	CHEMBL5186890
6.17	Kd	670	nM	CHEMBL5219336
6.17	IC50	680	nM	CHEMBL6176270
6.16	IC50	700	nM	CHEMBL4563024
6.16	IC50	700	nM	CHEMBL5176730
6.16	IC50	700	nM	CHEMBL4435048
6.16	IC50	700	nM	CHEMBL4870546
6.12	IC50	750	nM	CHEMBL5268705
6.12	IC50	760	nM	CHEMBL6167225
6.11	IC50	780	nM	CHEMBL5597797
6.11	IC50	770	nM	CHEMBL6167220
6.11	IC50	780	nM	CHEMBL6174917
6.11	IC50	770	nM	CHEMBL6176582
6.10	IC50	800	nM	CHEMBL5220148
6.10	IC50	800	nM	CHEMBL5397077

PubChem BioAssay actives

168 with measured affinity, of 438 total; 50 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
(E)-4-[2-[4-[3,5-dichloro-2-methyl-4-(2-nitroanilino)anilino]pyridine-3-carbonyl]hydrazinyl]-4-oxobut-2-enoic acid	1876796: Binding affinity to FTO (unknown origin) assessed as dissociation constant at 180 uM by isothermal titration calorimetry assay	kd	0.0280	uM
2-[2,6-dichloro-4-(3,5-dimethyl-1,2-oxazol-4-yl)anilino]benzoic acid	1926070: Inhibition of FTO (unknown origin) demethylation activity using m6A7-Broccoli RNA as substrate incubated for 3 mins under shaking condition and measured after 2 hrs by fluorescence based analysis	ic50	0.0600	uM
1-(5-phenylfuran-2-yl)-N-[(3-pyrrolidin-1-yloxetan-3-yl)methyl]methanamine	1886504: Inhibition of recombinant FTO (unknown origin) using m6A Broccoli as substrate incubated for 2 hrs	ic50	0.0700	uM
2-[[3-hydroxy-6-(4-nitroanilino)pyridine-2-carbonyl]amino]acetic acid	1916581: Inhibition of recombinant full length N-terminal hexahistidine-tagged human FTO expressed in Escherichia coli BL21 (DE3) incubated for 10 mins using 15-mer ssRNA oligonucleotide [AUUGUGG(m6A)-CUGCAGC as substrate by SPE-MS-based assay	ic50	0.0800	uM
1-(5-fluoro-1H-indol-3-yl)-N-[(3-pyrrolidin-1-yloxetan-3-yl)methyl]methanamine	1886504: Inhibition of recombinant FTO (unknown origin) using m6A Broccoli as substrate incubated for 2 hrs	ic50	0.1100	uM
2-[2-chloro-6-cyclopropyl-4-(3,5-dimethyl-1,2-oxazol-4-yl)anilino]-6-(1,4-oxazepan-4-ylmethyl)benzoic acid	1997599: Inhibition of FTO (unknown origin) using (5’-AUUGUCA(M6A)CAGCAGC-3’) as substrate incubated for 2 hrs by dot-blot assay	ic50	0.1200	uM
N-[(3-pyrrolidin-1-yloxetan-3-yl)methyl]-1-[4-(trifluoromethylsulfanyl)phenyl]methanamine	1886504: Inhibition of recombinant FTO (unknown origin) using m6A Broccoli as substrate incubated for 2 hrs	ic50	0.1600	uM
2-[2,6-dichloro-4-(5-methyl-1H-pyrazol-4-yl)anilino]benzoic acid	1869749: Inhibition of N-terminal His-tagged human FTO expressed in Escherichia coli BL21(DE3) by PAGE based assay	ic50	0.2000	uM
1-(5-phenylthiophen-2-yl)-N-[(3-pyrrolidin-1-yloxetan-3-yl)methyl]methanamine	1886504: Inhibition of recombinant FTO (unknown origin) using m6A Broccoli as substrate incubated for 2 hrs	ic50	0.2700	uM
2-[[3-hydroxy-6-[(5-nitro-2-pyridinyl)amino]pyridine-2-carbonyl]amino]acetic acid	1916581: Inhibition of recombinant full length N-terminal hexahistidine-tagged human FTO expressed in Escherichia coli BL21 (DE3) incubated for 10 mins using 15-mer ssRNA oligonucleotide [AUUGUGG(m6A)-CUGCAGC as substrate by SPE-MS-based assay	ic50	0.3300	uM
3-amino-6-chloro-N-(diaminomethylidene)-5-(dimethylamino)pyrazine-2-carboxamide	1926070: Inhibition of FTO (unknown origin) demethylation activity using m6A7-Broccoli RNA as substrate incubated for 3 mins under shaking condition and measured after 2 hrs by fluorescence based analysis	ic50	0.3400	uM
1-(5-methyl-1H-indol-3-yl)-N-[(3-pyrrolidin-1-yloxetan-3-yl)methyl]methanamine	1886504: Inhibition of recombinant FTO (unknown origin) using m6A Broccoli as substrate incubated for 2 hrs	ic50	0.3500	uM
1-(3,4-dimethylphenyl)-N-[(3-pyrrolidin-1-yloxetan-3-yl)methyl]methanamine	1886504: Inhibition of recombinant FTO (unknown origin) using m6A Broccoli as substrate incubated for 2 hrs	ic50	0.3500	uM
2-[2,6-dichloro-4-(3,5-dimethyl-1H-pyrazol-4-yl)anilino]-N-hydroxybenzamide	2119506: Inhibition of FTO (unknown origin)	ic50	0.4000	uM
2-[[3-hydroxy-6-[4-(methylcarbamoyl)anilino]pyridine-2-carbonyl]amino]acetic acid	1916581: Inhibition of recombinant full length N-terminal hexahistidine-tagged human FTO expressed in Escherichia coli BL21 (DE3) incubated for 10 mins using 15-mer ssRNA oligonucleotide [AUUGUGG(m6A)-CUGCAGC as substrate by SPE-MS-based assay	ic50	0.4300	uM
1-(6-fluoro-1H-indol-3-yl)-N-[[3-(3-fluoropyrrolidin-1-yl)oxetan-3-yl]methyl]methanamine	1886504: Inhibition of recombinant FTO (unknown origin) using m6A Broccoli as substrate incubated for 2 hrs	ic50	0.4400	uM
5-[4-(9-methoxy-3,3a,4,9b-tetrahydro-1H-chromeno[3,4-c]pyrrol-2-yl)butyl]-12-phenyl-8-thia-3,5,10,13-tetrazatricyclo[7.4.0.02,7]trideca-1(13),2(7),9,11-tetraene-4,6-dione	1926070: Inhibition of FTO (unknown origin) demethylation activity using m6A7-Broccoli RNA as substrate incubated for 3 mins under shaking condition and measured after 2 hrs by fluorescence based analysis	ic50	0.4900	uM
(Z)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-3-hydroxyprop-2-enamide	1926082: Inhibition of FTO (unknown origin) demethylation activity	ic50	0.5000	uM
2-[2,6-dichloro-4-(3,5-dimethyl-1H-pyrazol-4-yl)anilino]benzoic acid	1869749: Inhibition of N-terminal His-tagged human FTO expressed in Escherichia coli BL21(DE3) by PAGE based assay	ic50	0.5000	uM
(E)-4-[2-[4-[3,5-dichloro-4-(2-nitroanilino)anilino]pyridine-3-carbonyl]hydrazinyl]-4-oxobut-2-enoic acid	1876795: Inhibition of FTO (unknown origin) demethylation activity by HPLC assay	ic50	0.5700	uM
2-[2,6-dichloro-4-(2H-triazol-4-yl)anilino]benzoic acid	1869749: Inhibition of N-terminal His-tagged human FTO expressed in Escherichia coli BL21(DE3) by PAGE based assay	ic50	0.6000	uM
2-(2,7-dichloro-3-hydroxy-6-oxoxanthen-9-yl)benzoic acid	2119506: Inhibition of FTO (unknown origin)	ic50	0.6400	uM
1-(2,3-dihydro-1,4-benzodioxin-6-yl)-N-[(3-pyrrolidin-1-yloxetan-3-yl)methyl]methanamine	1886504: Inhibition of recombinant FTO (unknown origin) using m6A Broccoli as substrate incubated for 2 hrs	ic50	0.6700	uM
(E)-3-(3,4-dihydroxy-5-nitrophenyl)-2-(1,3-oxazinane-3-carbonyl)prop-2-enenitrile	1926082: Inhibition of FTO (unknown origin) demethylation activity	ic50	0.7000	uM
2-[2-chloro-4-(3,5-dimethyl-1,2-oxazol-4-yl)-6-fluoroanilino]benzoic acid	1869749: Inhibition of N-terminal His-tagged human FTO expressed in Escherichia coli BL21(DE3) by PAGE based assay	ic50	0.7000	uM
(Z)-2-(cyclobutanecarbonyl)-3-(3,4-dihydroxy-5-nitrophenyl)-3-hydroxyprop-2-enenitrile	1926082: Inhibition of FTO (unknown origin) demethylation activity	ic50	0.7500	uM
2,3,4,5,6-pentafluoro-N-[[1-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]triazol-4-yl]methyl]benzamide	2119506: Inhibition of FTO (unknown origin)	ic50	0.7800	uM
2-[[6-[(5-amino-2-pyridinyl)amino]-3-hydroxypyridine-2-carbonyl]amino]acetic acid	1916581: Inhibition of recombinant full length N-terminal hexahistidine-tagged human FTO expressed in Escherichia coli BL21 (DE3) incubated for 10 mins using 15-mer ssRNA oligonucleotide [AUUGUGG(m6A)-CUGCAGC as substrate by SPE-MS-based assay	ic50	0.8000	uM
2-[2,6-dichloro-4-(2H-tetrazol-5-yl)anilino]-6-(1,4-oxazepan-4-ylmethyl)benzoic acid	1997589: Inhibition of FTO (unknown origin)	ic50	0.8000	uM
(E)-4-[2-(4-benzylpyridine-3-carbonyl)hydrazinyl]-4-oxobut-2-enoic acid	1926033: Inhibition of human full length FTO expressed in Escherichia coli BL21 (DE3) Rosetta T1R cells using 3-methylthymidine as substrate incubated for 1 hr by HPLC analysis	ic50	0.8100	uM
1-(1H-indol-5-yl)-N-[(3-pyrrolidin-1-yloxetan-3-yl)methyl]methanamine	1886504: Inhibition of recombinant FTO (unknown origin) using m6A Broccoli as substrate incubated for 2 hrs	ic50	0.8100	uM
1-(6-fluoro-1H-indol-3-yl)-N-[(3-pyrrolidin-1-yloxetan-3-yl)methyl]methanamine	1886504: Inhibition of recombinant FTO (unknown origin) using m6A Broccoli as substrate incubated for 2 hrs	ic50	0.8300	uM
(2R)-2-amino-7-phosphonoheptanoic acid	1926070: Inhibition of FTO (unknown origin) demethylation activity using m6A7-Broccoli RNA as substrate incubated for 3 mins under shaking condition and measured after 2 hrs by fluorescence based analysis	ic50	0.8500	uM
1-(7-methoxy-1H-indol-3-yl)-N-[(3-pyrrolidin-1-yloxetan-3-yl)methyl]methanamine	1886504: Inhibition of recombinant FTO (unknown origin) using m6A Broccoli as substrate incubated for 2 hrs	ic50	0.8700	uM
2-[2,6-dichloro-4-(2H-tetrazol-5-yl)anilino]benzoic acid	1869749: Inhibition of N-terminal His-tagged human FTO expressed in Escherichia coli BL21(DE3) by PAGE based assay	ic50	0.9000	uM
2-[2-chloro-4-(3,5-dimethyl-1,2-oxazol-4-yl)-6-methylanilino]benzoic acid	1869749: Inhibition of N-terminal His-tagged human FTO expressed in Escherichia coli BL21(DE3) by PAGE based assay	ic50	0.9000	uM
1-(5-fluoro-1H-indol-3-yl)-N-[[3-(3-fluoropyrrolidin-1-yl)oxetan-3-yl]methyl]methanamine	1886504: Inhibition of recombinant FTO (unknown origin) using m6A Broccoli as substrate incubated for 2 hrs	ic50	0.9000	uM
2-[[2,4-dichloro-6-(3,5-dimethyl-1,2-oxazol-4-yl)-3-pyridinyl]amino]benzoic acid	1869749: Inhibition of N-terminal His-tagged human FTO expressed in Escherichia coli BL21(DE3) by PAGE based assay	ic50	0.9000	uM
2-[[3-hydroxy-6-(4-methoxycarbonylanilino)pyridine-2-carbonyl]amino]acetic acid	1916581: Inhibition of recombinant full length N-terminal hexahistidine-tagged human FTO expressed in Escherichia coli BL21 (DE3) incubated for 10 mins using 15-mer ssRNA oligonucleotide [AUUGUGG(m6A)-CUGCAGC as substrate by SPE-MS-based assay	ic50	0.9000	uM
1-(8-methylquinolin-3-yl)-N-[(3-pyrrolidin-1-yloxetan-3-yl)methyl]methanamine	1886504: Inhibition of recombinant FTO (unknown origin) using m6A Broccoli as substrate incubated for 2 hrs	ic50	0.9500	uM
1-[5-(2-chlorophenyl)furan-2-yl]-N-[(3-pyrrolidin-1-yloxetan-3-yl)methyl]methanamine	1886504: Inhibition of recombinant FTO (unknown origin) using m6A Broccoli as substrate incubated for 2 hrs	ic50	1.0000	uM
1-(1H-indol-3-yl)-N-[(3-pyrrolidin-1-yloxetan-3-yl)methyl]methanamine	1886504: Inhibition of recombinant FTO (unknown origin) using m6A Broccoli as substrate incubated for 2 hrs	ic50	1.0000	uM
2-[2,6-dichloro-4-(3,5-dimethyl-1,2-oxazol-4-yl)anilino]-5-fluorobenzoic acid	1869749: Inhibition of N-terminal His-tagged human FTO expressed in Escherichia coli BL21(DE3) by PAGE based assay	ic50	1.1000	uM
1-(4-methyl-1H-indol-3-yl)-N-[(3-pyrrolidin-1-yloxetan-3-yl)methyl]methanamine	1886504: Inhibition of recombinant FTO (unknown origin) using m6A Broccoli as substrate incubated for 2 hrs	ic50	1.1000	uM
4-methyl-2-phenyldiazenylphenol	1926070: Inhibition of FTO (unknown origin) demethylation activity using m6A7-Broccoli RNA as substrate incubated for 3 mins under shaking condition and measured after 2 hrs by fluorescence based analysis	ic50	1.1400	uM
(E)-3-(3,4-dihydroxy-5-nitrophenyl)-2-(piperidine-1-carbonyl)prop-2-enenitrile	1926082: Inhibition of FTO (unknown origin) demethylation activity	ic50	1.2000	uM
5,8-dihydroxy-1,2-bis[2-(2-hydroxyethylamino)ethylamino]anthracene-9,10-dione	1926070: Inhibition of FTO (unknown origin) demethylation activity using m6A7-Broccoli RNA as substrate incubated for 3 mins under shaking condition and measured after 2 hrs by fluorescence based analysis	ic50	1.2000	uM
2-[(3-hydroxy-6-naphthalen-1-ylpyridine-2-carbonyl)amino]acetic acid	1916588: Binding affinity to recombinant full length N-terminal hexahistidine-tagged human FTO expressed in Escherichia coli BL21 by competition-based NMR binding assay	kd	1.2000	uM
1,9-dimethylcarbazole	1926070: Inhibition of FTO (unknown origin) demethylation activity using m6A7-Broccoli RNA as substrate incubated for 3 mins under shaking condition and measured after 2 hrs by fluorescence based analysis	ic50	1.2300	uM
(8bR)-3,4,8b-trimethyl-2,3a-dihydro-1H-pyrrolo[2,3-b]indol-7-ol	1926070: Inhibition of FTO (unknown origin) demethylation activity using m6A7-Broccoli RNA as substrate incubated for 3 mins under shaking condition and measured after 2 hrs by fluorescence based analysis	ic50	1.2700	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects expression, increases reaction, increases phosphorylation, increases methylation, affects cotreatment (+5 more)	8
Benzo(a)pyrene	affects methylation, decreases expression	5
Valproic Acid	affects expression, decreases methylation, increases expression	4
Arsenic	affects reaction, affects binding, increases expression, increases mutagenesis, decreases methylation (+3 more)	3
Aflatoxin B1	affects expression, decreases methylation, increases methylation	3
bisphenol A	increases expression, affects expression, affects cotreatment	2
cadmium sulfate	decreases expression, increases abundance, increases expression	2
Cisplatin	decreases expression	2
Tobacco Smoke Pollution	decreases expression, increases expression	2
aristolochic acid I	decreases expression, increases expression	1
bisphenol F	affects cotreatment, increases expression	1
TAK-243	increases sumoylation	1
ML-792	decreases expression, decreases reaction, increases expression, increases reaction	1
dicrotophos	increases expression	1
quinone	decreases expression	1
2,4,6-tribromophenol	increases expression	1
methyleugenol	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
N-methyladenosine	decreases abundance, decreases methylation	1
butyraldehyde	decreases expression	1
benzo(e)pyrene	decreases methylation	1
aflatoxin B2	affects methylation	1
coumarin	increases phosphorylation	1
nafamostat	affects binding, decreases activity	1
artenimol	affects binding	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
pentanal	decreases expression	1
fumonisin B1	decreases expression	1
Irinotecan	decreases expression	1

ChEMBL screening assays

153 unique, capped per target: 153 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2344107	Binding	Inhibition of human hexahistidine-tagged full-length FTO expressed in Escherichia coli BL21 (DE3) using 3-methylthymidine as substrate assessed as inhibition of 3-methylthymidine conversion to thymidine after 1 hr by liquid chromatographic	Structural basis for inhibition of the fat mass and obesity associated protein (FTO). — J Med Chem

Cellosaurus cell lines

8 cell lines: 4 cancer cell line, 3 transformed cell line, 1 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A7NX	WAe001-A-72	Embryonic stem cell	Male
CVCL_B8W5	Abcam MCF-7 FTO KO	Cancer cell line	Female
CVCL_C0U1	HEK293T ALKBH5/FTO DKO	Transformed cell line	Female
CVCL_D9F4	Ubigene HEK293 FTO KO	Transformed cell line	Female
CVCL_F1MZ	HyCyte BEAS-2B KO-hFTO	Transformed cell line	Male
CVCL_SN97	HAP1 FTO (-) 1	Cancer cell line	Male
CVCL_SN98	HAP1 FTO (-) 2	Cancer cell line	Male
CVCL_SN99	HAP1 FTO (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01574313	PHASE4	COMPLETED	Effect of Stellate Ganglion Block on Meniere’s Disease
NCT02529475	PHASE4	TERMINATED	Evaluation of Inner Ear and Brain Structures With Contrast-enhanced MRI in Healthy Subjects (HYDROPS)
NCT04815187	PHASE4	ACTIVE_NOT_RECRUITING	Repurposed Use of Allergic Rhinitis and Allergic Asthma Drug to Reduce Vertigo and Hearing Loss in Meniere’s Disease
NCT03664674	PHASE3	COMPLETED	Phase 3 Study of OTO-104 in Subjects With Unilateral Meniere’s Disease
NCT04677972	PHASE3	COMPLETED	SPI-1005 for the Treatment of Meniere’s Disease
NCT05851508	PHASE3	RECRUITING	The Effecttiveness of Intratympanic Methylprednisolon Injections Compared to Placebo in the Treatment of Vertigo Attacks in Meniere’s Disease
NCT05420350	PHASE2	UNKNOWN	Lamotrigine and Bupropion for Meniere’s Disease
NCT06544434	PHASE2	RECRUITING	Laser Acupuncture for Meniere Disease
NCT04674735	PHASE1	WITHDRAWN	Safety of APSLXR in Patients Presenting Vertigo of Vestibular Origin or Meniere’s Disease
NCT04218123	PHASE2/PHASE3	COMPLETED	Assessing the Efficacy of a Serotonin and Norepinephrine Reuptake Inhibitor for Improving Meniere’s Disease Outcomes
NCT04766853	PHASE1/PHASE2	COMPLETED	Verification of the Efficacy/safety of the Intratympanic Drug Delivery for Hearing Loss
NCT04794842	EARLY_PHASE1	UNKNOWN	Comparing Topical Tetracaine Drops to Topical Focal Phenol for Local Anesthesia During Intratympanic Steroid Injection
NCT00599560	Not specified	COMPLETED	Vasopressin and V2 Receptor in Meniere’s Disease
NCT02371798	Not specified	WITHDRAWN	Unilateral Meniere Disease: Can Double Dose Gadolinium and Delayed Imaging Make the Diagnosis?
NCT03520322	Not specified	TERMINATED	A Study of a Mastoid Device in Subjects With Ménière’s Disease
NCT03795675	Not specified	ACTIVE_NOT_RECRUITING	CI Following VS Removal or Labyrinthectomy
NCT04370366	Not specified	RECRUITING	Imaging of Endolymphatic Hydrops at 7T MRI
NCT04569175	Not specified	COMPLETED	Non Enhanced Labyrinth Imaging for the Detection of Endolymphatic Hydrops in Meniere’s Disease NELI Study
NCT04686695	Not specified	COMPLETED	Transcutaneous Auricular Vagus Nerve Stimulation Treatment on Meniere Disease
NCT04835688	Not specified	UNKNOWN	Ventilation Tube Insertion for Unilateral Menière’s Disease
NCT04902963	Not specified	COMPLETED	What is the Tympanic Membrane Healing Time After Insertion of a Gelfoam PE Tube?
NCT04935970	Not specified	UNKNOWN	Metabolic Disorders and Vertigo
NCT05322538	Not specified	NOT_YET_RECRUITING	Menier’s Disease - Bone Density Study
NCT05328895	Not specified	COMPLETED	Transcutaneous Auricular Vagus Nerve Stimulation for Meniere Disease
NCT05424302	Not specified	RECRUITING	Effect of Peripheral Vestibular Disease Location on Outcomes Following Home-based Virtual Reality Vestibular Therapy
NCT05582148	Not specified	UNKNOWN	Meniere Disease and Hearing Aids
NCT05844657	Not specified	COMPLETED	Comprehensive Evaluation in Patients With Meniere’s Disease
NCT05960786	Not specified	COMPLETED	Treating the Symptoms of Vertigo in a Real-world Setting Using the OtoBand
NCT06278129	Not specified	UNKNOWN	Evaluation of the Diagnostic and Prognostic Efficacy of MRI in Acute Sensorineural Hearing Loss and Ménière’s Disease
NCT06544590	Not specified	COMPLETED	Transcutaneous Auricular Vagus Nerve Stimulation for Meniere Disease
NCT07272473	Not specified	RECRUITING	Effects of Cervical Mobilization on Dizziness, Balance, and Joint Position Sense in Patients With Meniere’s Disease
NCT00873678	Not specified	COMPLETED	Assessment of the Prevalence of Genes AHI1, NPHP1 and CEP290 in Joubert Syndrome
NCT01401998	Not specified	RECRUITING	ARPKD Database Study
NCT04874909	Not specified	COMPLETED	Classification, Functional Stratification and Biomarkers in Ciliopathy (CILLICORIRCM)