METTL2A

Summary

METTL2A (methyltransferase 2A, tRNA N3-cytidine, HGNC:25755) is a protein-coding gene on chromosome 17q23.2, encoding tRNA N(3)-cytidine methyltransferase METTL2A (Q96IZ6). S-adenosyl-L-methionine-dependent methyltransferase that mediates N(3)-methylcytidine modification of residue 32 of the tRNA anticodon loop of tRNA(Thr)(UGU) and tRNA(Arg)(CCU).

Enables tRNA (cytidine-3-)-methyltransferase activity. Involved in tRNA methylation. Located in cytoplasm.

Source: NCBI Gene 339175 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 67 total
• MANE Select transcript: NM_181725

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25755
Approved symbol	METTL2A
Name	methyltransferase 2A, tRNA N3-cytidine
Location	17q23.2
Locus type	gene with protein product
Status	Approved
Aliases	FLJ12760, METTL2
Ensembl gene	ENSG00000087995
Ensembl biotype	protein_coding
OMIM	618902
Entrez	339175

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 5 protein_coding, 2 retained_intron

ENST00000311506, ENST00000333483, ENST00000582027, ENST00000616852, ENST00000922183, ENST00000922184, ENST00000922185

RefSeq mRNA: 1 — MANE Select: NM_181725 NM_181725

CCDS: CCDS45752

Canonical transcript exons

ENST00000311506 — 9 exons

Exon	Start	End
ENSE00001330457	62423897	62424012
ENSE00001468921	62448575	62453385
ENSE00002518691	62424219	62424310
ENSE00003459713	62444837	62444943
ENSE00003482245	62447701	62447766
ENSE00003516144	62427788	62427837
ENSE00003535475	62435232	62435292
ENSE00003610911	62426299	62426654
ENSE00003684899	62440617	62440756

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 89.26.

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
colonic epithelium	UBERON:0000397	89.26	gold quality
mucosa of transverse colon	UBERON:0004991	86.71	gold quality
adrenal tissue	UBERON:0018303	85.78	gold quality
islet of Langerhans	UBERON:0000006	84.64	gold quality
lower esophagus mucosa	UBERON:0035834	84.43	gold quality
cortical plate	UBERON:0005343	84.07	gold quality
stromal cell of endometrium	CL:0002255	83.62	gold quality
ganglionic eminence	UBERON:0004023	83.28	gold quality
skeletal muscle tissue	UBERON:0001134	83.26	gold quality
ventricular zone	UBERON:0003053	83.21	gold quality
esophagus mucosa	UBERON:0002469	82.73	gold quality
heart left ventricle	UBERON:0002084	82.53	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	82.22	gold quality
hindlimb stylopod muscle	UBERON:0004252	81.86	gold quality
heart	UBERON:0000948	81.79	gold quality
right lobe of liver	UBERON:0001114	81.65	gold quality
muscle of leg	UBERON:0001383	81.65	gold quality
gastrocnemius	UBERON:0001388	81.59	gold quality
pancreas	UBERON:0001264	81.58	gold quality
muscle tissue	UBERON:0002385	81.34	gold quality
tonsil	UBERON:0002372	81.24	gold quality
right adrenal gland	UBERON:0001233	81.21	gold quality
adrenal gland	UBERON:0002369	81.20	gold quality
endometrium	UBERON:0001295	81.17	gold quality
right atrium auricular region	UBERON:0006631	81.12	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.07	gold quality
right adrenal gland cortex	UBERON:0035827	81.07	gold quality
apex of heart	UBERON:0002098	80.93	gold quality
left adrenal gland	UBERON:0001234	80.76	gold quality
esophagus	UBERON:0001043	80.64	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-CURD-97	yes	159.08
E-ANND-3	yes	4.65

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

50 targeting METTL2A, 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-4425	100.00	67.59	1049
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-4639-5P	99.81	67.37	1028
HSA-MIR-187-5P	99.74	70.26	1404
HSA-MIR-4719	99.73	72.10	3329
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-379-3P	99.69	69.60	1524
HSA-MIR-411-3P	99.69	69.63	1524
HSA-MIR-3942-3P	99.57	69.03	2854
HSA-MIR-4437	99.52	65.29	1266
HSA-MIR-4735-5P	99.43	68.49	1780
HSA-MIR-4505	99.27	67.81	2678
HSA-MIR-5787	99.22	67.86	2628
HSA-MIR-6504-3P	99.17	69.31	2891
HSA-MIR-10399-5P	99.17	69.87	2610
HSA-MIR-4717-3P	99.06	66.34	1072
HSA-MIR-7151-3P	99.04	69.72	2370
HSA-MIR-876-3P	98.76	68.23	945
HSA-MIR-384	98.71	67.34	1229

Literature-anchored findings (GeneRIF, showing 3)

• Data, including data from studies using mutant/knockout mice and cell lines from such mice, suggest that METTL2 and METTL6 (but not METTL8) contribute to post-transcriptional methylation of cytidine (formation of 3-methylcytidine) in tRNA; METTL2 methylates tRNA(Thr) and tRNA(Arg); METTL6 interacts with seryl-tRNA synthetase and methylates tRNA(Ser); METTL8 catalyzes post-transcriptional methylation of cytidine in mRNA. (PMID:28655767)
• Mutually exclusive substrate selection strategy by human m3C RNA transferases METTL2A and METTL6. (PMID:34268557)
• Integrative analysis of m3C associated genes reveals METTL2A as a potential oncogene in breast Cancer. (PMID:36266694)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	mettl2a	ENSDARG00000008105
mus_musculus	Mettl2	ENSMUSG00000020691
rattus_norvegicus	Mettl2	ENSRNOG00000006131

Paralogs (3): METTL8 (ENSG00000123600), METTL2B (ENSG00000165055), METTL6 (ENSG00000206562)

Protein

Protein identifiers

tRNA N(3)-cytidine methyltransferase METTL2A — Q96IZ6 (reviewed: Q96IZ6)

Alternative names: Methyltransferase-like protein 2A

All UniProt accessions (2): Q96IZ6, A0A087WW35

UniProt curated annotations — full annotation on UniProt →

Function. S-adenosyl-L-methionine-dependent methyltransferase that mediates N(3)-methylcytidine modification of residue 32 of the tRNA anticodon loop of tRNA(Thr)(UGU) and tRNA(Arg)(CCU). N(3)-methylcytidine methylation by METTL2A requires the N6-threonylcarbamoylation of tRNA (t6A37) by the EKC/KEOPS complex as prerequisite.

Subunit / interactions. Monomer. Interacts with DALRD3.

Subcellular location. Cytoplasm.

Similarity. Belongs to the methyltransferase superfamily. METL family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q96IZ6-1	1	yes
Q96IZ6-2	2

RefSeq proteins (1): NP_859076* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR013217	Methyltransf_12	Domain
IPR026113	METTL2/6/8-like	Family
IPR029063	SAM-dependent_MTases_sf	Homologous_superfamily

Pfam: PF08242

Catalyzed reactions (Rhea), 2 shown:

• cytidine(32) in tRNA(Thr) + S-adenosyl-L-methionine = N(3)-methylcytidine(32) in tRNA(Thr) + S-adenosyl-L-homocysteine + H(+) (RHEA:50960)
• cytidine(32) in tRNA(Arg)(CCU) + S-adenosyl-L-methionine = N(3)-methylcytidine(32) in tRNA(Arg)(CCU) + S-adenosyl-L-homocysteine + H(+) (RHEA:60912)

UniProt features (18 total): binding site 7, sequence conflict 5, modified residue 3, initiator methionine 1, chain 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96IZ6-F1	82.34	0.65

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 (7): 78; 82; 188; 213; 239; 240; 260

Post-translational modifications (3): 4, 154, 2

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 60 (showing top): GOBP_TRNA_METABOLIC_PROCESS, GOBP_RNA_METHYLATION, TERAMOTO_OPN_TARGETS_CLUSTER_7, GOBP_RNA_MODIFICATION, GOBP_TRNA_METHYLATION, NRF2_Q4, RYTTCCTG_ETS2_B, GOBP_METHYLATION, NIKOLSKY_BREAST_CANCER_17Q21_Q25_AMPLICON, GOBP_TRNA_PROCESSING, GOBP_TRNA_MODIFICATION, SANSOM_APC_TARGETS, SANSOM_APC_TARGETS_REQUIRE_MYC, GOMF_RNA_METHYLTRANSFERASE_ACTIVITY, GOMF_S_ADENOSYLMETHIONINE_DEPENDENT_METHYLTRANSFERASE_ACTIVITY

GO Biological Process (5): tRNA metabolic process (GO:0006399), tRNA modification (GO:0006400), tRNA methylation (GO:0030488), tRNA processing (GO:0008033), methylation (GO:0032259)

GO Molecular Function (6): tRNA (cytidine-N3)-methyltransferase activity (GO:0052735), protein binding (GO:0005515), methyltransferase activity (GO:0008168), RNA methyltransferase activity (GO:0008173), S-adenosylmethionine-dependent methyltransferase activity (GO:0008757), transferase activity (GO:0016740)

GO Cellular Component (1): cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
methyltransferase activity	2
RNA metabolic process	1
tRNA processing	1
RNA modification	1
RNA methylation	1
tRNA modification	1
RNA processing	1
tRNA metabolic process	1
metabolic process	1
tRNA (cytidine) methyltransferase activity	1
binding	1
transferase activity, transferring one-carbon groups	1
catalytic activity, acting on RNA	1
catalytic activity	1
intracellular anatomical structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

940 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
METTL2A	EFCAB3	Q8N7B9	638
METTL2A	DALRD3	Q5D0E6	602
METTL2A	TRMT10A	Q8TBZ6	582
METTL2A	TRMT10B	Q6PF06	564
METTL2A	SARS1	P49591	539
METTL2A	METTL25	Q8N6Q8	528
METTL2A	M0R2C6	M0R2C6	474
METTL2A	SARS2	Q9NP81	473
METTL2A	METTL21C	Q5VZV1	470
METTL2A	MARCHF10	Q8NA82	453
METTL2A	TLK2	Q86UE8	452
METTL2A	METTL1	Q9UBP6	440
METTL2A	ADAT3	Q96EY9	435
METTL2A	TRMT10C	Q7L0Y3	434
METTL2A	TRIT1	Q9H3H1	427

IntAct

16 interactions, top by confidence:

A	B	Type	Score
DALRD3	METTL2A	psi-mi:“MI:0915”(physical association)	0.500
DALRD3	METTL2B	psi-mi:“MI:0914”(association)	0.500
METTL2A	RRBP1	psi-mi:“MI:0915”(physical association)	0.400
METTL2A	nleD	psi-mi:“MI:0915”(physical association)	0.370
METTL2A	CFTR	psi-mi:“MI:0915”(physical association)	0.370
CFTR	METTL2A	psi-mi:“MI:0915”(physical association)	0.370
MAPK6	METTL2A	psi-mi:“MI:0915”(physical association)	0.370
M		psi-mi:“MI:0914”(association)	0.350
METTL2A	NDUFS6	psi-mi:“MI:0914”(association)	0.350
METTL2A	ACACB	psi-mi:“MI:0914”(association)	0.350
METTL2B	EIF3F	psi-mi:“MI:0914”(association)	0.350
METTL6	EIF3F	psi-mi:“MI:0914”(association)	0.350
DALRD3		psi-mi:“MI:0914”(association)	0.350
METTL2A		psi-mi:“MI:0914”(association)	0.350

BioGRID (31): METTL2A (Affinity Capture-RNA), METTL2B (Affinity Capture-MS), ID4 (Affinity Capture-MS), CPNE7 (Affinity Capture-MS), NDUFAF7 (Affinity Capture-MS), MTIF2 (Affinity Capture-MS), UBR4 (Affinity Capture-MS), NDUFS1 (Affinity Capture-MS), NDUFS6 (Affinity Capture-MS), TOP3A (Affinity Capture-MS), MCCC1 (Affinity Capture-MS), NDUFAF5 (Affinity Capture-MS), UBR2 (Affinity Capture-MS), RRBP1 (Proximity Label-MS), MTIF2 (Affinity Capture-MS)

ESM2 similar proteins: A0A0R4IB93, A0JMU5, A1A4L5, A2PYH4, A2RUV5, B3M1E1, B3P4N5, B4GZ20, B4HJC0, B4KA23, B4LVS8, B4NKI9, B4PVH6, B4QVW6, B6DMK2, D3Z4R1, O75417, O93530, O94830, Q07G10, Q0P5B2, Q15326, Q28ES8, Q29B63, Q4KLT3, Q4R6F3, Q5M8E6, Q5ZIJ9, Q5ZJM3, Q6GQ76, Q6NRS1, Q6NTR1, Q6P1Q9, Q6ZPR6, Q7ZU90, Q80Y20, Q84MA1, Q8BMK1, Q8BYH3, Q8MNT9

Diamond homologs: A2AUU0, A8KBL7, Q0P5B2, Q5M8E6, Q5ZHP8, Q6P1Q9, Q86BS6, Q8BMK1, Q96IZ6, Q9H825, G0REX6, O74386, Q08641, Q5ATG8, Q5RDV8, Q6AXU8, Q8BVH9, Q8T199, Q8TCB7, Q9P7L6, A0A0C6E0I7, A1JRM2, A4TJK8, A7FID3, A9QYY1, B1JLL8, B2K316, Q1C823, Q1CJH3, Q66AU7, Q7CIB7, A0A1D6NER6, C8YTM5

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	58
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1138 predictions. Top by Δscore:

Variant	Effect	Δscore
17:62424310:GGTG:G	donor_loss	1.0000
17:62426297:A:AG	acceptor_gain	1.0000
17:62426297:AGTT:A	acceptor_gain	1.0000
17:62426298:G:GA	acceptor_gain	1.0000
17:62426298:GTT:G	acceptor_gain	1.0000
17:62426298:GTTG:G	acceptor_gain	1.0000
17:62426652:G:GT	donor_gain	1.0000
17:62427838:G:GG	donor_gain	1.0000
17:62435230:A:AG	acceptor_gain	1.0000
17:62435231:G:GG	acceptor_gain	1.0000
17:62440702:G:GT	donor_gain	1.0000
17:62440702:G:T	donor_gain	1.0000
17:62440752:GACAA:G	donor_gain	1.0000
17:62440757:G:GG	donor_gain	1.0000
17:62444834:CA:C	acceptor_loss	1.0000
17:62444835:A:AC	acceptor_loss	1.0000
17:62444835:AG:A	acceptor_gain	1.0000
17:62444836:GG:G	acceptor_gain	1.0000
17:62444836:GGAT:G	acceptor_gain	1.0000
17:62444939:AAAAG:A	donor_loss	1.0000
17:62444940:AAAGG:A	donor_loss	1.0000
17:62444942:AGG:A	donor_loss	1.0000
17:62444943:GGT:G	donor_loss	1.0000
17:62444944:G:C	donor_loss	1.0000
17:62444945:T:G	donor_loss	1.0000
17:62448568:A:AG	acceptor_gain	1.0000
17:62448569:C:G	acceptor_gain	1.0000
17:62448570:A:AG	acceptor_gain	1.0000
17:62448571:C:G	acceptor_gain	1.0000
17:62448573:A:AG	acceptor_gain	1.0000

AlphaMissense

2509 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:62426328:T:A	W78R	0.999
17:62426328:T:C	W78R	0.999
17:62426337:T:C	F81L	0.999
17:62426339:C:A	F81L	0.999
17:62426339:C:G	F81L	0.999
17:62426379:T:A	W95R	0.999
17:62426379:T:C	W95R	0.999
17:62440728:T:C	F261L	0.999
17:62440730:T:A	F261L	0.999
17:62440730:T:G	F261L	0.999
17:62448682:T:A	W364R	0.999
17:62448682:T:C	W364R	0.999
17:62426330:G:C	W78C	0.998
17:62426330:G:T	W78C	0.998
17:62426349:C:G	H85D	0.998
17:62426361:T:C	F89L	0.998
17:62426363:T:A	F89L	0.998
17:62426363:T:G	F89L	0.998
17:62426374:G:C	R93T	0.998
17:62426375:A:C	R93S	0.998
17:62426375:A:T	R93S	0.998
17:62444899:G:C	R291P	0.998
17:62444901:G:C	D292H	0.998
17:62444902:A:C	D292A	0.998
17:62448638:G:C	R349P	0.998
17:62448641:T:C	L350P	0.998
17:62448677:G:C	R362P	0.998
17:62426338:T:C	F81S	0.997
17:62426369:G:C	K91N	0.997
17:62426369:G:T	K91N	0.997

dbSNP variants (sampled 300 via entrez): RS1000205750 (17:62422156 T>C,G), RS1000377396 (17:62439507 T>A,C), RS1000431522 (17:62427286 C>T), RS1000553319 (17:62444322 C>T), RS1000605822 (17:62444710 G>A), RS1000768573 (17:62438353 G>A), RS1000769871 (17:62431508 C>T), RS1000831161 (17:62439679 G>A,T), RS1001054886 (17:62450697 C>T), RS1001442351 (17:62449554 T>TA), RS1001516569 (17:62422229 C>A), RS1001521945 (17:62450947 C>T), RS1001701279 (17:62425862 G>A,T), RS1001979116 (17:62423827 G>A,T), RS1002025988 (17:62425524 C>G)

Disease associations

OMIM: gene MIM:618902 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST003159_4	Objective response to lithium treatment	4.000000e-07

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

10 total (human), top 10 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
aristolochic acid I	increases expression	1
triphenyl phosphate	affects expression	1
di-n-butylphosphoric acid	affects expression	1
cylindrospermopsin	increases expression	1
CGP 52608	affects binding, increases reaction	1
abrine	increases expression	1
Atrazine	decreases expression	1
Smoke	decreases expression	1
Tretinoin	decreases expression	1
Lactic Acid	decreases expression	1

Clinical trials (associated diseases)

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