GFPT1

Summary

GFPT1 (glutamine–fructose-6-phosphate transaminase 1, HGNC:4241) is a protein-coding gene on chromosome 2p13.3, encoding Glutamine–fructose-6-phosphate aminotransferase [isomerizing] 1 (Q06210). Rate-limiting enzyme of the hexosamine biosynthetic pathway (HBP) that catalyzes the formation of glucosamine-6-phosphate from fructose-6-phosphate and glutamine, thereby controlling the flux of glucose into this pathway. It is a selective cancer dependency (DepMap: 44.4% of cell lines).

This gene encodes the first and rate-limiting enzyme of the hexosamine pathway and controls the flux of glucose into the hexosamine pathway. The product of this gene catalyzes the formation of glucosamine 6-phosphate.

Source: NCBI Gene 2673 — RefSeq curated summary.

At a glance

• Gene–disease (curated): congenital myasthenic syndrome 12 (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 658 total — 29 pathogenic, 19 likely-pathogenic
• Phenotypes (HPO): 64
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 44.4% of screened cell lines
• MANE Select transcript: NM_001244710

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4241
Approved symbol	GFPT1
Name	glutamine–fructose-6-phosphate transaminase 1
Location	2p13.3
Locus type	gene with protein product
Status	Approved
Aliases	GFAT, GFA, GFAT1
Ensembl gene	ENSG00000198380
Ensembl biotype	protein_coding
OMIM	138292
Entrez	2673

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 22 protein_coding, 1 nonsense_mediated_decay

ENST00000357308, ENST00000361060, ENST00000494201, ENST00000674438, ENST00000674507, ENST00000852899, ENST00000852900, ENST00000852901, ENST00000852902, ENST00000852903, ENST00000852904, ENST00000852905, ENST00000852906, ENST00000912110, ENST00000955842, ENST00000955843, ENST00000955844, ENST00000955845, ENST00000955846, ENST00000955847, ENST00000955848, ENST00000955849, ENST00000955850

RefSeq mRNA: 2 — MANE Select: NM_001244710 NM_001244710, NM_002056

CCDS: CCDS33216, CCDS58713

Canonical transcript exons

ENST00000357308 — 20 exons

Exon	Start	End
ENSE00001130001	69350078	69350183
ENSE00001164472	69329297	69329424
ENSE00001164477	69337898	69338055
ENSE00001164480	69342152	69342249
ENSE00001164492	69348171	69348334
ENSE00001164504	69363545	69363670
ENSE00001164512	69326914	69327075
ENSE00001164517	69328271	69328438
ENSE00001164529	69329684	69329798
ENSE00001353023	69319780	69326233
ENSE00002453863	69338445	69338565
ENSE00002515280	69345904	69345999
ENSE00003470909	69387065	69387227
ENSE00003476079	69359268	69359326
ENSE00003541392	69358329	69358463
ENSE00003588163	69354489	69354568
ENSE00003610388	69356496	69356557
ENSE00003642172	69354259	69354312
ENSE00003658898	69374006	69374113
ENSE00003686248	69370001	69370108

Expression profiles

Bgee: expression breadth ubiquitous, 287 present calls, max score 97.99.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 45.8758 / max 613.0174, expressed in 1814 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
28905	39.8108	1814
28906	5.3030	1611
28904	0.7621	320

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of sigmoid colon	UBERON:0004993	97.99	gold quality
colonic mucosa	UBERON:0000317	97.78	gold quality
secondary oocyte	CL:0000655	97.77	gold quality
islet of Langerhans	UBERON:0000006	97.42	gold quality
rectum	UBERON:0001052	97.02	gold quality
stromal cell of endometrium	CL:0002255	96.60	gold quality
corpus epididymis	UBERON:0004359	96.20	gold quality
jejunal mucosa	UBERON:0000399	95.98	gold quality
calcaneal tendon	UBERON:0003701	95.47	gold quality
oocyte	CL:0000023	95.40	gold quality
cartilage tissue	UBERON:0002418	95.24	gold quality
ileal mucosa	UBERON:0000331	95.15	gold quality
tendon	UBERON:0000043	94.91	gold quality
palpebral conjunctiva	UBERON:0001812	94.54	gold quality
duodenum	UBERON:0002114	94.48	gold quality
choroid plexus epithelium	UBERON:0003911	94.24	gold quality
mucosa of transverse colon	UBERON:0004991	94.22	gold quality
bronchial epithelial cell	CL:0002328	94.05	gold quality
sperm	CL:0000019	93.96	gold quality
colonic epithelium	UBERON:0000397	93.82	gold quality
parotid gland	UBERON:0001831	93.79	gold quality
pancreas	UBERON:0001264	93.36	gold quality
placenta	UBERON:0001987	93.04	gold quality
esophagus squamous epithelium	UBERON:0006920	92.89	gold quality
gall bladder	UBERON:0002110	92.60	gold quality
male germ cell	CL:0000015	92.55	gold quality
epithelium of nasopharynx	UBERON:0001951	92.54	gold quality
epithelium of bronchus	UBERON:0002031	92.53	gold quality
bronchus	UBERON:0002185	92.48	gold quality
pericardium	UBERON:0002407	92.21	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	15.08
E-GEOD-125970	yes	14.64
E-CURD-7	no	736.26
E-MTAB-6075	no	451.72

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): HIF1A

miRNA regulators (miRDB)

271 targeting GFPT1, 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-6867-5P	100.00	82.21	3464
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-4481	100.00	66.42	1669
HSA-LET-7A-3P	100.00	74.03	3932
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-3163	100.00	77.23	8605
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-371B-5P	99.99	75.34	4759
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-513B-5P	99.99	69.96	2150

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 44.4% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• expression profiles of GFAT1 mRNA in various human tissues using reverse transcriptase-polymerase chain reaction. The identification and cDNA cloning of a novel GFAT1 splice variant expressed abundantly in skeletal muscle and heart is reported. (PMID:11587069)
• A novel variant of glutamine: fructose-6-phosphate amidotransferase-1 (GFAT1) mRNA is selectively expressed in striated muscle. (PMID:11679416)
• An increased concentration of wild-type GFAT in mesangial cells is enhanced both TGF-beta1 and fibronectin (PMID:12802498)
• Genetic variation in GFPT1 is unlikely to have a major impact on susceptibility to diabetic nephropathy. (PMID:14988277)
• Variants in the GFPT1 gene show suggestive evidence of an association with diabetic nephropathy among African-American individuals, and increased GFPT1 gene expression may characterize Caucasian subjects with diabetic nephropathy. (PMID:15308130)
• On the basis of the docking results, a binding pocket of human GFAT1 dimer for UDP-GlcNAc is defined. (PMID:15595739)
• two polymorphisms in the 5’-flanking region of GFAT, of which the -913 polymorphism seems to alter the risk for obesity and intramyocellular lipid accumulation in male subjects. (PMID:15613432)
• A novel single nucleotide polymorphism identified at position -1412 (G to C) had a functional effect on promoter activity and EMSA revealed specific binding of nuclear proteins to this region. (PMID:15878746)
• Testing for association of an +36T>C polymorphism in the glutamine: fructose-6-phosphate amidotransferase 1 gene and type 2 diabetes in Japanese and Caucasians. (PMID:17024311)
• These findings suggest for the first time that hGfat1 may be regulated by kinases other than PKA. (PMID:17941647)
• The first structures of the isomerase domain of the human GFAT in the presence of cyclic glucose-6-phosphate and linear glucosamine-6-phosphate was reported. (PMID:19059404)
• The phosphorylation of GFAT1 at Ser243 by AMPK has an important role in the regulation of the GFAT1 enzymatic activity. (PMID:19170765)
• Downregulation of the GFPT1 is associated with neuromuscular transmission defect. (PMID:21310273)
• This study demonstrated that Congenital myasthenic syndrome with tubular aggregates caused by GFPT1 mutations. (PMID:21975507)
• GFPT1 is the key enzyme in the hexosamine biosynthesis pathway. Mutations in GFPT1 cause defective glycosylation in the proteins of the neuromuscular junction. (PMID:22987706)
• Two GFPT1 untranslated mutations may cause limb-girdle myasthenia by reducing GFPT1 expression and ultimately impairing protein glycosylation. (PMID:23488891)
• Inhibition of GFPT1 enzymatic activity or siRNA silencing of GFPT1 expression resulted in reduced AChR expression. (PMID:23569079)
• The results found no correlation between end plate morphology and physiology or between genotype and phenotype in GFPT1-myasthenia. (PMID:23794683)
• Mapping of the regulatory site of glucosamine-6P synthase identified critical residues necessary for catalysis. (PMID:24075873)
• 3’-UTR mutation creates a microRNA target site in the GFPT1 gene of patients with congenital myasthenic syndrome (PMID:25765662)
• Increased GFPT1 expression is associated with triple-negative breast cancer. (PMID:26715276)
• GNPDA1 siRNA induced GFAT2 which was hardly measurable in these cells under standard culture conditions, GNPDA2 siRNA increased GFAT1, and GFAT1 siRNA increased the expression of hyaluronan synthase 2 (HAS2). Silencing of GFAT1 stimulated GNPDA1 and GDPDA2, and inhibited cell migration. (PMID:26887390)
• Findings indicate that GFAT1 functions as a novel suppressor of EMT and tumor metastasis in gastric cancer. (PMID:27509259)
• mTORC2 responds to glutamine catabolite levels to modulate the hexosamine biosynthesis enzyme GFAT1, and is essential for proper expression and nuclear accumulation of the GFAT1 transcriptional regulator, Xbp1s. (PMID:27570073)
• high GFAT1 expression is identified as an independent predictor of adverse clinical outcome in our small number of pancreatic cancer patients, and the practical prognostic nomogram model may help clinicians in decision making and the design of clinical studies. (PMID:27996048)
• GFAT1 phosphorylation by AMPK promotes VEGF-induced angiogenesis. (PMID:28008135)
• High GFAT1 expression is associated with hepatocellular carcinoma. (PMID:28186970)
• The AMPK-GFAT1 signaling axis serves as an important communication point between two nutrient-sensitive signaling pathways and is likely to play a significant role in controlling physiological processes in many other tissues. (PMID:28336748)
• study reports nine new mutations of GFPT1 in limb-girdle congenital myasthenic syndrome (LG-CMS) (PMID:28712002)
• These results suggest that 2-deoxy-d-glucose reduces N-glycosylation of proteins following the increase of phosphorylation of GFAT1 and results in the inhibition of cell growth mediated by endoplasmic reticulum stress in pancreatic cancer cells. (PMID:29753740)
• The Gfpt1tm1d/tm1d model allows for further investigation of pathophysiological consequences on genes and pathways downstream of GFPT1 likely to involve misglycosylation or hypoglycosylation of neuromuscular junction and muscle targets. (PMID:29905857)
• We also showed that IL-8 stimulation of colon and lung cancer cells-induced glucose uptake and expressions of glucose transporter 3 (GLUT3) and glucosamine fructose-6-phosphate aminotransferase (GFAT), a regulator of glucose flux to the hexosamine biosynthetic pathway, resulting in enhancement of protein O-GlcNAcylation (PMID:30305725)
• GFPT1 variants and defects in other enzymes of this pathway have previously been associated with congenital myasthenia. These findings identify leukoencephalopathy as a previously unrecognized phenotype in GFPT1-related disease and suggest that mitochondrial dysfunction could contribute to this disorder. (PMID:30635494)
• MTOR2/C-MYC/GFAT1 axis is responsible for the modulation on the crosstalk between glycolysis and glutaminolysis in glioblastoma cells. (PMID:30771196)
• The longevity-associated G451E of GFAT1 variant shows drastically reduced sensitivity to UDP-GlcNAc inhibition. (PMID:32019926)
• GFAT1/HBP/O-GlcNAcylation Axis Regulates beta-Catenin Activity to Promote Pancreatic Cancer Aggressiveness. (PMID:32149084)
• LncRNA ELFN1-AS1 promotes esophageal cancer progression by up-regulating GFPT1 via sponging miR-183-3p. (PMID:32229685)
• High GFPT1 expression predicts unfavorable outcomes in patients with resectable pancreatic ductal adenocarcinoma. (PMID:33517899)
• Inhibition of GFAT1 in lung cancer cells destabilizes PD-L1 protein. (PMID:34270713)
• Cardiomyocyte protein O-GlcNAcylation is regulated by GFAT1 not GFAT2. (PMID:34735873)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	gfpt1	ENSDARG00000057465
mus_musculus	Gfpt1	ENSMUSG00000029992
rattus_norvegicus	Gfpt1	ENSRNOG00000018507

Paralogs (1): GFPT2 (ENSG00000131459)

Protein

Protein identifiers

Glutamine–fructose-6-phosphate aminotransferase [isomerizing] 1 — Q06210 (reviewed: Q06210)

Alternative names: D-fructose-6-phosphate amidotransferase 1, Glutamine:fructose-6-phosphate amidotransferase 1, Hexosephosphate aminotransferase 1

All UniProt accessions (4): A0A6I8PRN4, A0A6I8PRT6, A0A6I8PTT9, Q06210

UniProt curated annotations — full annotation on UniProt →

Function. Rate-limiting enzyme of the hexosamine biosynthetic pathway (HBP) that catalyzes the formation of glucosamine-6-phosphate from fructose-6-phosphate and glutamine, thereby controlling the flux of glucose into this pathway. Inhibited by UDP-N-acetylglucosamine (UDP-GlcNAc) through a feedback loop. Fine-tunes the metabolic fluctuations of UDP-GlcNAc and its impacts on hyaluronan synthesis during tissue remodeling. Via control of the HPB, regulates the availability of precursors for N- and O-linked protein glycosylation and modulates peripheral clock oscillation.

Subunit / interactions. Homodimer; forms an asymmetric dimer. Homotetramer.

Tissue specificity. Predominantly expressed in skeletal muscle. Not expressed in brain. Seems to be selectively expressed in striated muscle.

Disease relevance. Myasthenic syndrome, congenital, 12 (CMS12) [MIM:610542] A form of congenital myasthenic syndrome, a group of disorders characterized by failure of neuromuscular transmission, including pre-synaptic, synaptic, and post-synaptic disorders that are not of autoimmune origin. Clinical features are easy fatigability and muscle weakness. CMS12 is characterized by onset of proximal muscle weakness in the first decade. Individuals with this condition have a recognizable pattern of weakness of shoulder and pelvic girdle muscles, and sparing of ocular or facial muscles. EMG classically shows a decremental response to repeated nerve stimulation, a sign of neuromuscular junction dysfunction. Affected individuals show a favorable response to acetylcholinesterase (AChE) inhibitors. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Inhibited by UDP-GlcNAc.

Pathway. Nucleotide-sugar biosynthesis; UDP-N-acetyl-alpha-D-glucosamine biosynthesis; alpha-D-glucosamine 6-phosphate from D-fructose 6-phosphate: step 1/1.

Isoforms (2)

UniProt ID	Names	Canonical?
Q06210-1	1, GFAT1m	yes
Q06210-2	2

RefSeq proteins (2): NP_001231639, NP_002047 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001347	SIS_dom	Domain
IPR005855	GFAT	Family
IPR017932	GATase_2_dom	Domain
IPR029055	Ntn_hydrolases_N	Homologous_superfamily
IPR035466	GlmS/AgaS_SIS	Domain
IPR035490	GlmS/FrlB_SIS	Domain
IPR046348	SIS_dom_sf	Homologous_superfamily
IPR047084	GFAT_N	Domain

Pfam: PF01380, PF13522

Enzyme classification (BRENDA):

• EC 2.6.1.16 — glutamine-fructose-6-phosphate transaminase (isomerizing) (BRENDA: 38 organisms, 20 substrates, 132 inhibitors, 95 Km, 53 kcat entries)

Substrate kinetics (BRENDA)

6 substrates with measured Km, best-characterized 6. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
D-FRUCTOSE 6-PHOSPHATE	0.2–6.5	42
L-GLUTAMINE	0.04–5.1	32
L-GAMMA-GLUTAMYL-P-NITROANILIDE	0.0064–12.2	11
L-GLUTAMATE	0.2–2.36	6
D-GLUCOSE 6-PHOSPHATE	16	1
L-GAMMA -GLUTAMYL-P-NITROANILIDE	0.67	1

Catalyzed reactions (Rhea), 1 shown:

• D-fructose 6-phosphate + L-glutamine = D-glucosamine 6-phosphate + L-glutamate (RHEA:13237)

UniProt features (125 total): strand 33, binding site 30, helix 29, sequence variant 13, turn 7, domain 3, mutagenesis site 3, modified residue 2, initiator methionine 1, chain 1, splice variant 1, region of interest 1, active site 1

Structure

Experimental structures (PDB)

16 structures.

PDB	Method	Resolution (Å)
2ZJ3	X-RAY DIFFRACTION	1.9
2ZJ4	X-RAY DIFFRACTION	2.2
7NDL	X-RAY DIFFRACTION	2.22
6R4H	X-RAY DIFFRACTION	2.24
2V4M	X-RAY DIFFRACTION	2.29
6SVO	X-RAY DIFFRACTION	2.33
6R4E	X-RAY DIFFRACTION	2.35
6ZMK	X-RAY DIFFRACTION	2.38
6R4J	X-RAY DIFFRACTION	2.42
6SVM	X-RAY DIFFRACTION	2.48
6R4F	X-RAY DIFFRACTION	2.5
6R4G	X-RAY DIFFRACTION	2.5
6SVP	X-RAY DIFFRACTION	2.53
6R4I	X-RAY DIFFRACTION	2.59
6SVQ	X-RAY DIFFRACTION	2.72
6ZMJ	X-RAY DIFFRACTION	2.77

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q06210-F1	93.01	0.87

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 (1): 2 (glutamine amidotransferase activity)

Ligand- & substrate-binding residues (30): 98; 99; 108; 124; 148; 328; 361; 361; 373; 373; 394; 395 …

Post-translational modifications (2): 103, 261

Mutagenesis-validated functional residues (3):

Position	Phenotype
325	increased sensitivity to udp-glcnac feedback inhibition. reduced sensitivity to udp-glcnac feedback inhibition; when ass
469	no change in binding with udp-glcnac. drastically reduced sensitivity to udp-glcnac feedback inhibition. reduced sensiti
479	loss of binding with udp-glcnac and loss of udp-glcnac feedback inhibition.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-381038	XBP1(S) activates chaperone genes
R-HSA-4085023	Defective GFPT1 causes CMSTA1
R-HSA-446210	Synthesis of UDP-N-acetyl-glucosamine

MSigDB gene sets: 343 (showing top): GOBP_CIRCADIAN_RHYTHM, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, REACTOME_UNFOLDED_PROTEIN_RESPONSE_UPR, HOFFMANN_SMALL_PRE_BII_TO_IMMATURE_B_LYMPHOCYTE_DN, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_PROTEIN_N_LINKED_GLYCOSYLATION, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_CIRCADIAN_REGULATION_OF_GENE_EXPRESSION, GOBP_AMINO_SUGAR_BIOSYNTHETIC_PROCESS, GOBP_NUCLEOSIDE_PHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, SHAFFER_IRF4_TARGETS_IN_PLASMA_CELL_VS_MATURE_B_LYMPHOCYTE

GO Biological Process (9): fructose 6-phosphate metabolic process (GO:0006002), UDP-N-acetylglucosamine metabolic process (GO:0006047), UDP-N-acetylglucosamine biosynthetic process (GO:0006048), energy reserve metabolic process (GO:0006112), protein N-linked glycosylation (GO:0006487), circadian regulation of gene expression (GO:0032922), rhythmic process (GO:0048511), carbohydrate derivative metabolic process (GO:1901135), carbohydrate derivative biosynthetic process (GO:1901137)

GO Molecular Function (5): L-glutamine:D-fructose-6-phosphate transaminase (isomerizing) activity (GO:0004360), carbohydrate derivative binding (GO:0097367), protein binding (GO:0005515), transaminase activity (GO:0008483), transferase activity (GO:0016740)

GO Cellular Component (2): cytosol (GO:0005829), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
IRE1alpha activates chaperones	1
Diseases associated with glycosylation precursor biosynthesis	1
Synthesis of substrates in N-glycan biosythesis	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
carbohydrate derivative metabolic process	2
binding	2
organophosphate metabolic process	1
amino sugar metabolic process	1
nucleotide-sugar metabolic process	1
UDP-N-acetylglucosamine metabolic process	1
nucleotide-sugar biosynthetic process	1
amino sugar biosynthetic process	1
energy derivation by oxidation of organic compounds	1
glycoprotein biosynthetic process	1
circadian rhythm	1
regulation of gene expression	1
biological_process	1
metabolic process	1
biosynthetic process	1
amino acid transaminase activity	1
transferase activity, transferring nitrogenous groups	1
catalytic activity	1
cytoplasm	1
cellular anatomical structure	1
extracellular vesicle	1

Protein interactions and networks

STRING

2540 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GFPT1	GNPNAT1	Q96EK6	808
GFPT1	UAP1	Q16222	789
GFPT1	PGM3	O95394	773
GFPT1	DPAGT1	Q9H3H5	773
GFPT1	OGA	O60502	758
GFPT1	DOK7	Q18PE1	714
GFPT1	OGT	O15294	702
GFPT1	ALG14	Q96F25	700
GFPT1	NAGK	Q9UJ70	679
GFPT1	COLQ	Q9Y215	671
GFPT1	GNPDA1	P46926	630
GFPT1	INS	P01308	629
GFPT1	GMPPB	Q9Y5P6	627
GFPT1	RAPSN	Q13702	623
GFPT1	CHRNE	Q04844	623

IntAct

69 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
SLC17A5	LGALS8	psi-mi:“MI:0914”(association)	0.640
GFPT2	GFPT1	psi-mi:“MI:0915”(physical association)	0.620
GFPT2	GFPT1	psi-mi:“MI:0914”(association)	0.620
CFTR	HAX1	psi-mi:“MI:0914”(association)	0.610
	TK2	psi-mi:“MI:0915”(physical association)	0.400
GFPT1	MAPK8	psi-mi:“MI:0915”(physical association)	0.370
JUN	TPM3	psi-mi:“MI:0914”(association)	0.350
E6	TRAFD1	psi-mi:“MI:0914”(association)	0.350
	PGRMC1	psi-mi:“MI:0914”(association)	0.350
BVLF1	VWA8	psi-mi:“MI:0914”(association)	0.350
	TBKBP1	psi-mi:“MI:0914”(association)	0.350
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350
Prdm16	ESYT2	psi-mi:“MI:0914”(association)	0.350
Mecom	ESYT2	psi-mi:“MI:0914”(association)	0.350
LRRK2		psi-mi:“MI:0914”(association)	0.350
SMYD2	HSPA4L	psi-mi:“MI:0914”(association)	0.350
TEX101	PSMD12	psi-mi:“MI:0914”(association)	0.350
P		psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350

BioGRID (189): GFPT1 (Affinity Capture-MS), GFPT1 (Affinity Capture-RNA), ASNS (Co-fractionation), CRK (Co-fractionation), GARS (Co-fractionation), GFPT1 (Co-fractionation), GFPT1 (Co-fractionation), GFPT1 (Co-fractionation), GFPT1 (Co-fractionation), GFPT1 (Co-fractionation), GFPT1 (Co-fractionation), GFPT1 (Co-fractionation), GFPT1 (Co-fractionation), GFPT1 (Co-fractionation), GFPT1 (Co-fractionation)

ESM2 similar proteins: A2P2R3, A6ZME2, A6ZMR9, B3LLX6, B3LM95, C7GL41, C7GRE4, C8ZET7, C8ZF72, D4A2Z8, O26293, O60060, O74942, O93937, P04046, P07258, P07259, P14742, P20054, P27515, P31327, P32874, P38690, P41390, P41831, P44098, P47856, P52418, P53704, P93757, Q06210, Q08DQ2, Q09740, Q09794, Q0G9T0, Q39469, Q4KMC4, Q4UIN6, Q67X99, Q6BJG4

Diamond homologs: A2P2R3, A6ZME2, B3LLX6, C7GL41, C8ZET7, O26060, O26273, O57981, O66648, O68280, O68956, O83833, O86781, O94808, P14742, P17169, P44708, P47856, P53704, P57138, P57963, P59499, P72720, P82808, P94323, Q06210, Q08DQ2, Q09740, Q4KMC4, Q56213, Q56275, Q5E279, Q5JH71, Q5L3P0, Q5L589, Q5NHQ9, Q5NRH4, Q5PKV9, Q5QZH5, Q663R1

SIGNOR signaling

10 interactions.

A	Effect	B	Mechanism
CAMK2A	up-regulates	GFPT1	phosphorylation
PRKAA1	up-regulates	GFPT1	phosphorylation
PRKAA1	down-regulates	GFPT1	phosphorylation
GFPT1	“down-regulates quantity”	“D-fructofuranose 6-phosphate(2-)”	“chemical modification”
GFPT1	“down-regulates quantity”	“L-glutamine zwitterion”	“chemical modification”
GFPT1	“up-regulates quantity”	“2-ammonio-2-deoxy-D-glucopyranose 6-phosphate(1-)”	“chemical modification”
GFPT1	“up-regulates quantity”	L-glutamate(1-)	“chemical modification”
GFPT1	up-regulates	Hexosamine_biosynthesis
GFPT1	up-regulates	Protein_glycosylation
PRKCA	“down-regulates activity”	GFPT1	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	29
Likely pathogenic	19
Uncertain significance	272
Likely benign	222
Benign	68

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1067128	NM_001244710.2(GFPT1):c.44C>T (p.Thr15Met)	Pathogenic
1069341	NC_000002.11:g.(?69553299)(69614213_?)del	Pathogenic
1070025	NM_001244710.2(GFPT1):c.931C>T (p.Arg311Ter)	Pathogenic
1070689	NM_001244710.2(GFPT1):c.1290dup (p.Arg431fs)	Pathogenic
1073758	NM_001244710.2(GFPT1):c.686dup (p.Ala229_Arg230insTer)	Pathogenic
1252034	NM_001244710.2(GFPT1):c.686-1G>A	Pathogenic
1455957	NM_001244710.2(GFPT1):c.769_772del (p.Ser257fs)	Pathogenic
1927249	NM_001244710.2(GFPT1):c.728_729del (p.Gln243fs)	Pathogenic
1949433	NM_001244710.2(GFPT1):c.1851T>G (p.Tyr617Ter)	Pathogenic
2002398	NM_001244710.2(GFPT1):c.1687C>T (p.Arg563Ter)	Pathogenic
2424021	NC_000002.11:g.(?69583608)(69583709_?)del	Pathogenic
2424022	NC_000002.11:g.(?69573016)(69575486_?)del	Pathogenic
2719778	NM_001244710.2(GFPT1):c.1291C>T (p.Arg431Ter)	Pathogenic
29736	NM_001244710.2(GFPT1):c.224dup (p.Gln76fs)	Pathogenic
29737	NM_001244710.2(GFPT1):c.719G>A (p.Trp240Ter)	Pathogenic
29738	NM_001244710.2(GFPT1):c.1096G>T (p.Asp366Tyr)	Pathogenic
29740	NM_001244710.2(GFPT1):c.621del (p.Leu207_Leu208insTer)	Pathogenic
3010186	NM_001244710.2(GFPT1):c.741dup (p.Lys248fs)	Pathogenic
3668591	NM_001244710.2(GFPT1):c.762C>A (p.Cys254Ter)	Pathogenic
444502	NM_001244710.2(GFPT1):c.738_739del (p.Gly247fs)	Pathogenic
4768063	NM_001244710.2(GFPT1):c.714dup (p.Arg239fs)	Pathogenic
4804077	NM_001244710.2(GFPT1):c.2T>G (p.Met1Arg)	Pathogenic
540353	NM_001244710.2(GFPT1):c.686-2A>G	Pathogenic
570975	NM_001244710.2(GFPT1):c.982C>T (p.Gln328Ter)	Pathogenic
583230	NM_001244710.2(GFPT1):c.197_201del (p.Val66fs)	Pathogenic
631477	NM_001244710.2(GFPT1):c.41G>T (p.Arg14Leu)	Pathogenic
631478	NM_001244710.2(GFPT1):c.452C>A (p.Thr151Lys)	Pathogenic
836225	NM_001244710.2(GFPT1):c.89_90del (p.Leu30fs)	Pathogenic
859066	NM_001244710.2(GFPT1):c.964C>T (p.Arg322Ter)	Pathogenic
1184876	NM_001244710.2(GFPT1):c.1265_1268del (p.Phe422fs)	Likely pathogenic

SpliceAI

3092 predictions. Top by Δscore:

Variant	Effect	Δscore
2:69326907:GACTT:G	donor_loss	1.0000
2:69326908:ACTTA:A	donor_loss	1.0000
2:69326909:CTTAC:C	donor_loss	1.0000
2:69326910:TTA:T	donor_loss	1.0000
2:69326911:T:TG	donor_loss	1.0000
2:69326912:A:AC	donor_gain	1.0000
2:69326912:ACAT:A	donor_gain	1.0000
2:69326913:C:CA	donor_gain	1.0000
2:69326913:CA:C	donor_gain	1.0000
2:69326913:CAT:C	donor_gain	1.0000
2:69326913:CATC:C	donor_gain	1.0000
2:69327071:CGCCC:C	acceptor_gain	1.0000
2:69327073:CCC:C	acceptor_gain	1.0000
2:69327074:CC:C	acceptor_gain	1.0000
2:69327074:CCC:C	acceptor_gain	1.0000
2:69327075:CC:C	acceptor_gain	1.0000
2:69327075:CCTA:C	acceptor_loss	1.0000
2:69327076:C:CC	acceptor_gain	1.0000
2:69327076:C:T	acceptor_gain	1.0000
2:69327076:CTA:C	acceptor_loss	1.0000
2:69327077:T:C	acceptor_loss	1.0000
2:69328266:CTTA:C	donor_loss	1.0000
2:69328268:TA:T	donor_loss	1.0000
2:69328269:ACCTG:A	donor_gain	1.0000
2:69328270:C:A	donor_loss	1.0000
2:69328270:CCTG:C	donor_gain	1.0000
2:69328270:CCTGC:C	donor_gain	1.0000
2:69328435:TTTT:T	acceptor_gain	1.0000
2:69328436:TTT:T	acceptor_gain	1.0000
2:69328437:TT:T	acceptor_gain	1.0000

AlphaMissense

4624 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:69328377:C:T	G596D	1.000
2:69328379:A:C	H595Q	1.000
2:69328379:A:T	H595Q	1.000
2:69328382:T:A	K594N	1.000
2:69328382:T:G	K594N	1.000
2:69329298:A:G	L575P	1.000
2:69329787:G:C	S498R	1.000
2:69329787:G:T	S498R	1.000
2:69329789:T:G	S498R	1.000
2:69337904:A:C	S492R	1.000
2:69337904:A:T	S492R	1.000
2:69337906:T:G	S492R	1.000
2:69337982:G:C	N466K	1.000
2:69337982:G:T	N466K	1.000
2:69337993:C:A	G463W	1.000
2:69338055:C:A	G442V	1.000
2:69338055:C:T	G442D	1.000
2:69342170:A:C	S395R	1.000
2:69342170:A:T	S395R	1.000
2:69342172:T:G	S395R	1.000
2:69342198:C:G	R386P	1.000
2:69363606:C:A	W96C	1.000
2:69363606:C:G	W96C	1.000
2:69363608:A:G	W96R	1.000
2:69363608:A:T	W96R	1.000
2:69326207:T:A	K694N	0.999
2:69326207:T:G	K694N	0.999
2:69326208:T:A	K694I	0.999
2:69326211:G:T	A693D	0.999
2:69326214:A:G	L692P	0.999

dbSNP variants (sampled 300 via entrez): RS1000022209 (2:69348009 A>T), RS1000032786 (2:69363037 G>C), RS1000040568 (2:69387165 G>A), RS1000173531 (2:69377929 A>G), RS1000229560 (2:69344111 T>C), RS1000259575 (2:69388838 A>C), RS1000282181 (2:69384295 C>T), RS1000283370 (2:69343908 A>C), RS1000434510 (2:69351033 T>C), RS1000490853 (2:69340301 A>G), RS1000506120 (2:69379289 A>C), RS1000555691 (2:69345567 C>G,T), RS1000582711 (2:69346105 CA>C), RS1000587018 (2:69354623 T>C), RS1000617627 (2:69345183 G>A)

Disease associations

OMIM: gene MIM:138292 | disease phenotypes: MIM:610542, MIM:601462, MIM:614750, MIM:608931

GenCC curated gene-disease

Disease	Classification	Inheritance
congenital myasthenic syndrome 12	Definitive	Autosomal recessive
congenital myasthenic syndromes with glycosylation defect	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
congenital myasthenic syndrome 12	Definitive	AR

Mondo (6): congenital myasthenic syndrome 12 (MONDO:0012518), hereditary ataxia (MONDO:0100309), congenital myasthenic syndrome (MONDO:0018940), congenital myasthenic syndrome 13 (MONDO:0013883), congenital myasthenic syndrome 4C (MONDO:0012157), (MONDO:0018144)

Orphanet (3): Congenital myasthenic syndrome with glycosylation defect (Orphanet:353327), Congenital myasthenic syndrome (Orphanet:590), Hereditary ataxia (Orphanet:183518)

HPO phenotypes

64 total (30 of 64 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000218	High palate
HP:0000276	Long face
HP:0000303	Mandibular prognathia
HP:0000467	Neck muscle weakness
HP:0000486	Strabismus
HP:0000508	Ptosis
HP:0000597	Ophthalmoparesis
HP:0000689	Dental malocclusion
HP:0001252	Hypotonia
HP:0001260	Dysarthria
HP:0001270	Motor delay
HP:0001284	Areflexia
HP:0001288	Gait disturbance
HP:0001290	Generalized hypotonia
HP:0001371	Flexion contracture
HP:0001382	Joint hypermobility
HP:0001558	Decreased fetal movement
HP:0001612	Weak cry
HP:0001763	Pes planus
HP:0002015	Dysphagia
HP:0002359	Frequent falls
HP:0002421	Poor head control
HP:0002460	Distal muscle weakness
HP:0002515	Waddling gait
HP:0002650	Scoliosis
HP:0002747	Respiratory insufficiency due to muscle weakness
HP:0002804	Arthrogryposis multiplex congenita
HP:0002938	Lumbar hyperlordosis
HP:0003198	Myopathy

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST009200_20	Whole brain grey matter density	9.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0010306	Grey matter density measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D020294	Myasthenic Syndromes, Congenital	C10.668.758.800; C16.320.590
C531684	Hereditary spinal ataxia (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1909481 (SINGLE PROTEIN)

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

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
6.82	IC50	150	nM	CHEMBL1911372
6.52	Ki	300	nM	CHEMBL1911368
6.40	IC50	400	nM	CHEMBL1911373
6.16	Kd	685.8	nM	CHEMBL5653589
6.16	ED50	685.8	nM	CHEMBL5653589

PubChem BioAssay actives

5 with measured affinity, of 11 total; 4 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
(2S)-2-amino-3-[(2-bromoacetyl)amino]propanoic acid	625555: Irreversible inhibition of GFAT	ic50	0.1500	uM
N-[[6,7-dimethoxy-1-(3-propan-2-yloxybenzoyl)isoquinolin-4-yl]methyl]-1,1,1-trifluoromethanesulfonamide	625552: Noncompetitive inhibition of GFAT in presence of fructose-6-phosphate	ki	0.3000	uM
(2S)-2-amino-3-[[(E)-4-methoxy-4-oxobut-2-enoyl]amino]propanoic acid	625555: Irreversible inhibition of GFAT	ic50	0.4000	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148427: Binding affinity to human GFPT1 incubated for 45 mins by Kinobead based pull down assay	kd	0.6857	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, decreases expression	4
Cyclosporine	increases expression	4
sodium arsenite	decreases expression, increases expression	3
perfluorooctanoic acid	increases expression	3
Tobacco Smoke Pollution	affects expression, increases expression	3
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression, increases expression	2
2,2’,4,4’-tetrabromodiphenyl ether	increases expression, decreases expression	2
bisphenol S	increases expression	2
Benzo(a)pyrene	decreases expression	2
Nickel	increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tunicamycin	increases expression	2
Valproic Acid	increases expression, decreases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
Thapsigargin	increases expression	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
bisphenol F	increases expression	1
tremortin	increases expression	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, decreases expression	1
arsenite	affects binding, decreases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
ochratoxin A	increases expression	1
cupric chloride	increases expression	1
hydroquinone	increases expression	1
nivalenol	decreases expression	1
tamibarotene	affects expression	1
perfluorooctane sulfonic acid	increases expression	1

ChEMBL screening assays

8 unique, capped per target: 8 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1912253	Binding	Noncompetitive inhibition of GFAT in presence of fructose-6-phosphate	Discovery of 1-arylcarbonyl-6,7-dimethoxyisoquinoline derivatives as glutamine fructose-6-phosphate amidotransferase (GFAT) inhibitors. — Bioorg Med Chem Lett

Cellosaurus cell lines

7 cell lines: 6 induced pluripotent stem cell, 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A3WP	HPS2895	Induced pluripotent stem cell	Male
CVCL_A3WQ	HPS2896	Induced pluripotent stem cell	Male
CVCL_A3WR	HPS2897	Induced pluripotent stem cell	Male
CVCL_A3WS	HPS2898	Induced pluripotent stem cell	Male
CVCL_A3WT	HPS2899	Induced pluripotent stem cell	Male
CVCL_SP90	HAP1 GFPT1 (-)	Cancer cell line	Male
CVCL_UP24	HPS2894	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00202397	PHASE2	COMPLETED	Effect of Riluzole as a Symptomatic Approach in Patients With Chronic Cerebellar Ataxia
NCT01203592	PHASE1	COMPLETED	Efficacy of Albuterol in the Treatment of Congenital Myasthenic Syndromes
NCT06436742	PHASE1	RECRUITING	A Phase 1b Study to Investigate Safety and Tolerability of ARGX-119 in Adult Participants With DOK7-Congenital Myasthenic Syndromes (CMS)
NCT07226726	PHASE1	RECRUITING	Patients With Congenital Myasthenic Syndrome Will be Treated With Mesenchymal Stem Cell Exosome Solution
NCT01360164	PHASE1/PHASE2	UNKNOWN	Safety and Efficacy of Umbilical Cord Mesenchymal Stem Cell Therapy for Patients With Hereditary Ataxia
NCT00004306	Not specified	COMPLETED	Clinical and Molecular Correlations in Spinocerebellar Ataxia Type 10 (SCA10)
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT04750850	Not specified	COMPLETED	Core Stability Exercises and Hereditary Ataxia
NCT05160870	Not specified	UNKNOWN	Genotype-phenotype Correlation and Pathogenic Mechanism in Hereditary Ataxia
NCT05160883	Not specified	UNKNOWN	Neuroimaging Changes in Hereditary Ataxia
NCT06034886	Not specified	AVAILABLE	Expanded Access Protocol of Troriluzole in Patients With Spinocerebellar Ataxia (SCA)
NCT06152133	Not specified	COMPLETED	Telerehabilitation, Core Stability Exercises and Hereditary Ataxia (TRCore-ataxia)
NCT06267222	Not specified	ENROLLING_BY_INVITATION	Trans-spinal Electrical Stimulation in Individuals With Spinocerebellar Ataxia
NCT07092358	Not specified	RECRUITING	Hereditary Ataxia Research on Multi-Omics and Neuroclinical Insights in the Yangtze Delta
NCT07200505	Not specified	NOT_YET_RECRUITING	Telerehabilitation for Core Stability and Strength in Hereditary Ataxia
NCT00872950	Not specified	APPROVED_FOR_MARKETING	3,4-Diaminopyridine Use in Lambert-Eaton Myasthenic Syndrome(LEMS) and Congenital Myasthenic Syndromes (CMS)
NCT01403402	Not specified	RECRUITING	Congenital Muscle Disease Study of Patient and Family Reported Medical Information
NCT01474980	Not specified	COMPLETED	Pregnancy Outcomes in Congenital Myasthenie Syndrome
NCT02012933	Not specified	NO_LONGER_AVAILABLE	3,4-Diaminopyridine for Lambert-Eaton Myasthenic Syndrome (LEMS) and Congenital Myasthenia (CM)
NCT02189720	Not specified	APPROVED_FOR_MARKETING	Expanded Access Study Amifampridine Phosphate in Lambert-Eaton Myasthenic Syndrome (LEMS),Congenital Myasthenic Syndrome
NCT03062631	Not specified	NO_LONGER_AVAILABLE	Treatment Use of 3,4 Diaminopyridine in Congenital Myasthenia
NCT05408702	Not specified	COMPLETED	Exercise in Autoimmune Myasthenia Gravis and Myasthenic Syndromes
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening
NCT06078553	Not specified	RECRUITING	A Natural History Study in Participants With Congenital Myasthenic Syndromes (CMS) Due to Mutations in DOK7, MUSK, AGRN, or LRP4