METTL16

Summary

METTL16 (methyltransferase 16, RNA N6-adenosine, HGNC:28484) is a protein-coding gene on chromosome 17p13.3, encoding RNA N(6)-adenosine-methyltransferase METTL16 (Q86W50). RNA N6-methyltransferase that methylates adenosine residues at the N(6) position of a subset of RNAs and is involved in S-adenosyl-L-methionine homeostasis by regulating expression of MAT2A transcripts. It is a common-essential gene (DepMap: required in 96.8% of cancer cell lines).

Enables RNA binding activity and RNA methyltransferase activity. Involved in RNA processing and regulation of mRNA metabolic process. Located in cytoplasm and nucleus.

Source: NCBI Gene 79066 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 65 total — 1 likely-pathogenic
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 96.8% of screened cell lines (common-essential)
• MANE Select transcript: NM_024086

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28484
Approved symbol	METTL16
Name	methyltransferase 16, RNA N6-adenosine
Location	17p13.3
Locus type	gene with protein product
Status	Approved
Aliases	MGC3329
Ensembl gene	ENSG00000127804
Ensembl biotype	protein_coding
Entrez	79066

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 4 protein_coding_CDS_not_defined, 3 nonsense_mediated_decay, 2 protein_coding, 1 retained_intron

ENST00000263092, ENST00000381977, ENST00000571298, ENST00000571332, ENST00000571669, ENST00000574623, ENST00000574752, ENST00000576556, ENST00000576976, ENST00000577148

RefSeq mRNA: 1 — MANE Select: NM_024086 NM_024086

CCDS: CCDS42232

Canonical transcript exons

ENST00000263092 — 10 exons

Exon	Start	End
ENSE00001134133	2416049	2420596
ENSE00002258833	2511759	2511888
ENSE00003490363	2464208	2464350
ENSE00003511577	2473524	2473664
ENSE00003601645	2438109	2438198
ENSE00003623055	2502204	2502331
ENSE00003675570	2420731	2420904
ENSE00003682548	2477686	2477885
ENSE00003689063	2441490	2441559
ENSE00003787278	2467761	2467876

Expression profiles

Bgee: expression breadth ubiquitous, 269 present calls, max score 93.46.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 18.6303 / max 403.4021, expressed in 1801 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
163832	8.0605	1740
163831	6.5611	1694
163830	3.1591	1337
163829	0.4284	233
163828	0.4211	227

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	93.46	gold quality
gingival epithelium	UBERON:0001949	91.21	gold quality
buccal mucosa cell	CL:0002336	90.87	gold quality
sperm	CL:0000019	90.58	gold quality
saphenous vein	UBERON:0007318	90.42	gold quality
nipple	UBERON:0002030	90.32	gold quality
urethra	UBERON:0000057	90.28	gold quality
gingiva	UBERON:0001828	89.68	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	89.63	gold quality
germinal epithelium of ovary	UBERON:0001304	89.63	gold quality
ventricular zone	UBERON:0003053	89.60	gold quality
pigmented layer of retina	UBERON:0001782	89.59	gold quality
bronchial epithelial cell	CL:0002328	89.35	gold quality
skin of hip	UBERON:0001554	89.24	gold quality
upper leg skin	UBERON:0004262	88.93	gold quality
tibia	UBERON:0000979	87.86	gold quality
inferior vagus X ganglion	UBERON:0005363	87.85	gold quality
lateral globus pallidus	UBERON:0002476	87.82	gold quality
esophagus squamous epithelium	UBERON:0006920	87.38	gold quality
renal medulla	UBERON:0000362	87.12	gold quality
male germ cell	CL:0000015	87.10	gold quality
penis	UBERON:0000989	86.86	gold quality
cardia of stomach	UBERON:0001162	86.70	gold quality
adenohypophysis	UBERON:0002196	86.68	gold quality
heart right ventricle	UBERON:0002080	86.43	gold quality
adult organism	UBERON:0007023	86.37	gold quality
corpus callosum	UBERON:0002336	86.29	gold quality
pituitary gland	UBERON:0000007	86.28	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	86.11	gold quality
tendon	UBERON:0000043	86.07	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.89

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

70 targeting METTL16, 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-8485	100.00	77.57	4731
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-10401-5P	99.99	65.79	948
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-130B-5P	99.83	68.50	1888
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-548AZ-3P	99.82	70.56	3549
HSA-MIR-548BC	99.82	70.61	3524
HSA-MIR-548E-3P	99.82	70.59	3514
HSA-MIR-548F-3P	99.82	70.59	3540
HSA-MIR-8080	99.82	67.52	1342
HSA-MIR-548A-3P	99.76	70.58	3524
HSA-MIR-6885-3P	99.75	70.36	3187
HSA-MIR-187-5P	99.74	70.26	1404
HSA-MIR-4422	99.72	72.07	2908

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 96.8% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 38)

• RNA immunoprecipitation after in vivo UV cross-linking and an in situ proximity ligation assay for RNA-protein interactions confirmed an association between METTL16 and MALAT1 in cells. METTL16 is an abundant ( approximately 5 x 10(5) molecules per cell) nuclear protein in HeLa cells. (PMID:27872311)
• METTL16 that controls MAT2A intron retention in response to intracellular SAM levels; splicing of the MAT2A retained intron is rapidly induced upon Met depletion, and this effect requires a conserved hairpin which is a METTL16 m6A substrate. (PMID:28525753)
• Human METTL16 is a N(6)-methyladenosine methyltransferase that targets pre-mRNAs and various non-coding RNAs. (PMID:29051200)
• METTL16 is involved in MAT2A mRNA stability control. (PMID:29262316)
• A native gel-shift assay shows that METTL16 binds to the MALAT1 RNA triple helix, but monomeric METTL16_291 does not. Results provide insights into the molecular structure of METTL16, which is distinct from METTL3/METTL14. (PMID:29593291)
• We speculate that m4C839 is involved in the stabilization of 12S rRNA folding, therefore facilitating the assembly of the mitochondrial small ribosomal subunits. Taken together our data show that METTL15 is a novel protein necessary for efficient translation in human mitochondria (PMID:31665743)
• While METTL16 has been reported to be a nuclear protein, findings suggest that METTL16 is also a cytoplasmic methyltransferase that may alter its RNA binding preferences depending on its cellular localization. (PMID:31940410)
• Mechanistic insights into m6A modification of U6 snRNA by human METTL16. (PMID:32266935)
• Enzymatic characterization of three human RNA adenosine methyltransferases reveals diverse substrate affinities and reaction optima. (PMID:33428944)
• METTL16, Methyltransferase-Like Protein 16: Current Insights into Structure and Function. (PMID:33671635)
• METTL16 promotes cell proliferation by up-regulating cyclin D1 expression in gastric cancer. (PMID:34075693)
• Systematic analysis of molecular characterization and clinical relevance of m6A regulators in digestive system pan-cancers. (PMID:34102905)
• The pan-cancer analysis of the two types of uterine cancer uncovered clinical and prognostic associations with m6A RNA methylation regulators. (PMID:34110327)
• RNA methyltransferase METTL16: Targets and function. (PMID:34227247)
• The comprehensive interactomes of human adenosine RNA methyltransferases and demethylases reveal distinct functional and regulatory features. (PMID:34634806)
• METTL16 exerts an m(6)A-independent function to facilitate translation and tumorigenesis. (PMID:35145225)
• METTL16 promotes hepatocellular carcinoma progression through downregulating RAB11B-AS1 in an m(6)A-dependent manner. (PMID:35596159)
• METTL16 antagonizes MRE11-mediated DNA end resection and confers synthetic lethality to PARP inhibition in pancreatic ductal adenocarcinoma. (PMID:36138131)
• METTL16 epigenetically enhances GPX4 expression via m6A modification to promote breast cancer progression by inhibiting ferroptosis. (PMID:36434904)
• Clinical Significance of Methyltransferase-like 16 Expression in Epithelial Ovarian Cancer. (PMID:36474378)
• Elucidating the Kinetic Mechanism of Human METTL16. (PMID:36584291)
• METTL16 drives leukemogenesis and leukemia stem cell self-renewal by reprogramming BCAA metabolism. (PMID:36608679)
• METTL16 promotes translation and lung tumorigenesis by sequestering cytoplasmic eIF4E2. (PMID:36840945)
• METTL16 promotes glycolytic metabolism reprogramming and colorectal cancer progression. (PMID:37340443)
• METTL16 promotes osteosarcoma progression by downregulating VPS33B in an m[6] A-dependent manner. (PMID:37357526)
• Genetic Variations Within METTL16 and Susceptibility to Sudden Cardiac Death in Chinese Populations With Coronary Artery Disease. (PMID:37423176)
• Functional analysis of 3’-UTR hairpins supports a two-tiered model for posttranscriptional regulation of MAT2A by METTL16. (PMID:37567786)
• METTL16 controls Kaposi’s sarcoma-associated herpesvirus replication by regulating S-adenosylmethionine cycle. (PMID:37673880)
• The RNA methyltransferase METTL16 enhances cholangiocarcinoma growth through PRDM15-mediated FGFR4 expression. (PMID:37817227)
• METTL16 Inhibits the Malignant Progression of Epithelial Ovarian Cancer through the lncRNA MALAT1/beta-Catenin Axis. (PMID:37927399)
• METTL16-mediated N6-methyladenosine modification of Soga1 enables proper chromosome segregation and chromosomal stability in colorectal cancer. (PMID:38084791)
• Targeting key RNA methylation enzymes to improve the outcome of colorectal cancer chemotherapy (Review). (PMID:38131226)
• METTL16 promotes liver cancer stem cell self-renewal via controlling ribosome biogenesis and mRNA translation. (PMID:38302992)
• METTL16 inhibits papillary thyroid cancer tumorigenicity through m[6]A/YTHDC2/SCD1-regulated lipid metabolism. (PMID:38334797)
• METTL16 suppressed the proliferation and cisplatin-chemoresistance of bladder cancer by degrading PMEPA1 mRNA in a m6A manner through autophagy pathway. (PMID:38385084)
• A Mettl16/m[6]A/mybl2b/Igf2bp1 axis ensures cell cycle progression of embryonic hematopoietic stem and progenitor cells. (PMID:38605226)
• METTL16-SENP3-LTF axis confers ferroptosis resistance and facilitates tumorigenesis in hepatocellular carcinoma. (PMID:39218945)
• METTL16 Promotes Stability of SYNPO2L mRNA and leading to Cancer Cell Lung Metastasis by Secretion of COL10A1 and attract the Cancer-Associated Fibroblasts. (PMID:39247832)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	mettl16	ENSDARG00000055838
mus_musculus	Mettl16	ENSMUSG00000010554
rattus_norvegicus	Mettl16	ENSRNOG00000002764
drosophila_melanogaster	CG7544	FBGN0033994
caenorhabditis_elegans		WBGENE00014228

Protein

Protein identifiers

RNA N(6)-adenosine-methyltransferase METTL16 — Q86W50 (reviewed: Q86W50)

Alternative names: Methyltransferase 10 domain-containing protein, Methyltransferase-like protein 16, U6 small nuclear RNA (adenine-(43)-N(6))-methyltransferase

All UniProt accessions (5): Q86W50, I3L362, I3L3W3, I3L4V1, K7EKQ8

UniProt curated annotations — full annotation on UniProt →

Function. RNA N6-methyltransferase that methylates adenosine residues at the N(6) position of a subset of RNAs and is involved in S-adenosyl-L-methionine homeostasis by regulating expression of MAT2A transcripts. Able to N6-methylate a subset of mRNAs and U6 small nuclear RNAs (U6 snRNAs). In contrast to the METTL3-METTL14 heterodimer, only able to methylate a limited number of RNAs: requires both a 5’UACAGAGAA-3’ nonamer sequence and a specific RNA structure. Plays a key role in S-adenosyl-L-methionine homeostasis by mediating N6-methylation of MAT2A mRNAs, altering splicing of MAT2A transcripts: in presence of S-adenosyl-L-methionine, binds the 3’-UTR region of MAT2A mRNA and specifically N6-methylates the first hairpin of MAT2A mRNA, preventing recognition of their 3’-splice site by U2AF1/U2AF35, thereby inhibiting splicing and protein production of S-adenosylmethionine synthase. In S-adenosyl-L-methionine-limiting conditions, binds the 3’-UTR region of MAT2A mRNA but stalls due to the lack of a methyl donor, preventing N6-methylation and promoting expression of MAT2A. In addition to mRNAs, also able to mediate N6-methylation of U6 small nuclear RNA (U6 snRNA): specifically N6-methylates adenine in position 43 of U6 snRNAs. Also able to bind various lncRNAs, such as 7SK snRNA (7SK RNA) or 7SL RNA. Specifically binds the 3’-end of the MALAT1 long non-coding RNA.

Subunit / interactions. Interacts with MEPCE. Interacts with LARP7.

Subcellular location. Nucleus. Cytoplasm.

Activity regulation. Methyltransferase activity is autoinhibited by the K-loop region that blocks S-adenosyl-L-methionine-binding. Upon activation, K-loop changes conformation, allowing S-adenosyl-L-methionine-binding and subsequent methyltransferase activity. mRNA N6-adenosine-methyltransferase activity is inhibited by zinc.

Domain organisation. The VCR (vertebrate conserved) regions bind the first hairpin of MAT2A mRNAs. The VCR regions interact with the internal stem-loop within U6 snRNAs, inducing the conformational rearrangement of the A43-containing region of U6 snRNA, thereby modifying the RNA structure to become suitable for productive catalysis by the methyltransferase region. The K-loop region occludes the S-adenosyl-L-methionine-binding pocket. Upon activation, conformation of the K-loop changes, allowing S-adenosyl-L-methionine-binding.

Similarity. Belongs to the methyltransferase superfamily. METTL16/RlmF family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q86W50-1	1	yes
Q86W50-2	2

RefSeq proteins (1): NP_076991* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR010286	METTL16/RlmF	Family
IPR017182	METTL16/PsiM	Family
IPR029063	SAM-dependent_MTases_sf	Homologous_superfamily

Pfam: PF05971

Enzyme classification (BRENDA):

• EC 2.1.1.346 — U6 snRNA m6A methyltransferase (BRENDA: 4 organisms, 36 substrates, 2 inhibitors, 4 Km, 1 kcat entries)

Substrate kinetics (BRENDA)

2 substrates with measured Km, best-characterized 2. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ADENINE43 IN U6 SNRNA	—	2
S-ADENOSYL-L-METHIONINE	0.132–0.4	2

Catalyzed reactions (Rhea), 2 shown:

• adenosine in U6 snRNA + S-adenosyl-L-methionine = N(6)-methyladenosine in U6 snRNA + S-adenosyl-L-homocysteine + H(+) (RHEA:52808)
• an adenosine in mRNA + S-adenosyl-L-methionine = an N(6)-methyladenosine in mRNA + S-adenosyl-L-homocysteine + H(+) (RHEA:55584)

UniProt features (90 total): mutagenesis site 23, helix 19, strand 18, region of interest 8, binding site 6, compositionally biased region 3, sequence conflict 3, turn 3, modified residue 2, splice variant 2, sequence variant 2, chain 1

Structure

Experimental structures (PDB)

9 structures.

PDB	Method	Resolution (Å)
6DU4	X-RAY DIFFRACTION	1.7
6B91	X-RAY DIFFRACTION	1.94
2H00	X-RAY DIFFRACTION	2
6B92	X-RAY DIFFRACTION	2.1
6GFK	X-RAY DIFFRACTION	2.3
6GT5	X-RAY DIFFRACTION	2.45
6M1U	X-RAY DIFFRACTION	2.79
6GFN	X-RAY DIFFRACTION	2.86
6DU5	X-RAY DIFFRACTION	3.01

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q86W50-F1	79.44	0.54

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 (6): 82; 110; 114; 133; 164; 184

Post-translational modifications (2): 329, 463

Mutagenesis-validated functional residues (23):

Position	Phenotype
5–16	abolished methyltransferase activity.
5	does not affect methyltransferase activity.
5	reduced methyltransferase activity.
10	does not affect methyltransferase activity.
10	reduced methyltransferase activity.
12	does not affect methyltransferase activity.
14	does not affect methyltransferase activity.
16	does not affect methyltransferase activity.
26	does not affect methyltransferase activity; when associated with a-31.
31	does not affect methyltransferase activity; when associated with a-26.
39	does not affect methyltransferase activity.
47	reduced methyltransferase activity.
82	abolished methyltransferase activity in vitro.
133	abolished methyltransferase activity in vitro.
163	increased methyltransferase activity in vitro.
167	increased methyltransferase activity in vitro.
184	abolished methyltransferase activity in vitro.
185–186	abolishes methyltransferase activity.
187	abolishes methyltransferase activity.
200–204	abolished methyltransferase activity.
202–207	does not affect methyltransferase activity.
279	abolished methyltransferase activity.
282	abolished methyltransferase activity.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 128 (showing top): GOBP_RIBOSOME_BIOGENESIS, GOBP_REGULATION_OF_MRNA_CATABOLIC_PROCESS, GOBP_3_UTR_MEDIATED_MRNA_STABILIZATION, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_RNA_METHYLATION, GOBP_POST_TRANSCRIPTIONAL_REGULATION_OF_GENE_EXPRESSION, GOBP_RNA_MODIFICATION, GOBP_SULFUR_COMPOUND_BIOSYNTHETIC_PROCESS, GOBP_S_ADENOSYLMETHIONINE_METABOLIC_PROCESS, GOBP_REGULATION_OF_CATABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_CATABOLIC_PROCESS, GOBP_RNA_SPLICING, GOBP_REGULATION_OF_MRNA_SPLICING_VIA_SPLICEOSOME, FISCHER_DREAM_TARGETS, MODULE_48

GO Biological Process (14): mRNA processing (GO:0006397), mRNA catabolic process (GO:0006402), S-adenosylmethionine biosynthetic process (GO:0006556), post-transcriptional regulation of gene expression (GO:0010608), regulation of mRNA splicing, via spliceosome (GO:0048024), mRNA destabilization (GO:0061157), rRNA base methylation (GO:0070475), snRNA (adenine-N6)-methylation (GO:0120049), negative regulation of 3’-UTR-mediated mRNA stabilization (GO:1905869), RNA methylation (GO:0001510), RNA modification (GO:0009451), methylation (GO:0032259), regulation of mRNA stability (GO:0043488), positive regulation of mRNA catabolic process (GO:0061014)

GO Molecular Function (8): mRNA m(6)A methyltransferase activity (GO:0001734), RNA binding (GO:0003723), U6 snRNA 3’-end binding (GO:0030629), RNA stem-loop binding (GO:0035613), 23S rRNA (adenine(1618)-N(6))-methyltransferase activity (GO:0052907), U6 snRNA (adenine(43)-N6)-methyltransferase activity (GO:0120048), methyltransferase activity (GO:0008168), transferase activity (GO:0016740)

GO Cellular Component (2): nucleus (GO:0005634), cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
mRNA metabolic process	2
negative regulation of gene expression	2
positive regulation of mRNA catabolic process	2
regulation of mRNA catabolic process	2
RNA processing	1
RNA catabolic process	1
sulfur compound biosynthetic process	1
S-adenosylmethionine metabolic process	1
regulation of gene expression	1
mRNA splicing, via spliceosome	1
regulation of RNA splicing	1
regulation of mRNA processing	1
regulation of mRNA stability	1
RNA destabilization	1
rRNA methylation	1
snRNA modification	1
negative regulation of biological process	1
3’-UTR-mediated mRNA stabilization	1
regulation of 3’-UTR-mediated mRNA stabilization	1
RNA modification	1
macromolecule methylation	1
RNA metabolic process	1
macromolecule modification	1
metabolic process	1
regulation of RNA stability	1
mRNA catabolic process	1
positive regulation of catabolic process	1
positive regulation of mRNA metabolic process	1
mRNA methyltransferase activity	1
nucleic acid binding	1
U6 snRNA binding	1
RNA binding	1
rRNA (adenine-N6-)-methyltransferase activity	1
snRNA methyltransferase activity	1
transferase activity, transferring one-carbon groups	1
catalytic activity	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1328 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
METTL16	ZC3H13	Q5T200	997
METTL16	WTAP	Q15007	997
METTL16	VIRMA	Q69YN4	997
METTL16	RBM15	Q96T37	996
METTL16	METTL14	Q9HCE5	995
METTL16	METTL3	Q86U44	990
METTL16	RBM15B	Q8NDT2	966
METTL16	METTL5	Q9NRN9	951
METTL16	ZCCHC4	Q9H5U6	946
METTL16	CBLL1	Q75N03	926
METTL16	ALKBH5	Q6P6C2	836
METTL16	YTHDC1	Q96MU7	822
METTL16	YTHDF1	Q9BYJ9	809
METTL16	YTHDC2	Q9H6S0	807
METTL16	MAT2A	P31153	798

IntAct

16 interactions, top by confidence:

A	B	Type	Score
SLC39A9	B4GALT5	psi-mi:“MI:0914”(association)	0.530
CPSF6	DDX39A	psi-mi:“MI:0914”(association)	0.480
HCCS	MPZL1	psi-mi:“MI:0914”(association)	0.350
	TMEM223	psi-mi:“MI:0914”(association)	0.350
ORF4a	MPHOSPH10	psi-mi:“MI:0914”(association)	0.350
SSB	RPS3A	psi-mi:“MI:0914”(association)	0.350
GYPA	HYKK	psi-mi:“MI:0914”(association)	0.350
GPRC5D	FAM234B	psi-mi:“MI:0914”(association)	0.350
	POLRMT	psi-mi:“MI:0914”(association)	0.350
H2AP	GNPAT	psi-mi:“MI:0914”(association)	0.350
MAGEA8	B4GALT5	psi-mi:“MI:0914”(association)	0.350
KCNK3	ESYT2	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (45): METTL16 (Affinity Capture-MS), METTL16 (Co-fractionation), TCEA1 (Co-fractionation), METTL16 (Affinity Capture-MS), METTL16 (Affinity Capture-MS), MEPCE (Affinity Capture-MS), KPNA6 (Affinity Capture-MS), METTL16 (Affinity Capture-MS), METTL16 (Affinity Capture-MS), METTL16 (Affinity Capture-MS), METTL16 (Affinity Capture-MS), RNU6-1 (Protein-RNA), METTL16 (Affinity Capture-RNA), METTL16 (Affinity Capture-MS), METTL16 (Affinity Capture-MS)

ESM2 similar proteins: A4FUF0, A4Q9F4, D2XV59, E1C1R4, O94888, O95267, P42694, P54198, P79987, Q15139, Q49A26, Q4R8V9, Q4SS66, Q562D5, Q5R372, Q5R5M3, Q5R7T2, Q5RDU9, Q5REY7, Q5RKH0, Q5RKN4, Q5T6S3, Q5ZIA0, Q5ZJ17, Q5ZLS2, Q5ZLS7, Q61666, Q62101, Q6DC64, Q6DFV5, Q6P5G6, Q6ZPY2, Q6ZWH5, Q70Z35, Q75Q39, Q80VL1, Q86W50, Q8BY87, Q8BYN5, Q8CIW5

Diamond homologs: A0A286LEZ7, A0KHV5, A0KRF2, A1JU40, A1RQ03, A1SBR7, A3DAC9, A3QJF9, A4TM00, A4Y1N1, A5F7R5, A5VZ65, A6H0G2, A6T6Q1, A6WHK9, A7FGU1, A7MEZ1, A8GBT4, A8HA69, A9KVB0, A9R6I2, B0KQK4, B0TM80, B1JBB3, B1JH95, B1KP42, B2K7Y6, B5XYT7, B8E3W0, C3K6G1, C3LMU1, C6D8Y7, O42662, P0DPA9, Q09357, Q0I0H7, Q11XA9, Q15VI3, Q1I5F5, Q290Z2

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	49
Likely benign	5
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
3063512	GRCh37/hg19 17p13.3(chr17:2264478-2570762)x3	Likely pathogenic

SpliceAI

3155 predictions. Top by Δscore:

Variant	Effect	Δscore
17:2420727:GTAC:G	donor_loss	1.0000
17:2420728:TACCT:T	donor_loss	1.0000
17:2420729:ACC:A	donor_loss	1.0000
17:2420730:C:CA	donor_loss	1.0000
17:2420900:GGTGA:G	acceptor_gain	1.0000
17:2420901:GTGA:G	acceptor_gain	1.0000
17:2420902:TGA:T	acceptor_gain	1.0000
17:2420903:GA:G	acceptor_gain	1.0000
17:2420904:AC:A	acceptor_loss	1.0000
17:2420905:C:CC	acceptor_gain	1.0000
17:2420905:CTGCA:C	acceptor_loss	1.0000
17:2420906:T:C	acceptor_loss	1.0000
17:2420908:C:CT	acceptor_gain	1.0000
17:2420909:A:T	acceptor_gain	1.0000
17:2420923:A:C	acceptor_gain	1.0000
17:2425418:CAG:C	donor_gain	1.0000
17:2441488:ACC:A	donor_gain	1.0000
17:2441489:CCC:C	donor_gain	1.0000
17:2441556:CCAT:C	acceptor_gain	1.0000
17:2441557:CATC:C	acceptor_gain	1.0000
17:2464204:TTA:T	donor_loss	1.0000
17:2464205:TA:T	donor_loss	1.0000
17:2464206:A:AC	donor_gain	1.0000
17:2464206:ACCT:A	donor_loss	1.0000
17:2464207:C:CA	donor_loss	1.0000
17:2464207:C:CC	donor_gain	1.0000
17:2464207:CCTTA:C	donor_gain	1.0000
17:2464346:ACTCC:A	acceptor_gain	1.0000
17:2464347:CTCC:C	acceptor_gain	1.0000
17:2464347:CTCCC:C	acceptor_gain	1.0000

AlphaMissense

3685 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:2438133:A:C	S288R	1.000
17:2438133:A:T	S288R	1.000
17:2438135:T:G	S288R	1.000
17:2438136:C:A	W287C	1.000
17:2438136:C:G	W287C	1.000
17:2438138:A:G	W287R	1.000
17:2438138:A:T	W287R	1.000
17:2438140:G:T	A286D	1.000
17:2438150:A:G	W283R	1.000
17:2438150:A:T	W283R	1.000
17:2438151:T:A	R282S	1.000
17:2438151:T:G	R282S	1.000
17:2438152:C:A	R282I	1.000
17:2438152:C:G	R282T	1.000
17:2438165:C:G	G278R	1.000
17:2441503:A:G	L262P	1.000
17:2441503:A:T	L262H	1.000
17:2441526:G:C	S254R	1.000
17:2441526:G:T	S254R	1.000
17:2441528:T:G	S254R	1.000
17:2441539:C:T	G250E	1.000
17:2441540:C:G	G250R	1.000
17:2441540:C:T	G250R	1.000
17:2441550:G:C	S246R	1.000
17:2441550:G:T	S246R	1.000
17:2441552:T:G	S246R	1.000
17:2441558:A:G	W244R	1.000
17:2441558:A:T	W244R	1.000
17:2464231:A:C	S235R	1.000
17:2464231:A:T	S235R	1.000

dbSNP variants (sampled 300 via entrez): RS1000002512 (17:2449497 C>T), RS1000010457 (17:2452732 A>G), RS1000050927 (17:2492754 A>G), RS1000138064 (17:2449140 C>G), RS1000152506 (17:2487968 G>A,T), RS1000155483 (17:2428439 T>A,C), RS1000163027 (17:2455733 A>T), RS1000192583 (17:2445553 A>C), RS1000269475 (17:2497841 C>T), RS1000283265 (17:2510797 G>T), RS1000296066 (17:2455468 G>A), RS1000352201 (17:2465378 C>A), RS1000380888 (17:2492356 G>C), RS1000388039 (17:2420387 C>T), RS1000403052 (17:2465227 C>T)

Disease associations

OMIM: gene `` | disease phenotypes:

GenCC curated gene-disease

Mondo (1): neurodevelopmental disorder (MONDO:0700092)

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST006943_17	Feeling miserable	2.000000e-11
GCST90002403_693	Red blood cell count	2.000000e-09
GCST90020028_1408	Hip circumference adjusted for BMI	9.000000e-09

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0009598	feeling miserable measurement
EFO:0004305	erythrocyte count
EFO:0008039	BMI-adjusted hip circumference

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5465326 (SINGLE PROTEIN)

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

ChEMBL bioactivities

3 potent at pChembl≥5 of 8 total, top 3 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.77	IC50	1700	nM	CHEMBL5596594
5.17	IC50	6800	nM	CHEMBL5598517
5.17	IC50	6800	nM	CHEMBL5596977

PubChem BioAssay actives

3 with measured affinity, of 11 total; 3 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-[[5-(5-bromo-2-oxoindol-3-yl)-4-hydroxythiophen-2-yl]sulfamoyl]benzoic acid	2122178: Inhibition of METTL16 (unknown origin)	ic50	1.7000	uM
N-[(5Z)-5-(5-bromo-1-methyl-2-oxoindol-3-ylidene)-4-oxothiophen-2-yl]-4-methoxybenzenesulfonamide	2122178: Inhibition of METTL16 (unknown origin)	ic50	6.8000	uM
4-methoxy-N-[(5Z)-5-(1-methyl-5-nitro-2-oxoindol-3-ylidene)-4-oxothiophen-2-yl]benzenesulfonamide	2122178: Inhibition of METTL16 (unknown origin)	ic50	6.8000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Formaldehyde	decreases expression	2
Valproic Acid	affects expression, decreases expression	2
Aflatoxin B1	decreases methylation	2
FR900359	increases phosphorylation	1
geldanamycin	increases expression	1
triphenyl phosphate	affects expression	1
sodium arsenate	decreases expression	1
trichostatin A	affects expression	1
arsenite	affects binding, decreases reaction	1
sodium arsenite	decreases expression	1
benzo(e)pyrene	increases methylation	1
potassium chromate(VI)	increases expression	1
aflatoxin B2	decreases methylation	1
cadmium sulfate	increases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
clothianidin	increases expression	1
torcetrapib	increases expression	1
jinfukang	affects cotreatment, decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Air Pollutants	affects expression, increases abundance	1
Cisplatin	affects cotreatment, decreases expression	1
Doxorubicin	decreases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Lead	decreases expression	1
Methapyrilene	increases methylation	1
Ozone	increases abundance, affects expression	1
Plant Extracts	increases expression, affects cotreatment	1
Ribonucleotides	affects binding	1
Sodium Selenite	decreases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5317820	Binding	Inhibition of human METTL16 using 5’-GGU UGG CGU AGG CUA CAG AGA AGC CAA CC-3’ as substrate and SAM as cosubstrate at 10 uM incubated for 15 mins	Systematic Design of Adenosine Analogs as Inhibitors of a Clostridioides difficile-Specific DNA Adenine Methyltransferase Required for Normal Sporulation and Persistence. — J Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism
NCT03229928	Not specified	COMPLETED	Clinical Testing of a Real-Time Behavior Measurement Tool: Measuring Outcomes for CHAnge
NCT03232489	Not specified	UNKNOWN	Study for the Evaluation of the Feasibility of Applying Advanced MRI Scanning in Pediatric Clinical Practice