GNMT

Summary

GNMT (glycine N-methyltransferase, HGNC:4415) is a protein-coding gene on chromosome 6p21.1, encoding Glycine N-methyltransferase (Q14749). Catalyzes the methylation of glycine by using S-adenosylmethionine (AdoMet) to form N-methylglycine (sarcosine) with the concomitant production of S-adenosylhomocysteine (AdoHcy), a reaction regulated by the binding of 5-methyltetrahydrofolate.

The protein encoded by this gene is an enzyme that catalyzes the conversion of S-adenosyl-L-methionine (along with glycine) to S-adenosyl-L-homocysteine and sarcosine. This protein is found in the cytoplasm and acts as a homotetramer. Defects in this gene are a cause of GNMT deficiency (hypermethioninemia). Alternative splicing results in multiple transcript variants. Naturally occurring readthrough transcription occurs between the upstream CNPY3 (canopy FGF signaling regulator 3) gene and this gene and is represented with GeneID:107080644.

Source: NCBI Gene 27232 — RefSeq curated summary.

At a glance

• Gene–disease (curated): glycine N-methyltransferase deficiency (Strong, GenCC)
• GWAS associations: 4
• Clinical variants (ClinVar): 9 total
• Phenotypes (HPO): 4
• Druggable target: yes
• MANE Select transcript: NM_018960

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4415
Approved symbol	GNMT
Name	glycine N-methyltransferase
Location	6p21.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000124713
Ensembl biotype	protein_coding
OMIM	606628
Entrez	27232

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 6 protein_coding

ENST00000372808, ENST00000858684, ENST00000858685, ENST00000858686, ENST00000858687, ENST00000858688

RefSeq mRNA: 3 — MANE Select: NM_018960 NM_001318856, NM_001318865, NM_018960

CCDS: CCDS4876

Canonical transcript exons

ENST00000372808 — 6 exons

Exon	Start	End
ENSE00000850009	42962212	42962339
ENSE00000850010	42962762	42962878
ENSE00000850011	42963072	42963214
ENSE00000850012	42963328	42963449
ENSE00001458709	42963535	42963880
ENSE00001458743	42960754	42960973

Expression profiles

Bgee: expression breadth ubiquitous, 164 present calls, max score 98.12.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.8891 / max 326.8628, expressed in 127 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
67845	0.7574	84
67844	0.0742	24
67843	0.0575	25

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
body of pancreas	UBERON:0001150	98.12	gold quality
right lobe of liver	UBERON:0001114	98.00	gold quality
liver	UBERON:0002107	94.83	gold quality
body of stomach	UBERON:0001161	84.51	gold quality
pancreas	UBERON:0001264	83.02	gold quality
prostate gland	UBERON:0002367	79.88	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	77.88	gold quality
stomach	UBERON:0000945	77.37	gold quality
apex of heart	UBERON:0002098	77.24	gold quality
granulocyte	CL:0000094	76.89	gold quality
mucosa of stomach	UBERON:0001199	75.31	gold quality
pituitary gland	UBERON:0000007	73.91	gold quality
adenohypophysis	UBERON:0002196	73.74	gold quality
parotid gland	UBERON:0001831	73.46	gold quality
saliva-secreting gland	UBERON:0001044	72.04	gold quality
fundus of stomach	UBERON:0001160	71.84	gold quality
minor salivary gland	UBERON:0001830	71.64	gold quality
cortical plate	UBERON:0005343	71.29	gold quality
monocyte	CL:0000576	71.13	gold quality
mononuclear cell	CL:0000842	70.94	gold quality
leukocyte	CL:0000738	70.74	gold quality
right lung	UBERON:0002167	70.15	gold quality
heart left ventricle	UBERON:0002084	69.55	gold quality
cardiac ventricle	UBERON:0002082	69.10	gold quality
right hemisphere of cerebellum	UBERON:0014890	68.26	gold quality
cerebellar hemisphere	UBERON:0002245	67.93	gold quality
cerebellar cortex	UBERON:0002129	67.77	gold quality
mouth mucosa	UBERON:0003729	67.54	gold quality
spleen	UBERON:0002106	67.22	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	66.81	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-10553	yes	31.90
E-GEOD-81547	yes	18.28
E-ANND-3	yes	16.23

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR

miRNA regulators (miRDB)

6 targeting GNMT, 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-7161-5P	99.68	68.92	1592
HSA-MIR-548U	99.65	67.78	1463
HSA-MIR-6778-5P	98.19	66.59	1239
HSA-MIR-1291	96.28	65.89	1224
HSA-MIR-4300	95.85	64.56	1003
HSA-MIR-5591-5P	95.85	64.76	1002

Literature-anchored findings (GeneRIF, showing 31)

• compound heterzygotes in the gene that encodes GNMT have evidence of mild liver disease (PMID:11810299)
• Results suggest that GNMT alteration may be an early event in hepatocellular carcinoma development and that GNMT could be a new tumor susceptibility gene for hepatocellular carcinoma. (PMID:12566309)
• GNMT 1289 C–>T polymorphism influences plasma homocysteine and is responsive to folate intake. (PMID:16317120)
• GNMT is destabilized by a mutation. (PMID:17660255)
• Glycine N-methyltransferase is a favorable prognostic marker for human cholangiocarcinoma. (PMID:18624901)
• GNMT is a tumor suppressor gene for liver cancer, and it is associated with gender disparity in liver cancer susceptibility as shown in humans and in mouse models (PMID:19035462)
• A transgenic mouse model is used together with in vitro methods to study the ability of the GNMT transgene to block the cytotoxic or carcinogenic activity of aflatoxin B1, a known causal agent of human hepatocellular carcinoma. (PMID:19146867)
• Study identified a GNMT transcriptional start site at the 14th position upstream of the ATG codon; results indicate binding of the nuclear factor-Y (NF-Y) transcription factor to the CCAAT box (-71/-67) of the GNMT gene. (PMID:19439180)
• investigation of role of GNMT in methyl group homeostasis in liver: GNMT affects transmethylation kinetics, SAM synthesis, and conservation of methyl groups by limiting homocysteine remethylation flux; possible role of GNMT inactivation in hepatoma (PMID:21411609)
• GNMT may represent a novel marker of malignant progression and poor prognosis in prostate cancer (PMID:21572396)
• This study suggests that the glycine N-methyltransferase STRP1 phenotype could modulate urinary 1-hydroxypyrene and 8-hydroxy-2’-deoxyguanosine levels in coke-oven workers exposed to PAHs. (PMID:21691217)
• In conclusion, GNMT regulates hepatocellular carcinoma growth in part through interacting with DEPDC6/DEPTOR and modulating mTOR/raptor signaling pathway (PMID:22160218)
• This is the first report demonstrating that GNMT plays an important role in regulating cholesterol homeostasis via interaction with NPC2 (PMID:22183894)
• GNMT plays important role in maintaining normal function of brain; lack of GNMT causes dysfunction of important signaling pathways and results in alterations of neurotransmitter secretion as well as changes in neuropsychological behavior. (PMID:22264868)
• GNMT is a crucial regulator in cholesterol metabolism and in inflammation, and contributes to the pathogenesis of atherosclerosis. (PMID:22415010)
• Report SNPs that are highly associated with hepatic GNMT protein expression and the coordinate regulation of MAT1A levels. (PMID:22807109)
• single-nucleotide polymorphisms in VEGF, IL-10 and GNMT genes might have a synergistic role in the development of Prostate cancer (PMID:22850906)
• DNA hypermethylation plays an important role in the repression of GNMT in hepatocellular carcinoma (HCC), and loss of GNMT in human HCC could promote the establishment of aberrant DNA methylation patterns at specific gene promoters (PMID:23475283)
• GNMT is an androgen receptor-targeted gene with its functional androgen response element located at +19/+33 of the first exon. (PMID:23883094)
• The studies identify GNMT as a direct transcriptional target of the AR. (PMID:23997240)
• In men of European descent, the GNMT rs10948059 and short tandem repeat polymorphism 1 were associated with prostate cancer risk. (PMID:24800880)
• Elevated GNMT protein expression is associated with pathogenesis of hepatocellular carcinoma. (PMID:28205209)
• miR-224 can target the glycine N-methyltransferase (GNMT) mRNA coding sequence and plays an important role in GNMT suppression during liver tumorigenesis (PMID:30115977)
• Common glycine N-methyltransferase variant genotypes increase the risk of cleft lip with or without cleft palate. (PMID:30318092)
• Exosomal miR-224 can decrease the expression of GNMT by directly targeting the 3’-UTR of GNMT mRNA to promote the proliferation and invasion of hepatocellular carcinoma (HCC) cells. In addition, serum exosomal miR-224 may be used as a biomarker for the diagnosis of HCC and a prognostic factor for patients with HCC. (PMID:31057302)
• Total liver phosphatidylcholine content associates with non-alcoholic steatohepatitis and glycine N-methyltransferase expression. (PMID:31199045)
• Polymorphisms in GNMT and DNMT3b are associated with methotrexate treatment outcome in plaque psoriasis. (PMID:33714108)
• Downregulation of Methionine Cycle Genes MAT1A and GNMT Enriches Protein-Associated Translation Process and Worsens Hepatocellular Carcinoma Prognosis. (PMID:35008908)
• Chemical Biopsy for GNMT as Noninvasive and Tumorigenesis-Relevant Diagnosis of Liver Cancer. (PMID:36602057)
• Folic Acid Ameliorates Renal Injury in Experimental Obstructive Nephropathy: Role of Glycine N-Methyltransferase. (PMID:37047834)
• ERVK13-1/miR-873-5p/GNMT Axis Promotes Metastatic Potential in Human Bladder Cancer though Sarcosine Production. (PMID:38003554)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	gnmt	ENSDARG00000006840
mus_musculus	Gnmt	ENSMUSG00000002769
rattus_norvegicus	Gnmt	ENSRNOG00000016349
drosophila_melanogaster	Gnmt	FBGN0038074

Protein

Protein identifiers

Glycine N-methyltransferase — Q14749 (reviewed: Q14749)

All UniProt accessions (3): A0A0S2Z5F2, Q14749, V9HW60

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the methylation of glycine by using S-adenosylmethionine (AdoMet) to form N-methylglycine (sarcosine) with the concomitant production of S-adenosylhomocysteine (AdoHcy), a reaction regulated by the binding of 5-methyltetrahydrofolate. Plays an important role in the regulation of methyl group metabolism by regulating the ratio between S-adenosyl-L-methionine and S-adenosyl-L-homocysteine.

Subunit / interactions. Homotetramer.

Subcellular location. Cytoplasm.

Tissue specificity. Expressed only in liver, pancreas, and prostate.

Disease relevance. Glycine N-methyltransferase deficiency (GNMT deficiency) [MIM:606664] The only clinical abnormalities in patients with this deficiency are mild hepatomegaly and chronic elevation of serum transaminases. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Inhibited by 5-methyltetrahydrofolate monoglutamate and by 5-methyltetrahydrofolate pentaglutamate, inhibition is much more effective by the pentaglutamate form than by the monoglutamate form. Two molecules of 5-methyltetrahydrofolate are bound per tetramer. The binding sites are localized between subunits. Inhibitor binding may preclude movements of the polypeptide chain that are necessary for enzyme activity.

Similarity. Belongs to the class I-like SAM-binding methyltransferase superfamily. Glycine N-methyltransferase family.

RefSeq proteins (3): NP_001305785, NP_001305794, NP_061833* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR014369	Gly/Sar_N_MeTrfase	Family
IPR029063	SAM-dependent_MTases_sf	Homologous_superfamily
IPR041698	Methyltransf_25	Domain

Pfam: PF13649

Enzyme classification (BRENDA):

• EC 2.1.1.20 — glycine N-methyltransferase (BRENDA: 9 organisms, 19 substrates, 34 inhibitors, 40 Km, 29 kcat entries)

Substrate kinetics (BRENDA)

4 substrates with measured Km, best-characterized 4. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
S-ADENOSYL-L-METHIONINE	0.014–1.136	17
GLY	0.0122–30	10
GLYCINE	0.13–38.8	10
S-ADENOSYLMETHIONINE	0.03–0.1	2

Catalyzed reactions (Rhea), 1 shown:

• glycine + S-adenosyl-L-methionine = sarcosine + S-adenosyl-L-homocysteine + H(+) (RHEA:19937)

UniProt features (58 total): binding site 16, strand 12, helix 11, modified residue 7, sequence conflict 4, sequence variant 3, turn 3, initiator methionine 1, chain 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
1R74	X-RAY DIFFRACTION	2.55
2AZT	X-RAY DIFFRACTION	2.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q14749-F1	88.75	0.69

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 (16): 86–88; 117–118; 139–142; 178; 217; 223; 242; 242; 4; 6; 6; 22 …

Post-translational modifications (7): 2, 10, 34, 46, 193, 198, 203

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-2408508	Metabolism of ingested SeMet, Sec, MeSec into H2Se
R-HSA-389661	Glyoxylate metabolism and glycine degradation
R-HSA-9925561	Developmental Lineage of Pancreatic Acinar Cells

MSigDB gene sets: 167 (showing top): GOBP_PROTEIN_HOMOTETRAMERIZATION, GNF2_GSTM1, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, GNF2_HPN, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, MODULE_404, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, MODULE_379, GOBP_S_ADENOSYLMETHIONINE_METABOLIC_PROCESS, MARTINEZ_RB1_TARGETS_DN, GOBP_REGULATION_OF_CARBOHYDRATE_METABOLIC_PROCESS, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM4

GO Biological Process (9): glycogen metabolic process (GO:0005977), regulation of gluconeogenesis (GO:0006111), L-methionine metabolic process (GO:0006555), one-carbon metabolic process (GO:0006730), methylation (GO:0032259), obsolete S-adenosylhomocysteine metabolic process (GO:0046498), S-adenosylmethionine metabolic process (GO:0046500), protein homotetramerization (GO:0051289), obsolete sarcosine metabolic process (GO:1901052)

GO Molecular Function (9): folic acid binding (GO:0005542), glycine binding (GO:0016594), glycine N-methyltransferase activity (GO:0017174), identical protein binding (GO:0042802), S-adenosyl-L-methionine binding (GO:1904047), protein binding (GO:0005515), methyltransferase activity (GO:0008168), S-adenosylmethionine-dependent methyltransferase activity (GO:0008757), 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
Selenoamino acid metabolism	1
Metabolism of amino acids and derivatives	1
Developmental Cell Lineages of the Exocrine Pancreas	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
carboxylic acid binding	2
cation binding	2
cellular anatomical structure	2
energy reserve metabolic process	1
glucan metabolic process	1
gluconeogenesis	1
regulation of glucose metabolic process	1
regulation of carbohydrate biosynthetic process	1
sulfur amino acid metabolic process	1
L-amino acid metabolic process	1
proteinogenic amino acid metabolic process	1
small molecule metabolic process	1
metabolic process	1
sulfur compound metabolic process	1
protein homooligomerization	1
protein tetramerization	1
vitamin binding	1
modified amino acid binding	1
heterocyclic compound binding	1
amino acid binding	1
N-methyltransferase activity	1
S-adenosylmethionine-dependent methyltransferase activity	1
protein binding	1
sulfur compound binding	1
binding	1
transferase activity, transferring one-carbon groups	1
methyltransferase activity	1
catalytic activity	1
cytoplasm	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1022 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GNMT	SARDH	Q9UL12	912
GNMT	BHMT	Q93088	830
GNMT	AHCY	P23526	752
GNMT	MAT1A	Q00266	742
GNMT	MTR	Q99707	719
GNMT	MTHFR	P42898	702
GNMT	DMGDH	Q9UI17	691
GNMT	H7C2H4	H7C2H4	686
GNMT	P0DN79	P0DN79	686
GNMT	MAT2B	Q9NZL9	635
GNMT	MAT2A	P31153	620
GNMT	PEMT	Q9UBM1	608
GNMT	CTH	P32929	600
GNMT	GAMT	Q14353	594
GNMT	SHMT1	P34896	591

IntAct

82 interactions, top by confidence:

A	B	Type	Score
GNMT	ARRB1	psi-mi:“MI:0915”(physical association)	0.890
ARRB1	GNMT	psi-mi:“MI:0915”(physical association)	0.890
ARRB1	GNMT	psi-mi:“MI:0403”(colocalization)	0.890
GNMT	GNMT	psi-mi:“MI:0915”(physical association)	0.800
NTAQ1	GNMT	psi-mi:“MI:0915”(physical association)	0.670
GNMT	NTAQ1	psi-mi:“MI:0915”(physical association)	0.670
GCD7	GNMT	psi-mi:“MI:0915”(physical association)	0.560
GNMT	TAE1	psi-mi:“MI:0915”(physical association)	0.560
GNMT	GCD7	psi-mi:“MI:0915”(physical association)	0.560
GNMT	GNMT	psi-mi:“MI:0915”(physical association)	0.560
GNMT	DRC12	psi-mi:“MI:0915”(physical association)	0.560
HPRT1	GNMT	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (50): GNMT (Two-hybrid), GNMT (Two-hybrid), ADAMTSL4 (Two-hybrid), WDYHV1 (Two-hybrid), KRTAP4-2 (Two-hybrid), KRTAP10-3 (Two-hybrid), NOTCH2NL (Two-hybrid), GNMT (Two-hybrid), PLEKHF2 (Two-hybrid), NIF3L1 (Two-hybrid), GNMT (Two-hybrid), NUDT18 (Two-hybrid), GNMT (Two-hybrid), HDAC7 (Two-hybrid), GNMT (Affinity Capture-Western)

ESM2 similar proteins: A1Z3X3, A3KFX0, A4GWN3, E9Q4Z2, O00763, P13255, P50747, P82922, Q0J035, Q14749, Q1LZ96, Q28559, Q28C34, Q29513, Q29555, Q3TFD2, Q3UHE1, Q3UX43, Q5E9L7, Q5IH13, Q5IH14, Q5ZJT0, Q60HG1, Q64311, Q68EN5, Q6NWD4, Q6NYU2, Q6Q0N3, Q6ZN16, Q80YV4, Q86UY8, Q8BJQ9, Q8C092, Q8C5H8, Q8N6S4, Q8NFZ0, Q8TDX6, Q91W86, Q91XQ2, Q91YY4

Diamond homologs: A0AK43, A1TSA0, A3MZ07, A5W7G3, A6TBT7, A7MPA9, A7MU79, A7ZP50, A8A296, A9KGL7, A9MJY3, A9NBI0, B0KTX4, B0UUV6, B0V5X4, B0VMN8, B1IXV6, B1J5G4, B1LLI3, B1X8C6, B2I023, B2TW20, B2VIL6, B3H0C8, B4SYU8, B4TBE3, B4TPG0, B5BCS0, B5EYW1, B5FNR7, B5R249, B5RCA1, B5XNZ3, B5YX17, B6I7I7, B6J1W2, B6J5Y2, B7H2Y9, B7IBN2, B7LAP9

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
PKA	unknown	GNMT	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 32 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Processive synthesis on the C-strand of the telomere	5	181.3×	2e-09
Telomere C-strand (Lagging Strand) Synthesis	5	181.3×	2e-09
Removal of the Flap Intermediate from the C-strand	5	151.1×	4e-09
Telomere Extension By Telomerase	5	108.8×	2e-08
Polymerase switching on the C-strand of the telomere	5	100.7×	3e-08
Packaging Of Telomere Ends	5	52.3×	7e-07
Recognition and association of DNA glycosylase with site containing an affected purine	5	48.5×	8e-07
Cleavage of the damaged purine	5	48.5×	8e-07

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of telomere maintenance	5	94.6×	2e-07

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	4
Likely benign	2
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

801 predictions. Top by Δscore:

Variant	Effect	Δscore
6:42960972:GG:G	donor_gain	1.0000
6:42960973:GG:G	donor_gain	1.0000
6:42962196:C:CA	acceptor_gain	1.0000
6:42962199:T:TA	acceptor_gain	1.0000
6:42962200:G:A	acceptor_gain	1.0000
6:42962203:C:CA	acceptor_gain	1.0000
6:42962210:A:AG	acceptor_gain	1.0000
6:42962210:AG:A	acceptor_gain	1.0000
6:42962210:AGGGT:A	acceptor_gain	1.0000
6:42962211:G:GT	acceptor_gain	1.0000
6:42962211:GG:G	acceptor_gain	1.0000
6:42962211:GGGTG:G	acceptor_gain	1.0000
6:42962335:GTGGG:G	donor_gain	1.0000
6:42962337:GGG:G	donor_gain	1.0000
6:42962338:GGG:G	donor_gain	1.0000
6:42962338:GGGTA:G	donor_loss	1.0000
6:42962340:G:GC	donor_loss	1.0000
6:42962341:T:G	donor_loss	1.0000
6:42962752:T:A	acceptor_gain	1.0000
6:42962758:CTAGT:C	acceptor_loss	1.0000
6:42962759:TA:T	acceptor_loss	1.0000
6:42962760:A:AG	acceptor_gain	1.0000
6:42962760:A:G	acceptor_loss	1.0000
6:42962761:G:GA	acceptor_gain	1.0000
6:42962761:GT:G	acceptor_gain	1.0000
6:42962761:GTC:G	acceptor_gain	1.0000
6:42962761:GTCA:G	acceptor_gain	1.0000
6:42962761:GTCAT:G	acceptor_gain	1.0000
6:42962876:AAG:A	donor_gain	1.0000
6:42962877:AG:A	donor_gain	1.0000

AlphaMissense

1935 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:42962255:A:C	S84R	1.000
6:42962257:T:A	S84R	1.000
6:42962257:T:G	S84R	1.000
6:42960964:G:A	C66Y	0.999
6:42960965:T:G	C66W	0.999
6:42960972:G:T	G69W	0.999
6:42962220:C:T	S72F	0.999
6:42962277:T:C	M91T	0.999
6:42962336:T:A	W111R	0.999
6:42962336:T:C	W111R	0.999
6:42960858:T:A	W31R	0.998
6:42960858:T:C	W31R	0.998
6:42960860:G:C	W31C	0.998
6:42960860:G:T	W31C	0.998
6:42960973:G:A	G69E	0.998
6:42962220:C:A	S72Y	0.998
6:42962267:A:C	S88R	0.998
6:42962268:G:T	S88I	0.998
6:42962269:T:A	S88R	0.998
6:42962269:T:G	S88R	0.998
6:42962278:G:A	M91I	0.998
6:42962278:G:C	M91I	0.998
6:42962278:G:T	M91I	0.998
6:42962338:G:C	W111C	0.998
6:42962338:G:T	W111C	0.998
6:42962779:T:A	W118R	0.998
6:42962779:T:C	W118R	0.998
6:42962839:T:C	C138R	0.998
6:42962841:C:G	C138W	0.998
6:42962850:C:A	N141K	0.998

dbSNP variants (sampled 300 via entrez): RS1000421413 (6:42959963 C>A), RS1000528575 (6:42963027 G>A), RS1000598444 (6:42961878 T>A), RS1001052245 (6:42964324 C>G,T), RS1002318103 (6:42959271 C>T), RS1002944587 (6:42961744 G>A,T), RS1002998791 (6:42961940 A>C), RS1003266448 (6:42960272 G>A,C), RS1003728272 (6:42960652 C>T), RS1004410365 (6:42962031 A>T), RS1004733162 (6:42963732 C>G), RS1004741384 (6:42960748 G>A,C), RS1006987072 (6:42963898 T>C), RS1007841525 (6:42959517 G>A,C), RS1007989413 (6:42962560 C>T)

Disease associations

OMIM: gene MIM:606628 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
glycine N-methyltransferase deficiency	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
glycine N-methyltransferase deficiency	Limited	AR

Mondo (1): glycine N-methyltransferase deficiency (MONDO:0011698)

Orphanet (0):

HPO phenotypes

4 total (4 of 4 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0002240	Hepatomegaly
HP:0002910	Elevated circulating hepatic transaminase concentration
HP:0003235	Hypermethioninemia

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST002391_1	Plasma homocysteine levels (post-methionine load test)	2.000000e-63
GCST006585_1655	Blood protein levels	2.000000e-61
GCST010243_166	Apolipoprotein B levels	3.000000e-21
GCST010245_24	LDL cholesterol levels	1.000000e-09

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004578	homocysteine measurement
EFO:0004615	apolipoprotein B measurement
EFO:0004611	low density lipoprotein cholesterol measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523295 (SINGLE PROTEIN)

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs10948059	Toxicity	3	mercaptopurine	Acute lymphoblastic leukemia

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs10948059	GNMT	3	5.50	1	mercaptopurine

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
8.07	IC50	8.6	nM	CHEMBL4874278
6.82	IC50	150	nM	CHEMBL4850353
6.58	IC50	260	nM	CHEMBL4875728
6.41	IC50	390	nM	CHEMBL4869943
6.19	IC50	640	nM	CHEMBL4849284
5.94	IC50	1150	nM	CHEMBL4870702
5.66	IC50	2200	nM	CHEMBL4857500
5.57	IC50	2700	nM	CHEMBL4868791

PubChem BioAssay actives

7 with measured affinity, of 6100 total; 7 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
3-[[(2S,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methylsulfanylmethyl]benzoic acid	1777104: Inhibition of N-terminal His-tagged human recombinant Glycine-N-methyltransferase (1 to 295 residues) expressed in Escherichia coli using glycine and SAM as substrate incubated for 30 mins by HTRF assay	ic50	0.0086	uM
(2R,3R,4S,5S)-2-(6-aminopurin-9-yl)-5-(naphthalen-2-ylmethylsulfanylmethyl)oxolane-3,4-diol	1777104: Inhibition of N-terminal His-tagged human recombinant Glycine-N-methyltransferase (1 to 295 residues) expressed in Escherichia coli using glycine and SAM as substrate incubated for 30 mins by HTRF assay	ic50	0.2600	uM
(2R,3R,4S,5S)-2-(6-aminopurin-9-yl)-5-[2-(2H-triazol-4-yl)ethylsulfanylmethyl]oxolane-3,4-diol	1777104: Inhibition of N-terminal His-tagged human recombinant Glycine-N-methyltransferase (1 to 295 residues) expressed in Escherichia coli using glycine and SAM as substrate incubated for 30 mins by HTRF assay	ic50	0.3900	uM
5-[[(2S,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methylsulfanylmethyl]-1,2-dihydropyrazol-3-one	1777104: Inhibition of N-terminal His-tagged human recombinant Glycine-N-methyltransferase (1 to 295 residues) expressed in Escherichia coli using glycine and SAM as substrate incubated for 30 mins by HTRF assay	ic50	0.6400	uM
3-[1-[[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl]triazol-4-yl]propanoic acid	1777104: Inhibition of N-terminal His-tagged human recombinant Glycine-N-methyltransferase (1 to 295 residues) expressed in Escherichia coli using glycine and SAM as substrate incubated for 30 mins by HTRF assay	ic50	1.1500	uM
3-[[(2S,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolane-2-carbonyl]amino]benzoic acid	1777104: Inhibition of N-terminal His-tagged human recombinant Glycine-N-methyltransferase (1 to 295 residues) expressed in Escherichia coli using glycine and SAM as substrate incubated for 30 mins by HTRF assay	ic50	2.2000	uM
4-[[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl-(2-phenylethyl)amino]butanoic acid	1777104: Inhibition of N-terminal His-tagged human recombinant Glycine-N-methyltransferase (1 to 295 residues) expressed in Escherichia coli using glycine and SAM as substrate incubated for 30 mins by HTRF assay	ic50	2.7000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression, decreases methylation	6
Aflatoxin B1	decreases reaction, increases abundance, affects localization, decreases response to substance, affects expression (+2 more)	6
Tetrachlorodibenzodioxin	affects cotreatment, decreases expression, affects expression	4
lasiocarpine	decreases expression	2
methyleugenol	decreases expression	2
2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline	decreases expression	2
Acetaminophen	decreases expression	2
N-Nitrosopyrrolidine	decreases expression	2
Cyclosporine	decreases expression	2
aristolochic acid I	increases expression	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
pirinixic acid	decreases expression	1
bisphenol A	affects expression	1
senecionine	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	decreases expression	1
aflatoxin Q1	decreases secretion	1
2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine	decreases expression	1
aflatoxin B1-DNA adduct	decreases reaction, increases abundance	1
perfluorooctane sulfonic acid	decreases expression	1
tebuconazole	decreases expression	1
cylindrospermopsin	decreases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
2-palmitoylglycerol	increases expression	1
clothianidin	decreases expression	1
nutlin 3	affects cotreatment, increases expression	1
abrine	decreases expression	1
pyrachlostrobin	decreases expression	1
enzalutamide	decreases expression	1

ChEMBL screening assays

6 unique, capped per target: 3 admet, 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4416339	ADMET	Inhibition of human GNMT expressed in Escherichia coli at 10 uM assessed as reduction in SAH level using glycine as substrate in presence of SAM incubated for 30 mins by LC-MS/MS analysis relative to control	High-Affinity Alkynyl Bisubstrate Inhibitors of Nicotinamide N-Methyltransferase (NNMT). — J Med Chem
CHEMBL5227826	Binding	Induction of GNMT in human H7GPL cells assessed as fold increase in promoter-driven luciferase reporter expression at 10 uM measured after 24 hrs by luminescence assay relative to control	Discovery of an Orally Efficacious MYC Inhibitor for Liver Cancer Using a GNMT-Based High-Throughput Screening System and Structure-Activity Relationship Analysis. — J Med Chem

Clinical trials (associated diseases)

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