METTL6

Summary

METTL6 (methyltransferase 6, tRNA N3-cytidine, HGNC:28343) is a protein-coding gene on chromosome 3p25.1, encoding tRNA N(3)-cytidine methyltransferase METTL6 (Q8TCB7). S-adenosyl-L-methionine-dependent methyltransferase that mediates N(3)-methylcytidine modification of residue 32 of the tRNA anticodon loop of tRNA(Ser), including tRNA(Ser)(UGA) and tRNA(Ser)(GCU).

Enables enzyme binding activity and tRNA (cytidine-3-)-methyltransferase activity. Involved in tRNA methylation. Located in cytoplasm and nucleus.

Source: NCBI Gene 131965 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 58 total
• MANE Select transcript: NM_152396

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28343
Approved symbol	METTL6
Name	methyltransferase 6, tRNA N3-cytidine
Location	3p25.1
Locus type	gene with protein product
Status	Approved
Aliases	MGC24132
Ensembl gene	ENSG00000206562
Ensembl biotype	protein_coding
OMIM	618903
Entrez	131965

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 14 protein_coding, 3 protein_coding_CDS_not_defined

ENST00000383789, ENST00000383790, ENST00000443029, ENST00000450816, ENST00000453819, ENST00000458728, ENST00000485131, ENST00000489881, ENST00000584799, ENST00000598878, ENST00000907532, ENST00000916127, ENST00000916128, ENST00000916129, ENST00000916130, ENST00000916131, ENST00000962394

RefSeq mRNA: 5 — MANE Select: NM_152396 NM_001301790, NM_001301791, NM_001301792, NM_001330662, NM_152396

CCDS: CCDS43056, CCDS77706, CCDS87051

Canonical transcript exons

ENST00000383790 — 6 exons

Exon	Start	End
ENSE00001498684	15424955	15425089
ENSE00001498685	15426287	15426635
ENSE00001932751	15409760	15411437
ENSE00003481005	15414021	15414162
ENSE00003628756	15415772	15415942
ENSE00003901162	15427402	15427544

Expression profiles

Bgee: expression breadth ubiquitous, 222 present calls, max score 93.96.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.3648 / max 78.0778, expressed in 1759 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
41272	5.6843	1721
41273	1.2434	859
41271	0.3209	125
41270	0.1163	38

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
body of pancreas	UBERON:0001150	93.96	gold quality
right testis	UBERON:0004534	90.35	gold quality
left testis	UBERON:0004533	90.20	gold quality
sperm	CL:0000019	90.16	gold quality
cortical plate	UBERON:0005343	89.42	gold quality
pancreas	UBERON:0001264	89.35	gold quality
ventricular zone	UBERON:0003053	89.28	gold quality
buccal mucosa cell	CL:0002336	88.44	gold quality
testis	UBERON:0000473	88.38	gold quality
calcaneal tendon	UBERON:0003701	87.27	gold quality
ganglionic eminence	UBERON:0004023	86.97	gold quality
prefrontal cortex	UBERON:0000451	86.03	gold quality
stromal cell of endometrium	CL:0002255	85.81	gold quality
islet of Langerhans	UBERON:0000006	85.36	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.83	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	84.64	gold quality
Brodmann (1909) area 9	UBERON:0013540	84.48	gold quality
anterior cingulate cortex	UBERON:0009835	84.41	gold quality
smooth muscle tissue	UBERON:0001135	83.96	gold quality
adrenal tissue	UBERON:0018303	83.83	gold quality
hypothalamus	UBERON:0001898	83.17	gold quality
bone marrow cell	CL:0002092	83.02	gold quality
right frontal lobe	UBERON:0002810	82.91	gold quality
nucleus accumbens	UBERON:0001882	82.59	gold quality
monocyte	CL:0000576	82.52	gold quality
leukocyte	CL:0000738	82.49	gold quality
amygdala	UBERON:0001876	82.48	gold quality
spinal cord	UBERON:0002240	82.46	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	82.31	gold quality
right ovary	UBERON:0002118	82.14	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	5.13

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

82 targeting METTL6, 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-1277-5P	100.00	73.95	5056
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-4650-5P	99.98	64.69	999
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509
HSA-MIR-548C-5P	99.94	71.24	3488
HSA-MIR-548D-5P	99.94	71.23	3502
HSA-MIR-548H-5P	99.94	71.24	3488
HSA-MIR-548I	99.94	71.25	3481
HSA-MIR-548J-5P	99.94	71.14	3489

Literature-anchored findings (GeneRIF, showing 5)

• 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)
• METTL6 is a tRNA m(3)C methyltransferase that regulates pluripotency and tumor cell growth. (PMID:32923617)
• Mutually exclusive substrate selection strategy by human m3C RNA transferases METTL2A and METTL6. (PMID:34268557)
• Crystal structure of human METTL6, the m(3)C methyltransferase. (PMID:34862464)
• Structural basis for METTL6-mediated m3C RNA methylation. (PMID:34922197)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	mettl6	ENSDARG00000070085
mus_musculus	Mettl6	ENSMUSG00000021891
rattus_norvegicus	Mettl6	ENSRNOG00000089254
drosophila_melanogaster	CG34195	FBGN0085224
caenorhabditis_elegans		WBGENE00014205

Paralogs (3): METTL2A (ENSG00000087995), METTL8 (ENSG00000123600), METTL2B (ENSG00000165055)

Protein

Protein identifiers

tRNA N(3)-cytidine methyltransferase METTL6 — Q8TCB7 (reviewed: Q8TCB7)

Alternative names: Methyltransferase-like protein 6

All UniProt accessions (5): B4DDX3, H7C1L4, H7C3H9, M0R0W0, Q8TCB7

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(Ser), including tRNA(Ser)(UGA) and tRNA(Ser)(GCU). Interaction with SARS1/SerRS is required for N(3)-methylcytidine methylation.

Subunit / interactions. Monomer. Interacts with SARS1/SerRS; interaction is mediated via tRNA(Ser) and is required for N(3)-methylcytidine methylation.

Subcellular location. Cytoplasm. Nucleus.

Similarity. Belongs to the methyltransferase superfamily. METL family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8TCB7-1	1	yes
Q8TCB7-2	2

RefSeq proteins (5): NP_001288719, NP_001288720, NP_001288721, NP_001317591, NP_689609* (*=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), 1 shown:

• cytidine(32) in tRNA(Ser) + S-adenosyl-L-methionine = N(3)-methylcytidine(32) in tRNA(Ser) + S-adenosyl-L-homocysteine + H(+) (RHEA:50956)

UniProt features (54 total): binding site 15, helix 14, strand 11, mutagenesis site 8, turn 3, chain 1, splice variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
7EZG	X-RAY DIFFRACTION	1.9
8P7B	ELECTRON MICROSCOPY	2.42
7F1E	X-RAY DIFFRACTION	2.59
8OWX	X-RAY DIFFRACTION	2.6
8OWY	X-RAY DIFFRACTION	3.2
8P7C	ELECTRON MICROSCOPY	3.7
8P7D	ELECTRON MICROSCOPY	4.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8TCB7-F1	92.22	0.81

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 (15): 45; 136; 136; 137; 137; 157; 157; 49; 49; 61; 85; 87 …

Mutagenesis-validated functional residues (8):

Position	Phenotype
49	decreased affinity for s-adenosyl-l-methionine.
61	decreased affinity for s-adenosyl-l-methionine.
85	strongly decreased affinity for s-adenosyl-l-methionine.
93	does not affect affinity for s-adenosyl-l-methionine.
110	nearly abolished affinity for s-adenosyl-l-methionine.
111	decreased affinity for s-adenosyl-l-methionine.
161	strongly reduced rna (cytosine-3-)-methyltransferase activity.
217	strongly reduced rna (cytosine-3-)-methyltransferase activity.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 133 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_UP, GOBP_TRNA_METABOLIC_PROCESS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_RNA_METHYLATION, KEGG_HISTIDINE_METABOLISM, GOBP_RNA_MODIFICATION, TCF11_01, GOBP_TRNA_METHYLATION, TGANTCA_AP1_C, LASTOWSKA_NEUROBLASTOMA_COPY_NUMBER_DN, WHN_B, GOBP_METHYLATION, GOBP_TRNA_PROCESSING, KEGG_TYROSINE_METABOLISM, GOBP_TRNA_MODIFICATION

GO Biological Process (4): tRNA modification (GO:0006400), tRNA methylation (GO:0030488), tRNA processing (GO:0008033), methylation (GO:0032259)

GO Molecular Function (7): enzyme binding (GO:0019899), 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 (2): nucleus (GO:0005634), cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
methyltransferase activity	2
tRNA processing	1
RNA modification	1
RNA methylation	1
tRNA modification	1
RNA processing	1
tRNA metabolic process	1
metabolic process	1
protein binding	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 membrane-bounded organelle	1
intracellular anatomical structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1190 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
METTL6	SARS1	P49591	726
METTL6	M0R2C6	M0R2C6	690
METTL6	SARS2	Q9NP81	690
METTL6	TRMT10B	Q6PF06	608
METTL6	EAF1	Q96JC9	601
METTL6	DALRD3	Q5D0E6	600
METTL6	TRMT10C	Q7L0Y3	560
METTL6	TRMT10A	Q8TBZ6	533
METTL6	RSPRY1	Q96DX4	525
METTL6	NSUN7	Q8NE18	496
METTL6	METTL14	Q9HCE5	490
METTL6	TRDMT1	O14717	486
METTL6	CLXN	Q9HAE3	484
METTL6	METTL5	Q9NRN9	475
METTL6	NSUN5	Q96P11	475

IntAct

21 interactions, top by confidence:

A	B	Type	Score
METTL6	SARS1	psi-mi:“MI:0213”(methylation reaction)	0.700
METTL6	SARS1	psi-mi:“MI:0407”(direct interaction)	0.700
	METTL6	psi-mi:“MI:0213”(methylation reaction)	0.640
	METTL6	psi-mi:“MI:0407”(direct interaction)	0.640
GPANK1	METTL6	psi-mi:“MI:0915”(physical association)	0.560
METTL6	TYW5	psi-mi:“MI:0914”(association)	0.530
	METTL6	psi-mi:“MI:0407”(direct interaction)	0.520
	METTL6	psi-mi:“MI:0407”(direct interaction)	0.440
METTL6	ALDH1A2	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
GPANK1	METTL6	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (32): CCT7 (Affinity Capture-MS), STIM1 (Affinity Capture-MS), PLS1 (Affinity Capture-MS), PDLIM5 (Affinity Capture-MS), WNK1 (Affinity Capture-MS), TYW5 (Affinity Capture-MS), DENND4A (Affinity Capture-MS), FOXC1 (Affinity Capture-MS), PLS1 (Affinity Capture-MS), WNK1 (Affinity Capture-MS), STIM1 (Affinity Capture-MS), DENND4A (Affinity Capture-MS), TYW5 (Affinity Capture-MS), PDLIM5 (Affinity Capture-MS), FOXC1 (Affinity Capture-MS)

ESM2 similar proteins: A0A1E4S2P1, A2BGU9, G5EDL5, G8JVR4, O02218, O16881, O18391, O74421, P0DO69, P0DO70, P34913, P34914, P37059, P53219, P56523, P80299, P91143, Q02337, Q09315, Q0IIS3, Q0KHU5, Q0V9K2, Q22943, Q25489, Q2KHV5, Q2TAP9, Q54M29, Q5BKM6, Q5RDV8, Q5XI79, Q5ZJZ5, Q62730, Q6AXU8, Q6CGE1, Q6GQ37, Q6Q2C2, Q74Z47, Q7L592, Q7QBJ0, Q80XN0

Diamond homologs: A2AUU0, A8KBL7, G0REX6, O74386, Q08641, Q0P5B2, Q5ATG8, Q5M8E6, Q5RDV8, Q5ZHP8, Q6AXU8, Q6P1Q9, Q86BS6, Q8BMK1, Q8BVH9, Q8T199, Q8TCB7, Q96IZ6, Q9H825, 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

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	46
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1779 predictions. Top by Δscore:

Variant	Effect	Δscore
3:15411265:AGGAT:A	donor_gain	1.0000
3:15415767:CTAA:C	donor_loss	1.0000
3:15415768:TAA:T	donor_loss	1.0000
3:15415769:AAC:A	donor_loss	1.0000
3:15415771:C:CT	donor_loss	1.0000
3:15415938:TTTTG:T	acceptor_gain	1.0000
3:15415939:TTTG:T	acceptor_gain	1.0000
3:15415940:TTG:T	acceptor_gain	1.0000
3:15415941:TG:T	acceptor_gain	1.0000
3:15415943:C:CC	acceptor_gain	1.0000
3:15425090:C:CC	acceptor_gain	1.0000
3:15427878:TCGTT:T	donor_gain	1.0000
3:15427881:TT:T	donor_gain	1.0000
3:15427883:G:GG	donor_gain	1.0000
3:15429909:TTA:T	acceptor_loss	1.0000
3:15429910:TA:T	acceptor_loss	1.0000
3:15429911:A:AC	acceptor_loss	1.0000
3:15429911:A:AG	acceptor_gain	1.0000
3:15429911:AGAT:A	acceptor_gain	1.0000
3:15429912:G:GG	acceptor_gain	1.0000
3:15429912:GAT:G	acceptor_gain	1.0000
3:15429912:GATG:G	acceptor_gain	1.0000
3:15429912:GATGA:G	acceptor_gain	1.0000
3:15430003:TCCCT:T	donor_gain	1.0000
3:15430004:CCCT:C	donor_gain	1.0000
3:15430005:CCT:C	donor_gain	1.0000
3:15430005:CCTG:C	donor_loss	1.0000
3:15430006:CT:C	donor_gain	1.0000
3:15430006:CTG:C	donor_loss	1.0000
3:15430007:TGT:T	donor_loss	1.0000

AlphaMissense

1888 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:15411328:G:C	F261L	0.997
3:15411328:G:T	F261L	0.997
3:15411330:A:G	F261L	0.997
3:15415829:A:C	F158L	0.997
3:15415829:A:T	F158L	0.997
3:15415831:A:G	F158L	0.997
3:15426377:C:A	W45C	0.997
3:15426377:C:G	W45C	0.997
3:15426379:A:G	W45R	0.997
3:15426379:A:T	W45R	0.997
3:15414131:C:G	R188P	0.996
3:15414132:G:T	R188S	0.996
3:15426328:A:G	W62R	0.996
3:15426328:A:T	W62R	0.996
3:15426368:A:C	F48L	0.996
3:15426368:A:T	F48L	0.996
3:15426370:A:G	F48L	0.996
3:15414031:A:C	F221L	0.995
3:15414031:A:T	F221L	0.995
3:15414033:A:G	F221L	0.995
3:15414056:C:G	R213T	0.995
3:15426332:T:A	R60S	0.995
3:15426332:T:G	R60S	0.995
3:15426333:C:G	R60T	0.995
3:15426311:A:C	F67L	0.994
3:15426311:A:T	F67L	0.994
3:15426313:A:G	F67L	0.994
3:15426326:C:A	W62C	0.994
3:15426326:C:G	W62C	0.994
3:15426338:T:A	K58N	0.994

dbSNP variants (sampled 300 via entrez): RS1000000393 (3:15384792 T>G), RS1000028728 (3:15426696 T>C), RS1000062227 (3:15427819 C>T), RS1000121476 (3:15427090 G>A), RS1000143824 (3:15419211 G>A), RS1000198183 (3:15381112 G>C), RS1000331106 (3:15399552 G>A,T), RS1000349960 (3:15427608 C>A,T), RS1000386969 (3:15399359 C>A,T), RS1000426681 (3:15387792 T>C), RS1000531754 (3:15422060 G>A,C), RS1000543913 (3:15416151 T>C), RS1000558395 (3:15423865 G>C), RS1000600144 (3:15405615 A>G), RS1000660458 (3:15416430 AT>A)

Disease associations

OMIM: gene MIM:618903 | 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
GCST006479_106	Diverticular disease	3.000000e-18

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0009959	diverticular disease

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

22 total (human), top 22 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, decreases expression	4
dicrotophos	decreases expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
beta-lapachone	decreases expression, increases expression	1
arsenite	affects binding, increases reaction	1
sodium arsenite	increases abundance, increases expression	1
di-n-butylphosphoric acid	affects expression	1
Resveratrol	affects cotreatment, decreases expression, increases expression	1
Arsenic	increases abundance, increases expression	1
Atrazine	decreases expression	1
Cadmium	increases expression, increases abundance	1
Cisplatin	increases response to substance	1
Hydralazine	affects cotreatment, increases expression	1
Methyl Methanesulfonate	increases expression	1
Nickel	decreases expression	1
Plant Extracts	affects cotreatment, decreases expression, increases expression	1
Testosterone	decreases expression	1
Cyclosporine	increases expression	1
Asbestos, Crocidolite	increases methylation	1
Antirheumatic Agents	decreases expression	1
Cadmium Chloride	increases expression, increases abundance	1
Lactic Acid	decreases expression	1

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_SY09	HAP1 METTL6 (-) 1	Cancer cell line	Male
CVCL_SY10	HAP1 METTL6 (-) 2	Cancer cell line	Male
CVCL_SY11	HAP1 METTL6 (-) 3	Cancer cell line	Male
CVCL_SY12	HAP1 METTL6 (-) 4	Cancer cell line	Male

Clinical trials (associated diseases)

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