GATM

Summary

GATM (glycine amidinotransferase, HGNC:4175) is a protein-coding gene on chromosome 15q21.1, encoding Glycine amidinotransferase, mitochondrial (P50440). Transamidinase that catalyzes the transfer of the amidino group of L-arginine onto the amino moiety of acceptor metabolites such as glycine, beta-alanine, gamma-aminobutyric acid (GABA) and taurine yielding the corresponding guanidine derivatives.

This gene encodes a mitochondrial enzyme that belongs to the amidinotransferase family. This enzyme is involved in creatine biosynthesis, whereby it catalyzes the transfer of a guanido group from L-arginine to glycine, resulting in guanidinoacetic acid, the immediate precursor of creatine. Mutations in this gene cause arginine:glycine amidinotransferase deficiency, an inborn error of creatine synthesis characterized by cognitive disability, language impairment, and behavioral disorders.

Source: NCBI Gene 2628 — RefSeq curated summary.

At a glance

• Gene–disease (curated): AGAT deficiency (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 22
• Clinical variants (ClinVar): 666 total — 18 pathogenic, 20 likely-pathogenic
• Phenotypes (HPO): 69
• MANE Select transcript: NM_001482

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4175
Approved symbol	GATM
Name	glycine amidinotransferase
Location	15q21.1
Locus type	gene with protein product
Status	Approved
Aliases	AGAT
Ensembl gene	ENSG00000171766
Ensembl biotype	protein_coding
OMIM	602360
Entrez	2628

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 15 protein_coding, 4 nonsense_mediated_decay, 4 retained_intron, 3 protein_coding_CDS_not_defined

ENST00000396659, ENST00000458245, ENST00000527933, ENST00000558118, ENST00000558163, ENST00000558336, ENST00000558362, ENST00000558537, ENST00000558916, ENST00000559885, ENST00000560538, ENST00000561148, ENST00000561376, ENST00000674905, ENST00000675158, ENST00000675323, ENST00000675701, ENST00000675974, ENST00000676090, ENST00000887711, ENST00000887712, ENST00000887713, ENST00000887714, ENST00000887715, ENST00000887716, ENST00000887717

RefSeq mRNA: 2 — MANE Select: NM_001482 NM_001321015, NM_001482

CCDS: CCDS10122

Canonical transcript exons

ENST00000396659 — 9 exons

Exon	Start	End
ENSE00001847421	45361124	45362221
ENSE00001879768	45378385	45378544
ENSE00003478448	45363900	45364016
ENSE00003525729	45364797	45364860
ENSE00003592356	45368070	45368260
ENSE00003597982	45366371	45366508
ENSE00003619044	45366046	45366210
ENSE00003630636	45376601	45376819
ENSE00003666656	45369326	45369521

Expression profiles

Bgee: expression breadth ubiquitous, 289 present calls, max score 99.74.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 22.3253 / max 3529.2777, expressed in 962 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
149696	21.2731	733
149706	0.6128	319
149697	0.1490	79
149707	0.0745	20
149703	0.0728	10
149705	0.0436	11
149698	0.0379	16
149704	0.0206	6
149701	0.0166	6
149702	0.0164	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
body of pancreas	UBERON:0001150	99.74	gold quality
adult organism	UBERON:0007023	99.55	gold quality
right lobe of liver	UBERON:0001114	99.48	gold quality
jejunal mucosa	UBERON:0000399	99.47	gold quality
liver	UBERON:0002107	99.46	gold quality
renal medulla	UBERON:0000362	99.20	gold quality
corpus callosum	UBERON:0002336	99.20	gold quality
nephron tubule	UBERON:0001231	99.15	gold quality
adult mammalian kidney	UBERON:0000082	99.14	gold quality
trigeminal ganglion	UBERON:0001675	99.12	gold quality
olfactory bulb	UBERON:0002264	99.04	gold quality
spinal cord	UBERON:0002240	98.86	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	98.85	gold quality
ventricular zone	UBERON:0003053	98.83	gold quality
inferior vagus X ganglion	UBERON:0005363	98.73	gold quality
dorsal root ganglion	UBERON:0000044	98.68	gold quality
kidney epithelium	UBERON:0004819	98.64	gold quality
subthalamic nucleus	UBERON:0001906	98.46	gold quality
pancreas	UBERON:0001264	98.42	gold quality
duodenum	UBERON:0002114	98.39	gold quality
upper leg skin	UBERON:0004262	98.39	gold quality
amygdala	UBERON:0001876	98.26	gold quality
superior vestibular nucleus	UBERON:0007227	98.26	gold quality
tibial nerve	UBERON:0001323	98.20	gold quality
caudate nucleus	UBERON:0001873	98.00	gold quality
renal glomerulus	UBERON:0000074	97.98	gold quality
jejunum	UBERON:0002115	97.88	gold quality
skin of hip	UBERON:0001554	97.87	gold quality
medulla oblongata	UBERON:0001896	97.84	gold quality
metanephric glomerulus	UBERON:0004736	97.84	gold quality

Single-cell (SCXA)

Detected in 10 experiment(s), a significant marker in 9.

Experiment	Marker?	Max mean expression
E-MTAB-8381	yes	745.58
E-HCAD-9	yes	58.49
E-GEOD-134144	yes	46.54
E-HCAD-10	yes	44.75
E-MTAB-10553	yes	40.79
E-GEOD-81547	yes	28.89
E-MTAB-5061	yes	20.56
E-CURD-112	yes	17.11
E-HCAD-31	no	3.10
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GLI1, HNF4A

miRNA regulators (miRDB)

129 targeting GATM, 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-4768-5P	100.00	69.49	2861
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-MIR-98-5P	99.98	72.33	1787
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-557	99.96	70.01	1640

Literature-anchored findings (GeneRIF, showing 17)

• AGAT mRNA expression was significantly elevated in all heart failure patients and returned to normal levels after recovery, suggesting a specific response to heart failure involving elevated local creatine synthesis. (PMID:16820567)
• GATM sequencing revealed a homozygous single nucleotide insertion 1111_1112insA, producing a frame-shift at Met-371 and premature termination at codon 376. (PMID:20682460)
• promiscuous activity of AGAT, a key enzyme in creatine synthesis, plays a pivotal role in homoarginine synthesis (PMID:23010440)
• Genome-wide association reveals that plasma homoarginine is strongly associated with single nucleotide polymorphisms in the AGAT gene. (PMID:24004504)
• Meta-analysis yielded a marginal, but null, association of GATM rs9806699 with statin-induced myopathy. (PMID:25863251)
• AGAT deficiency is a treatable intellectual disability. (PMID:26490222)
• Data suggest that creatine is provided equally by diet and by endogenous synthesis from arginine and glycine with successive involvement of arginine glycine amidinotransferase [AGAT] and guanidinoacetate methyl transferase [GAMT]. [REVIEW] (PMID:26542286)
• Results show the functional characterization of rare missense variants in GATM which cause GATM deficiency. Seven of them report 0% of wild-type GATM activity indicating a putative pathogenicity. (PMID:27233232)
• Measurements of creatine and guanidinoacetate in plasma are recommended for the diagnosis of AGAT and GAMT deficiency.Definitive confirmation of the diagnosis requires DNA sequencing of the appropriate gene and (if molecular analysis is ambiguous) measurement of AGAT or GAMT enzyme activity or of CRTR-mediated transport . (PMID:28055022)
• Here, we provide genetic, histologic, cell biologic, and structural evidence for the association between monoallelic GATM mutations and a genetic disorder characterized by renal Fanconi syndrome and progressive kidney failure. (PMID:29654216)
• The association of GATM polymorphism with statin-induced myopathy: a systematic review and meta-analysis. (PMID:33051696)
• Correlation between single-nucleotide polymorphisms and statin-induced myopathy: a mixed-effects model meta-analysis. (PMID:33150478)
• Polymorphism in the GATM Locus Associated with Dialysis-Independent Chronic Kidney Disease but Not Dialysis-Dependent Kidney Failure. (PMID:34071541)
• A novel variant in GATM causes idiopathic renal Fanconi syndrome and predicts progression to end-stage kidney disease. (PMID:36148635)
• Association of Familial Fanconi Syndrome with a Novel GATM Variant. (PMID:37286521)
• Evidence of an intracellular creatine-sensing mechanism that modulates creatine biosynthesis via AGAT expression in human HAP1 cells. (PMID:38104212)
• ClinGen variant curation expert panel recommendations for classification of variants in GAMT, GATM and SLC6A8 for cerebral creatine deficiency syndromes. (PMID:38452609)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	gatm	ENSDARG00000036239
mus_musculus	Gatm	ENSMUSG00000027199
rattus_norvegicus	Gatm	ENSRNOG00000000168

Protein

Protein identifiers

Glycine amidinotransferase, mitochondrial — P50440 (reviewed: P50440)

Alternative names: L-arginine:glycine amidinotransferase, Transamidinase

All UniProt accessions (11): P50440, A0A140VK19, A0A6Q8PF48, A0A6Q8PFC6, A0A6Q8PGA2, A0A6Q8PHC6, H0YKW9, H0YL75, H0YLC6, H0YMX4, H0YN43

UniProt curated annotations — full annotation on UniProt →

Function. Transamidinase that catalyzes the transfer of the amidino group of L-arginine onto the amino moiety of acceptor metabolites such as glycine, beta-alanine, gamma-aminobutyric acid (GABA) and taurine yielding the corresponding guanidine derivatives. Catalyzes the rate-limiting step of creatine biosynthesis, namely the transfer of the amidino group from L-arginine to glycine to generate guanidinoacetate, which is then methylated by GAMT to form creatine. Provides creatine as a source for ATP generation in tissues with high energy demands, in particular skeletal muscle, heart and brain.

Subunit / interactions. Homodimer. There is an equilibrium between the monomeric and dimeric forms, shifted towards the side of the monomer.

Subcellular location. Mitochondrion inner membrane Cytoplasm.

Tissue specificity. Expressed in brain, heart, kidney, liver, lung, salivary gland and skeletal muscle tissue, with the highest expression in kidney. Biallelically expressed in placenta and fetal tissues.

Disease relevance. Cerebral creatine deficiency syndrome 3 (CCDS3) [MIM:612718] An autosomal recessive disorder characterized by developmental delay/regression, intellectual disability, severe disturbance of expressive and cognitive speech, and severe depletion of creatine/phosphocreatine in the brain. Most patients develop a myopathy characterized by muscle weakness and atrophy later in life. The disease is caused by variants affecting the gene represented in this entry. Fanconi renotubular syndrome 1 (FRTS1) [MIM:134600] A form of Fanconi renotubular syndrome, a disease due to a generalized dysfunction of the proximal kidney tubule resulting in decreased solute and water reabsorption. Patients have polydipsia and polyuria with phosphaturia, glycosuria and aminoaciduria. They may develop hypophosphatemic rickets or osteomalacia, acidosis and a tendency toward dehydration. Some eventually develop renal insufficiency. FRTS1 inheritance is autosomal dominant. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. One chain folds into a compact single domain composed of repeating units, five beta-beta-alpha-beta modules, which surround the central active site.

Induction. Expression is elevated in the myocardium during heart failure, and decreased in inter-uterine growth restriction (IUGR)-associated placenta.

Pathway. Amine and polyamine biosynthesis; creatine biosynthesis; creatine from L-arginine and glycine: step 1/2.

Similarity. Belongs to the amidinotransferase family.

Isoforms (3)

UniProt ID	Names	Canonical?
P50440-1	1, Mitochondrial	yes
P50440-2	2, Cytoplasmic
P50440-3	3

RefSeq proteins (2): NP_001307944, NP_001473* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR033195	AmidinoTrfase	Family

Enzyme classification (BRENDA):

• EC 2.1.4.1 — glycine amidinotransferase (BRENDA: 24 organisms, 51 substrates, 25 inhibitors, 35 Km, 2 kcat entries)

Substrate kinetics (BRENDA)

10 substrates with measured Km, best-characterized 10. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ARGININE	1.8–14.3	10
GLYCINE	0.89–18	8
ETHANOLAMINE	163–450	4
3-AMINOPROPIONIC ACID	57.4–57.5	2
4-AMINOBUTYRIC ACID	24.9–27.2	2
5-AMINOVALERIC ACID	23.5–23.9	2
LYSINE	23–23.5	2
L-ARGININE	3.5	1
ORNITHINE	0.011	1
TAURINE	392	1

Catalyzed reactions (Rhea), 4 shown:

• L-arginine + glycine = guanidinoacetate + L-ornithine (RHEA:13201)
• 4-aminobutanoate + L-arginine = 4-guanidinobutanoate + L-ornithine (RHEA:75939)
• beta-alanine + L-arginine = 3-guanidinopropanoate + L-ornithine (RHEA:75943)
• taurine + L-arginine = taurocyamine + L-ornithine (RHEA:75947)

UniProt features (92 total): sequence variant 22, strand 22, helix 16, mutagenesis site 9, binding site 5, sequence conflict 4, turn 4, modified residue 3, active site 3, splice variant 2, transit peptide 1, chain 1

Structure

Experimental structures (PDB)

11 structures.

PDB	Method	Resolution (Å)
1JDW	X-RAY DIFFRACTION	1.9
2JDW	X-RAY DIFFRACTION	2.1
8JDW	X-RAY DIFFRACTION	2.3
7JDW	X-RAY DIFFRACTION	2.37
1JDX	X-RAY DIFFRACTION	2.4
3JDW	X-RAY DIFFRACTION	2.4
4JDW	X-RAY DIFFRACTION	2.5
6JDW	X-RAY DIFFRACTION	2.5
9JDW	X-RAY DIFFRACTION	2.5
5JDW	X-RAY DIFFRACTION	2.6
2JDX	X-RAY DIFFRACTION	2.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P50440-F1	90.24	0.85

Functional residue map

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

Catalytic / active sites (3): 254; 303; 407 (amidino-cysteine intermediate)

Ligand- & substrate-binding residues (5): 170; 305; 322; 354; 355

Post-translational modifications (3): 46, 49, 385

Mutagenesis-validated functional residues (9):

Position	Phenotype
170	complete loss of activity.
233	complete loss of activity; when associated with s-407.
254	significantly reduced activity.
303	complete loss of activity.
305	complete loss of activity.
322	significantly reduced activity.
355	significantly reduced activity.
407	complete loss of activity; when associated with k-233.
410	no effect on activity.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-71288	Creatine metabolism

MSigDB gene sets: 458 (showing top): GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_UP, VERHAAK_AML_WITH_NPM1_MUTATED_DN, LEE_NEURAL_CREST_STEM_CELL_DN, GOBP_COGNITION, GRUETZMANN_PANCREATIC_CANCER_DN, GOBP_BEHAVIOR, CROONQUIST_NRAS_SIGNALING_UP, BROWNE_HCMV_INFECTION_16HR_UP, TOMLINS_PROSTATE_CANCER_DN, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_BIOSYNTHETIC_PROCESS, MODULE_503, MODULE_66, KRASNOSELSKAYA_ILF3_TARGETS_DN, CAIRO_HEPATOBLASTOMA_CLASSES_DN

GO Biological Process (5): creatine metabolic process (GO:0006600), creatine biosynthetic process (GO:0006601), learning or memory (GO:0007611), muscle atrophy (GO:0014889), positive regulation of cold-induced thermogenesis (GO:0120162)

GO Molecular Function (4): amidinotransferase activity (GO:0015067), glycine amidinotransferase activity (GO:0015068), protein binding (GO:0005515), transferase activity (GO:0016740)

GO Cellular Component (6): mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), mitochondrial intermembrane space (GO:0005758), extracellular exosome (GO:0070062), cytoplasm (GO:0005737), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Metabolism of amino acids and derivatives	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
modified amino acid metabolic process	1
monocarboxylic acid metabolic process	1
creatine metabolic process	1
modified amino acid biosynthetic process	1
monocarboxylic acid biosynthetic process	1
behavior	1
cognition	1
muscle adaptation	1
positive regulation of multicellular organismal process	1
cold-induced thermogenesis	1
regulation of cold-induced thermogenesis	1
transferase activity, transferring one-carbon groups	1
amidinotransferase activity	1
binding	1
catalytic activity	1
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
mitochondrial envelope	1
organelle envelope lumen	1
extracellular vesicle	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

2589 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GATM	GAMT	Q14353	968
GATM	SLC6A8	P48029	934
GATM	CKMT1B	P12532	800
GATM	SLC30A4	O14863	774
GATM	SLC28A2	O43868	773
GATM	SLC34A1	Q06495	747
GATM	DUOX1	Q9NRD9	727
GATM	DUOX2	Q9NRD8	685
GATM	AZIN2	Q96A70	647
GATM	GRIK1	P39086	611
GATM	AFG2B	Q9BVQ7	585
GATM	HAPLN1	P10915	573
GATM	SHMT1	P34896	559
GATM	NCDN	Q9UBB6	549
GATM	AGXT	P21549	534

IntAct

57 interactions, top by confidence:

A	B	Type	Score
GATM	GRB10	psi-mi:“MI:0915”(physical association)	0.560
	GATM	psi-mi:“MI:0915”(physical association)	0.560
TNFAIP1	GATM	psi-mi:“MI:0915”(physical association)	0.560
SCGB1A1	GATM	psi-mi:“MI:0915”(physical association)	0.560
GATM	BECN1	psi-mi:“MI:0915”(physical association)	0.560
EIF2B4	GATM	psi-mi:“MI:0915”(physical association)	0.560
GATM	LPIN1	psi-mi:“MI:0915”(physical association)	0.560
GATM	ITGB3BP	psi-mi:“MI:0915”(physical association)	0.560
COMMD10	GATM	psi-mi:“MI:0915”(physical association)	0.560
GATM	ADAMTSL4	psi-mi:“MI:0915”(physical association)	0.560
SIRPG	GATM	psi-mi:“MI:0915”(physical association)	0.560
GATM	TMEM185A	psi-mi:“MI:0915”(physical association)	0.560
GATM	RPUSD4	psi-mi:“MI:0915”(physical association)	0.560
WDR88	GATM	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (12): GATM (Affinity Capture-MS), GATM (Affinity Capture-MS), GATM (Affinity Capture-MS), GATM (Affinity Capture-MS), DBT (Affinity Capture-MS), GATM (Proximity Label-MS), GATM (Affinity Capture-MS), GATM (Affinity Capture-MS), GATM (Proximity Label-MS), GATM (Two-hybrid), GATM (Affinity Capture-MS), GATM (Two-hybrid)

ESM2 similar proteins: A0PW79, A1U5W7, A4T6Q0, A4XRA9, A4YK54, A5E8V7, A5EXR1, A6VA75, A6VWS0, B2HDL4, B3PNI8, B7UY35, C0MBK4, C0MD79, C1AXW8, C3PEE7, C4LA78, O50175, P08078, P13981, P23793, P29780, P50440, P50441, P50442, P74535, Q02I59, Q03NY8, Q09359, Q0S4V3, Q11G43, Q1QI14, Q2HJ74, Q2Y8M6, Q4R806, Q54258, Q54264, Q5RFB9, Q6AA78, Q6P832

Diamond homologs: P08078, P29780, P50440, P50441, P50442, Q2HJ74, Q4R806, Q54258, Q54264, Q5RFB9, Q6P832, Q6PH19, Q9D964, Q9I9K9, Q9IAJ6, Q9RBU1

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	18
Likely pathogenic	20
Uncertain significance	301
Likely benign	275
Benign	37

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1387616	NM_001482.3(GATM):c.724_725del (p.Gly242fs)	Pathogenic
1456298	NM_001482.3(GATM):c.401T>G (p.Leu134Ter)	Pathogenic
21299	NM_001482.3(GATM):c.484+1G>T	Pathogenic
2446450	NM_001482.3(GATM):c.629G>A (p.Trp210Ter)	Pathogenic
2799740	NM_001482.3(GATM):c.41_48dup (p.Val17fs)	Pathogenic
2836363	NM_001482.3(GATM):c.76C>T (p.Arg26Ter)	Pathogenic
2842677	NM_001482.3(GATM):c.551del (p.Met184fs)	Pathogenic
2844980	NM_001482.3(GATM):c.1079dup (p.Met360fs)	Pathogenic
2850245	NM_001482.3(GATM):c.207C>A (p.Tyr69Ter)	Pathogenic
3243810	NC_000015.9:g.(?45661504)(45670651_?)del	Pathogenic
3638018	NM_001482.3(GATM):c.92G>A (p.Trp31Ter)	Pathogenic
3638316	NM_001482.3(GATM):c.964C>T (p.Arg322Ter)	Pathogenic
3721886	NM_001482.3(GATM):c.5_33del (p.Leu2fs)	Pathogenic
4734408	NM_001482.3(GATM):c.141dup (p.Asn48fs)	Pathogenic
55918	NM_001482.3(GATM):c.1111dup (p.Met371fs)	Pathogenic
55919	NM_001482.3(GATM):c.505C>T (p.Arg169Ter)	Pathogenic
7302	NM_001482.3(GATM):c.446G>A (p.Trp149Ter)	Pathogenic
917493	NM_001482.3(GATM):c.958C>T (p.Pro320Ser)	Pathogenic
1175866	NM_001482.3(GATM):c.566G>A (p.Arg189His)	Likely pathogenic
1339450	NM_001482.3(GATM):c.259T>C (p.Cys87Arg)	Likely pathogenic
1478699	NM_001482.3(GATM):c.553G>C (p.Ala185Pro)	Likely pathogenic
1702865	NM_001482.3(GATM):c.965G>C (p.Arg322Pro)	Likely pathogenic
205617	NM_001482.3(GATM):c.778C>T (p.Arg260Ter)	Likely pathogenic
2446451	NM_001482.3(GATM):c.1238G>A (p.Arg413Gln)	Likely pathogenic
2699241	NM_001482.3(GATM):c.288+2_288+11del	Likely pathogenic
2709818	NM_001482.3(GATM):c.70-2A>C	Likely pathogenic
2709887	NM_001482.3(GATM):c.979-1_979insT	Likely pathogenic
2747701	NM_001482.3(GATM):c.1043-1G>C	Likely pathogenic
2751845	NM_001482.3(GATM):c.676-1G>C	Likely pathogenic
2760560	NM_001482.3(GATM):c.289-1_292del	Likely pathogenic

SpliceAI

1314 predictions. Top by Δscore:

Variant	Effect	Δscore
15:45362223:T:A	acceptor_loss	1.0000
15:45363894:ACAT:A	donor_loss	1.0000
15:45363895:CAT:C	donor_loss	1.0000
15:45363896:ATACC:A	donor_loss	1.0000
15:45363897:TAC:T	donor_loss	1.0000
15:45363898:A:AC	donor_gain	1.0000
15:45363898:AC:A	donor_gain	1.0000
15:45363899:C:CA	donor_loss	1.0000
15:45363899:C:CC	donor_gain	1.0000
15:45363899:CC:C	donor_gain	1.0000
15:45363899:CCCAG:C	donor_gain	1.0000
15:45363903:G:C	donor_gain	1.0000
15:45364013:TGAT:T	acceptor_gain	1.0000
15:45364014:GAT:G	acceptor_gain	1.0000
15:45364014:GATC:G	acceptor_loss	1.0000
15:45364016:TC:T	acceptor_loss	1.0000
15:45364017:C:CC	acceptor_gain	1.0000
15:45364017:CTA:C	acceptor_loss	1.0000
15:45364018:T:A	acceptor_loss	1.0000
15:45364790:AACAT:A	donor_loss	1.0000
15:45364791:ACAT:A	donor_loss	1.0000
15:45364792:CATAC:C	donor_loss	1.0000
15:45364793:ATACC:A	donor_loss	1.0000
15:45364794:TACC:T	donor_loss	1.0000
15:45364795:A:AC	donor_gain	1.0000
15:45364796:C:CT	donor_gain	1.0000
15:45364796:C:G	donor_loss	1.0000
15:45364796:CCGT:C	donor_gain	1.0000
15:45364856:TCAAT:T	acceptor_gain	1.0000
15:45364857:CAAT:C	acceptor_gain	1.0000

AlphaMissense

2783 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:45368236:T:A	D170V	1.000
15:45368236:T:G	D170A	1.000
15:45362140:C:G	R414P	0.999
15:45362141:G:T	R414S	0.999
15:45362159:A:G	W408R	0.999
15:45362159:A:T	W408R	0.999
15:45362160:G:C	C407W	0.999
15:45362161:C:T	C407Y	0.999
15:45362162:A:G	C407R	0.999
15:45362165:G:C	H406D	0.999
15:45362173:C:T	G403E	0.999
15:45363976:A:C	N361K	0.999
15:45363976:A:T	N361K	0.999
15:45363990:A:G	W357R	0.999
15:45363990:A:T	W357R	0.999
15:45364836:A:G	W335R	0.999
15:45364836:A:T	W335R	0.999
15:45366059:C:G	R322P	0.999
15:45366109:A:C	D305E	0.999
15:45366109:A:T	D305E	0.999
15:45366110:T:A	D305V	0.999
15:45366115:A:C	H303Q	0.999
15:45366115:A:T	H303Q	0.999
15:45366117:G:C	H303D	0.999
15:45366186:A:G	W280R	0.999
15:45366186:A:T	W280R	0.999
15:45366202:G:C	N274K	0.999
15:45366202:G:T	N274K	0.999
15:45366374:G:C	S270R	0.999
15:45366374:G:T	S270R	0.999

dbSNP variants (sampled 300 via entrez): RS1000044286 (15:45367008 C>T), RS1000093876 (15:45374101 C>T), RS1000115871 (15:45368565 T>C), RS1000124752 (15:45373695 A>C,G), RS1000236459 (15:45392932 A>G), RS1000272552 (15:45394708 T>C), RS1000343408 (15:45366344 G>A), RS1000343472 (15:45380202 G>A,C), RS1000363817 (15:45399856 T>C), RS1000373680 (15:45400229 T>A), RS1000399082 (15:45366698 C>T), RS1000433689 (15:45387862 T>C), RS1000621646 (15:45378394 G>A,C), RS1000643072 (15:45393481 A>G), RS1000696432 (15:45385201 A>G)

Disease associations

OMIM: gene MIM:602360 | disease phenotypes: MIM:612718, MIM:134600, MIM:618603, MIM:606369

GenCC curated gene-disease

Disease	Classification	Inheritance
AGAT deficiency	Definitive	Autosomal recessive
Fanconi renotubular syndrome 1	Strong	Autosomal dominant
primary Fanconi syndrome	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
Fanconi renotubular syndrome 1	Moderate	AD
AGAT deficiency	Definitive	AR

Mondo (6): AGAT deficiency (MONDO:0012996), Fanconi renotubular syndrome 1 (MONDO:0024525), intellectual disability (MONDO:0001071), neurodevelopmental disorder with hypotonia and variable intellectual and behavioral abnormalities (MONDO:0032829), Lennox-Gastaut syndrome (MONDO:0016532), primary Fanconi syndrome (MONDO:0007600)

Orphanet (3): L-Arginine:glycine amidinotransferase deficiency (Orphanet:35704), Lennox-Gastaut syndrome (Orphanet:2382), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

69 total (30 of 69 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000083	Renal insufficiency
HP:0000117	Renal phosphate wasting
HP:0000124	Renal tubular dysfunction
HP:0000708	Atypical behavior
HP:0000717	Autism
HP:0000750	Delayed speech and language development
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001288	Gait disturbance
HP:0001324	Muscle weakness
HP:0001344	Absent speech
HP:0001508	Failure to thrive
HP:0001510	Growth delay
HP:0001824	Weight loss
HP:0001942	Metabolic acidosis
HP:0001943	Hypoglycemia
HP:0001944	Dehydration
HP:0001992	Organic aciduria
HP:0002049	Proximal renal tubular acidosis
HP:0002148	Hypophosphatemia
HP:0002150	Hypercalciuria
HP:0002206	Pulmonary fibrosis
HP:0002653	Bone pain
HP:0002659	Increased susceptibility to fractures
HP:0002748	Rickets
HP:0002749	Osteomalacia

GWAS associations

22 associations (top):

Study	Trait	p-value
GCST000397_2	Renal function and chronic kidney disease	6.000000e-14
GCST000649_17	Chronic kidney disease	5.000000e-22
GCST002196_1	Homoarginine levels	1.000000e-45
GCST002388_5	Serum metabolite levels	9.000000e-12
GCST003372_53	Glomerular filtration rate (creatinine)	1.000000e-42
GCST003374_9	Chronic kidney disease	2.000000e-11
GCST003401_34	Glomerular filtration rate in non diabetics (creatinine)	5.000000e-41
GCST003790_2	Glomerular filtration rate	2.000000e-08
GCST003790_42	Glomerular filtration rate	5.000000e-12
GCST004292_6	Glomerular filtration rate (creatinine)	3.000000e-43
GCST007344_44	Estimated glomerular filtration rate	1.000000e-33
GCST007721_4	Urinary potassium to creatinine ratio	9.000000e-14
GCST007877_16	Creatinine levels	1.000000e-26
GCST008058_190	Estimated glomerular filtration rate	6.000000e-244
GCST008059_101	Estimated glomerular filtration rate	6.000000e-216
GCST008061_1	Estimated glomerular filtration rate	2.000000e-12
GCST008064_42	Chronic kidney disease	2.000000e-16
GCST008746_28	Estimated glomerular filtration rate in diabetes	2.000000e-17
GCST008790_48	Urinary albumin-to-creatinine ratio	9.000000e-16
GCST008794_1	Urinary albumin-to-creatinine ratio	9.000000e-15
GCST008928_9	Phosphatidylcholine-ether levels	3.000000e-08
GCST012020_479	Serum metabolite levels	4.000000e-43

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0009882	urinary potassium to creatinine ratio
EFO:0007778	urinary albumin to creatinine ratio
EFO:0010227	phosphatidylcholine ether measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065768	Lennox Gastaut Syndrome	C10.228.140.490.493.750; C16.320.495
C567192	Arginine-Glycine Amidinotransferase Deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs9806699	Toxicity	4	HMG-CoA reductase inhibitors;simvastatin	Myocardial Infarction

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1346268	GATM	3	3.00	1	simvastatin
rs9806699	GATM	4	-1.75	1	HMG-CoA reductase inhibitors;simvastatin

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — Arginine:glycine amidinotransferase

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Acetaminophen	decreases expression, increases expression	4
trichostatin A	affects cotreatment, decreases expression	3
Air Pollutants	decreases expression, increases abundance	3
Valproic Acid	affects expression, increases expression	3
Cyclosporine	decreases expression, decreases methylation	3
Aflatoxin B1	affects expression, decreases expression, decreases methylation	3
methylmercuric chloride	decreases expression	2
sodium arsenite	decreases expression, increases methylation	2
Estradiol	affects cotreatment, decreases expression	2
Formaldehyde	decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
methyleugenol	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	increases expression	1
sulforaphane	decreases expression	1
cobaltous chloride	decreases expression	1
ferrous chloride	decreases expression	1
nickel sulfate	decreases expression	1
pentanal	increases expression	1
pentabromodiphenyl ether	decreases expression	1
CGP 52608	affects binding, increases reaction	1
entinostat	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
MRK 003	decreases expression	1
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	increases expression, increases response to substance	1
jinfukang	affects cotreatment, increases expression	1
incobotulinumtoxinA	decreases expression	1
(+)-JQ1 compound	increases expression	1

Cellosaurus cell lines

4 cell lines: 2 cancer cell line, 1 transformed cell line, 1 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_C7LC	GM27955	Transformed cell line	Female
CVCL_C7LD	GM28589	Induced pluripotent stem cell	Female
CVCL_E1Y2	HAP1 GATM (-) 1	Cancer cell line	Male
CVCL_E1Y3	HAP1 GATM (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT01370486	PHASE4	WITHDRAWN	Melatonin Versus Placebo in the Lennox-Gastaut Syndrome: Neurophysiological and Neuropsychological Effects
NCT02731300	PHASE4	COMPLETED	Transcranial Direct Current Stimulation, Treatment of Childhood Drug-Resistant Lennox-Gastaut Syndrome, A Pilot Study
NCT04133480	PHASE4	WITHDRAWN	Investigation of Cognitive Outcomes With Cannabidiol Oral Solution
NCT05044819	PHASE4	ACTIVE_NOT_RECRUITING	Assessment of Potential for Chronic Liver Injury in Participants Treated With Epidiolex (Cannabidiol) Oral Solution
NCT06924827	PHASE4	NOT_YET_RECRUITING	A Study to Investigate the Transition of Children From ‘Artisanal Cannabidiol (CBD) to Epidiolex
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT00004776	PHASE3	COMPLETED	Phase III Randomized, Double-Blind, Placebo-Controlled Study of Oral Topiramate for Lennox-Gastaut Syndrome
NCT01146951	PHASE3	COMPLETED	A Placebo-Controlled, Double-Blind Comparative Study of E2080 in Lennox-Gastaut Syndrome Patients (Study E2080-J081-304)
NCT01151540	PHASE3	COMPLETED	A Long Term Extension Study of E2080 in Lennox-Gastaut Patients
NCT01160770	PHASE3	COMPLETED	Safety and Effectiveness of Open-Label Clobazam in Subjects With Lennox-Gastaut Syndrome
NCT01405053	PHASE3	COMPLETED	Study of Rufinamide in Pediatric Subjects 1 to Less Than 4 Years of Age With Lennox-Gastaut Syndrome Inadequately Controlled With Other Anti-epileptic Drugs
NCT02224560	PHASE3	COMPLETED	Efficacy and Safety of GWP42003-P for Seizures Associated With Lennox-Gastaut Syndrome in Children and Adults
NCT02224573	PHASE3	COMPLETED	An Open Label Extension Study of Cannabidiol (GWP42003-P) in Children and Adults With Dravet or Lennox-Gastaut Syndromes
NCT02224690	PHASE3	COMPLETED	A Study to Investigate the Efficacy and Safety of Cannabidiol (GWP42003-P; CBD) as Adjunctive Treatment for Seizures Associated With Lennox-Gastaut Syndrome in Children and Adults
NCT02318537	PHASE3	WITHDRAWN	Cannabidiol Oral Solution as an Adjunctive Therapy for Treatment of Participants With Inadequately Controlled Lennox-Gastaut Syndrome
NCT02834793	PHASE3	TERMINATED	Study of Perampanel as Adjunctive Treatment for Inadequately Controlled Seizures Associated With Lennox-Gastaut Syndrome
NCT03355209	PHASE3	COMPLETED	A Study to Investigate the Efficacy and Safety of ZX008 (Fenfluramine Hydrochloride) as an Adjunctive Therapy in Children and Adults With Lennox-Gastaut Syndrome
NCT03936777	PHASE3	COMPLETED	A Study to Investigate the Long-Term Safety of ZX008 (Fenfluramine Hydrochloride) Oral Solution in Children and Adults With Epileptic Encephalopathy Including Dravet Syndrome and Lennox-Gastaut Syndrome
NCT04611438	PHASE3	UNKNOWN	Research on Cognitive Effect of Cannabidiol on Dravet Syndrome and Lennox-Gastaut SyndromeGastaut Syndrome
NCT04938427	PHASE3	COMPLETED	A Study of Soticlestat as an Add-on Therapy in Children, Teenagers, and Adults With Lennox-Gastaut Syndrome
NCT05066217	PHASE3	RECRUITING	An Efficacy and Safety Study of Clemizole HCl in Patients With Lennox-Gastaut Syndrome
NCT05163314	PHASE3	TERMINATED	A Study of Soticlestat as an Add-on Therapy in Children and Adults With Dravet Syndrome or Lennox-Gastaut Syndrome
NCT05219617	PHASE3	RECRUITING	Investigate Efficacy and Safety of Carisbamate as Adjunctive Treatment for Seizures Associated With LGS in Children and Adults
NCT06422377	PHASE3	TERMINATED	A Study Evaluating Soticlestat in Participants With Dravet Syndrome or Lennox-Gastaut Syndrome Who Have Been Exposed to Fenfluramine
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT02655198	PHASE2	UNKNOWN	Add-on Therapy With Low Dose Fenfluramine in Lennox Gastaut Epilepsy
NCT03635073	PHASE2	TERMINATED	A Study of Soticlestat in Adults and Children With Rare Epilepsies
NCT03650452	PHASE2	COMPLETED	A Phase 2, Multicenter, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy, Safety, and Tolerability of TAK-935 (OV935) as an Adjunctive Therapy in Pediatric Participants With Developmental and/or Epileptic Encephalopathies
NCT05339126	PHASE2	ACTIVE_NOT_RECRUITING	RNS System LGS Feasibility Study
NCT05626634	PHASE2	COMPLETED	Open-label, Long-term Safety Study of LP352 in Subjects With Developmental and Epileptic Encephalopathy
NCT06401538	PHASE2	RECRUITING	BMB-101 in Absence Epilepsy and DEE
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities