AS3MT

Summary

AS3MT (arsenite methyltransferase, HGNC:17452) is a protein-coding gene on chromosome 10q24.32, encoding Arsenite methyltransferase (Q9HBK9). Catalyzes the transfer of a methyl group from AdoMet to trivalent arsenicals producing methylated and dimethylated arsenicals.

AS3MT catalyzes the transfer of a methyl group from S-adenosyl-L-methionine (AdoMet) to trivalent arsenical and may play a role in arsenic metabolism (Lin et al., 2002 [PubMed 11790780]).

Source: NCBI Gene 57412 — RefSeq curated summary.

At a glance

• GWAS associations: 45
• Clinical variants (ClinVar): 37 total
• Druggable target: yes
• MANE Select transcript: NM_020682

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17452
Approved symbol	AS3MT
Name	arsenite methyltransferase
Location	10q24.32
Locus type	gene with protein product
Status	Approved
Aliases	CYT19
Ensembl gene	ENSG00000214435
Ensembl biotype	protein_coding
OMIM	611806
Entrez	57412

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000369880, ENST00000942423

RefSeq mRNA: 1 — MANE Select: NM_020682 NM_020682

CCDS: CCDS41567

Canonical transcript exons

ENST00000369880 — 11 exons

Exon	Start	End
ENSE00003506800	102878849	102878991
ENSE00003529361	102874592	102874661
ENSE00003551016	102890544	102890678
ENSE00003576807	102876954	102877035
ENSE00003587396	102873097	102873233
ENSE00003643519	102870084	102870211
ENSE00003649607	102900593	102901899
ENSE00003661944	102872448	102872598
ENSE00003680896	102878379	102878510
ENSE00003683637	102869805	102869845
ENSE00003851131	102869470	102869593

Expression profiles

Bgee: expression breadth ubiquitous, 133 present calls, max score 99.34.

FANTOM5 (CAGE): breadth broad, TPM avg 2.2498 / max 55.3051, expressed in 756 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
106775	2.0643	754
106776	0.1162	65
106777	0.0409	16
205978	0.0285	10

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right adrenal gland	UBERON:0001233	99.34	gold quality
right adrenal gland cortex	UBERON:0035827	99.30	gold quality
left adrenal gland	UBERON:0001234	99.17	gold quality
left adrenal gland cortex	UBERON:0035825	99.17	gold quality
adrenal tissue	UBERON:0018303	98.56	gold quality
adrenal gland	UBERON:0002369	97.13	gold quality
right lobe of liver	UBERON:0001114	89.90	gold quality
liver	UBERON:0002107	89.72	gold quality
apex of heart	UBERON:0002098	89.16	gold quality
heart left ventricle	UBERON:0002084	89.04	gold quality
ganglionic eminence	UBERON:0004023	87.74	gold quality
ventricular zone	UBERON:0003053	87.73	gold quality
right atrium auricular region	UBERON:0006631	87.35	gold quality
heart	UBERON:0000948	87.04	gold quality
spleen	UBERON:0002106	83.58	gold quality
adult mammalian kidney	UBERON:0000082	82.91	gold quality
calcaneal tendon	UBERON:0003701	82.48	gold quality
cerebellar cortex	UBERON:0002129	81.98	gold quality
cerebellar hemisphere	UBERON:0002245	81.98	gold quality
cerebellum	UBERON:0002037	81.96	gold quality
cortex of kidney	UBERON:0001225	81.71	gold quality
body of pancreas	UBERON:0001150	81.43	gold quality
mucosa of stomach	UBERON:0001199	81.30	gold quality
cortical plate	UBERON:0005343	81.17	gold quality
right hemisphere of cerebellum	UBERON:0014890	80.52	gold quality
caudate nucleus	UBERON:0001873	80.31	gold quality
kidney	UBERON:0002113	79.95	gold quality
putamen	UBERON:0001874	79.85	gold quality
nucleus accumbens	UBERON:0001882	79.67	gold quality
hindlimb stylopod muscle	UBERON:0004252	79.67	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.05

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

58 targeting AS3MT, 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-5692A	100.00	74.40	6850
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-3682-5P	99.93	67.97	1163
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-3140-3P	99.88	68.47	2069
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-MIR-548AJ-5P	99.78	71.12	3085
HSA-MIR-548F-5P	99.78	71.02	3093
HSA-MIR-548G-5P	99.78	71.12	3085
HSA-MIR-548X-5P	99.78	71.12	3085
HSA-MIR-6885-3P	99.75	70.36	3187
HSA-MIR-3680-3P	99.75	72.51	3095
HSA-MIR-4524A-3P	99.72	66.85	2406
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-12124	99.68	69.17	2700
HSA-MIR-4804-3P	99.65	67.78	866
HSA-MIR-9851-3P	99.63	69.68	1110
HSA-MIR-4276	99.56	67.66	2514

Literature-anchored findings (GeneRIF, showing 40)

• Heterologous expression of rat AS3MT in human urothelial cells…confers capacity to methylate inorganic arsenic and alters its cytotoxicity and that of methylated arsenicals. (PMID:15808521)
• a strong genetic association between polymorphisms of CYT19 and D:M ratio (urinary dimethylarsenic(V) to monomethylarsenic(V))in drinking water exposed Mexican children, not adults. (PMID:15929903)
• inherited variation in AS3MT may contribute to variation in arsenic metabolism (PMID:16407288)
• is strongly associated with the ratio of urinary dimethylarsinic acid to monomethylarsonic acid (D/M) in children (7-11 years) but not in adults (18-79 years) (PMID:17306849)
• Our results indicate that genetic polymorphisms in AS3MT contribute to inter-individual variation in arsenic biotransformation and, therefore, may contribute to inter-individual variations in risk of arsenic toxicity and arsenic carcinogenesis. (PMID:17850829)
• mutation frequencies of AS3MT in Asian populations were relatively lower than those of African and Caucasian populations: frequencies of mutation in the Mongolian, Korean, and Japanese populations were 0.040, 0.010, and 0.010, respectively (PMID:17889916)
• Individuals with the AS3MT(287)Thr variant display increased arsenic methylation and thus associated with increased risk for the toxic and genotoxic effects of arsenic exposure (PMID:18334919)
• Our findings indicate that genetic susceptibility to arsenic toxicity in Asian is different from Africans and Caucasians. (PMID:18588996)
• intronic single-nucleotide polymorphisms in the AS3MT gene are related to inter-individual variation in arsenic metabolism; The present study is the first to demonstrate genetic heterogeneity in a wide distribution of 5 intronic polymorphisms in AS3MT (PMID:18976679)
• Results describe the effects of selenium(IV) on the structure and function of recombinant human arsenic (+3 oxidation state) methyltransferase (AS3MT) purified from the cytoplasm of Escherichia coli. (PMID:19159958)
• The cysteine residues at positions 156, 206, and 250 play important roles in the enzymatic function and structure of the hAS3MT. (PMID:19167370)
• The relationship between single nucleotide polymorphisms of AS3MT and hair and urine levels of arsenic in male and female Vietnamese are reported. (PMID:19371612)
• These data link the AS3MT-catalyzed methylation of iAs to specific genomic responses in human cells exposed to iAs(III). (PMID:19411561)
• The present study is the first to demonstrate the existence of genetic heterogeneity in a world wide distribution of 18 single nucleotide polymorphisms in AS3MT (PMID:19932709)
• Investigation of 46 SNPs [Mexico]: Genetic association analysis with arsenic metabolism confirmed the previously observed association between AS3MT variants, including this large cluster of linked polymorphisms, and arsenic methylation efficiency (PMID:20014157)
• Data suggest that the inhibitory effect of the ions (Co(2+), Mn(2+), and Zn(2+)) or selenite on AS3MT activity might be via the interactions of them with free Cys residues in human AS3MT to form inactive protein adducts. (PMID:20129672)
• As3MT effects organic arsenic metabolism (PMID:20532380)
• Distribution of 18 SNPs in AS3MT was assessed in healthy individuals in Mexico and Germany: 38 Mestizo, 69 Nahuas, 50 Huicholes, and 32 Germans. (PMID:20571777)
• an ordered sequence for the binding of SAM and arsenite to the hAS3MT; whereas, no interactions between GSH and the hAS3MT were detected. (PMID:20621156)
• enzymatic activity, kinetics, thermal stability and secondary structures of mutant enzyme (PMID:20971157)
• Polymorphisms in AS3MT significantly predicted As metabolism across these two very different populations, suggesting that AS3MT may have an impact on As metabolite patterns in populations worldwide. (PMID:21247820)
• investigation of the roles of AS3MT in the effects of arsenicals, carcinogens found ubiquitously in nature: metabolism, toxicity, and accumulation of arsenicals in hepatocytes (PMID:21537954)
• Two SNPs, AS3MT 12390 (rs3740393) and 14458 (rs11191439) were consistently related to arsenic methylation regardless of the populations examined for the analysis. (PMID:21731446)
• These data suggest that the expression pattern of splicing variants of the As3MT gene may affect the capacity for arsenic methylation in cells. (PMID:22005461)
• Genetic polymorphisms GSTO and As3MT modify arsenic metabolism as evidenced by altered urinary arsenic excretion (PMID:22339537)
• Coronary heart disease and its main risk factors were associated with low-level arsenic exposure, AS3MT polymorphism or both. Hypertension was associated with higher arsenic exposure, while hyperlipidemia was associated AS3MT polymorphism. (PMID:22341486)
• Pregnancy and the AS3MT genotype independently influence the arsenic methylation phenotype (PMID:22547080)
• structural insights into the mechanism of substrate binding and catalysis (PMID:22712827)
• Single nucleotide polymorphisms (SNPs) in arsenic methyltransferase and methylene-tetrahydrofolate reductase is associated with bladder cancer in those exposed to low concentrations of inorganic arsenic. SNPs in glutathione S-transferase omega-1 are not. (PMID:22747749)
• analysis of rapid equilibrium kinetics of arsenite methylation catalyzed by recombinant human arsenic (+3 oxidation state) methyltransferase (hAS3MT) (PMID:22955273)
• Data raise the possibility that, during a few thousand years, natural selection for tolerance to the environmental stressor arsenic may have increased the frequency of protective variants of AS3MT. (PMID:23070617)
• Individuals with M287T and G4965C AS3MT polymorphisms had higher levels of urinary DMAs(III) and were more frequently diabetic than the respective wild-type carriers, although the excess was not statistically significant (PMID:23093101)
• the AS3MT haplotype status strongly predicted DNA methylation and gene expression of AS3MT as well as several genes in 10q2 (PMID:23341986)
• Five N6AMT1 single nucleotide polymorphisms and two N6AMT1 haplotypes were significantly associated with the percentage of methylarsonic acid in urine, even after adjusting for arsenic (+3 oxidation state) methyltransferase haplotype. (PMID:23665909)
• Residues Asp76, 84, 102 and 150 greatly influence hAS3MT catalytic activity, affecting S-adenosylmethionine-binding or methyl transfer. (PMID:23742935)
• A hypomethylated region in the AS3MT promoter was associated with higher arsenic exposure.Arsenic exposure influences the epigenetic regulation of AS3MT. (PMID:24154821)
• Genetic polymorphisms in AS3MT gene in a Western Chinese population influenced urinary arsenic metabolism from arsenic in drinking water. (PMID:24239724)
• when workers were classified according to their AS3MT Met287Thr genotypes, significantly higher micronucleus values were for those carrying the variant allele [odds ratio (OR), 3.4 (1.6-5.2); P=0.0003)] (PMID:24361376)
• AS3MT SNPs were associated with arsenic metabolism efficiency and arsenic toxicity in exposed individuals. (PMID:24536095)
• Low-level arsenic exposure is associated with cognitive functioning; however, this association is modified by an AS3MT gene. (PMID:24621105)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	as3mt	ENSDARG00000027572
mus_musculus	As3mt	ENSMUSG00000003559
rattus_norvegicus	As3mt	ENSRNOG00000020081
caenorhabditis_elegans		WBGENE00019675
caenorhabditis_elegans		WBGENE00019961
caenorhabditis_elegans		WBGENE00019963
caenorhabditis_elegans		WBGENE00019968

Paralogs (4): COQ5 (ENSG00000110871), METTL27 (ENSG00000165171), TMT1B (ENSG00000170439), TMT1A (ENSG00000185432)

Protein

Protein identifiers

Arsenite methyltransferase — Q9HBK9 (reviewed: Q9HBK9)

Alternative names: Methylarsonite methyltransferase, S-adenosyl-L-methionine:arsenic(III) methyltransferase

All UniProt accessions (1): Q9HBK9

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the transfer of a methyl group from AdoMet to trivalent arsenicals producing methylated and dimethylated arsenicals. It methylates arsenite to form methylarsonate, Me-AsO(3)H(2), which is reduced by methylarsonate reductase to methylarsonite, Me-As(OH)2. Methylarsonite is also a substrate and it is converted into the much less toxic compound dimethylarsinate (cacodylate), Me(2)As(O)-OH.

Subcellular location. Cytoplasm. Cytosol.

Miscellaneous. Devoid of methyltransferase activity.

Similarity. Belongs to the methyltransferase superfamily. Arsenite methyltransferase family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9HBK9-1	1	yes
Q9HBK9-2	2, 31.1 kDa, delta4,5

RefSeq proteins (1): NP_065733* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR025714	Methyltranfer_dom	Domain
IPR026669	Arsenite_MeTrfase-like	Family
IPR029063	SAM-dependent_MTases_sf	Homologous_superfamily

Pfam: PF13847

Enzyme classification (BRENDA):

• EC 2.1.1.137 — arsenite methyltransferase (BRENDA: 54 organisms, 46 substrates, 14 inhibitors, 39 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

3 substrates with measured Km, best-characterized 3. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ARSENITE	0.0012–0.0185	27
S-ADENOSYL-L-METHIONINE	0.0031–0.0512	8
METHYLARSONATE	0.0007–0.003	4

Catalyzed reactions (Rhea), 3 shown:

• arsenic triglutathione + 3 [thioredoxin]-dithiol + 3 S-adenosyl-L-methionine = trimethylarsine + 3 [thioredoxin]-disulfide + 3 glutathione + 3 S-adenosyl-L-homocysteine + 3 H(+) (RHEA:69432)
• arsenic triglutathione + [thioredoxin]-dithiol + S-adenosyl-L-methionine + 2 H2O = methylarsonous acid + [thioredoxin]-disulfide + 3 glutathione + S-adenosyl-L-homocysteine + H(+) (RHEA:69460)
• arsenic triglutathione + 2 [thioredoxin]-dithiol + 2 S-adenosyl-L-methionine + H2O = dimethylarsinous acid + 2 [thioredoxin]-disulfide + 3 glutathione + 2 S-adenosyl-L-homocysteine + 2 H(+) (RHEA:69464)

UniProt features (10 total): sequence conflict 4, sequence variant 3, chain 1, modified residue 1, splice variant 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
8XT7	X-RAY DIFFRACTION	2.59

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9HBK9-F1	88.02	0.71

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (1): 335

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-156581	Methylation
R-HSA-1430728	Metabolism
R-HSA-156580	Phase II - Conjugation of compounds
R-HSA-211859	Biological oxidations

MSigDB gene sets: 103 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_DN, REACTOME_BIOLOGICAL_OXIDATIONS, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_DN, GRAESSMANN_RESPONSE_TO_MC_AND_SERUM_DEPRIVATION_DN, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM1, GOBP_TOXIN_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_METABOLIC_PROCESS, RICKMAN_HEAD_AND_NECK_CANCER_A, LASTOWSKA_NEUROBLASTOMA_COPY_NUMBER_DN, GOBP_METHYLATION, IVANOVA_HEMATOPOIESIS_INTERMEDIATE_PROGENITOR, GOMF_S_ADENOSYLMETHIONINE_DEPENDENT_METHYLTRANSFERASE_ACTIVITY, REACTOME_PHASE_II_CONJUGATION_OF_COMPOUNDS, TCANNTGAY_SREBP1_01, GOMF_TRANSFERASE_ACTIVITY_TRANSFERRING_ONE_CARBON_GROUPS

GO Biological Process (3): toxin metabolic process (GO:0009404), arsonoacetate metabolic process (GO:0018872), methylation (GO:0032259)

GO Molecular Function (3): arsenite methyltransferase activity (GO:0030791), methyltransferase activity (GO:0008168), transferase activity (GO:0016740)

GO Cellular Component (2): cytosol (GO:0005829), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Phase II - Conjugation of compounds	1
Biological oxidations	1
Metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
secondary metabolic process	1
xenobiotic metabolic process	1
carboxylic acid metabolic process	1
metabolic process	1
S-adenosylmethionine-dependent methyltransferase activity	1
transferase activity, transferring one-carbon groups	1
catalytic activity	1
cytoplasm	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1586 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AS3MT	BORCS7	Q96B45	798
AS3MT	CNNM2	Q9H8M5	690
AS3MT	GSTO1	P78417	623
AS3MT	GSTO2	Q9H4Y5	620
AS3MT	NT5C2	P49902	618
AS3MT	ARSH	Q5FYA8	613
AS3MT	HEMK2	Q9Y5N5	611
AS3MT	PNP	P00491	543
AS3MT	WBP1L	Q9NX94	541
AS3MT	ARL3	P36405	533
AS3MT	POM121L2	Q96KW2	464
AS3MT	ARSD	P51689	460
AS3MT	ITIH3	Q06033	460
AS3MT	COQ5	Q5HYK3	452
AS3MT	STS	P08842	447

IntAct

5 interactions, top by confidence:

A	B	Type	Score
TCF15	TCF4	psi-mi:“MI:0914”(association)	0.350
LEPR	ANKLE2	psi-mi:“MI:0914”(association)	0.350
	AS3MT	psi-mi:“MI:0915”(physical association)	0.000
AS3MT		psi-mi:“MI:0915”(physical association)	0.000

BioGRID (8): AS3MT (Reconstituted Complex), AS3MT (Affinity Capture-MS), AS3MT (Affinity Capture-MS), AS3MT (Affinity Capture-MS), AS3MT (Affinity Capture-MS), AS3MT (Affinity Capture-MS), AS3MT (Affinity Capture-MS), AS3MT (Proximity Label-MS)

ESM2 similar proteins: A0A024RBG1, A2VE79, A3KMI0, A7E320, B0R160, B6CHA3, F4JLK2, F6UA42, O22951, O45830, O59761, O95989, P0C027, P0C028, P32271, Q08C92, Q09790, Q566C7, Q58CW0, Q5RAF0, Q5RDX4, Q5U243, Q6NPD7, Q6P5D3, Q7TMI3, Q7TPK1, Q7YTB0, Q8BJM7, Q8CIG3, Q8L7W2, Q8NB78, Q8NFP7, Q8R2U6, Q8VDF2, Q8VHT6, Q91WU5, Q96G61, Q96PU4, Q96T88, Q99321

Diamond homologs: A0A0D3MJQ5, A0AK43, A1AI22, A1SRS4, A4WFY5, A5F4E5, A5ISZ9, A6QH20, A6TGL3, A6U1T9, A6UFF7, A6W0X8, A7GN50, A7MTX1, A7X2H6, A7ZU40, A8A6U0, A8ACY2, A8GXR2, A9MIY3, A9MY97, A9VMC2, B1IW72, B1LM21, B1XAJ7, B2TVI4, B4SZ73, B4TBR3, B4TNX9, B5BIX9, B5EZU8, B5FNW6, B5QW73, B5RFM8, B5XYI1, B5YY82, B6I4H5, B7GHP8, B7L996, B7LU01

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	35
Likely benign	0
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

2184 predictions. Top by Δscore:

Variant	Effect	Δscore
10:102869590:GACA:G	donor_gain	1.0000
10:102869594:G:GG	donor_gain	1.0000
10:102870064:A:AG	acceptor_gain	1.0000
10:102870064:ACT:A	acceptor_gain	1.0000
10:102873093:TTAG:T	acceptor_loss	1.0000
10:102873094:TAG:T	acceptor_loss	1.0000
10:102873229:GTTGT:G	donor_gain	1.0000
10:102873230:TTGT:T	donor_gain	1.0000
10:102873231:TGTGT:T	donor_loss	1.0000
10:102873232:GT:G	donor_gain	1.0000
10:102873234:G:GA	donor_loss	1.0000
10:102873234:G:GG	donor_gain	1.0000
10:102874671:A:T	donor_gain	1.0000
10:102874713:GGT:G	donor_gain	1.0000
10:102876952:AGCAT:A	acceptor_gain	1.0000
10:102876953:GC:G	acceptor_gain	1.0000
10:102876953:GCATG:G	acceptor_gain	1.0000
10:102878871:A:AG	acceptor_gain	1.0000
10:102878987:TTAAG:T	donor_loss	1.0000
10:102878988:TAAG:T	donor_loss	1.0000
10:102878988:TAAGG:T	donor_loss	1.0000
10:102878989:AAG:A	donor_loss	1.0000
10:102878989:AAGG:A	donor_loss	1.0000
10:102878990:AGGTA:A	donor_loss	1.0000
10:102878991:GGTA:G	donor_loss	1.0000
10:102878991:GGTAA:G	donor_loss	1.0000
10:102878992:G:A	donor_loss	1.0000
10:102878993:T:A	donor_loss	1.0000
10:102890540:TTAG:T	acceptor_loss	1.0000
10:102890541:TAG:T	acceptor_loss	1.0000

AlphaMissense

2462 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:102878879:G:C	R258P	0.968
10:102876975:A:C	S184R	0.956
10:102876977:T:A	S184R	0.956
10:102876977:T:G	S184R	0.956
10:102878441:T:C	F225L	0.954
10:102878443:C:A	F225L	0.954
10:102878443:C:G	F225L	0.954
10:102878860:T:C	F252L	0.948
10:102878862:T:A	F252L	0.948
10:102878862:T:G	F252L	0.948
10:102874625:A:C	K164N	0.940
10:102874625:A:T	K164N	0.940
10:102878442:T:C	F225S	0.938
10:102878878:C:A	R258S	0.938
10:102874593:T:C	S154P	0.934
10:102890587:T:C	L310S	0.933
10:102878454:G:C	R229P	0.932
10:102874598:C:A	N155K	0.930
10:102874598:C:G	N155K	0.930
10:102872512:A:C	S79R	0.929
10:102872514:T:A	S79R	0.929
10:102872514:T:G	S79R	0.929
10:102872532:C:G	C85W	0.926
10:102878864:T:A	V253D	0.926
10:102874657:T:C	L175P	0.924
10:102878875:T:C	F257L	0.924
10:102878877:T:A	F257L	0.924
10:102878877:T:G	F257L	0.924
10:102873166:T:C	F131L	0.921
10:102873168:T:A	F131L	0.921

dbSNP variants (sampled 300 via entrez): RS1000054821 (10:102888219 C>T), RS1000134191 (10:102901490 G>A,C), RS1000168209 (10:102898160 A>C), RS1000216360 (10:102894524 A>T), RS1000267314 (10:102894912 A>G), RS1000482742 (10:102895353 C>G,T), RS1000493329 (10:102901927 A>G), RS1000509751 (10:102871817 G>A,T), RS1000681263 (10:102879018 T>C), RS1000696126 (10:102874347 G>A), RS1000748905 (10:102887408 T>C), RS1000840600 (10:102882606 T>A), RS1000923160 (10:102890291 C>G,T), RS1000968035 (10:102868682 G>A), RS1001082513 (10:102896431 A>T)

Disease associations

OMIM: gene MIM:611806 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

45 associations (top):

Study	Trait	p-value
GCST000395_3	Systolic blood pressure	7.000000e-24
GCST001421_1	Arsenic metabolism	3.000000e-09
GCST001851_9	Schizophrenia	3.000000e-07
GCST001877_13	Autism spectrum disorder, attention deficit-hyperactivity disorder, bipolar disorder, major depressive disorder, and schizophrenia (combined)	1.000000e-08
GCST001942_1	Prostate cancer	5.000000e-10
GCST002149_2	Schizophrenia	4.000000e-13
GCST002497_1	Blood pressure	4.000000e-09
GCST002539_4	Schizophrenia	6.000000e-19
GCST003151_2	White matter lesion progression	1.000000e-06
GCST003880_1	Schizophrenia	8.000000e-10
GCST004258_2	Diastolic blood pressure (long-term average)	8.000000e-09
GCST004259_3	Mean arterial pressure (long-term average)	1.000000e-11
GCST004521_172	Autism spectrum disorder or schizophrenia	4.000000e-14
GCST004521_78	Autism spectrum disorder or schizophrenia	1.000000e-16
GCST004946_86	Schizophrenia	4.000000e-20
GCST005195_1	Coronary artery disease	5.000000e-15
GCST005196_36	Coronary artery disease	4.000000e-15
GCST005956_50	Waist-to-hip ratio adjusted for BMI	8.000000e-06
GCST005958_15	Waist-to-hip ratio adjusted for BMI (age >50)	4.000000e-06
GCST005962_36	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	6.000000e-07
GCST006168_33	Pulse pressure x alcohol consumption interaction (2df test)	1.000000e-29
GCST006168_59	Pulse pressure x alcohol consumption interaction (2df test)	4.000000e-23
GCST006171_14	Pulse pressure x alcohol consumption (light vs heavy) interaction (2df test)	7.000000e-10
GCST006171_6	Pulse pressure x alcohol consumption (light vs heavy) interaction (2df test)	8.000000e-11
GCST006231_42	Mean arterial pressure	2.000000e-11
GCST006434_20	Systolic blood pressure x alcohol consumption interaction (2df test)	6.000000e-13
GCST006803_4	Schizophrenia	7.000000e-18
GCST007323_57	Risk-taking tendency (4-domain principal component model)	1.000000e-15
GCST007325_25	General risk tolerance (MTAG)	4.000000e-08
GCST007929_45	Medication use (calcium channel blockers)	6.000000e-10

EFO canonical traits (21, from GWAS)

EFO ID	Trait name
EFO:0006335	systolic blood pressure
EFO:0004880	urinary arsenic measurement
EFO:0006340	mean arterial pressure
EFO:0007746	white matter lesion progression measurement
EFO:0006336	diastolic blood pressure
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0004329	alcohol drinking
EFO:0005763	pulse pressure measurement
EFO:0008579	risk-taking behaviour
EFO:0009930	Calcium channel blocker use measurement
EFO:0004337	intelligence
EFO:0004784	self reported educational attainment
EFO:0005670	smoking initiation
EFO:0004346	neuroimaging measurement
EFO:0009863	anxiety measurement
EFO:0004980	appendicular lean mass
EFO:0009749	age at first sexual intercourse measurement
EFO:0010701	mean reticulocyte volume
EFO:0009188	Red cell distribution width

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295950 (SINGLE PROTEIN)

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

PharmGKB variants

3 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs11191439	AS3MT		0.00	0
rs3740390	AS3MT		0.00	0
rs3740393	AS3MT		0.00	0

ChEMBL bioactivities

9 potent at pChembl≥5 of 11 total, top 9 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.85	IC50	1400	nM	CHEMBL4281164
5.82	IC50	1500	nM	CHEMBL4295161
5.75	IC50	1800	nM	CHEMBL3422652
5.54	IC50	2900	nM	CHEMBL4287966
5.52	IC50	3000	nM	CHEMBL3422654
5.48	IC50	3300	nM	CHEMBL3422653
5.44	IC50	3600	nM	CHEMBL4280063
5.30	IC50	5000	nM	CHEMBL3421643
5.08	IC50	8300	nM	CHEMBL3422659

PubChem BioAssay actives

9 with measured affinity, of 13 total; 9 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
2-amino-5-[(3-aminophenyl)methoxy]-1-methylindole-3-carbonitrile	1420365: Inhibition of human AS3MT using NaAsO2 as substrate preincubated for 30 minutes followed by substrate addition measured after 90 mins in presence of SAM	ic50	1.4000	uM
2-amino-N-[4-[2-amino-3-cyano-1-(cyclopropylmethyl)indol-5-yl]oxyphenyl]acetamide	1420365: Inhibition of human AS3MT using NaAsO2 as substrate preincubated for 30 minutes followed by substrate addition measured after 90 mins in presence of SAM	ic50	1.5000	uM
2-amino-N-[4-(2-amino-3-cyano-1-ethylindol-5-yl)oxyphenyl]acetamide	1420365: Inhibition of human AS3MT using NaAsO2 as substrate preincubated for 30 minutes followed by substrate addition measured after 90 mins in presence of SAM	ic50	1.8000	uM
2-amino-N-[3-[(2-amino-3-cyano-1-methylindol-5-yl)oxymethyl]phenyl]-3-hydroxypropanamide	1420365: Inhibition of human AS3MT using NaAsO2 as substrate preincubated for 30 minutes followed by substrate addition measured after 90 mins in presence of SAM	ic50	2.9000	uM
(2S)-2-amino-N-[4-[(2-amino-3-cyano-1H-indol-5-yl)oxy]phenyl]-3-hydroxypropanamide	1420365: Inhibition of human AS3MT using NaAsO2 as substrate preincubated for 30 minutes followed by substrate addition measured after 90 mins in presence of SAM	ic50	3.0000	uM
2-amino-N-[4-(2-amino-3-cyano-1-methylindol-5-yl)oxyphenyl]acetamide	1420365: Inhibition of human AS3MT using NaAsO2 as substrate preincubated for 30 minutes followed by substrate addition measured after 90 mins in presence of SAM	ic50	3.3000	uM
2-amino-5-phenylmethoxy-1H-indole-3-carbonitrile	1420365: Inhibition of human AS3MT using NaAsO2 as substrate preincubated for 30 minutes followed by substrate addition measured after 90 mins in presence of SAM	ic50	3.6000	uM
(2R)-2-amino-N-[4-[(2-amino-3-cyano-1H-indol-5-yl)oxy]phenyl]-3-hydroxypropanamide	1420365: Inhibition of human AS3MT using NaAsO2 as substrate preincubated for 30 minutes followed by substrate addition measured after 90 mins in presence of SAM	ic50	5.0000	uM
2-amino-N-[4-[2-amino-3-cyano-1-[2-(dimethylamino)-2-oxoethyl]indol-5-yl]oxyphenyl]acetamide	1420365: Inhibition of human AS3MT using NaAsO2 as substrate preincubated for 30 minutes followed by substrate addition measured after 90 mins in presence of SAM	ic50	8.3000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Arsenic	increases reaction, decreases reaction, decreases expression, affects abundance, increases metabolic processing (+10 more)	46
sodium arsenite	decreases expression, increases reaction, increases metabolic processing, decreases stability, increases methylation (+7 more)	10
Arsenicals	affects reaction, decreases expression, increases methylation, affects response to substance, affects methylation (+2 more)	8
Cacodylic Acid	increases metabolic processing, increases expression, affects abundance, affects metabolic processing, affects response to substance (+2 more)	7
arsenite	decreases reaction, affects binding, increases methylation, increases chemical synthesis, increases metabolic processing (+1 more)	6
monomethylarsonic acid	increases expression, affects abundance, affects response to substance, increases abundance, affects metabolic processing (+2 more)	6
dimethylarsinous acid	affects abundance, affects binding, increases methylation, increases metabolic processing, increases reaction (+3 more)	5
Valproic Acid	affects cotreatment, decreases expression, affects expression	5
monomethylarsonous acid	affects response to substance, increases chemical synthesis, increases methylation, increases expression, decreases reaction (+1 more)	4
Arsenic Trioxide	increases stability, affects binding, increases reaction, increases expression, affects response to substance (+2 more)	4
Glutathione	increases reduction, affects folding, affects binding, increases methylation, increases reaction (+2 more)	3
S-Adenosylmethionine	affects binding, increases reaction, increases methylation	3
sodium arsenate	increases expression	2
tris(2-carboxyethyl)phosphine	affects folding, affects binding, increases methylation, increases reaction, increases chemical synthesis (+1 more)	2
Cysteine	affects binding, increases methylation, increases reaction, increases chemical synthesis, increases reduction (+1 more)	2
Environmental Pollutants	affects response to substance, decreases expression	2
Nickel	decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Cyclosporine	decreases expression	2
fluorene-9-bisphenol	increases expression	1
bisphenol A	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
butyraldehyde	decreases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
arsenotriglutathione	affects binding	1
K 7174	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, affects cotreatment	1
abrine	decreases expression	1
methylarsonite	increases chemical synthesis, increases reaction	1
dorsomorphin	affects cotreatment, decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4266987	Binding	Inhibition of human AS3MT using NaAsO2 as substrate preincubated for 30 minutes followed by substrate addition measured after 90 mins in presence of SAM	Novel inhibitors of As(III) S-adenosylmethionine methyltransferase (AS3MT) identified by virtual screening. — Bioorg Med Chem Lett

Clinical trials (associated diseases)

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