METTL18

Summary

METTL18 (methyltransferase 18, RPL3 N3(tau)-histidine, HGNC:28793) is a protein-coding gene on chromosome 1q24.2, encoding Histidine protein methyltransferase 1 homolog (O95568). Protein-L-histidine N-tele-methyltransferase that specifically monomethylates RPL3, thereby regulating translation elongation.

Enables heat shock protein binding activity and protein-L-histidine N-tele-methyltransferase activity. Involved in peptidyl-lysine monomethylation; regulation of gene expression; and regulation of ribosome biogenesis. Located in cytosol and nucleolus. Part of protein-containing complex.

Source: NCBI Gene 92342 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 3 total
• MANE Select transcript: NM_033418

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28793
Approved symbol	METTL18
Name	methyltransferase 18, RPL3 N3(tau)-histidine
Location	1q24.2
Locus type	gene with protein product
Status	Approved
Aliases	MGC9084, AsTP2, HPM1
Ensembl gene	ENSG00000171806
Ensembl biotype	protein_coding
OMIM	615255
Entrez	92342

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 9 protein_coding

ENST00000303469, ENST00000310392, ENST00000454472, ENST00000910251, ENST00000910252, ENST00000910253, ENST00000910254, ENST00000937804, ENST00000937805

RefSeq mRNA: 3 — MANE Select: NM_033418 NM_001320199, NM_001320201, NM_033418

CCDS: CCDS1284

Canonical transcript exons

ENST00000310392 — 2 exons

Exon	Start	End
ENSE00001173049	169792529	169793897
ENSE00001192697	169794815	169794907

Expression profiles

Bgee: expression breadth ubiquitous, 271 present calls, max score 87.23.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 4.5402 / max 104.1038, expressed in 1500 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
15864	4.1640	1474
15863	0.3762	199

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	87.23	gold quality
calcaneal tendon	UBERON:0003701	85.58	gold quality
tendon	UBERON:0000043	84.33	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.70	gold quality
granulocyte	CL:0000094	82.77	gold quality
epithelium of nasopharynx	UBERON:0001951	82.47	gold quality
nasopharynx	UBERON:0001728	82.45	gold quality
palpebral conjunctiva	UBERON:0001812	81.72	gold quality
hair follicle	UBERON:0002073	81.58	silver quality
tendon of biceps brachii	UBERON:0008188	81.41	gold quality
amniotic fluid	UBERON:0000173	81.37	gold quality
germinal epithelium of ovary	UBERON:0001304	80.28	gold quality
islet of Langerhans	UBERON:0000006	80.27	gold quality
lymph node	UBERON:0000029	79.97	gold quality
ventricular zone	UBERON:0003053	78.63	gold quality
parietal pleura	UBERON:0002400	78.55	gold quality
spleen	UBERON:0002106	78.31	gold quality
mucosa of transverse colon	UBERON:0004991	78.31	gold quality
ganglionic eminence	UBERON:0004023	77.92	gold quality
cortical plate	UBERON:0005343	77.78	gold quality
rectum	UBERON:0001052	77.67	gold quality
pleura	UBERON:0000977	76.98	gold quality
endothelial cell	CL:0000115	76.93	gold quality
esophagus squamous epithelium	UBERON:0006920	76.92	gold quality
pancreas	UBERON:0001264	76.88	gold quality
leukocyte	CL:0000738	76.46	gold quality
oral cavity	UBERON:0000167	76.41	gold quality
endometrium	UBERON:0001295	76.27	gold quality
body of pancreas	UBERON:0001150	75.92	gold quality
skin of hip	UBERON:0001554	75.88	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-MTAB-7303	no	122.69
E-ANND-3	no	2.22

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 2)

• Human METTL18 is a histidine-specific methyltransferase that targets RPL3 and affects ribosome biogenesis and function. (PMID:33693809)
• METTL18-mediated histidine methylation of RPL3 modulates translation elongation for proteostasis maintenance. (PMID:35674491)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	mettl18	ENSDARG00000074588
mus_musculus	Mettl18	ENSMUSG00000041396
rattus_norvegicus	Mettl18	ENSRNOG00000025189
drosophila_melanogaster	CG17219	FBGN0031494
caenorhabditis_elegans		WBGENE00010450

Protein

Protein identifiers

Histidine protein methyltransferase 1 homolog — O95568 (reviewed: O95568)

Alternative names: Arsenic-transactivated protein 2, Methyltransferase-like protein 18

All UniProt accessions (2): O95568, Q5TI78

UniProt curated annotations — full annotation on UniProt →

Function. Protein-L-histidine N-tele-methyltransferase that specifically monomethylates RPL3, thereby regulating translation elongation. Histidine methylation of RPL3 regulates translation elongation by slowing ribosome traversal on tyrosine codons: slower elongation provides enough time for proper folding of synthesized proteins and prevents cellular aggregation of tyrosine-rich proteins.

Subunit / interactions. Interacts with GRWD1 and members of the heat shock protein 90 and 70 families; these proteins may possibly be methylation substrates for the enzyme.

Subcellular location. Cytoplasm. Cytosol. Nucleus. Nucleolus.

Post-translational modifications. Monomethylated at His-154 through automethylation. Automethylation at His-154 positively regulates the methyltransferase activity toward RPL3. Probably methylated on other residues.

Similarity. Belongs to the methyltransferase superfamily. METTL18 family.

RefSeq proteins (3): NP_001307128, NP_001307130, NP_219486* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR019410	Methyltransf_16	Family
IPR029063	SAM-dependent_MTases_sf	Homologous_superfamily

Pfam: PF13489

Catalyzed reactions (Rhea), 1 shown:

• L-histidyl-[protein] + S-adenosyl-L-methionine = N(tele)-methyl-L-histidyl-[protein] + S-adenosyl-L-homocysteine + H(+) (RHEA:19369)

UniProt features (50 total): strand 15, helix 11, binding site 5, sequence variant 5, mutagenesis site 4, modified residue 3, region of interest 2, compositionally biased region 2, chain 1, short sequence motif 1, turn 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
4RFQ	X-RAY DIFFRACTION	2.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O95568-F1	74.51	0.51

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 (5): 293; 168–172; 195; 216–218; 268–270

Post-translational modifications (3): 72, 77, 154

Mutagenesis-validated functional residues (4):

Position	Phenotype
154	no effect on automethylation. loss of protein-l-histidine n-tele-methyltransferase activity toward rpl3.
193–197	abolished protein-l-histidine n-tele-methyltransferase activity.
217	loss of protein-l-histidine n-tele-methyltransferase activity.
250–251	decreased localization to the nucleus.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 117 (showing top): GOBP_RIBOSOME_BIOGENESIS, BORCZUK_MALIGNANT_MESOTHELIOMA_UP, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GOBP_REGULATION_OF_TRANSLATIONAL_ELONGATION, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_TRANSLATION, GOBP_POST_TRANSCRIPTIONAL_REGULATION_OF_GENE_EXPRESSION, GOBP_PEPTIDYL_LYSINE_MODIFICATION, WCTCNATGGY_UNKNOWN, GOBP_TRANSLATIONAL_ELONGATION, GOBP_METHYLATION, GOBP_RIBONUCLEOPROTEIN_COMPLEX_BIOGENESIS, GOBP_PEPTIDYL_LYSINE_METHYLATION, FOX_Q2, GOBP_REGULATION_OF_TRANSLATION

GO Biological Process (7): regulation of translation (GO:0006417), regulation of translational elongation (GO:0006448), peptidyl-lysine monomethylation (GO:0018026), regulation of ribosome biogenesis (GO:0090069), regulation of rRNA processing (GO:2000232), cytoplasmic translation (GO:0002181), methylation (GO:0032259)

GO Molecular Function (5): protein-L-histidine N-tele-methyltransferase activity (GO:0018064), heat shock protein binding (GO:0031072), protein binding (GO:0005515), methyltransferase activity (GO:0008168), transferase activity (GO:0016740)

GO Cellular Component (5): nucleus (GO:0005634), nucleolus (GO:0005730), cytosol (GO:0005829), protein-containing complex (GO:0032991), cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
translation	2
cellular anatomical structure	2
post-transcriptional regulation of gene expression	1
regulation of protein metabolic process	1
translational elongation	1
regulation of translation	1
peptidyl-lysine methylation	1
ribosome biogenesis	1
regulation of cellular component biogenesis	1
rRNA processing	1
regulation of gene expression	1
regulation of RNA metabolic process	1
metabolic process	1
N-methyltransferase activity	1
protein methyltransferase activity	1
S-adenosylmethionine-dependent methyltransferase activity	1
protein binding	1
binding	1
transferase activity, transferring one-carbon groups	1
catalytic activity	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular membraneless organelle	1
cytoplasm	1
cellular_component	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

986 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
METTL18	METTL21A	Q8WXB1	735
METTL18	METTL22	Q9BUU2	717
METTL18	VCPKMT	Q9H867	717
METTL18	RPL3	P39023	705
METTL18	ETFBKMT	Q8IXQ9	687
METTL18	KIN	O60870	665
METTL18	METTL9	Q9H1A3	651
METTL18	METTL23	Q86XA0	628
METTL18	EEF1AKMT3	Q96AZ1	601
METTL18	EEF2KMT	Q96G04	601
METTL18	METTL21C	Q5VZV1	592
METTL18	EEF1AKMT2	Q5JPI9	589
METTL18	CAMKMT	Q7Z624	585
METTL18	EEF1AKMT1	Q8WVE0	571
METTL18	METTL27	Q8N6F8	561

IntAct

25 interactions, top by confidence:

A	B	Type	Score
PRICKLE3	SIAH2	psi-mi:“MI:0914”(association)	0.530
PRICKLE3	METTL18	psi-mi:“MI:0914”(association)	0.530
METTL18	rl3_rl3l_human	psi-mi:“MI:0915”(physical association)	0.500
B3GALT4	METTL18	psi-mi:“MI:0915”(physical association)	0.370
YAE1	METTL18	psi-mi:“MI:0915”(physical association)	0.370
METTL18	RGS2	psi-mi:“MI:0915”(physical association)	0.370
ESR1	ESYT2	psi-mi:“MI:0914”(association)	0.350
SSX2	SSX5	psi-mi:“MI:0914”(association)	0.350
rl3_rl3l_human	MPHOSPH10	psi-mi:“MI:0914”(association)	0.350
S100B	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
CCL3	KRBA1	psi-mi:“MI:0914”(association)	0.350
FNDC8	ZNF609	psi-mi:“MI:0914”(association)	0.350
TMEM45B	METTL18	psi-mi:“MI:0914”(association)	0.350
TTC39A	METTL18	psi-mi:“MI:0914”(association)	0.350
MND1	SH3PXD2B	psi-mi:“MI:0914”(association)	0.350
SMAD4	SBNO1	psi-mi:“MI:0914”(association)	0.350
PHKA2	STK25	psi-mi:“MI:0914”(association)	0.350
PTGES2	COX7A2L	psi-mi:“MI:0914”(association)	0.350
FCGRT	WBP4	psi-mi:“MI:0914”(association)	0.350
TAGAP	METTL18	psi-mi:“MI:0914”(association)	0.350
IMPA1	METTL18	psi-mi:“MI:0914”(association)	0.350
RPL3	GTPBP10	psi-mi:“MI:0914”(association)	0.350
PHYHIP	METTL18	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (66): LAMB4 (Co-fractionation), METTL18 (Affinity Capture-MS), METTL18 (Affinity Capture-MS), METTL18 (Affinity Capture-MS), METTL18 (Two-hybrid), METTL18 (Affinity Capture-MS), METTL18 (Affinity Capture-RNA), METTL18 (Affinity Capture-MS), METTL18 (Affinity Capture-MS), METTL18 (Affinity Capture-MS), METTL18 (Affinity Capture-MS), METTL18 (Affinity Capture-MS), RPL3 (Affinity Capture-MS), METTL18 (Affinity Capture-MS), METTL18 (Affinity Capture-MS)

ESM2 similar proteins: A4D126, A4II32, A6NDL7, A6QP81, B0K012, E1B8U2, E1BCH6, O55055, O95568, P50747, Q149N8, Q28IN4, Q2KIJ2, Q2T9W2, Q3U2J5, Q498D5, Q4AC99, Q4KM84, Q58DC7, Q5RE14, Q5VZV1, Q6DJF8, Q6GQ33, Q6GR37, Q6ZMV9, Q7SY78, Q7TPQ3, Q80WC9, Q8BLU2, Q8BSE0, Q8C436, Q8CDZ2, Q8K2I9, Q8NE18, Q8NFZ0, Q8WXB1, Q95LL7, Q96EN8, Q96LZ7, Q9BTF0

Diamond homologs: A2AA28, A4FV42, A4FV98, A4IGU3, A6NDL7, A6QP81, A7IQW5, D3YWP0, F4JNX3, O14118, O95568, P0CU27, P40389, P47163, P53970, Q28IN4, Q2KIJ2, Q4KM84, Q55DL2, Q58DC7, Q5BLD8, Q5RE14, Q5RJL2, Q5VZV1, Q6DJF8, Q86XA0, Q8BLU2, Q8C436, Q8CDZ2, Q8R1C6, Q8WXB1, Q96AZ1, Q9BUU2, Q9CQL0, Q9CZ09, Q9H867, Q4I2X5, Q7VAM5, Q9UTQ8, P38347

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	3
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

135 predictions. Top by Δscore:

Variant	Effect	Δscore
1:169793893:CAGCT:C	acceptor_gain	0.9900
1:169793894:AGCT:A	acceptor_gain	0.9800
1:169793896:CT:C	acceptor_gain	0.9800
1:169793897:TC:T	acceptor_loss	0.9800
1:169793898:C:A	acceptor_loss	0.9800
1:169793898:C:CC	acceptor_gain	0.9800
1:169793895:GCT:G	acceptor_gain	0.9600
1:169793896:CTC:C	acceptor_gain	0.9600
1:169793897:TCT:T	acceptor_gain	0.9600
1:169793898:C:G	acceptor_gain	0.9600
1:169794685:T:A	donor_gain	0.9000
1:169794565:TA:T	donor_gain	0.8900
1:169794150:TAC:T	donor_gain	0.8600
1:169794199:G:C	donor_gain	0.8600
1:169794628:T:C	donor_gain	0.8600
1:169794648:CGGG:C	donor_gain	0.8600
1:169794152:C:CT	donor_gain	0.8500
1:169794346:ATGG:A	donor_gain	0.8400
1:169793894:A:T	acceptor_gain	0.8300
1:169794206:G:A	donor_gain	0.8300
1:169794270:TC:T	donor_gain	0.8200
1:169794324:C:A	donor_gain	0.8200
1:169794149:C:CT	donor_gain	0.8100
1:169794150:T:TT	donor_gain	0.8100
1:169794153:C:CT	donor_gain	0.8100
1:169794258:T:TA	donor_gain	0.8100
1:169794243:T:C	donor_gain	0.7900
1:169794614:C:A	donor_gain	0.7900
1:169794631:A:AC	donor_gain	0.7900
1:169794632:C:CC	donor_gain	0.7900

AlphaMissense

2466 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:169792725:T:A	K324I	0.997
1:169792888:A:G	W270R	0.994
1:169792888:A:T	W270R	0.994
1:169792727:G:C	S323R	0.993
1:169792727:G:T	S323R	0.993
1:169792729:T:G	S323R	0.993
1:169792724:T:A	K324N	0.992
1:169792724:T:G	K324N	0.992
1:169792815:T:A	E294V	0.992
1:169793172:A:G	L175P	0.992
1:169793183:A:C	C171W	0.991
1:169793189:C:A	W169C	0.991
1:169793189:C:G	W169C	0.991
1:169793191:A:G	W169R	0.991
1:169793191:A:T	W169R	0.991
1:169792712:A:C	F328L	0.988
1:169792712:A:T	F328L	0.988
1:169792714:A:G	F328L	0.988
1:169793047:C:G	D217H	0.988
1:169792886:C:A	W270C	0.986
1:169792886:C:G	W270C	0.986
1:169793108:A:C	C196W	0.986
1:169793185:A:G	C171R	0.985
1:169793046:T:G	D217A	0.984
1:169792731:G:T	A322D	0.983
1:169793100:C:T	G199D	0.983
1:169792819:A:G	S293P	0.982
1:169793109:C:T	C196Y	0.982
1:169792613:C:A	R361S	0.979
1:169792613:C:G	R361S	0.979

dbSNP variants (sampled 300 via entrez): RS1000357893 (1:169795914 G>A,T), RS1001074639 (1:169792627 C>G,T), RS1001750158 (1:169795552 G>T), RS1003874865 (1:169793846 A>G), RS1005117596 (1:169796580 C>A,G,T), RS1005497624 (1:169795011 C>G,T), RS1007169086 (1:169796388 T>C), RS1007699631 (1:169792030 C>T), RS1008289849 (1:169793806 A>C,G), RS1008466643 (1:169794147 C>G), RS1008797172 (1:169792905 C>A,T), RS1010059911 (1:169794669 T>C,G), RS1010112457 (1:169794927 C>A), RS1010660820 (1:169792191 A>C,T), RS1012460739 (1:169792246 T>C)

Disease associations

OMIM: gene MIM:615255 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases methylation, affects expression, decreases expression	4
Vorinostat	decreases expression, increases expression	2
Air Pollutants	decreases expression, increases abundance, affects expression, affects cotreatment	2
Ozone	decreases expression, increases abundance, affects expression, affects cotreatment	2
aristolochic acid I	decreases expression	1
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, decreases expression, increases abundance	1
2,5,2’,5’-tetrachlorobiphenyl	increases expression	1
trichostatin A	affects expression	1
sodium arsenite	affects expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
ferrous chloride	decreases expression	1
methacrylaldehyde	decreases expression, increases abundance, affects cotreatment	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
MT19c compound	increases expression	1
Resveratrol	increases expression	1
Acetaminophen	decreases expression	1
Acrolein	affects cotreatment, decreases expression, increases abundance	1
Cadmium	increases abundance, increases expression	1
Estradiol	decreases expression	1
Formaldehyde	decreases expression	1
Methyl Methanesulfonate	increases expression	1
Potassium Chloride	decreases response to substance, decreases expression	1
Quercetin	decreases expression	1
Dronabinol	decreases expression, decreases response to substance	1
Thimerosal	increases expression	1
Urethane	decreases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	affects expression	1

Cellosaurus cell lines

6 cell lines: 3 transformed cell line, 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_F1XD	HEK293T METTL18 KO	Transformed cell line	Female
CVCL_F1XF	HEK293T SETD3-METTL18 DKO	Transformed cell line	Female
CVCL_F1XG	HEK293T METTL18 KO METTL18-HA	Transformed cell line	Female
CVCL_SX96	HAP1 METTL18 (-) 1	Cancer cell line	Male
CVCL_SX97	HAP1 METTL18 (-) 2	Cancer cell line	Male
CVCL_SX98	HAP1 METTL18 (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

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