GAMT

Summary

GAMT (guanidinoacetate N-methyltransferase, HGNC:4136) is a protein-coding gene on chromosome 19p13.3, encoding Guanidinoacetate N-methyltransferase (Q14353). Converts guanidinoacetate to creatine, using S-adenosylmethionine as the methyl donor.

The protein encoded by this gene is a methyltransferase that converts guanidoacetate to creatine, using S-adenosylmethionine as the methyl donor. Defects in this gene have been implicated in neurologic syndromes and muscular hypotonia, probably due to creatine deficiency and accumulation of guanidinoacetate in the brain of affected individuals. Two transcript variants encoding different isoforms have been described for this gene. Pseudogenes of this gene are found on chromosomes 2 and 13.

Source: NCBI Gene 2593 — RefSeq curated summary.

At a glance

• Gene–disease (curated): guanidinoacetate methyltransferase deficiency (Definitive, ClinGen)
• Clinical variants (ClinVar): 641 total — 55 pathogenic, 51 likely-pathogenic
• Phenotypes (HPO): 45
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_000156

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4136
Approved symbol	GAMT
Name	guanidinoacetate N-methyltransferase
Location	19p13.3
Locus type	gene with protein product
Status	Approved
Aliases	PIG2, TP53I2
Ensembl gene	ENSG00000130005
Ensembl biotype	protein_coding
OMIM	601240
Entrez	2593

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 13 protein_coding, 1 retained_intron

ENST00000252288, ENST00000447102, ENST00000591788, ENST00000640164, ENST00000640762, ENST00000902470, ENST00000902471, ENST00000902472, ENST00000902473, ENST00000902474, ENST00000902475, ENST00000902476, ENST00000902477, ENST00000970136

RefSeq mRNA: 2 — MANE Select: NM_000156 NM_000156, NM_138924

CCDS: CCDS12064, CCDS45897

Canonical transcript exons

ENST00000252288 — 6 exons

Exon	Start	End
ENSE00000753080	1399793	1399938
ENSE00000753081	1399524	1399587
ENSE00000753082	1399128	1399195
ENSE00001055667	1397026	1397499
ENSE00001699690	1398916	1399026
ENSE00001763756	1401296	1401542

Expression profiles

Bgee: expression breadth ubiquitous, 258 present calls, max score 99.36.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 16.5567 / max 492.3425, expressed in 1677 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
178014	16.5567	1677

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
hindlimb stylopod muscle	UBERON:0004252	99.36	gold quality
right lobe of liver	UBERON:0001114	99.21	gold quality
gastrocnemius	UBERON:0001388	99.08	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	99.02	gold quality
triceps brachii	UBERON:0001509	98.86	gold quality
vastus lateralis	UBERON:0001379	98.51	gold quality
quadriceps femoris	UBERON:0001377	98.32	gold quality
gluteal muscle	UBERON:0002000	98.17	gold quality
diaphragm	UBERON:0001103	98.12	gold quality
biceps brachii	UBERON:0001507	98.02	gold quality
skeletal muscle tissue	UBERON:0001134	97.96	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	97.88	gold quality
body of pancreas	UBERON:0001150	97.81	gold quality
muscle organ	UBERON:0001630	97.78	gold quality
skeletal muscle organ	UBERON:0014892	97.78	gold quality
muscle of leg	UBERON:0001383	97.62	gold quality
apex of heart	UBERON:0002098	97.51	gold quality
liver	UBERON:0002107	97.50	gold quality
corpus epididymis	UBERON:0004359	97.12	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	95.58	gold quality
muscle tissue	UBERON:0002385	95.42	gold quality
tibialis anterior	UBERON:0001385	94.99	gold quality
deltoid	UBERON:0001476	94.73	gold quality
right atrium auricular region	UBERON:0006631	94.53	gold quality
heart left ventricle	UBERON:0002084	94.40	gold quality
right testis	UBERON:0004534	94.36	gold quality
cardiac ventricle	UBERON:0002082	94.19	gold quality
left testis	UBERON:0004533	93.93	gold quality
right frontal lobe	UBERON:0002810	93.75	gold quality
cardiac atrium	UBERON:0002081	93.72	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-CURD-98	yes	658.52
E-MTAB-10553	yes	31.17
E-MTAB-9388	yes	12.55
E-CURD-112	yes	8.84
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): RBPJ

miRNA regulators (miRDB)

12 targeting GAMT, 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-6778-3P	99.96	67.29	2693
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-651-5P	99.64	68.49	1104
HSA-MIR-4437	99.52	65.29	1266
HSA-MIR-504-3P	99.30	67.18	1745
HSA-MIR-939-3P	98.97	65.07	2347
HSA-MIR-3130-5P	98.14	66.00	711
HSA-MIR-526B-5P	97.41	67.99	1074
HSA-MIR-939-5P	97.10	65.80	1579
HSA-MIR-3126-5P	96.87	65.83	912
HSA-MIR-6875-5P	96.87	65.49	958
HSA-MIR-1343-5P	96.48	66.06	1506

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 18)

• Mutations in the GAMT gene are responsible for GAMT deficiency, since overexpression of the GAMT open reading frame restores GAMT activity in GAMT-deficient fibroblasts. (PMID:16899382)
• compound heterozygous mutations in the GAMT gene may be causitive in guanidinoacetate methyltransferase deficiency masquerading as a mitochondrial encephalopathy [case report] (PMID:17171576)
• the carrier rate of the c.59G>C; p.Trp20Ser mutation in GAMT is relatively high in these islands, as well as in other parts of Portugal. (PMID:17336114)
• Five novel mutations were identified in GAMT from 8 patients with GAMT deficiency. (PMID:19027335)
• Body fluids from 10 GAMT deficient patients were analysed using (1)H NMR spectroscopy. (PMID:19288536)
• impact of creatine deficiency syndrome mutations, CRTR and GAMT on metabolic stress was analyzed in patient fibroblast cultures (PMID:21140503)
• GAMT genes may not be directly involved in human male infertility (PMID:21190923)
• Two novel heterozygous variants with sequence deletion and sequence insertion in the GAMT gene have been identified in newborns with guanidinoacetate methyltransferase deficiency. (PMID:23031365)
• Study reports six novel pathogenic mutations in GAMT gene in patients with Guanidinoacetate methyltransferase deficiency. (PMID:24415674)
• As early diagnosis results in normal neurodevelopmental outcome, GAMT deficiency should be included in newborn screening programs to diagnose individuals at the asymptomatic stage of the disease (PMID:26003046)
• The estimated incidence of GAMT deficiency is 1:250,000 newborns based on our pilot study. (PMID:26319512)
• 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)
• 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)
• We unveil PFN2 and GAMT as molecular determinants of Charcot-Marie-Tooth type 2 neuropathy, with possible indications of the role of PFN2 in the pathogenesis and disease progression. (PMID:29449460)
• Here, we report 9 and 10-year-old cousins with GAMT deficiency caused by a novel mutation who both exhibited neurodevelopmental retardation, seizures, behavioral problems, and autism that began during early infancy. A novel nonsense mutation in the GAMT gene that caused cessation of synthesis of the protein encoded by this gene was identified in these patients. (PMID:31559727)
• Elastic net-based identification of GAMT as potential diagnostic marker for early-stage gastric cancer. (PMID:34990904)
• Identification of novel variations in SLC6A8 and GAMT genes causing cerebral creatine deficiency syndrome. (PMID:35588794)
• 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	gamt	ENSDARG00000070844
mus_musculus	Gamt	ENSMUSG00000020150
rattus_norvegicus	Gamt	ENSRNOG00000024577

Protein

Protein identifiers

Guanidinoacetate N-methyltransferase — Q14353 (reviewed: Q14353)

All UniProt accessions (4): Q14353, A0A1W2PR36, K7EM34, V9HWB2

UniProt curated annotations — full annotation on UniProt →

Function. Converts guanidinoacetate to creatine, using S-adenosylmethionine as the methyl donor. Important in nervous system development.

Subunit / interactions. Monomer.

Tissue specificity. Expressed in liver.

Disease relevance. Cerebral creatine deficiency syndrome 2 (CCDS2) [MIM:612736] An autosomal recessive disorder characterized by developmental delay and regression, intellectual disability, severe disturbance of expressive and cognitive speech, intractable seizures, movement disturbances, severe depletion of creatine and phosphocreatine in the brain, and accumulation of guanidinoacetic acid in brain and body fluids. The disease is caused by variants affecting the gene represented in this entry.

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

Similarity. Belongs to the class I-like SAM-binding methyltransferase superfamily. RMT2 methyltransferase family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q14353-1	1	yes
Q14353-2	2

RefSeq proteins (2): NP_000147, NP_620279 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR016550	GuanidinoAc_N-MeTrfase	Family
IPR026480	RMT2_dom	Domain
IPR029063	SAM-dependent_MTases_sf	Homologous_superfamily
IPR051038	RMT2/GAMT_Mtase	Family

Enzyme classification (BRENDA):

• EC 2.1.1.2 — guanidinoacetate N-methyltransferase (BRENDA: 9 organisms, 9 substrates, 14 inhibitors, 20 Km, 7 kcat entries)

Substrate kinetics (BRENDA)

2 substrates with measured Km, best-characterized 2. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
S-ADENOSYL-L-METHIONINE	0.002–0.049	10
GUANIDINOACETATE	0.011–2.3	9

Catalyzed reactions (Rhea), 1 shown:

• guanidinoacetate + S-adenosyl-L-methionine = creatine + S-adenosyl-L-homocysteine + H(+) (RHEA:10656)

UniProt features (78 total): sequence variant 35, helix 15, binding site 10, strand 10, turn 3, initiator methionine 1, chain 1, modified residue 1, splice variant 1, domain 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
3ORH	X-RAY DIFFRACTION	1.86

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q14353-F1	96.73	0.97

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 (10): 135; 135; 171–172; 20; 42; 46; 50; 69–74; 90–92; 117–118

Post-translational modifications (1): 2

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-71288	Creatine metabolism
R-HSA-8986944	Transcriptional Regulation by MECP2

MSigDB gene sets: 239 (showing top): OUELLET_OVARIAN_CANCER_INVASIVE_VS_LMP_DN, GRUETZMANN_PANCREATIC_CANCER_DN, GNF2_GSTM1, GOBP_REGULATION_OF_DEVELOPMENTAL_GROWTH, GNF2_HPN, GOBP_GROWTH, GOBP_MALE_GAMETE_GENERATION, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_BIOSYNTHETIC_PROCESS, BROWNE_HCMV_INFECTION_48HR_DN, SMITH_TERT_TARGETS_DN, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, GOBP_REGULATION_OF_MULTICELLULAR_ORGANISM_GROWTH, GOBP_MUSCLE_CONTRACTION

GO Biological Process (7): creatine metabolic process (GO:0006600), creatine biosynthetic process (GO:0006601), muscle contraction (GO:0006936), spermatogenesis (GO:0007283), animal organ morphogenesis (GO:0009887), methylation (GO:0032259), regulation of multicellular organism growth (GO:0040014)

GO Molecular Function (4): methyltransferase activity (GO:0008168), guanidinoacetate N-methyltransferase activity (GO:0030731), protein binding (GO:0005515), transferase activity (GO:0016740)

GO Cellular Component (3): nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Metabolism of amino acids and derivatives	1
Generic Transcription Pathway	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
muscle system process	1
developmental process involved in reproduction	1
male gamete generation	1
anatomical structure morphogenesis	1
animal organ development	1
metabolic process	1
multicellular organism growth	1
regulation of developmental growth	1
regulation of multicellular organismal process	1
transferase activity, transferring one-carbon groups	1
S-adenosylmethionine-dependent methyltransferase activity	1
binding	1
catalytic activity	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cytoplasm	1

Protein interactions and networks

STRING

2098 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GAMT	GATM	P50440	968
GAMT	SLC6A8	P48029	944
GAMT	PEMT	Q9UBM1	643
GAMT	CKMT1B	P12532	604
GAMT	GNMT	Q14749	594
GAMT	MAT1A	Q00266	578
GAMT	GPRIN1	Q7Z2K8	566
GAMT	CKMT2	P17540	530
GAMT	MAT2A	P31153	511
GAMT	FXYD1	O00168	504
GAMT	BHMT	Q93088	489
GAMT	SARDH	Q9UL12	468
GAMT	MTG1	Q9BT17	447
GAMT	WDR25	Q64LD2	445
GAMT	PNPO	Q9NVS9	441

IntAct

33 interactions, top by confidence:

A	B	Type	Score
GAMT	FARS2	psi-mi:“MI:0915”(physical association)	0.560
GAMT	TRIM39	psi-mi:“MI:0915”(physical association)	0.560
GAMT	RAB24	psi-mi:“MI:0915”(physical association)	0.560
GAMT	FARS2	psi-mi:“MI:0914”(association)	0.560
FSD1	UBFD1	psi-mi:“MI:0914”(association)	0.530
TAS2R41	YKT6	psi-mi:“MI:0914”(association)	0.530
LHFPL4	ATP5F1B	psi-mi:“MI:0914”(association)	0.530
CRYZL1	GAMT	psi-mi:“MI:0915”(physical association)	0.400
TERF1	GAMT	psi-mi:“MI:0915”(physical association)	0.370
GAMT	TERF2IP	psi-mi:“MI:0915”(physical association)	0.370
POT1	GAMT	psi-mi:“MI:0915”(physical association)	0.370
FOS	GAMT	psi-mi:“MI:0915”(physical association)	0.370
GAMT	CSNK2B	psi-mi:“MI:0915”(physical association)	0.370
CENPM	DNM1L	psi-mi:“MI:0914”(association)	0.350
SERBP1	UBA6	psi-mi:“MI:0914”(association)	0.350
WIF1	SMCHD1	psi-mi:“MI:0914”(association)	0.350
RNF4	KPNA3	psi-mi:“MI:0914”(association)	0.350
DNAJB6	SCAMP1	psi-mi:“MI:0914”(association)	0.350
MYO1B	ZMPSTE24	psi-mi:“MI:0914”(association)	0.350
ANKRD16	RHOA	psi-mi:“MI:0914”(association)	0.350
CHRNB3	GAMT	psi-mi:“MI:0914”(association)	0.350
GOLGA2	FTL	psi-mi:“MI:0914”(association)	0.350
GAMT	TRIM39	psi-mi:“MI:0915”(physical association)	0.000
GAMT	RAB24	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (35): FARS2 (Affinity Capture-MS), FARS2 (Affinity Capture-MS), GAMT (Affinity Capture-MS), GAMT (Affinity Capture-MS), GAMT (Proximity Label-MS), RAB24 (Two-hybrid), TRIM39 (Two-hybrid), GAMT (Affinity Capture-MS), GAMT (Affinity Capture-MS), GAMT (Affinity Capture-MS), FARS2 (Affinity Capture-MS), LPAR1 (Affinity Capture-MS), GAMT (Affinity Capture-MS), GAMT (Affinity Capture-MS), GAMT (Affinity Capture-MS)

ESM2 similar proteins: F4JGR5, O04300, O09171, O22666, O35490, O89000, P11029, P11497, P21343, P43490, P80607, Q01587, Q12882, Q13085, Q14353, Q28007, Q28559, Q28943, Q2TBQ3, Q2TBU2, Q40281, Q42450, Q52I78, Q5HZ68, Q5I597, Q5M8Y1, Q5M8Z0, Q5R660, Q5R895, Q5RFG2, Q5SWU9, Q5XGM3, Q6NYG8, Q6PBF6, Q6Z4G3, Q71N41, Q7X999, Q7ZXG7, Q8CHR6, Q8H8T0

Diamond homologs: O35969, P10868, Q10170, Q14353, Q2TBQ3, Q2TZM9, Q4IQK7, Q4X1R1, Q5B058, Q5HZ68, Q6CPN1, Q6FMP0, Q6PBF6, Q71N41, Q759W1, Q7ZXG7, P0CQ68, P0CQ69, Q03305, Q6BNS9, Q6CBX2, Q7SCW9

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
MECP2	“up-regulates quantity by expression”	GAMT	“post transcriptional regulation”
GAMT	up-regulates	Neuron_maturation
GAMT	up-regulates	Neurite_outgrowth

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	55
Likely pathogenic	51
Uncertain significance	235
Likely benign	242
Benign	25

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1075655	NM_000156.6(GAMT):c.289C>T (p.Gln97Ter)	Pathogenic
1076411	NM_000156.6(GAMT):c.414_415del (p.Ser140fs)	Pathogenic
1098274	NM_000156.6(GAMT):c.158_181+7del	Pathogenic
1184466	NM_000156.6(GAMT):c.313_314insTG (p.Arg105fs)	Pathogenic
1312506	NM_000156.6(GAMT):c.497T>C (p.Leu166Pro)	Pathogenic
1374093	NM_000156.6(GAMT):c.305G>A (p.Trp102Ter)	Pathogenic
1391239	NM_000156.6(GAMT):c.432G>A (p.Trp144Ter)	Pathogenic
1409758	NM_000156.6(GAMT):c.526dup (p.Glu176fs)	Pathogenic
1422935	NM_000156.6(GAMT):c.504C>G (p.Tyr168Ter)	Pathogenic
1452336	NM_000156.6(GAMT):c.470_476del (p.Phe157fs)	Pathogenic
1452750	NM_000156.6(GAMT):c.2T>C (p.Met1Thr)	Pathogenic
1453224	NM_000156.6(GAMT):c.440_441dup (p.Gln148fs)	Pathogenic
1454624	NC_000019.9:g.(?1398895)(1401475_?)del	Pathogenic
1454825	NM_000156.6(GAMT):c.534dup (p.Lys179fs)	Pathogenic
1458883	NM_000156.6(GAMT):c.536del (p.Lys179fs)	Pathogenic
1740532	NM_000156.6(GAMT):c.442C>T (p.Gln148Ter)	Pathogenic
1998188	NM_000156.6(GAMT):c.65del (p.Ala22fs)	Pathogenic
2030841	NC_000019.10:g.1399939del	Pathogenic
205584	NM_000156.6(GAMT):c.522G>A (p.Trp174Ter)	Pathogenic
2083318	NM_000156.6(GAMT):c.289del (p.Gln97fs)	Pathogenic
2084043	NM_000156.6(GAMT):c.370del (p.Leu124fs)	Pathogenic
2089258	NM_000156.6(GAMT):c.608_621del (p.Arg203fs)	Pathogenic
21065	NM_000156.6(GAMT):c.327G>A (p.Lys109=)	Pathogenic
2419155	NM_000156.6(GAMT):c.134G>A (p.Trp45Ter)	Pathogenic
2446458	NM_000156.6(GAMT):c.391G>C (p.Gly131Arg)	Pathogenic
2446459	NM_000156.6(GAMT):c.403G>T (p.Asp135Tyr)	Pathogenic
2570638	NM_000156.6(GAMT):c.590T>C (p.Leu197Pro)	Pathogenic
2675837	NM_000156.6(GAMT):c.235C>T (p.Gln79Ter)	Pathogenic
2743645	NM_000156.6(GAMT):c.503_517del (p.Tyr168_Thr172del)	Pathogenic
2843680	NM_000156.6(GAMT):c.306G>A (p.Trp102Ter)	Pathogenic

SpliceAI

863 predictions. Top by Δscore:

Variant	Effect	Δscore
19:1398880:T:TA	donor_gain	1.0000
19:1398945:TGG:T	donor_gain	1.0000
19:1399022:TGGTT:T	acceptor_gain	1.0000
19:1399023:GGTT:G	acceptor_gain	1.0000
19:1399024:GTT:G	acceptor_gain	1.0000
19:1399024:GTTCT:G	acceptor_loss	1.0000
19:1399025:TT:T	acceptor_gain	1.0000
19:1399026:TCT:T	acceptor_loss	1.0000
19:1399027:C:CC	acceptor_gain	1.0000
19:1399027:CT:C	acceptor_loss	1.0000
19:1399028:T:G	acceptor_loss	1.0000
19:1399029:G:C	acceptor_gain	1.0000
19:1399123:ACCAC:A	donor_loss	1.0000
19:1399127:CC:C	donor_loss	1.0000
19:1399191:GATCC:G	acceptor_gain	1.0000
19:1399192:ATCC:A	acceptor_gain	1.0000
19:1399193:TCC:T	acceptor_gain	1.0000
19:1399194:CC:C	acceptor_gain	1.0000
19:1399194:CCC:C	acceptor_gain	1.0000
19:1399195:CC:C	acceptor_gain	1.0000
19:1399196:C:CC	acceptor_gain	1.0000
19:1399196:CTGC:C	acceptor_loss	1.0000
19:1399197:T:C	acceptor_loss	1.0000
19:1399199:C:CT	acceptor_gain	1.0000
19:1399201:C:CT	acceptor_gain	1.0000
19:1401291:GCTAC:G	donor_loss	1.0000
19:1401292:CTA:C	donor_loss	1.0000
19:1401293:TA:T	donor_loss	1.0000
19:1401294:ACCT:A	donor_loss	1.0000
19:1401295:C:CA	donor_loss	1.0000

AlphaMissense

1540 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:1399913:A:C	F69L	0.998
19:1399913:A:T	F69L	0.998
19:1399915:A:G	F69L	0.998
19:1401342:C:A	W45C	0.997
19:1401342:C:G	W45C	0.997
19:1401344:A:G	W45R	0.997
19:1401344:A:T	W45R	0.997
19:1399183:T:A	D135V	0.995
19:1401339:C:A	E46D	0.995
19:1401339:C:G	E46D	0.995
19:1401370:A:G	I36T	0.995
19:1401351:C:A	M42I	0.993
19:1401351:C:G	M42I	0.993
19:1401351:C:T	M42I	0.993
19:1398976:G:C	N170K	0.992
19:1398976:G:T	N170K	0.992
19:1399182:G:C	D135E	0.992
19:1399182:G:T	D135E	0.992
19:1399183:T:G	D135A	0.992
19:1397465:A:G	F202S	0.991
19:1399911:C:A	G70V	0.991
19:1401340:T:A	E46V	0.991
19:1401343:C:A	W45L	0.991
19:1399178:A:C	Y137D	0.990
19:1399911:C:T	G70D	0.990
19:1399915:A:T	F69I	0.990
19:1398979:G:C	C169W	0.988
19:1399007:A:G	L160P	0.988
19:1399844:A:C	N92K	0.988
19:1399844:A:T	N92K	0.988

dbSNP variants (sampled 300 via entrez): RS1000156979 (19:1401577 C>T), RS1000257437 (19:1402922 G>A,C), RS1000450870 (19:1398124 G>A), RS1000672626 (19:1396848 C>A,G), RS1000737326 (19:1397850 G>A), RS1001008844 (19:1401629 G>A,C), RS1001265927 (19:1403269 A>C,T), RS1001547377 (19:1399462 A>G), RS1002165125 (19:1399288 T>A,C), RS1002726509 (19:1397248 A>G), RS1003431575 (19:1400543 G>A), RS1003442305 (19:1403024 T>A), RS1003474895 (19:1403285 T>C), RS1004290291 (19:1398406 AT>A,ATT,ATTT), RS1004715502 (19:1401228 G>A)

Disease associations

OMIM: gene MIM:601240 | disease phenotypes: MIM:300352, MIM:612736, MIM:168600

GenCC curated gene-disease

Disease	Classification	Inheritance
guanidinoacetate methyltransferase deficiency	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
guanidinoacetate methyltransferase deficiency	Definitive	AR

Mondo (5): cerebral creatine deficiency syndrome (MONDO:0000456), guanidinoacetate methyltransferase deficiency (MONDO:0012999), intellectual disability (MONDO:0001071), late-onset Parkinson disease (MONDO:0008199), congenital nervous system disorder (MONDO:0002320)

Orphanet (4): Creatine deficiency syndrome (Orphanet:79172), Guanidinoacetate methyltransferase deficiency (Orphanet:382), Hereditary late-onset Parkinson disease (Orphanet:411602), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

45 total (30 of 45 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000708	Atypical behavior
HP:0000717	Autism
HP:0000718	Aggressive behavior
HP:0000750	Delayed speech and language development
HP:0000752	Hyperactivity
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001276	Hypertonia
HP:0001332	Dystonia
HP:0001336	Myoclonus
HP:0001337	Tremor
HP:0001344	Absent speech
HP:0001347	Hyperreflexia
HP:0002061	Lower limb spasticity
HP:0002063	Rigidity
HP:0002069	Bilateral tonic-clonic seizure
HP:0002071	Abnormality of extrapyramidal motor function
HP:0002072	Chorea
HP:0002123	Generalized myoclonic seizure
HP:0002305	Athetosis
HP:0002373	Febrile seizure (within the age range of 3 months to 6 years)
HP:0002376	Developmental regression
HP:0002384	Focal impaired awareness seizure
HP:0002385	Paraparesis
HP:0002457	Abnormal head movements
HP:0002465	Poor speech

GWAS associations

0 associations (top):

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
C537622	Guanidinoacetate methyltransferase deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523290 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, increases methylation	5
bisphenol A	affects expression, decreases expression, increases expression	4
Fluorouracil	affects reaction, decreases expression, increases expression, affects cotreatment, affects response to substance	3
Cyclosporine	decreases expression	3
Air Pollutants	decreases expression, increases abundance	2
Benzo(a)pyrene	decreases methylation, increases expression	2
Particulate Matter	decreases expression, increases abundance	2
aristolochic acid I	decreases expression	1
methylmercuric chloride	decreases expression	1
propionaldehyde	increases expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
senkirkine	decreases expression	1
heliotrine	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	decreases expression	1
butyraldehyde	increases expression	1
gossypol acetic acid	increases expression	1
nivalenol	decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
entinostat	increases expression	1
K 7174	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
jinfukang	affects cotreatment, increases expression	1
LDN 193189	affects cotreatment, increases expression	1
NSC 689534	affects binding, decreases expression	1
Acetaminophen	decreases expression	1
Ammonia	increases expression	1
Carmustine	decreases expression	1
Cisplatin	affects cotreatment, increases expression	1
Copper	affects binding, decreases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4416338	ADMET	Inhibition of human GAMT expressed in Escherichia coli at 10 uM assessed as reduction in SAH level using guanidineacetic acid 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

Cellosaurus cell lines

16 cell lines: 6 transformed cell line, 4 cancer cell line, 3 induced pluripotent stem cell, 3 finite cell line

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

Cellosaurus	Name	Category	Sex
CVCL_C7LX	GM28577	Induced pluripotent stem cell	Female
CVCL_C7M4	GM28070	Transformed cell line	Male
CVCL_C7M5	GM28096	Finite cell line	Male
CVCL_D1MP	Abcam K-562 GAMT KO	Cancer cell line	Female
CVCL_D2J9	Abcam Raji GAMT KO	Cancer cell line	Male
CVCL_D3A1	GM28756	Transformed cell line	Female
CVCL_D3A2	GM28757	Transformed cell line	Male
CVCL_D6WN	GM29115	Induced pluripotent stem cell	Male
CVCL_D6XM	GM28379	Finite cell line	Female
CVCL_D6YP	GM28782	Transformed cell line	Male

Clinical trials (associated diseases)

211 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
NCT00455143	PHASE4	TERMINATED	Cognitive Protection - Dexmedetomidine and Cognitive Reserve
NCT00561678	PHASE4	COMPLETED	Perioperative Cognitive Function - Dexmedetomidine and Cognitive Reserve
NCT01807481	PHASE4	UNKNOWN	Phase IV Study to Evaluate the Efficacy and Safety of Mircera in PD
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
NCT07015671	PHASE3	COMPLETED	Bioavailability and Bioequivalence Study of ER Torsemide and Spironolactone FDC Tablet in Healthy Subjects
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
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
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT03942458	PHASE1	COMPLETED	Pharmacokinetics and Pharmacodynamics of Vicagrel in Healthy Adult Subjects of Different CYP2C19
NCT07195825	PHASE1	RECRUITING	A Clinical Study to Evaluate the Safety, and Tolerability of BBM-P002 in the Treatment of Parkinson’s Disease
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population