GYS1

Summary

GYS1 (glycogen synthase 1, HGNC:4706) is a protein-coding gene on chromosome 19q13.33, encoding Glycogen [starch] synthase, muscle (P13807). Glycogen synthase participates in the glycogen biosynthetic process along with glycogenin and glycogen branching enzyme.

The protein encoded by this gene catalyzes the addition of glucose monomers to the growing glycogen molecule through the formation of alpha-1,4-glycoside linkages. Mutations in this gene are associated with muscle glycogen storage disease. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 2997 — RefSeq curated summary.

At a glance

• Gene–disease (curated): glycogen storage disease due to muscle and heart glycogen synthase deficiency (Definitive, ClinGen)
• Clinical variants (ClinVar): 752 total — 32 pathogenic, 12 likely-pathogenic
• Phenotypes (HPO): 41
• Druggable target: yes
• MANE Select transcript: NM_002103

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4706
Approved symbol	GYS1
Name	glycogen synthase 1
Location	19q13.33
Locus type	gene with protein product
Status	Approved
Aliases	GSY
Ensembl gene	ENSG00000104812
Ensembl biotype	protein_coding
OMIM	138570
Entrez	2997

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 8 protein_coding, 3 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000263276, ENST00000323798, ENST00000457974, ENST00000472004, ENST00000484289, ENST00000496048, ENST00000594220, ENST00000917525, ENST00000917526, ENST00000960031, ENST00000960032, ENST00000960033

RefSeq mRNA: 2 — MANE Select: NM_002103 NM_001161587, NM_002103

CCDS: CCDS12747, CCDS54292

Canonical transcript exons

ENST00000323798 — 16 exons

Exon	Start	End
ENSE00001058868	48970928	48971023
ENSE00001058871	48985461	48985605
ENSE00001058873	48969775	48969855
ENSE00001058877	48970546	48970709
ENSE00001129914	48985850	48986035
ENSE00001129928	48991302	48991483
ENSE00001850177	48968130	48969611
ENSE00003479458	48992995	48993309
ENSE00003485571	48982720	48982837
ENSE00003486817	48974213	48974339
ENSE00003503525	48978098	48978157
ENSE00003512913	48974620	48974733
ENSE00003575253	48982255	48982375
ENSE00003588054	48977924	48978002
ENSE00003598710	48987194	48987385
ENSE00003660284	48981530	48981636

Expression profiles

Bgee: expression breadth ubiquitous, 257 present calls, max score 98.23.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 29.1722 / max 624.2264, expressed in 1813 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
181973	25.4767	1813
181968	1.3485	58
181971	0.9818	30
181970	0.8952	30
181969	0.2351	30
181974	0.2350	93

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
hindlimb stylopod muscle	UBERON:0004252	98.23	gold quality
apex of heart	UBERON:0002098	97.92	gold quality
gastrocnemius	UBERON:0001388	97.88	gold quality
vastus lateralis	UBERON:0001379	97.32	gold quality
muscle of leg	UBERON:0001383	97.30	gold quality
quadriceps femoris	UBERON:0001377	97.26	gold quality
muscle organ	UBERON:0001630	97.21	gold quality
triceps brachii	UBERON:0001509	97.00	gold quality
skeletal muscle tissue	UBERON:0001134	96.76	gold quality
heart left ventricle	UBERON:0002084	96.68	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	96.51	gold quality
tibialis anterior	UBERON:0001385	96.46	gold quality
cardiac ventricle	UBERON:0002082	96.45	gold quality
gluteal muscle	UBERON:0002000	96.15	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	96.05	gold quality
biceps brachii	UBERON:0001507	95.83	gold quality
muscle tissue	UBERON:0002385	95.51	gold quality
diaphragm	UBERON:0001103	95.38	gold quality
right atrium auricular region	UBERON:0006631	95.33	gold quality
heart	UBERON:0000948	94.74	gold quality
cardiac atrium	UBERON:0002081	94.55	gold quality
deltoid	UBERON:0001476	94.51	gold quality
left ventricle myocardium	UBERON:0006566	93.91	gold quality
body of tongue	UBERON:0011876	93.48	gold quality
lower esophagus mucosa	UBERON:0035834	92.40	gold quality
esophagus mucosa	UBERON:0002469	91.59	gold quality
esophagus	UBERON:0001043	91.35	gold quality
mucosa of transverse colon	UBERON:0004991	91.32	gold quality
lower esophagus muscularis layer	UBERON:0035833	91.24	gold quality
lower esophagus	UBERON:0013473	91.23	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.40
E-MTAB-2983	no	216.81
E-HCAD-13	no	2.90

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): HIF1A

miRNA regulators (miRDB)

50 targeting GYS1, 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-4425	100.00	67.59	1049
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-7152-3P	99.97	67.47	849
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-3180-5P	99.82	69.12	2422
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-1299	99.77	71.24	2389
HSA-MIR-4320	99.75	65.80	793
HSA-MIR-29B-2-5P	99.67	68.98	1726
HSA-MIR-1249-5P	99.61	66.55	2049
HSA-MIR-6797-5P	99.61	66.55	2084
HSA-MIR-6752-5P	99.59	67.32	1243
HSA-MIR-516B-5P	99.56	66.33	1495
HSA-MIR-4472	99.56	66.08	1478
HSA-MIR-203A-3P	99.49	70.56	2806
HSA-MIR-6081	99.48	66.07	1446
HSA-MIR-302A-5P	99.39	68.21	1913
HSA-MIR-940	99.37	66.14	2064
HSA-MIR-6808-5P	99.31	66.23	2150
HSA-MIR-6893-5P	99.31	66.25	2119
HSA-MIR-504-3P	99.30	67.18	1745

Literature-anchored findings (GeneRIF, showing 20)

• the M416V polymorphism of glycogen synthase 1 gene is not associated with insulin resistance in type 2 diabetes (PMID:12870167)
• Data show that myotubes defective in glycogen synthase (GS) activity express insulin-responsive glycogen synthase kinase-3alpha, suggesting that failure of insulin to decrease GS phosphorylation involves abnormal activity of another kinase or phosphatase. (PMID:15194499)
• Phosphorylation at site 2 in the elderly and at site 3a + 3b in young twins had a genetic component. (PMID:15855312)
• no nuclear export signal was identified in the sequence of the protein, the region comprising amino acids 555-633, which has an Arg-rich cluster involved in the allosteric activation is crucial for its nuclear concentration and aggregation. (PMID:15955076)
• Exercise unmaskd the effect associated with the GYS1 polymorphism, rendering carriers of this allele less susceptible to the protective effect of exercise on the risk of cardiovascular mortality. (PMID:17356695)
• 3 siblings were identified with profound muscle glycogen deficiency and homozygous stop mutations in GYS1 (PMID:17928598)
• Pioglitazone treatment improved insulin-stimulated glucose metabolism and glycogen synthase activity in PCOS. (PMID:18544618)
• After overnight low muscle glycogen level and/or in response to exhausting exercise-induced glycogenolysis, GSY is associated with spherical structures at the I-band of sarcomeres. (PMID:19339242)
• Dysregulation of glycogen synthase phosphorylation plays a major role in impaired insulin regulation of GS in obesity and type 2 diabetes mellitus. (PMID:19837931)
• The regulation of glucose-6-phosphate dehydrogenase and glycogen synthase activities by insulin superfamily peptides in myometrium of pregnant women and its impairments under different types of diabetes mellitus (PMID:20017397)
• GYS1 regulation by HIF plays a central role in the hypoxic accumulation of glycogen, and hypoxia also upregulates the expression of UTP:glucose-1-phosphate urydylyltransferase (UGP2) and 1,4-alpha glucan branching enzyme (GBE1) (PMID:20300197)
• The present findings demonstrate that physical inactivity-induced insulin resistance in muscle is associated with lower content/activity of key proteins in glucose transport/phosphorylation and storage. (PMID:22403297)
• Allosteric regulation and the relationship between phosphorylation and the kinetics of glycogen synthase. [Review] (PMID:23134486)
• Data suggest that although COOH-terminal dephosphorylation is likely necessary for GS activation, protein kinase Akt-2- (Akt2)-dependent NH2-terminal dephosphorylation is site for “fine-tuning” insulin-mediated GS activation in skeletal muscle. (PMID:23321478)
• over-expression of muscle glycogen synthase (MGS)was detected in diabetic human kidney (PMID:25371328)
• Overexpression of GYS1, MIF, and MYC is associated with adverse outcome and poor response to azacitidine in myelodysplastic syndromes and acute myeloid leukemia (PMID:25487600)
• High glycogen synthase 1 expression is associated with myeloid leukemia. (PMID:25703587)
• Insulin-stimulated glycogen synthase (GS) activity was completely ablated during hyperinsulinemic hypoglycemia, and catecholamine signaling via cAMP-dependent protein kinase (PKA) and phosphorylation of inhibiting sites on GS all increased. (PMID:28596236)
• Pulmonary glycogen deficiency as a new potential cause of respiratory distress syndrome. (PMID:33219378)
• The structural mechanism of human glycogen synthesis by the GYS1-GYG1 complex. (PMID:35793618)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	gys1	ENSDARG00000016875
mus_musculus	Gys1	ENSMUSG00000003865
rattus_norvegicus	Gys1	ENSRNOG00000020812
drosophila_melanogaster	Glys	FBGN0266064
caenorhabditis_elegans		WBGENE00001793

Paralogs (1): GYS2 (ENSG00000111713)

Protein

Protein identifiers

Glycogen [starch] synthase, muscle — P13807 (reviewed: P13807)

Alternative names: Glycogen synthase 1

All UniProt accessions (2): P13807, M0QYU1

UniProt curated annotations — full annotation on UniProt →

Function. Glycogen synthase participates in the glycogen biosynthetic process along with glycogenin and glycogen branching enzyme. Extends the primer composed of a few glucose units formed by glycogenin by adding new glucose units to it. In this context, glycogen synthase transfers the glycosyl residue from UDP-Glc to the non-reducing end of alpha-1,4-glucan.

Subunit / interactions. Part of the GYS1-GYG1 complex, a heterooctamer composed of a tetramer of GYS1 and 2 dimers of GYG1, where each GYS1 protomer binds to one GYG1 subunit (via GYG1 C-terminus); the GYS1 tetramer may dissociate from GYG1 dimers to continue glycogen polymerization on its own.

Tissue specificity. Expressed in skeletal muscle and most other cell types where glycogen is present.

Post-translational modifications. Phosphorylation at Ser-8 by AMPK inactivates the enzyme activity. Primed phosphorylation at Ser-657 (site 5) by CSNK2A1 and CSNK2A2 is required for inhibitory phosphorylation at Ser-641 (site 3a), Ser-645 (site 3b), Ser-649 (site 3c) and Ser-653 (site 4) by GSK3A an GSK3B. Phosphorylated at Ser-641 by DYRK2, leading to inactivation. Phosphorylated at Ser-641 by PASK, leading to inactivation; phosphorylation by PASK is inhibited by glycogen. Dephosphorylation at Ser-641 and Ser-645 by PP1 activates the enzyme.

Disease relevance. Muscle glycogen storage disease 0 (GSD0b) [MIM:611556] Metabolic disorder characterized by fasting hypoglycemia presenting in infancy or early childhood. The role of muscle glycogen is to provide critical energy during bursts of activity and sustained muscle work. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Allosteric activation by glucose-6-phosphate. Phosphorylation reduces enzyme activity by constraining a tense conformation of the tetramer through inter-subunit interaction. Phosphorylation reduces the activity towards UDP-glucose. When in the non-phosphorylated state, glycogen synthase does not require glucose-6-phosphate as an allosteric activator; when phosphorylated it does.

Pathway. Glycan biosynthesis; glycogen biosynthesis.

Similarity. Belongs to the glycosyltransferase 3 family.

Isoforms (2)

UniProt ID	Names	Canonical?
P13807-1	1	yes
P13807-2	2

RefSeq proteins (2): NP_001155059, NP_002094* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008631	Glycogen_synth	Family

Pfam: PF05693

Enzyme classification (BRENDA):

• EC 2.4.1.11 — glycogen(starch) synthase (BRENDA: 32 organisms, 47 substrates, 106 inhibitors, 50 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
UDP-GLUCOSE	0.0005–21.3	24
ADP-GLUCOSE	4.1–46.9	5
AMYLOPECTIN	2–10	2
GLYCOGEN	2.4–4.6	2
DTDP-GLUCOSE	4	1
GDP-GLUCOSE	3.9	1

Catalyzed reactions (Rhea), 1 shown:

• (1->4)-alpha-D-glucosyl + UDP-alpha-D-glucose = (1->4)-alpha-D-glucosyl + UDP + H(+) (RHEA:18549)

UniProt features (109 total): helix 26, strand 24, binding site 17, modified residue 15, turn 8, sequence variant 8, compositionally biased region 4, sequence conflict 4, chain 1, region of interest 1, splice variant 1

Structure

Experimental structures (PDB)

9 structures.

PDB	Method	Resolution (Å)
7ZBN	ELECTRON MICROSCOPY	2.62
8Z0A	ELECTRON MICROSCOPY	2.84
7Q0B	ELECTRON MICROSCOPY	3
7Q13	ELECTRON MICROSCOPY	3
8CVX	ELECTRON MICROSCOPY	3.5
8CVZ	ELECTRON MICROSCOPY	3.52
8CVY	ELECTRON MICROSCOPY	3.6
7Q12	ELECTRON MICROSCOPY	3.7
7Q0S	ELECTRON MICROSCOPY	4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P13807-F1	84.83	0.72

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 (17): 292 (in other chain); 294; 297; 301; 331; 331; 501; 510; 512; 513; 515; 582 …

Post-translational modifications (15): 8, 11, 412, 641, 645, 649, 652, 653, 657, 698, 700, 710, 721, 727, 731

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-3322077	Glycogen synthesis
R-HSA-3785653	Myoclonic epilepsy of Lafora
R-HSA-3814836	Glycogen storage disease type XV (GYG1)
R-HSA-3828062	Glycogen storage disease type 0 (muscle GYS1)

MSigDB gene sets: 235 (showing top): MOOTHA_GLYCOGEN_METABOLISM, GOBP_POLYSACCHARIDE_BIOSYNTHETIC_PROCESS, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_DN, GRAESSMANN_RESPONSE_TO_MC_AND_SERUM_DEPRIVATION_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, CEBPB_01, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY, GTGCCTT_MIR506, CEBP_Q2, MCBRYAN_PUBERTAL_BREAST_4_5WK_DN, AAACCAC_MIR140, GGAANCGGAANY_UNKNOWN, GROSS_HYPOXIA_VIA_HIF1A_DN, GOBP_CARBOHYDRATE_METABOLIC_PROCESS

GO Biological Process (3): glycogen biosynthetic process (GO:0005978), heart development (GO:0007507), glycogen metabolic process (GO:0005977)

GO Molecular Function (7): alpha-1,4-glucan glucosyltransferase (UDP-glucose donor) activity (GO:0004373), D-glucose binding (GO:0005536), glycogen synthase activity, transferring glucose-1-phosphate (GO:0061547), catalytic activity (GO:0003824), protein binding (GO:0005515), transferase activity (GO:0016740), glycosyltransferase activity (GO:0016757)

GO Cellular Component (4): cytoplasm (GO:0005737), cytosol (GO:0005829), membrane (GO:0016020), inclusion body (GO:0016234)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Glycogen storage diseases	3
Glycogen metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
intracellular anatomical structure	2
glycogen metabolic process	1
glucan biosynthetic process	1
animal organ development	1
circulatory system development	1
energy reserve metabolic process	1
glucan metabolic process	1
alpha-1,4-glucan glucosyltransferase (NDP-glucose donor) activity	1
UDP-glucosyltransferase activity	1
monosaccharide binding	1
transferase activity, transferring phosphorus-containing groups	1
molecular_function	1
binding	1
catalytic activity	1
transferase activity	1
cytoplasm	1

Protein interactions and networks

STRING

2517 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GYS1	EPM2A	O95278	906
GYS1	PPP1R3C	Q9UQK1	885
GYS1	NHLRC1	Q6VVB1	877
GYS1	AGL	P35573	841
GYS1	GYG1	P46976	838
GYS1	GBE1	Q04446	809
GYS1	PYGM	P11217	784
GYS1	PYGL	P06737	778
GYS1	PYGB	P11216	774
GYS1	PASK	Q96RG2	722
GYS1	UGP2	Q16851	716
GYS1	PPP1CC	P36873	706
GYS1	GYG2	O15488	699
GYS1	SLC1A5	Q15758	671
GYS1	UCK2	Q9BZX2	662

IntAct

230 interactions, top by confidence:

A	B	Type	Score
CEP290	CCP110	psi-mi:“MI:2364”(proximity)	0.890
GYS1	GYG1	psi-mi:“MI:0915”(physical association)	0.840
GYG1	GYS1	psi-mi:“MI:0915”(physical association)	0.840
PPP1CB	CCDC85C	psi-mi:“MI:0914”(association)	0.750
PPP1CC	CCDC85C	psi-mi:“MI:0914”(association)	0.740
GSK3B	GYS1	psi-mi:“MI:0217”(phosphorylation reaction)	0.730
GYS1	IHO1	psi-mi:“MI:0915”(physical association)	0.720
IHO1	GYS1	psi-mi:“MI:0915”(physical association)	0.720
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
PPP1R3C	GYS1	psi-mi:“MI:0915”(physical association)	0.670
PPP1CA	CCDC85C	psi-mi:“MI:0914”(association)	0.670
PPP1CA	CCDC85C	psi-mi:“MI:2364”(proximity)	0.670
GYG2	GYS1	psi-mi:“MI:0914”(association)	0.660
GYS1	GYG2	psi-mi:“MI:0914”(association)	0.660
MAPK7	PFDN6	psi-mi:“MI:0914”(association)	0.640
GABARAPL1	IPO5	psi-mi:“MI:0914”(association)	0.590
PPP2R2D	ENSA	psi-mi:“MI:0914”(association)	0.570
AIMP2	GYS1	psi-mi:“MI:0915”(physical association)	0.560
GYS1	AIMP2	psi-mi:“MI:0915”(physical association)	0.560
GYS1	CDCA8	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (153): GYS1 (Two-hybrid), AIMP2 (Two-hybrid), CCDC36 (Two-hybrid), GYS1 (Reconstituted Complex), GYS1 (Affinity Capture-MS), GYS1 (Affinity Capture-MS), GYS1 (Affinity Capture-MS), GYS1 (Affinity Capture-MS), GYS1 (Affinity Capture-MS), GYS1 (Two-hybrid), GYS1 (Affinity Capture-MS), GYG2 (Two-hybrid), GYS1 (Affinity Capture-MS), GYS1 (Proximity Label-MS), GYS1 (Proximity Label-MS)

ESM2 similar proteins: A1A5G6, A7Z064, G5EEK9, G5EGP4, O13742, O97681, P00347, P00365, P04035, P09610, P10759, P13807, P15920, P16393, P17625, P20715, P23109, P25286, P30628, P32563, P37296, P38329, P54840, P57103, P70549, Q00955, Q01237, Q01290, Q01432, Q09573, Q1W675, Q29466, Q29512, Q54E04, Q5R422, Q5R6N3, Q5R9H0, Q8AVM5, Q8MJ26, Q8RWZ7

Diamond homologs: A2RRU1, A7MB78, J9VTK7, O93869, P13807, P13834, P17625, P23337, P27472, P54840, Q55GH4, Q5R9H0, Q8MJ26, Q8VCB3, Q9U2D9, Q9VFC8, Q9Z1E4

SIGNOR signaling

30 interactions.

A	Effect	B	Mechanism
GSK3A	down-regulates	GYS1	phosphorylation
“MYOD1/SWI/SNF complex”	“up-regulates quantity by expression”	GYS1	“transcriptional regulation”
GSK3B	“down-regulates activity”	GYS1	phosphorylation
INSR	“up-regulates activity”	GYS1
GYS1	“down-regulates quantity”	UDP-alpha-D-glucose(2-)	“chemical modification”
GYS1	“up-regulates quantity”	α-D-glucosyl-glycogenin	“chemical modification”
PPP1R3C	up-regulates	GYS1	binding
PPP1R3B	up-regulates	GYS1	binding
PPP1R3A	up-regulates	GYS1	dephosphorylation
GYS1	up-regulates	Glycogen_synthesis
PASK	“down-regulates activity”	GYS1	phosphorylation
PRKACA	unknown	GYS1	phosphorylation
CSNK2A1	unknown	GYS1	phosphorylation
PRKACA	“down-regulates activity”	GYS1	phosphorylation
DYRK1A	“down-regulates activity”	GYS1	phosphorylation
DYRK1B	“down-regulates activity”	GYS1	phosphorylation
AMPK	“down-regulates activity”	GYS1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 121 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Macroautophagy	11	14.6×	9e-08
Autophagy	7	11.9×	3e-04
Regulation of PLK1 Activity at G2/M Transition	7	10.2×	6e-04
Loss of Nlp from mitotic centrosomes	5	9.1×	7e-03
Loss of proteins required for interphase microtubule organization from the centrosome	5	9.1×	7e-03
AURKA Activation by TPX2	5	8.8×	8e-03
M Phase	7	5.3×	1e-02

GO biological processes:

GO term	Partners	Fold	FDR
glycogen biosynthetic process	5	42.6×	1e-05
glycogen metabolic process	7	33.5×	5e-07
autophagosome maturation	7	22.3×	6e-06
mitophagy	7	20.2×	9e-06
regulation of cytokinesis	5	19.1×	6e-04
autophagosome assembly	8	16.3×	6e-06
regulation of circadian rhythm	5	11.8×	5e-03
positive regulation of autophagy	5	9.5×	1e-02

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	32
Likely pathogenic	12
Uncertain significance	338
Likely benign	276
Benign	37

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1064610	NM_002103.5(GYS1):c.1646-1_1647del	Pathogenic
1069149	NM_002103.5(GYS1):c.699_700del (p.Arg236fs)	Pathogenic
1073960	NC_000019.9:g.(?49485502)(49486104_?)del	Pathogenic
1074189	NM_002103.5(GYS1):c.913C>T (p.Gln305Ter)	Pathogenic
1430475	NM_002103.5(GYS1):c.546G>A (p.Trp182Ter)	Pathogenic
1432649	NM_002103.5(GYS1):c.405_420del (p.Asp135fs)	Pathogenic
1433467	NM_002103.5(GYS1):c.929del (p.Gly310fs)	Pathogenic
1455547	NC_000019.9:g.(?49477450)(49478010_?)del	Pathogenic
1466408	NM_002103.5(GYS1):c.678+2T>G	Pathogenic
16057	NM_002103.5(GYS1):c.1384C>T (p.Arg462Ter)	Pathogenic
1948472	NM_002103.5(GYS1):c.359del (p.Gly120fs)	Pathogenic
2138317	NM_002103.5(GYS1):c.1230-2A>G	Pathogenic
2146827	NM_002103.5(GYS1):c.7_8del (p.Leu3fs)	Pathogenic
2182696	NM_002103.5(GYS1):c.721C>T (p.Arg241Ter)	Pathogenic
2416446	NM_002103.5(GYS1):c.583C>T (p.Arg195Ter)	Pathogenic
2705242	NM_002103.5(GYS1):c.1192_1193insCAAGG (p.Glu398fs)	Pathogenic
2770149	NM_002103.5(GYS1):c.169G>T (p.Glu57Ter)	Pathogenic
2818809	NM_002103.5(GYS1):c.1539del (p.Tyr514fs)	Pathogenic
3248454	NC_000019.9:g.(?49494539)(49494760_?)del	Pathogenic
3248455	NC_000019.9:g.(?49484767)(49486114_?)del	Pathogenic
3347888	NM_002103.5(GYS1):c.1716_1717del (p.Tyr572_Ser573delinsTer)	Pathogenic
3618810	NM_002103.5(GYS1):c.502C>T (p.Gln168Ter)	Pathogenic
3717524	NM_002103.5(GYS1):c.1234del (p.Ser412fs)	Pathogenic
3725421	NM_002103.5(GYS1):c.1358C>G (p.Ser453Ter)	Pathogenic
4086079	NM_002103.5(GYS1):c.630G>C (p.Gly210=)	Pathogenic
4086080	NM_002103.5(GYS1):c.678+1G>C	Pathogenic
4761937	NM_002103.5(GYS1):c.198dup (p.Pro67fs)	Pathogenic
4798670	NM_002103.5(GYS1):c.1793G>A (p.Trp598Ter)	Pathogenic
4819256	GYS1, IVS9, A-G, -2	Pathogenic
4819257	GYS1, IVS14, A-G, -2	Pathogenic

SpliceAI

2357 predictions. Top by Δscore:

Variant	Effect	Δscore
19:48969767:CCACT:C	donor_loss	1.0000
19:48969768:CACTC:C	donor_loss	1.0000
19:48969769:ACTCA:A	donor_loss	1.0000
19:48969770:CTCA:C	donor_loss	1.0000
19:48969771:TCACC:T	donor_loss	1.0000
19:48969772:CACC:C	donor_loss	1.0000
19:48969773:A:AC	donor_gain	1.0000
19:48969773:ACCG:A	donor_gain	1.0000
19:48969773:ACCGC:A	donor_loss	1.0000
19:48969774:C:CC	donor_gain	1.0000
19:48969774:CCG:C	donor_gain	1.0000
19:48969774:CCGC:C	donor_gain	1.0000
19:48969851:TAGTA:T	acceptor_gain	1.0000
19:48969852:AGTA:A	acceptor_gain	1.0000
19:48969853:GTA:G	acceptor_gain	1.0000
19:48969854:TA:T	acceptor_gain	1.0000
19:48969855:ACTAG:A	acceptor_loss	1.0000
19:48969856:C:CA	acceptor_loss	1.0000
19:48969856:C:CC	acceptor_gain	1.0000
19:48970541:CCTA:C	donor_loss	1.0000
19:48970544:A:AC	donor_gain	1.0000
19:48970544:AC:A	donor_gain	1.0000
19:48970545:C:A	donor_gain	1.0000
19:48970545:C:CC	donor_gain	1.0000
19:48970545:CCCG:C	donor_gain	1.0000
19:48970545:CCCGG:C	donor_gain	1.0000
19:48970560:T:TA	donor_gain	1.0000
19:48970711:T:G	acceptor_loss	1.0000
19:48970858:T:TA	donor_gain	1.0000
19:48970910:AGGGG:A	donor_gain	1.0000

AlphaMissense

4840 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:48970561:C:A	W598C	1.000
19:48970561:C:G	W598C	1.000
19:48970563:A:G	W598R	1.000
19:48970563:A:T	W598R	1.000
19:48970580:A:G	L592P	1.000
19:48970583:C:G	R591P	1.000
19:48970592:C:G	R588P	1.000
19:48970594:G:C	N587K	1.000
19:48970594:G:T	N587K	1.000
19:48970598:C:G	R586P	1.000
19:48970610:C:G	R582P	1.000
19:48970709:C:T	G549D	1.000
19:48970928:C:G	G549R	1.000
19:48970969:C:T	G535D	1.000
19:48970971:G:C	F534L	1.000
19:48970971:G:T	F534L	1.000
19:48970973:A:G	F534L	1.000
19:48970975:C:T	G533D	1.000
19:48970995:A:C	S526R	1.000
19:48970995:A:T	S526R	1.000
19:48970997:T:G	S526R	1.000
19:48971005:C:A	G523V	1.000
19:48971005:C:T	G523E	1.000
19:48971006:C:G	G523R	1.000
19:48971006:C:T	G523R	1.000
19:48971016:G:C	C519W	1.000
19:48971017:C:T	C519Y	1.000
19:48971018:A:G	C519R	1.000
19:48974222:A:G	Y514H	1.000
19:48974224:C:T	G513D	1.000

dbSNP variants (sampled 300 via entrez): RS1000020582 (19:48983788 A>T), RS1000048525 (19:48973094 C>T), RS1000151382 (19:48968413 T>C), RS1000197725 (19:48979033 G>A), RS1000222027 (19:48969484 T>TCGG), RS1000257583 (19:48993805 G>A,C), RS1000412323 (19:48983034 T>C), RS1000551471 (19:48970646 A>AAGTGAGCTGTAG), RS1000684948 (19:48970439 G>A,C), RS1000708874 (19:48976439 G>A), RS1000736568 (19:48975911 C>A,T), RS1000832962 (19:48977777 T>C), RS1000870894 (19:48968725 G>A), RS1000894089 (19:48973110 G>A), RS1001048528 (19:48967726 C>T)

Disease associations

OMIM: gene MIM:138570 | disease phenotypes: MIM:611556, MIM:232200

GenCC curated gene-disease

Disease	Classification	Inheritance
glycogen storage disease due to muscle and heart glycogen synthase deficiency	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
glycogen storage disease due to muscle and heart glycogen synthase deficiency	Definitive	AR

Mondo (2): glycogen storage disease due to muscle and heart glycogen synthase deficiency (MONDO:0012693), disorder of glycogen metabolism (MONDO:0002412)

Orphanet (2): Glycogen storage disease due to muscle and heart glycogen synthase deficiency (Orphanet:137625), Glycogen storage disease (Orphanet:79201)

HPO phenotypes

41 total (30 of 41 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001250	Seizure
HP:0001279	Syncope
HP:0001297	Stroke
HP:0001324	Muscle weakness
HP:0001638	Cardiomyopathy
HP:0001639	Hypertrophic cardiomyopathy
HP:0001645	Sudden cardiac death
HP:0001695	Cardiac arrest
HP:0001699	Sudden death
HP:0001712	Left ventricular hypertrophy
HP:0001943	Hypoglycemia
HP:0002069	Bilateral tonic-clonic seizure
HP:0002875	Exertional dyspnea
HP:0003200	Ragged-red muscle fibers
HP:0003326	Myalgia
HP:0003546	Exercise intolerance
HP:0003551	Difficulty climbing stairs
HP:0003554	Type 2 muscle fiber atrophy
HP:0003621	Juvenile onset
HP:0003701	Proximal muscle weakness
HP:0003738	Exercise-induced myalgia
HP:0003756	Skeletal myopathy
HP:0003803	Type 1 muscle fiber predominance
HP:0005144	Ventricular septal hypertrophy
HP:0005184	Prolonged QTc interval
HP:0009763	Limb pain
HP:0011463	Childhood onset
HP:0012270	Decreased muscle glycogen content
HP:0012378	Fatigue

GWAS associations

0 associations (top):

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D006008	Glycogen Storage Disease	C16.320.565.202.449; C18.452.648.202.449
C566917	Glycogen Storage Disease 0, Muscle (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4000 (SINGLE PROTEIN)

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

Binding affinities (BindingDB)

78 measured of 78 human assays (78 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(2S)-1-[3-[[4-(4,5-difluoro-2-methoxyphenyl)phenoxy]methyl]benzoyl]pyrrolidine-2-carboxylic acid	EC50	10 nM	US-9290487: Pharmaceutical composition for treating diabetes
(2S)-1-[3-[[4-[2-(cyanomethoxy)-4,5-difluorophenyl]phenoxy]methyl]benzoyl]pyrrolidine-2-carboxylic acid	EC50	15 nM	US-9290487: Pharmaceutical composition for treating diabetes
(2S)-1-[3-[[4-(4,5-difluoro-2-prop-2-ynoxyphenyl)phenoxy]methyl]benzoyl]pyrrolidine-2-carboxylic acid	EC50	17 nM	US-9290487: Pharmaceutical composition for treating diabetes
(2S)-1-[3-[[4-(4,5-difluoro-1-benzofuran-7-yl)phenoxy]methyl]benzoyl]pyrrolidine-2-carboxylic acid	EC50	22 nM	US-9290487: Pharmaceutical composition for treating diabetes
(2S)-1-[3-[[4-(4,5-difluoro-2-methylsulfanylphenyl)phenoxy]methyl]benzoyl]pyrrolidine-2-carboxylic acid	EC50	29 nM	US-9290487: Pharmaceutical composition for treating diabetes
(2S)-1-[3-[[4-(4,5-difluoro-2,3-dihydro-1-benzofuran-7-yl)phenoxy]methyl]benzoyl]pyrrolidine-2-carboxylic acid	EC50	31 nM	US-9290487: Pharmaceutical composition for treating diabetes
(2S)-1-[3-[[4-(6,7-difluoro-1H-indol-4-yl)phenoxy]methyl]benzoyl]pyrrolidine-2-carboxylic acid	EC50	34 nM	US-9290487: Pharmaceutical composition for treating diabetes
(2S)-1-[3-[[4-(6,7-difluoro-1-benzofuran-5-yl)phenoxy]methyl]benzoyl]pyrrolidine-2-carboxylic acid	EC50	35 nM	US-9290487: Pharmaceutical composition for treating diabetes
(2S)-1-[3-[[4-[2-(cyanomethylsulfanyl)-4,5-difluorophenyl]phenoxy]methyl]benzoyl]pyrrolidine-2-carboxylic acid	EC50	38 nM	US-9290487: Pharmaceutical composition for treating diabetes
(2S)-1-[3-[[4-(4,5-difluoro-1-benzothiophen-7-yl)phenoxy]methyl]benzoyl]pyrrolidine-2-carboxylic acid	EC50	42 nM	US-9290487: Pharmaceutical composition for treating diabetes
(2S)-1-[3-[[4-[4,5-difluoro-3-(hydroxymethyl)-1-benzofuran-7-yl]phenoxy]methyl]benzoyl]pyrrolidine-2-carboxylic acid	EC50	44 nM	US-9290487: Pharmaceutical composition for treating diabetes
(2S)-1-[3-[[4-[4,5-difluoro-2-[(E)-hydroxyiminomethyl]-1-benzofuran-7-yl]phenoxy]methyl]benzoyl]pyrrolidine-2-carboxylic acid	EC50	45 nM	US-9290487: Pharmaceutical composition for treating diabetes
(2S)-1-[3-[[4-(4,5-difluoro-3-methyl-1-benzofuran-7-yl)phenoxy]methyl]benzoyl]pyrrolidine-2-carboxylic acid	EC50	54 nM	US-9290487: Pharmaceutical composition for treating diabetes
(2S)-1-[3-[[4-[3-(cyanomethylamino)-4,5-difluorophenyl]phenoxy]methyl]benzoyl]pyrrolidine-2-carboxylic acid	EC50	54 nM	US-9290487: Pharmaceutical composition for treating diabetes
(2S)-1-[3-[[4-[4,5-difluoro-2-[(E)-hydroxyiminomethyl]phenyl]phenoxy]methyl]benzoyl]pyrrolidine-2-carboxylic acid	EC50	61 nM	US-9290487: Pharmaceutical composition for treating diabetes
(2S)-1-[3-[[4-(4,6-difluoro-1-benzofuran-7-yl)phenoxy]methyl]benzoyl]pyrrolidine-2-carboxylic acid	EC50	64 nM	US-9290487: Pharmaceutical composition for treating diabetes
(2S)-1-[3-[[4-[4,5-difluoro-2-(methoxymethyl)-1-benzofuran-7-yl]phenoxy]methyl]benzoyl]pyrrolidine-2-carboxylic acid	EC50	65 nM	US-9290487: Pharmaceutical composition for treating diabetes
(2S)-1-[3-[[4-(7-fluoro-1-benzofuran-5-yl)phenoxy]methyl]benzoyl]pyrrolidine-2-carboxylic acid	EC50	70 nM	US-9290487: Pharmaceutical composition for treating diabetes
(2S)-1-[3-[[4-(4,5-difluoro-2-formylphenyl)phenoxy]methyl]benzoyl]pyrrolidine-2-carboxylic acid	EC50	70 nM	US-9290487: Pharmaceutical composition for treating diabetes
(2S)-1-[3-[[4-[4,5-difluoro-2-(hydroxymethyl)-1-benzothiophen-7-yl]phenoxy]methyl]benzoyl]pyrrolidine-2-carboxylic acid	EC50	74 nM	US-9290487: Pharmaceutical composition for treating diabetes
(2S)-1-[3-[[4-[4,5-difluoro-2-(2-oxopropylsulfanyl)phenyl]phenoxy]methyl]benzoyl]pyrrolidine-2-carboxylic acid	EC50	83 nM	US-9290487: Pharmaceutical composition for treating diabetes
(2S)-1-[3-[[4-(4,5-difluoro-3-methyl-1-benzothiophen-7-yl)phenoxy]methyl]benzoyl]pyrrolidine-2-carboxylic acid	EC50	85 nM	US-9290487: Pharmaceutical composition for treating diabetes
(2S)-1-[3-[[4-(5,6-difluoro-2H-chromen-8-yl)phenoxy]methyl]benzoyl]pyrrolidine-2-carboxylic acid	EC50	100 nM	US-9290487: Pharmaceutical composition for treating diabetes
(2S)-1-[3-[[4-(7,8-difluoro-2H-chromen-5-yl)phenoxy]methyl]benzoyl]pyrrolidine-2-carboxylic acid	EC50	100 nM	US-9290487: Pharmaceutical composition for treating diabetes
(2S)-1-[3-[[4-(6,7-difluoro-2-methyl-1H-indol-4-yl)phenoxy]methyl]benzoyl]pyrrolidine-2-carboxylic acid	EC50	100 nM	US-9290487: Pharmaceutical composition for treating diabetes
(2S)-1-[3-[[4-(4-fluoro-1-benzofuran-7-yl)phenoxy]methyl]benzoyl]pyrrolidine-2-carboxylic acid	EC50	110 nM	US-9290487: Pharmaceutical composition for treating diabetes
(2S)-1-[3-[[4-(4,5-difluoro-2-methyl-1-benzofuran-7-yl)phenoxy]methyl]benzoyl]pyrrolidine-2-carboxylic acid	EC50	110 nM	US-9290487: Pharmaceutical composition for treating diabetes
(2S)-1-[3-[[4-(4,5-difluoro-2-prop-2-enoxyphenyl)phenoxy]methyl]benzoyl]pyrrolidine-2-carboxylic acid	EC50	110 nM	US-9290487: Pharmaceutical composition for treating diabetes
(2S)-1-[3-[[4-(4,5-difluoro-2-sulfanylphenyl)phenoxy]methyl]benzoyl]pyrrolidine-2-carboxylic acid	EC50	110 nM	US-9290487: Pharmaceutical composition for treating diabetes
(2S)-1-[3-[[4-[3-(cyanomethoxy)-4,5-difluorophenyl]phenoxy]methyl]benzoyl]pyrrolidine-2-carboxylic acid	EC50	120 nM	US-9290487: Pharmaceutical composition for treating diabetes
(2S)-1-[3-[[4-[4,5-difluoro-2-(2-hydroxyethylsulfanyl)phenyl]phenoxy]methyl]benzoyl]pyrrolidine-2-carboxylic acid	EC50	130 nM	US-9290487: Pharmaceutical composition for treating diabetes
(2S)-1-[3-[[4-(6,7-difluoro-1-benzofuran-4-yl)phenoxy]methyl]benzoyl]pyrrolidine-2-carboxylic acid	EC50	140 nM	US-9290487: Pharmaceutical composition for treating diabetes
(2S)-1-[3-[[4-(2-carbamimidoyl-4,5-difluoro-1-benzofuran-7-yl)phenoxy]methyl]benzoyl]pyrrolidine-2-carboxylic acid	EC50	140 nM	US-9290487: Pharmaceutical composition for treating diabetes
(2S)-1-[3-[[4-(4,5-difluoro-1-benzofuran-7-yl)phenoxy]methyl]benzoyl]-2,5-dihydropyrrole-2-carboxylic acid	EC50	140 nM	US-9290487: Pharmaceutical composition for treating diabetes
(2S)-1-[3-[[4-[3-(cyanomethyl)-4,5-difluoro-1-benzofuran-7-yl]phenoxy]methyl]benzoyl]pyrrolidine-2-carboxylic acid	EC50	150 nM	US-9290487: Pharmaceutical composition for treating diabetes
(2S)-1-[3-[[4-(3,4-difluoro-5-prop-2-ynoxyphenyl)phenoxy]methyl]benzoyl]pyrrolidine-2-carboxylic acid	EC50	150 nM	US-9290487: Pharmaceutical composition for treating diabetes
(2S)-1-[3-[[4-(4,5-difluoro-1-benzofuran-7-yl)phenoxy]methyl]benzoyl]azetidine-2-carboxylic acid	EC50	150 nM	US-9290487: Pharmaceutical composition for treating diabetes
(2S)-1-[3-[[4-(1H-indol-4-yl)phenoxy]methyl]benzoyl]pyrrolidine-2-carboxylic acid	EC50	160 nM	US-9290487: Pharmaceutical composition for treating diabetes
(2S)-1-[3-[[4-(4,5-difluoro-1-benzofuran-7-yl)-2-fluorophenoxy]methyl]benzoyl]pyrrolidine-2-carboxylic acid	EC50	160 nM	US-9290487: Pharmaceutical composition for treating diabetes
(2S)-1-[3-[[4-(5-fluoro-2,2-dimethyl-3H-1-benzofuran-7-yl)phenoxy]methyl]benzoyl]pyrrolidine-2-carboxylic acid	EC50	180 nM	US-9290487: Pharmaceutical composition for treating diabetes
(2S)-1-[3-[[4-[2-(2-cyanoethylsulfanyl)-4,5-difluorophenyl]phenoxy]methyl]benzoyl]pyrrolidine-2-carboxylic acid	EC50	190 nM	US-9290487: Pharmaceutical composition for treating diabetes
(2S)-1-[3-[[4-[4,5-difluoro-2-(hydroxymethyl)-1-benzofuran-7-yl]phenoxy]methyl]benzoyl]pyrrolidine-2-carboxylic acid	EC50	200 nM	US-9290487: Pharmaceutical composition for treating diabetes
(2S)-1-[3-[[4-[4,5-difluoro-2-(methoxymethyl)-1-benzothiophen-7-yl]phenoxy]methyl]benzoyl]pyrrolidine-2-carboxylic acid	EC50	200 nM	US-9290487: Pharmaceutical composition for treating diabetes
(2S)-1-[3-[[4-(8-fluoro-2H-chromen-5-yl)phenoxy]methyl]benzoyl]pyrrolidine-2-carboxylic acid	EC50	210 nM	US-9290487: Pharmaceutical composition for treating diabetes
(2S)-1-[3-[[4-[3,4-difluoro-5-(2-oxopropoxy)phenyl]phenoxy]methyl]benzoyl]pyrrolidine-2-carboxylic acid	EC50	220 nM	US-9290487: Pharmaceutical composition for treating diabetes
(2S)-2-[[3-[[4-(4,5-difluoro-1-benzofuran-7-yl)phenoxy]methyl]benzoyl]-methylamino]propanoic acid	EC50	220 nM	US-9290487: Pharmaceutical composition for treating diabetes
(2S)-1-[3-[[4-(7-fluoro-1H-indol-4-yl)phenoxy]methyl]benzoyl]pyrrolidine-2-carboxylic acid	EC50	230 nM	US-9290487: Pharmaceutical composition for treating diabetes
(2S)-1-[3-[[4-(1,3-benzodioxol-4-yl)phenoxy]methyl]benzoyl]pyrrolidine-2-carboxylic acid	EC50	250 nM	US-9290487: Pharmaceutical composition for treating diabetes
(2S)-1-[3-[[4-(5-fluoro-2,3-dihydro-1-benzofuran-7-yl)phenoxy]methyl]benzoyl]pyrrolidine-2-carboxylic acid	EC50	260 nM	US-9290487: Pharmaceutical composition for treating diabetes
(2S)-1-[3-[[4-(1-benzofuran-7-yl)phenoxy]methyl]benzoyl]pyrrolidine-2-carboxylic acid	EC50	260 nM	US-9290487: Pharmaceutical composition for treating diabetes

ChEMBL bioactivities

124 potent at pChembl≥5 of 135 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.00	EC50	10	nM	CHEMBL2381135
7.82	EC50	15	nM	CHEMBL3939308
7.77	EC50	17	nM	CHEMBL3923783
7.66	EC50	22	nM	CHEMBL3964800
7.54	EC50	29	nM	CHEMBL3892250
7.51	EC50	31	nM	CHEMBL3984217
7.47	EC50	34	nM	CHEMBL3951499
7.46	EC50	35	nM	CHEMBL3930496
7.42	EC50	38	nM	CHEMBL3919754
7.38	EC50	42	nM	CHEMBL3962120
7.36	EC50	44	nM	CHEMBL3894610
7.35	EC50	45	nM	CHEMBL3894918
7.27	EC50	54	nM	CHEMBL3983074
7.27	EC50	54	nM	CHEMBL3964590
7.21	EC50	61	nM	CHEMBL3951200
7.19	EC50	64	nM	CHEMBL3914400
7.19	EC50	65	nM	CHEMBL3914944
7.16	EC50	70	nM	CHEMBL3916911
7.16	EC50	70	nM	CHEMBL3951399
7.13	EC50	74	nM	CHEMBL3958415
7.08	EC50	83	nM	CHEMBL3895969
7.07	EC50	85	nM	CHEMBL3924913
7.05	EC50	90	nM	CHEMBL3219430
7.00	EC50	100	nM	CHEMBL2381136
7.00	EC50	100	nM	CHEMBL3219434
7.00	EC50	100	nM	CHEMBL3219419
7.00	EC50	100	nM	CHEMBL3923410
7.00	EC50	100	nM	CHEMBL3960218
7.00	EC50	100	nM	CHEMBL3947838
6.96	EC50	110	nM	CHEMBL3219436
6.96	EC50	110	nM	CHEMBL3934872
6.96	EC50	110	nM	CHEMBL3900860
6.96	EC50	110	nM	CHEMBL3903307
6.96	EC50	110	nM	CHEMBL3924985
6.92	EC50	120	nM	CHEMBL3219432
6.92	EC50	120	nM	CHEMBL3219428
6.92	EC50	120	nM	CHEMBL3902392
6.89	EC50	130	nM	CHEMBL3219429
6.89	EC50	130	nM	CHEMBL3900565
6.85	EC50	140	nM	CHEMBL2381135
6.85	EC50	140	nM	CHEMBL3938234
6.85	EC50	140	nM	CHEMBL3922618
6.85	EC50	140	nM	CHEMBL3900368
6.82	EC50	150	nM	CHEMBL3898301
6.82	EC50	150	nM	CHEMBL3902705
6.82	EC50	150	nM	CHEMBL3960389
6.80	EC50	160	nM	CHEMBL3931148
6.80	EC50	160	nM	CHEMBL3983737
6.75	EC50	180	nM	CHEMBL3909790
6.72	EC50	190	nM	CHEMBL3890481

PubChem BioAssay actives

29 with measured affinity, of 146 total; 28 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
2-[[3-[[4-(4,5-difluoro-2-methoxyphenyl)phenoxy]methyl]benzoyl]-methylamino]acetic acid	746928: Activation of human recombinant muscle GYS1 expressed in insect sf9 cells using glycogen and UDP-glucose as substrates by spectrophotometry	ec50	0.1000	uM
(2S)-1-[3-[[4-(4,5-difluoro-2-methoxyphenyl)phenoxy]methyl]benzoyl]pyrrolidine-2-carboxylic acid	746928: Activation of human recombinant muscle GYS1 expressed in insect sf9 cells using glycogen and UDP-glucose as substrates by spectrophotometry	ec50	0.1400	uM
2-[7-[[4-(4,5-difluoro-2-methoxyphenyl)phenoxy]methyl]-3-oxo-1H-indazol-2-yl]acetic acid	746928: Activation of human recombinant muscle GYS1 expressed in insect sf9 cells using glycogen and UDP-glucose as substrates by spectrophotometry	ec50	0.2000	uM
7-[[4-(4,5-difluoro-2-methylphenyl)phenoxy]methyl]-2-[(2R)-2,3-dihydroxypropyl]-1H-indazol-3-one	746928: Activation of human recombinant muscle GYS1 expressed in insect sf9 cells using glycogen and UDP-glucose as substrates by spectrophotometry	ec50	0.2300	uM
7-[[4-(4,5-difluoro-2-methylphenyl)phenoxy]methyl]-2-methyl-1H-indazol-3-one	746928: Activation of human recombinant muscle GYS1 expressed in insect sf9 cells using glycogen and UDP-glucose as substrates by spectrophotometry	ec50	0.2400	uM
7-[[4-(4,5-difluoro-2-methoxyphenyl)phenoxy]methyl]-2-[(2S)-2,3-dihydroxypropyl]-1H-indazol-3-one	746928: Activation of human recombinant muscle GYS1 expressed in insect sf9 cells using glycogen and UDP-glucose as substrates by spectrophotometry	ec50	0.2500	uM
7-[[4-(2-chloro-4,5-difluorophenyl)phenoxy]methyl]-2-[(2R)-2,3-dihydroxypropyl]-1H-indazol-3-one	746928: Activation of human recombinant muscle GYS1 expressed in insect sf9 cells using glycogen and UDP-glucose as substrates by spectrophotometry	ec50	0.2600	uM
7-[[4-(4,5-difluoro-2-methoxyphenyl)phenoxy]methyl]-2-[(2R)-2,3-dihydroxypropyl]-1H-indazol-3-one	746928: Activation of human recombinant muscle GYS1 expressed in insect sf9 cells using glycogen and UDP-glucose as substrates by spectrophotometry	ec50	0.2700	uM
7-[[4-(2-chloro-4,5-difluorophenyl)phenoxy]methyl]-2-[(2S)-2,3-dihydroxypropyl]-1H-indazol-3-one	746928: Activation of human recombinant muscle GYS1 expressed in insect sf9 cells using glycogen and UDP-glucose as substrates by spectrophotometry	ec50	0.3000	uM
7-[[4-(4,5-difluoro-2-methoxyphenyl)phenoxy]methyl]-2-methyl-1H-indazol-3-one	746928: Activation of human recombinant muscle GYS1 expressed in insect sf9 cells using glycogen and UDP-glucose as substrates by spectrophotometry	ec50	0.3200	uM
7-[[4-(4,5-difluoro-2-methylphenyl)phenoxy]methyl]-2-[(2S)-2,3-dihydroxypropyl]-1H-indazol-3-one	746928: Activation of human recombinant muscle GYS1 expressed in insect sf9 cells using glycogen and UDP-glucose as substrates by spectrophotometry	ec50	0.3400	uM
7-[[4-(4,5-difluoro-2-methoxyphenyl)phenoxy]methyl]-2-(2-methoxyethyl)-1H-indazol-3-one	746928: Activation of human recombinant muscle GYS1 expressed in insect sf9 cells using glycogen and UDP-glucose as substrates by spectrophotometry	ec50	0.3700	uM
2-[7-[[4-(4,5-difluoro-2-methylphenyl)phenoxy]methyl]-3-oxo-1H-indazol-2-yl]acetic acid	746928: Activation of human recombinant muscle GYS1 expressed in insect sf9 cells using glycogen and UDP-glucose as substrates by spectrophotometry	ec50	0.4200	uM
2-[(2S)-2,3-dihydroxypropyl]-7-[[4-(2,4,5-trifluorophenyl)phenoxy]methyl]-1H-indazol-3-one	746928: Activation of human recombinant muscle GYS1 expressed in insect sf9 cells using glycogen and UDP-glucose as substrates by spectrophotometry	ec50	0.5800	uM
2-[(2R)-2,3-dihydroxypropyl]-7-[[4-(2,4,5-trifluorophenyl)phenoxy]methyl]-1H-indazol-3-one	746928: Activation of human recombinant muscle GYS1 expressed in insect sf9 cells using glycogen and UDP-glucose as substrates by spectrophotometry	ec50	0.6800	uM
2-(2-hydroxyethyl)-7-[[4-(2,4,5-trifluorophenyl)phenoxy]methyl]-1H-indazol-3-one	746928: Activation of human recombinant muscle GYS1 expressed in insect sf9 cells using glycogen and UDP-glucose as substrates by spectrophotometry	ec50	0.7700	uM
2-(2-methoxyethyl)-7-[[4-(2,4,5-trifluorophenyl)phenoxy]methyl]-1H-indazol-3-one	746928: Activation of human recombinant muscle GYS1 expressed in insect sf9 cells using glycogen and UDP-glucose as substrates by spectrophotometry	ec50	0.7900	uM
7-[[4-(2,4,5-trifluorophenyl)phenoxy]methyl]-1H-2,1-benzoxazol-3-one	746928: Activation of human recombinant muscle GYS1 expressed in insect sf9 cells using glycogen and UDP-glucose as substrates by spectrophotometry	ec50	1.0000	uM
2-[3-oxo-7-[[4-(2,4,5-trifluorophenyl)phenoxy]methyl]-1H-indazol-2-yl]acetic acid	746928: Activation of human recombinant muscle GYS1 expressed in insect sf9 cells using glycogen and UDP-glucose as substrates by spectrophotometry	ec50	1.2000	uM
4-[4-(4-hydroxyphenyl)-5-(trifluoromethyl)-1H-pyrazol-3-yl]benzene-1,2,3-triol	1605619: Competitive inhibition of C-terminal 6His-tagged human GYS1 using UDPG as substrate in presence of G-6-P by 14C-glucose incorporation based Michaelis-Menton plot analysis	ki	1.3100	uM
7-[[4-(4,5-difluoro-2-methoxyphenyl)phenoxy]methyl]-2-(4-fluorophenyl)-1H-indazol-3-one	746928: Activation of human recombinant muscle GYS1 expressed in insect sf9 cells using glycogen and UDP-glucose as substrates by spectrophotometry	ec50	1.3700	uM
7-[[4-(4,5-difluoro-2-methylphenyl)phenoxy]methyl]-2-(4-fluorophenyl)-1H-indazol-3-one	746928: Activation of human recombinant muscle GYS1 expressed in insect sf9 cells using glycogen and UDP-glucose as substrates by spectrophotometry	ec50	1.4700	uM
2-methyl-7-[[4-(2,4,5-trifluorophenyl)phenoxy]methyl]-1H-indazol-3-one	746928: Activation of human recombinant muscle GYS1 expressed in insect sf9 cells using glycogen and UDP-glucose as substrates by spectrophotometry	ec50	1.7800	uM
7-[[4-(2-chloro-4,5-difluorophenyl)phenoxy]methyl]-2-pyridin-3-yl-1H-indazol-3-one	746928: Activation of human recombinant muscle GYS1 expressed in insect sf9 cells using glycogen and UDP-glucose as substrates by spectrophotometry	ec50	1.8600	uM
2-pyridin-3-yl-7-[[4-(2,4,5-trifluorophenyl)phenoxy]methyl]-1H-indazol-3-one	746928: Activation of human recombinant muscle GYS1 expressed in insect sf9 cells using glycogen and UDP-glucose as substrates by spectrophotometry	ec50	4.0100	uM
3-[[4-(4,5-difluoro-2-methoxyphenyl)phenoxy]methyl]-N-(2-hydroxyethyl)-N-methylbenzamide	746928: Activation of human recombinant muscle GYS1 expressed in insect sf9 cells using glycogen and UDP-glucose as substrates by spectrophotometry	ec50	4.1000	uM
4-[4-(4-nitrophenyl)-5-(trifluoromethyl)-1H-pyrazol-3-yl]benzene-1,2,3-triol	1605610: Inhibition of C-terminal 6His-tagged wild type human GYS1 using UDPG as substrate in presence of 1 mM G-6-P by 14C-glucose incorporation assay	ic50	6.5400	uM
4-[4-(4-hydroxyphenyl)-1H-pyrazol-5-yl]benzene-1,2,3-triol	1605610: Inhibition of C-terminal 6His-tagged wild type human GYS1 using UDPG as substrate in presence of 1 mM G-6-P by 14C-glucose incorporation assay	ic50	9.8200	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases abundance, increases expression, decreases expression, affects cotreatment	3
Cyclosporine	decreases expression	3
bisphenol A	affects expression, decreases expression	2
bisphenol S	increases expression	2
Quercetin	decreases phosphorylation, increases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	decreases expression	1
bisphenol F	increases expression	1
moringin	affects cotreatment, increases expression	1
PF-06840003	decreases expression, decreases reaction	1
dicrotophos	increases expression	1
alpha phellandrene	increases expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
mono-(2-ethylhexyl)phthalate	increases phosphorylation	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
zinc chloride	decreases reaction, increases expression	1
cobaltous chloride	increases expression, decreases reaction	1
manganese chloride	increases abundance, increases expression, affects cotreatment	1
3-methyladenine	decreases phosphorylation, decreases reaction	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
cyanoginosin LR	increases expression, increases phosphorylation, decreases phosphorylation, decreases reaction, increases activity (+1 more)	1
di-n-butylphosphoric acid	affects expression	1
3-(3-chloro-4-hydroxyphenylamino)-4-(4-nitrophenyl)-1H-pyrrole-2,5-dione	decreases reaction, increases phosphorylation	1
bisphenol B	increases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, decreases expression	1
bisphenol AF	increases expression	1
Rosiglitazone	decreases phosphorylation, decreases reaction	1
Resveratrol	decreases reaction, increases phosphorylation	1
Arsenic Trioxide	decreases phosphorylation, decreases reaction	1
Glyphosate	decreases expression	1

ChEMBL screening assays

15 unique, capped per target: 15 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2384001	Binding	Activation of human recombinant muscle GYS1 expressed in insect sf9 cells using glycogen and UDP-glucose as substrates assessed as concentration required to 200% activation by spectrophotometry	Design and synthesis of 2-N-substituted indazolone derivatives as non-carboxylic acid glycogen synthase activators. — Bioorg Med Chem Lett

Cellosaurus cell lines

3 cell lines: 2 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1AY	Abcam HEK293 GYS1 KO	Transformed cell line	Female
CVCL_B1TD	Abcam HeLa GYS1 KO	Cancer cell line	Female
CVCL_E0E5	Ubigene HeLa GYS1 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02782741	PHASE3	COMPLETED	Study to Compare the Efficacy and Safety of Enzyme Replacement Therapies Avalglucosidase Alfa and Alglucosidase Alfa Administered Every Other Week in Patients With Late-onset Pompe Disease Who Have Not Been Previously Treated for Pompe Disease
NCT04808505	PHASE3	RECRUITING	A Study to Evaluate the Safety, Efficacy, PK, PD and Immunogenicity of Cipaglucosidase Alfa/Miglustat in IOPD Subjects Aged 0 to <18
NCT00765414	PHASE2	COMPLETED	Extension Study of Long-term Safety and Efficacy of Myozyme for a Single Patient With Pompe Disease Who Were Previously Enrolled in Genzyme Sponsored ERT Studies.
NCT02032524	PHASE2	COMPLETED	Avalglucosidase Alfa Extension Study
NCT03019406	PHASE2	ACTIVE_NOT_RECRUITING	A Study to Assess Safety and Efficacy of Avalglucosidase Alfa Administered Every Other Week in Pediatric Patients With Infantile-onset Pompe Disease Previously Treated With Alglucosidase Alfa
NCT06130228	PHASE2	UNKNOWN	Nutritional Therapy in Late-onset Pompe Disease
NCT06795152	Not specified	RECRUITING	Rare Glycogen Storage Diseases Natural History Study
NCT05095727	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	A Study of mRNA-3745 in Adult and Pediatric Participants With Glycogen Storage Disease Type 1a (GSD1a)
NCT00001342	Not specified	COMPLETED	Study of Glycogen Storage Disease and Associated Disorders
NCT00566878	Not specified	COMPLETED	Pompe Lactation Sub-Registry
NCT01461304	Not specified	NO_LONGER_AVAILABLE	Compassionate Use of Triheptanoin (C7) for Inherited Disorders of Energy Metabolism
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT02057731	Not specified	COMPLETED	Study of Glycogen Storage Disease Expression in Carriers
NCT02176096	Not specified	COMPLETED	Comparison of the Effect of a Novel Starch (Glycosade) Versus Gastrostomy Tube-Dextrose Infusion on Overnight Euglycaemia Control in Children With Glycogen Storage Disease Type I: Open Label Demonstration Trial
NCT02318966	Not specified	COMPLETED	Glycosade v UCCS in the Dietary Management of Hepatic GSD
NCT02338817	Not specified	TERMINATED	Clinical Evaluation of a Non-Invasive Hypoglycemia Detector in a Glycogen Storage Disease Population
NCT02385162	Not specified	WITHDRAWN	Biomarker for Glycogen Storage Diseases (BioGlycogen)
NCT03255213	Not specified	COMPLETED	Lingual Muscle Training in Late-Onset Pompe Disease (LOPD)
NCT03564561	Not specified	RECRUITING	Natural History of Pompe Disease
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT04292938	Not specified	COMPLETED	McArdle Disease Treatment by Ketogenic Diet
NCT04399694	Not specified	COMPLETED	Identification and Characterization of Novel Non-Coding Variants That Contribute to Genetic Disorders
NCT04929002	Not specified	ACTIVE_NOT_RECRUITING	Carbon-13 Magnetic Resonance Spectroscopy in Glycogen Storage Diseases
NCT05199246	Not specified	COMPLETED	Assessment of Safety and Acute Effects of a Lower-limb Powered Dermoskeleton in Patients With Neuromuscular Disorders
NCT05200702	Not specified	COMPLETED	Assessment of Safety and Acute Effects of a Knee-hip Powered Soft Exoskeleton in Patients With Neuromuscular Disorders
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening
NCT06396546	Not specified	RECRUITING	‘Glycogen Storage Diseases (GSDs) in Indian Children- Establishing an Indian GSD (I-GSD) Registry’
NCT06813443	Not specified	RECRUITING	Characterization of Patients With Cardiomyopathy to Identify Critical Patients Candidates for Cardiac Transplantation
NCT07136844	Not specified	RECRUITING	Gait Analysis Parameter and Upper Limb Evaluation in Adult Patients With Neurological or Metabolic Pathology
NCT07336394	Not specified	RECRUITING	Precision Diagnosis and Risk Stratification of Rare Cardiomyopathies Based on Novel Cardiac Magnetic Resonance Techniques
NCT07614139	Not specified	COMPLETED	Continuous Glucose Monitoring Alerts, Accuracy, and Patient Outcomes in Adults With Inherited Metabolic Disorders