AGL

Summary

AGL (amylo-alpha-1,6-glucosidase and 4-alpha-glucanotransferase, HGNC:321) is a protein-coding gene on chromosome 1p21.2, encoding Glycogen debranching enzyme (P35573). Multifunctional enzyme acting as 1,4-alpha-D-glucan:1,4-alpha-D-glucan 4-alpha-D-glycosyltransferase and amylo-1,6-glucosidase in glycogen degradation.

This gene encodes the glycogen debrancher enzyme which is involved in glycogen degradation. This enzyme has two independent catalytic activities which occur at different sites on the protein: a 4-alpha-glucotransferase activity and a amylo-1,6-glucosidase activity. Mutations in this gene are associated with glycogen storage disease although a wide range of enzymatic and clinical variability occurs which may be due to tissue-specific alternative splicing. Alternatively spliced transcripts encoding different isoforms have been described.

Source: NCBI Gene 178 — RefSeq curated summary.

At a glance

• Gene–disease (curated): glycogen storage disease III (Definitive, ClinGen)
• GWAS associations: 3
• Clinical variants (ClinVar): 3,087 total — 279 pathogenic, 257 likely-pathogenic
• Phenotypes (HPO): 25
• Druggable target: yes — 4 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_000642

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:321
Approved symbol	AGL
Name	amylo-alpha-1,6-glucosidase and 4-alpha-glucanotransferase
Location	1p21.2
Locus type	gene with protein product
Status	Approved
Aliases	GDE
Ensembl gene	ENSG00000162688
Ensembl biotype	protein_coding
OMIM	610860
Entrez	178

Gene structure

Transcript identifiers

Ensembl transcripts: 25 — 22 protein_coding, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000294724, ENST00000361302, ENST00000361915, ENST00000370161, ENST00000370163, ENST00000370165, ENST00000477753, ENST00000637337, ENST00000881254, ENST00000881255, ENST00000881256, ENST00000881257, ENST00000881258, ENST00000881259, ENST00000911800, ENST00000911801, ENST00000911802, ENST00000965590, ENST00000965591, ENST00000965592, ENST00000965593, ENST00000965594, ENST00000965595, ENST00000965596, ENST00000965597

RefSeq mRNA: 11 — MANE Select: NM_000642 NM_000028, NM_000642, NM_000643, NM_000644, NM_000646, NM_001425325, NM_001425326, NM_001425327, NM_001425328, NM_001425329, NM_001425332

CCDS: CCDS759, CCDS760

Canonical transcript exons

ENST00000361915 — 34 exons

Exon	Start	End
ENSE00001067103	99861503	99861713
ENSE00001067697	99921534	99924020
ENSE00001320682	99850361	99850415
ENSE00003792420	99916410	99916497
ENSE00003792529	99891606	99891739
ENSE00003792600	99870400	99870581
ENSE00003792768	99879923	99880046
ENSE00003792893	99880632	99880795
ENSE00003793011	99884120	99884244
ENSE00003793101	99864386	99864589
ENSE00003793329	99875154	99875256
ENSE00003793666	99915389	99915486
ENSE00003794086	99913527	99913738
ENSE00003794686	99892432	99892607
ENSE00003795010	99862257	99862423
ENSE00003795290	99870758	99870869
ENSE00003795342	99900636	99900861
ENSE00003795770	99881541	99881691
ENSE00003796394	99887978	99888108
ENSE00003797131	99875358	99875455
ENSE00003797369	99916598	99916731
ENSE00003797522	99891220	99891356
ENSE00003797575	99884569	99884703
ENSE00003797859	99912405	99912517
ENSE00003798031	99896286	99896388
ENSE00003799014	99910712	99910847
ENSE00003799205	99876458	99876597
ENSE00003799287	99881076	99881177
ENSE00003799391	99874687	99874810
ENSE00003799454	99902683	99902794
ENSE00003800586	99881292	99881447
ENSE00003800685	99850975	99851124
ENSE00003800822	99877641	99877828
ENSE00003801056	99884339	99884451

Expression profiles

Bgee: expression breadth ubiquitous, 294 present calls, max score 99.64.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 16.6350 / max 495.6818, expressed in 1777 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
4187	13.2530	1771
4196	1.0424	120
4190	1.0301	470
4191	0.6357	242
4188	0.1858	83
4193	0.1775	85
4189	0.1326	56
4192	0.0996	49
4195	0.0503	22
4194	0.0279	12

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
vastus lateralis	UBERON:0001379	99.64	gold quality
biceps brachii	UBERON:0001507	99.63	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	99.61	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	99.58	gold quality
quadriceps femoris	UBERON:0001377	99.48	gold quality
diaphragm	UBERON:0001103	99.27	gold quality
body of tongue	UBERON:0011876	98.83	gold quality
triceps brachii	UBERON:0001509	98.75	gold quality
deltoid	UBERON:0001476	98.12	gold quality
skeletal muscle tissue	UBERON:0001134	98.11	gold quality
gluteal muscle	UBERON:0002000	97.92	gold quality
tibialis anterior	UBERON:0001385	96.81	gold quality
tongue	UBERON:0001723	96.80	gold quality
heart right ventricle	UBERON:0002080	96.54	gold quality
choroid plexus epithelium	UBERON:0003911	96.51	gold quality
hindlimb stylopod muscle	UBERON:0004252	96.51	gold quality
muscle tissue	UBERON:0002385	96.39	gold quality
myocardium	UBERON:0002349	96.14	gold quality
muscle organ	UBERON:0001630	96.06	gold quality
skeletal muscle organ	UBERON:0014892	96.06	gold quality
superior surface of tongue	UBERON:0007371	95.56	gold quality
saphenous vein	UBERON:0007318	95.43	gold quality
visceral pleura	UBERON:0002401	95.22	gold quality
germinal epithelium of ovary	UBERON:0001304	95.20	gold quality
left ventricle myocardium	UBERON:0006566	95.12	gold quality
parietal pleura	UBERON:0002400	95.08	gold quality
muscle of leg	UBERON:0001383	94.93	gold quality
cardiac muscle of right atrium	UBERON:0003379	94.86	gold quality
gastrocnemius	UBERON:0001388	94.84	gold quality
blood vessel layer	UBERON:0004797	94.81	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-6819	yes	1711.30
E-MTAB-10018	yes	346.14
E-MTAB-7316	yes	22.56
E-ANND-3	yes	7.17

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ESR1

miRNA regulators (miRDB)

143 targeting AGL, 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-3163	100.00	77.23	8605
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502

Literature-anchored findings (GeneRIF, showing 26)

• Mutations associated with GSD III include R34X and Y1148X. (PMID:11924557)
• GSD-III patients have variable phenotypic characteristics. Administration of raw-corn-starch can effectively improve the disease outcome. We identified 8 new mutations on AGL gene through nucleotide sequence analysis. (PMID:15833157)
• it is likely that the AMPK-GDE association is a novel mechanism regulating AMPK activity and the resultant fatty acid oxidation and glucose uptake (PMID:15886229)
• AGL gene mutations may have roles in glycogen storage disease type III (PMID:17047887)
• These results indicate that binding to glycogen crucially regulates the stability of AGL and, further, that its ubiquitination may play an important role in the pathophysiology of both Lafora and Cori’s disease. (PMID:17908927)
• Current clinical and molecular knowledge about glycogenosis 3 and phenotype and genotype levels of this enzyme. [REVIEW] (PMID:17915576)
• a homozygous p.W1327X mutation leads to severe generalized glycogenosis types 3a & 3b within the same family; heterozygous p.W1327X mutation carriers may present with mild non-progressive neuromuscular symptoms, such as exercise-induced myalgia & fatigue (PMID:18924225)
• Mutations in the carbohydrate-binding domain of AGL lead to loss of all enzymatic activities and enhancing targeting for proteasomal degradation. (PMID:19299494)
• Six novel AGL mutations were identified. (PMID:19754354)
• Nine AGL mutations: six nonsense mutations , one deletion and two splicing mutation were identified in Turkish GSD III patients. (PMID:19834502)
• The present patient was found to be deficient in GDE activity and homozygous for a novel 1 bp deletion in AGL. This mutation is predicted to cause premature termination at codon 834 due to frame shift. (PMID:20158661)
• Mutations in amylo-1,6-glucosidase is associated with Glycogen Storage Disease Type III. (PMID:20648714)
• A founder effect discovered amongst Tunisian patients with glycogen storage disease type III and a c.3216_3217delGA mutation in the AGL gene. (PMID:22035446)
• Characterization of a novel homozygous single point mutation at the polypyrimidine tract of intron 21 of the AGL gene in two consanguineous siblings with glycogen storage disease type III. (PMID:23649758)
• We found that most patients with macular telangiectasia-2 possess retinal autoantibodies, the most prevalent of which were directed against AGL, RBP3, and CK-B. (PMID:23882694)
• study identified 10 different mutations in 8 Korean Glycogen storage disease type III patients; 5 mutations are novel and include 1 nonsense (c.1461G>A, p.W487X), 3 splicing (c.293+4_293+6delAGT in IVS4, c.460+1G>T in IVS5, c.2682-8A>G in IVS21) and 1 missense mutation (c.2591G>C, p.R864P) (PMID:24257475)
• AGL haplotype analyses suggested that c.1019delA and c.958+1G>A are founder mutations in Turkish patients, while p.R864X is a recurrent mutation. (PMID:25451950)
• A homozygous frameshift deletion, c.4456delT, in exon 33 of the AGL gene in Inuit children determines the cause of glycogen storage disease type IIIa and confirms a founder effect. (PMID:25602008)
• Haplotype analysis revealed that the mutation arises as a result of founder effect, not an independent event. (PMID:25827695)
• Point mutations in AGL gene are associated with glycogen storage disease type IIIa in a Chinese family. (PMID:26252094)
• Our study establishes HAS2-mediated HA synthesis as a driver of growth of bladder cancer with low AGL and provides preclinical rationale for personalized targeting of HAS2/HA signaling in patients with low amylo-alpha-1-6-glucosidase-4-alpha-glucanotransferase -expressing tumors. (PMID:26490312)
• AGL loss causes high SHMT2 expression and consequently increases glycine-dependent nucleotide synthesis leading to bladder cancer growth. (PMID:26975021)
• The study identified 31 novel mutations and extended the mutation spectrum of AGL in Chinese patients with glycogen storage disease type III. (PMID:26984562)
• This report of patients with GSD-III in Iran with 2 uncommon clinical presentations and 5 novel mutations in the AGL gene. (PMID:29794575)
• Six novel mutations were identified in GSD III patients. (PMID:31028654)
• Spectrum of amyloglucosidase mutations in Asian Indian patients with Glycogen storage disease type III. (PMID:32222031)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	aglb	ENSDARG00000100352
danio_rerio	agla	ENSDARG00000103811
danio_rerio		ENSDARG00000106630
mus_musculus	Agl	ENSMUSG00000033400
rattus_norvegicus	Agl	ENSRNOG00000016214
drosophila_melanogaster	CG9485	FBGN0034618
caenorhabditis_elegans		WBGENE00011050

Protein

Protein identifiers

Glycogen debranching enzyme — P35573 (reviewed: P35573)

Alternative names: Glycogen debrancher

All UniProt accessions (3): A0A0S2A4E4, A0A1C7CYW1, P35573

UniProt curated annotations — full annotation on UniProt →

Function. Multifunctional enzyme acting as 1,4-alpha-D-glucan:1,4-alpha-D-glucan 4-alpha-D-glycosyltransferase and amylo-1,6-glucosidase in glycogen degradation.

Subunit / interactions. Monomer. Interacts with NHLRC1/malin.

Subcellular location. Cytoplasm.

Tissue specificity. Liver, kidney and lymphoblastoid cells express predominantly isoform 1; whereas muscle and heart express not only isoform 1, but also muscle-specific isoform mRNAs (isoforms 2, 3 and 4). Isoforms 5 and 6 are present in both liver and muscle.

Post-translational modifications. The N-terminus is blocked. Ubiquitinated.

Disease relevance. Glycogen storage disease 3 (GSD3) [MIM:232400] A metabolic disorder associated with an accumulation of abnormal glycogen with short outer chains. It is clinically characterized by hepatomegaly, hypoglycemia, short stature, and variable myopathy. Glycogen storage disease type 3 includes different forms: GSD type 3A patients lack glycogen debrancher enzyme activity in both liver and muscle, while GSD type 3B patients are enzyme-deficient in liver only. In rare cases, selective loss of only 1 of the 2 debranching activities, glucosidase or transferase, results in GSD type 3C or type 3D, respectively. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. The products of the mRNAs termed isoforms 1 to 4 are identical.

Similarity. Belongs to the glycogen debranching enzyme family.

Isoforms (3)

UniProt ID	Names	Canonical?
P35573-1	1, 2, 3, 4	yes
P35573-2	5
P35573-3	6

RefSeq proteins (11): NP_000019, NP_000633, NP_000634, NP_000635, NP_000637, NP_001412254, NP_001412255, NP_001412256, NP_001412257, NP_001412258, NP_001412261 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006421	Glycogen_debranch_met	Family
IPR008928	6-hairpin_glycosidase_sf	Homologous_superfamily
IPR010401	AGL/Gdb1	Family
IPR017853	GH_hydrolase_sf	Homologous_superfamily
IPR029436	AGL_euk_N	Domain
IPR032788	AGL_central	Domain
IPR032790	GDE_C	Domain
IPR032792	AGL_glucanoTrfase	Domain

Pfam: PF06202, PF14699, PF14701, PF14702

Enzyme classification (BRENDA):

• EC 3.2.1.33 — amylo-alpha-1,6-glucosidase (BRENDA: 18 organisms, 164 substrates, 97 inhibitors, 31 Km, 16 kcat entries)

Substrate kinetics (BRENDA)

22 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
GLYCOGEN PHOSPHORYLASE LIMIT DEXTRIN	0.063–1.6	5
6-O-ALPHA-D-GLUCOSYL CYCLOMALTOHEPTAOSE	15.9–19.3	4
63-ALPHA-GLUCOSYL MALTOTETRAOSE	1.8–4.45	2
ALPHA-GLUCOSYL FLUORIDE	2.8–8.1	2
AMYLOPECTIN BETA-DEXTRIN	4.3–11	2
BETA-AMYLASE LIMIT DEXTRIN	3.8–7.2	2
D-GLUCOSE	32–43	2
6-O-ALPHA-MALTOSYL-BETA-CYCLODEXTRIN	12.23	1
6-O-ALPHA-MALTOTETRAOSYL-BETA-CYCLODEXTRIN	0.206	1
63-ALPHA-MALTOTRIOSYL MALTOTETRAOSE	5.6	1
MALTODECAOSE	0.64	1
MALTODODECAOSE	0.62	1
MALTONONAOSE	0.81	1
MALTOUNDECAOSE	0.51	1
AMYLOPECTIN	—	0

UniProt features (24 total): sequence variant 13, active site 3, region of interest 2, sequence conflict 2, splice variant 2, chain 1, modified residue 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
8ZEQ	ELECTRON MICROSCOPY	3.36

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P35573-F1	92.88	0.80

Functional residue map

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

Catalytic / active sites (3): 526; 529; 627

Post-translational modifications (1): 64

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-6798695	Neutrophil degranulation
R-HSA-70221	Glycogen breakdown (glycogenolysis)

MSigDB gene sets: 269 (showing top): RNGTGGGC_UNKNOWN, REACTOME_INNATE_IMMUNE_SYSTEM, MOOTHA_GLYCOGEN_METABOLISM, GOBP_POLYSACCHARIDE_BIOSYNTHETIC_PROCESS, GOCC_SECRETORY_GRANULE, GOBP_RESPONSE_TO_CORTICOSTEROID, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, IIZUKA_LIVER_CANCER_PROGRESSION_L1_G1_UP, PUJANA_CHEK2_PCC_NETWORK, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY, GOBP_POLYSACCHARIDE_CATABOLIC_PROCESS, BROWNE_HCMV_INFECTION_24HR_UP, HOSHIDA_LIVER_CANCER_SUBCLASS_S3, SMID_BREAST_CANCER_LUMINAL_B_UP, GROSS_HYPOXIA_VIA_HIF1A_ONLY

GO Biological Process (7): glycogen biosynthetic process (GO:0005978), glycogen catabolic process (GO:0005980), response to nutrient (GO:0007584), response to glucocorticoid (GO:0051384), carbohydrate metabolic process (GO:0005975), glycogen metabolic process (GO:0005977), response to hormone (GO:0009725)

GO Molecular Function (11): 4-alpha-glucanotransferase activity (GO:0004134), amylo-alpha-1,6-glucosidase activity (GO:0004135), polysaccharide binding (GO:0030247), polyubiquitin modification-dependent protein binding (GO:0031593), catalytic activity (GO:0003824), protein binding (GO:0005515), transferase activity (GO:0016740), glycosyltransferase activity (GO:0016757), hydrolase activity (GO:0016787), hydrolase activity, acting on glycosyl bonds (GO:0016798), carbohydrate binding (GO:0030246)

GO Cellular Component (9): extracellular region (GO:0005576), nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829), inclusion body (GO:0016234), sarcoplasmic reticulum (GO:0016529), secretory granule lumen (GO:0034774), isoamylase complex (GO:0043033), ficolin-1-rich granule lumen (GO:1904813)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Innate Immune System	1
Glycogen metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
glycogen metabolic process	2
response to chemical	2
binding	2
catalytic activity	2
intracellular anatomical structure	2
glucan biosynthetic process	1
glucan catabolic process	1
response to nutrient levels	1
response to corticosteroid	1
primary metabolic process	1
energy reserve metabolic process	1
glucan metabolic process	1
response to endogenous stimulus	1
hexosyltransferase activity	1
alpha-glucosidase activity	1
carbohydrate binding	1
modification-dependent protein binding	1
molecular_function	1
transferase activity	1
hydrolase activity	1
intracellular membrane-bounded organelle	1
cytoplasm	1
endoplasmic reticulum	1
sarcoplasm	1
secretory granule	1
cytoplasmic vesicle lumen	1
catalytic complex	1
intracellular organelle lumen	1
ficolin-1-rich granule	1

Protein interactions and networks

STRING

1562 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AGL	NOP53	Q9NZM5	983
AGL	EPM2A	O95278	874
AGL	NHLRC1	Q6VVB1	871
AGL	GYS1	P13807	841
AGL	MPV17	P39210	828
AGL	G6PC1	P35575	819
AGL	SCN9A	Q15858	810
AGL	GBE1	Q04446	808
AGL	G6PC3	Q9BUM1	804
AGL	PYGL	P06737	801
AGL	PYGM	P11217	799
AGL	PYGB	P11216	792
AGL	G6PC2	Q9NQR9	788
AGL	GYG1	P46976	724
AGL	GYG2	O15488	700

IntAct

42 interactions, top by confidence:

A	B	Type	Score
CDK5	FIBP	psi-mi:“MI:0914”(association)	0.840
STBD1	GABARAP	psi-mi:“MI:0914”(association)	0.760
GYG2	GYS1	psi-mi:“MI:0914”(association)	0.660
PRKAB2	PRKAB2	psi-mi:“MI:0914”(association)	0.550
STBD1	MID1	psi-mi:“MI:0914”(association)	0.530
CBX1	KPNA3	psi-mi:“MI:0914”(association)	0.530
PYGB	STBD1	psi-mi:“MI:0914”(association)	0.530
Ppp1r3b		psi-mi:“MI:0914”(association)	0.350
FOXA2	FOXN2	psi-mi:“MI:0914”(association)	0.350
PRNP	WDR91	psi-mi:“MI:0914”(association)	0.350
CUL1	LGALS8	psi-mi:“MI:0914”(association)	0.350
DCUN1D1	RGSL1	psi-mi:“MI:0914”(association)	0.350
COPS5	FBLL1	psi-mi:“MI:0914”(association)	0.350
CUL2	ANXA2P2	psi-mi:“MI:0914”(association)	0.350
CUL4B	APBB1	psi-mi:“MI:0914”(association)	0.350
CUL3	PXDNL	psi-mi:“MI:0914”(association)	0.350
CUL5	DDX3X	psi-mi:“MI:0914”(association)	0.350
ZDHHC5	IGKV2D-24	psi-mi:“MI:0914”(association)	0.350
MAP3K6	TGM1	psi-mi:“MI:0914”(association)	0.350
PHKG2	N4BP1	psi-mi:“MI:0914”(association)	0.350
MARK3	EIF3F	psi-mi:“MI:0914”(association)	0.350
PRKAG1	TGM1	psi-mi:“MI:0914”(association)	0.350
FASTK	TGM1	psi-mi:“MI:0914”(association)	0.350
AURKB	TARS3	psi-mi:“MI:0914”(association)	0.350
UVRAG	TUBAL3	psi-mi:“MI:0914”(association)	0.350
SH3GLB1		psi-mi:“MI:0914”(association)	0.350
GABARAPL2		psi-mi:“MI:0914”(association)	0.350
GABARAPL1		psi-mi:“MI:0914”(association)	0.350
RASSF5	AGL	psi-mi:“MI:0914”(association)	0.350

BioGRID (122): AGL (Affinity Capture-RNA), AGL (Affinity Capture-RNA), AGL (Co-fractionation), AGL (Co-fractionation), AGL (Co-fractionation), AGL (Co-fractionation), AGL (Co-fractionation), AGL (Co-fractionation), AGL (Co-fractionation), AGL (Co-fractionation), AGL (Co-fractionation), AGL (Co-fractionation), AGL (Co-fractionation), AGL (Co-fractionation), AGL (Co-fractionation)

ESM2 similar proteins: A1L4T4, A2XCT8, A2Z7C4, A7RIT9, A8BQB4, A9SCJ6, A9SDW6, A9SS00, A9VCM7, B7PRF6, C3ZAH2, C5WWY0, C5X1F5, D7T737, E0W481, F6HDT7, F6QS54, F6W3G8, F7FKV1, O48707, P35573, P35574, P46952, P46953, Q0VCA8, Q10RE5, Q28FT4, Q2LZI9, Q2PQH8, Q3B8C8, Q3ZBL1, Q562C9, Q5U3F8, Q5ZL43, Q6AWN0, Q6DIY2, Q6DIZ0, Q6P7I0, Q6PBX5, Q75HE6

Diamond homologs: A8BQB4, P35573, P35574, Q06625, Q2PQH8

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
NHLRC1	“down-regulates quantity by destabilization”	AGL	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 63 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
Activation of AMPK downstream of NMDARs	5	39.6×	3e-05
Macroautophagy	8	19.2×	3e-06
Regulation of TP53 Activity	5	13.8×	2e-03
Regulation of TP53 Activity through Phosphorylation	5	12.3×	3e-03
Neddylation	7	6.9×	3e-03

GO biological processes:

GO term	Partners	Fold	FDR
intrinsic apoptotic signaling pathway	5	30.4×	2e-04
G1/S transition of mitotic cell cycle	6	20.4×	2e-04
microtubule cytoskeleton organization	6	12.3×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

3087 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	279
Likely pathogenic	257
Uncertain significance	1070
Likely benign	1159
Benign	97

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1027598	NM_000642.3(AGL):c.1020del (p.Glu340fs)	Pathogenic
1068942	NM_000642.3(AGL):c.1537_1538del (p.Tyr512_Thr513insTer)	Pathogenic
1069089	NM_000642.3(AGL):c.716dup (p.Asn240fs)	Pathogenic
1069636	NM_000642.3(AGL):c.4220_4221del (p.Lys1407fs)	Pathogenic
1069998	NM_000642.3(AGL):c.1505_1514del (p.Cys502fs)	Pathogenic
1070173	NM_000642.3(AGL):c.328del (p.Asp110fs)	Pathogenic
1070363	NM_000642.3(AGL):c.2963del (p.Leu988fs)	Pathogenic
1070429	NM_000642.3(AGL):c.4027G>T (p.Glu1343Ter)	Pathogenic
1070447	NM_000642.3(AGL):c.3928G>T (p.Glu1310Ter)	Pathogenic
1070570	NM_000642.3(AGL):c.2793del (p.Lys932fs)	Pathogenic
1070714	NM_000642.3(AGL):c.4352G>A (p.Trp1451Ter)	Pathogenic
1071501	NM_000642.3(AGL):c.955C>T (p.Gln319Ter)	Pathogenic
1071635	NM_000642.3(AGL):c.1639C>T (p.Gln547Ter)	Pathogenic
1071920	NM_000642.3(AGL):c.966dup (p.Arg323fs)	Pathogenic
1072510	NM_000642.3(AGL):c.4258_4259insGGAGATTCCTTAAAGAACTAAAAGTAGGCTCNNNNNAAAAAGAAAACTTTAGATCCAG (p.Asp1420fs)	Pathogenic
1072797	NM_000642.3(AGL):c.582del (p.Thr193_Trp194insTer)	Pathogenic
1073425	NM_000642.3(AGL):c.2346del (p.Ile782fs)	Pathogenic
1075182	NM_000642.3(AGL):c.3756dup (p.Arg1253fs)	Pathogenic
1075611	NC_000001.10:g.(?100340233)(100343394_?)del	Pathogenic
1098	NM_000642.3(AGL):c.4456del (p.Ser1486fs)	Pathogenic
1101	AGL, EcoRI FRAGMENT INS	Pathogenic
1102	NM_000642.3(AGL):c.4342G>C (p.Gly1448Arg)	Pathogenic
1103	NM_000642.3(AGL):c.3965del (p.Val1322fs)	Pathogenic
1104	NM_000642.3(AGL):c.1999del (p.Gln667fs)	Pathogenic
1106	NM_000642.3(AGL):c.1222C>T (p.Arg408Ter)	Pathogenic
1107	NM_000642.3(AGL):c.3439A>G (p.Arg1147Gly)	Pathogenic
1108	NM_000642.3(AGL):c.3980G>A (p.Trp1327Ter)	Pathogenic
1180847	NM_000642.3(AGL):c.1587del (p.Ser530fs)	Pathogenic
1341524	NM_000642.3(AGL):c.1383G>A (p.Trp461Ter)	Pathogenic
1359613	NM_000642.3(AGL):c.825del (p.Ile275fs)	Pathogenic

SpliceAI

4687 predictions. Top by Δscore:

Variant	Effect	Δscore
1:99850972:TAGG:T	acceptor_loss	1.0000
1:99850973:AGG:A	acceptor_gain	1.0000
1:99850974:GGG:G	acceptor_gain	1.0000
1:99851122:AAGGT:A	donor_loss	1.0000
1:99851124:GGTC:G	donor_loss	1.0000
1:99851125:G:A	donor_loss	1.0000
1:99851125:G:GG	donor_gain	1.0000
1:99861501:AG:A	acceptor_gain	1.0000
1:99861502:GG:G	acceptor_gain	1.0000
1:99861712:GG:G	donor_gain	1.0000
1:99861713:GG:G	donor_gain	1.0000
1:99862253:TTA:T	acceptor_loss	1.0000
1:99862255:A:AG	acceptor_gain	1.0000
1:99862256:G:GC	acceptor_gain	1.0000
1:99862256:G:GT	acceptor_loss	1.0000
1:99862256:GAA:G	acceptor_gain	1.0000
1:99862256:GAAAT:G	acceptor_gain	1.0000
1:99862364:C:G	donor_gain	1.0000
1:99864544:G:GT	donor_gain	1.0000
1:99864545:A:T	donor_gain	1.0000
1:99874684:TA:T	acceptor_loss	1.0000
1:99874685:A:AG	acceptor_gain	1.0000
1:99874685:AG:A	acceptor_loss	1.0000
1:99874686:G:GC	acceptor_gain	1.0000
1:99874686:GA:G	acceptor_gain	1.0000
1:99874686:GAA:G	acceptor_gain	1.0000
1:99874686:GAAA:G	acceptor_gain	1.0000
1:99874806:CATGA:C	donor_gain	1.0000
1:99874807:A:G	donor_gain	1.0000
1:99874807:ATGA:A	donor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000149282 (1:99924163 G>T), RS1000171395 (1:99917786 A>G), RS1000171921 (1:99859980 G>A,T), RS1000217312 (1:99891291 T>A), RS1000243388 (1:99916994 G>C,T), RS1000269065 (1:99880283 C>T), RS1000273646 (1:99887870 A>G,T), RS1000329504 (1:99850520 C>T), RS1000360805 (1:99894042 G>A,T), RS1000369837 (1:99871750 G>A), RS1000408809 (1:99880713 A>T), RS1000548368 (1:99903783 C>T), RS1000606247 (1:99886292 A>G), RS1000710195 (1:99898973 A>G), RS1000784409 (1:99850084 C>A,G)

Disease associations

OMIM: gene MIM:610860 | disease phenotypes: MIM:232400, MIM:232200, MIM:156000, MIM:248600, MIM:615553

GenCC curated gene-disease

Disease	Classification	Inheritance
glycogen storage disease III	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
glycogen storage disease III	Definitive	AR

Mondo (6): glycogen storage disease III (MONDO:0009291), disorder of glycogen metabolism (MONDO:0002412), Meniere disease (MONDO:0007972), maple syrup urine disease (MONDO:0009563), autism spectrum disorder - epilepsy - arthrogryposis syndrome (MONDO:0014248), hereditary ataxia (MONDO:0100309)

Orphanet (6): Glycogen storage disease due to glycogen debranching enzyme deficiency (Orphanet:366), Glycogen storage disease (Orphanet:79201), Maple syrup urine disease (Orphanet:511), Autism spectrum disorder-epilepsy-arthrogryposis syndrome (Orphanet:370943), Hereditary ataxia (Orphanet:183518), NON RARE IN EUROPE: Menière disease (Orphanet:45360)

HPO phenotypes

25 total (25 of 25 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000219	Thin upper lip vermilion
HP:0000233	Thin vermilion border
HP:0000272	Malar flattening
HP:0000293	Full cheeks
HP:0000455	Broad nasal tip
HP:0000490	Deeply set eye
HP:0001256	Mild intellectual disability
HP:0001324	Muscle weakness
HP:0001395	Hepatic fibrosis
HP:0001638	Cardiomyopathy
HP:0001714	Ventricular hypertrophy
HP:0001943	Hypoglycemia
HP:0002155	Hypertriglyceridemia
HP:0002240	Hepatomegaly
HP:0002721	Immunodeficiency
HP:0002910	Elevated circulating hepatic transaminase concentration
HP:0003077	Hyperlipidemia
HP:0003198	Myopathy
HP:0003236	Elevated circulating creatine kinase concentration
HP:0003693	Distal amyotrophy
HP:0004322	Short stature
HP:0005280	Depressed nasal bridge
HP:0011800	Midface retrusion
HP:6000616	Reduced muscle glycogen debrancher enzyme activity

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST001764_6	White matter integrity (bipolar disorder risk interaction)	9.000000e-06
GCST003114_4	Carotid intima media thickness	4.000000e-07
GCST007734_1	Incident chronic kidney disease	1.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004641	white matter integrity

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D006008	Glycogen Storage Disease	C16.320.565.202.449; C18.452.648.202.449
D006010	Glycogen Storage Disease Type III	C16.320.565.202.449.520; C18.452.648.202.449.520
D008375	Maple Syrup Urine Disease	C10.228.140.163.100.520; C16.320.565.100.608; C16.320.565.189.520; C18.452.132.100.520; C18.452.648.100.608; C18.452.648.189.520
D008575	Meniere Disease	C09.218.568.217.500
C531684	Hereditary spinal ataxia (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5272 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

4 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 10,013 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1029	MIGLUSTAT	4	4,770
CHEMBL110458	MIGALASTAT	4	430
CHEMBL1086997	LUCERASTAT	3	74
CHEMBL307429	DUVOGLUSTAT	2	4,739

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

ChEMBL bioactivities

9 potent at pChembl≥5 of 16 total, top 8 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.40	IC50	4000	nM	CHEMBL1088158
5.08	IC50	8400	nM	CHEMBL80254
5.01	IC50	9800	nM	CHEMBL312653
5.00	IC50	1e+04	nM	DUVOGLUSTAT
5.00	IC50	1e+04	nM	MIGLUSTAT
5.00	IC50	1e+04	nM	CHEMBL574645
5.00	IC50	1e+04	nM	MIGALASTAT
5.00	IC50	1e+04	nM	LUCERASTAT

PubChem BioAssay actives

9 with measured affinity, of 27 total; 8 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
(2R,3S,4R,5S)-1-[5-(1-adamantylmethoxy)pentyl]-2-(hydroxymethyl)piperidine-3,4,5-triol	466673: Inhibition of glycogen glycogen de-branching enzyme by HPLC	ic50	4.0000	uM
(2R,3R,4R)-2-(hydroxymethyl)pyrrolidine-3,4-diol	324673: Inhibition of amylo-1,6-glucosidase	ic50	8.4000	uM
(2R,3R,4R,5R)-2,5-bis(hydroxymethyl)pyrrolidine-3,4-diol	324673: Inhibition of amylo-1,6-glucosidase	ic50	9.8000	uM
Migalastat	466673: Inhibition of glycogen glycogen de-branching enzyme by HPLC	ic50	10.0000	uM
(2R,3R,4R,5S)-2-(hydroxymethyl)piperidine-3,4,5-triol	466673: Inhibition of glycogen glycogen de-branching enzyme by HPLC	ic50	10.0000	uM
(2R,3S,4R,5S)-1-butyl-2-(hydroxymethyl)piperidine-3,4,5-triol	466673: Inhibition of glycogen glycogen de-branching enzyme by HPLC	ic50	10.0000	uM
Miglustat	466673: Inhibition of glycogen glycogen de-branching enzyme by HPLC	ic50	10.0000	uM
(2R,3R,4R,5S)-1-[5-(1-adamantylmethoxy)pentyl]-2-(hydroxymethyl)piperidine-3,4,5-triol	466673: Inhibition of glycogen glycogen de-branching enzyme by HPLC	ic50	10.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression, affects methylation, decreases expression	3
methylmercuric chloride	decreases expression	2
Acetaminophen	decreases expression	2
Air Pollutants	affects cotreatment, decreases expression, increases abundance	2
Benzo(a)pyrene	decreases expression, increases methylation	2
Cyclosporine	decreases expression	2
Particulate Matter	decreases expression, increases abundance	2
aristolochic acid I	decreases expression, increases expression	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, decreases expression, increases abundance	1
bisphenol A	increases expression	1
sodium arsenate	increases expression	1
2-methyl-4-isothiazolin-3-one	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cobaltous chloride	decreases expression	1
butyraldehyde	decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
methacrylaldehyde	affects cotreatment, decreases expression, increases abundance	1
beta-methylcholine	affects expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
motexafin gadolinium	decreases expression, affects cotreatment	1
bisphenol B	increases expression	1
abrine	decreases expression	1
licochalcone B	decreases expression	1
jinfukang	decreases expression	1
bisphenol AF	increases expression	1
Arsenic Trioxide	increases expression	1

ChEMBL screening assays

4 unique, capped per target: 4 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1099886	Binding	Inhibition of glycogen glycogen de-branching enzyme by HPLC	Dual-action lipophilic iminosugar improves glycemic control in obese rodents by reduction of visceral glycosphingolipids and buffering of carbohydrate assimilation. — J Med Chem

Cellosaurus cell lines

3 cell lines: 2 cancer cell line, 1 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_SB92	HAP1 AGL (-) 1	Cancer cell line	Male
CVCL_SB93	HAP1 AGL (-) 2	Cancer cell line	Male
CVCL_VE33	WAe001-A-14	Embryonic stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01574313	PHASE4	COMPLETED	Effect of Stellate Ganglion Block on Meniere’s Disease
NCT02529475	PHASE4	TERMINATED	Evaluation of Inner Ear and Brain Structures With Contrast-enhanced MRI in Healthy Subjects (HYDROPS)
NCT04815187	PHASE4	ACTIVE_NOT_RECRUITING	Repurposed Use of Allergic Rhinitis and Allergic Asthma Drug to Reduce Vertigo and Hearing Loss in Meniere’s Disease
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
NCT03664674	PHASE3	COMPLETED	Phase 3 Study of OTO-104 in Subjects With Unilateral Meniere’s Disease
NCT04677972	PHASE3	COMPLETED	SPI-1005 for the Treatment of Meniere’s Disease
NCT05851508	PHASE3	RECRUITING	The Effecttiveness of Intratympanic Methylprednisolon Injections Compared to Placebo in the Treatment of Vertigo Attacks in Meniere’s Disease
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
NCT05420350	PHASE2	UNKNOWN	Lamotrigine and Bupropion for Meniere’s Disease
NCT06544434	PHASE2	RECRUITING	Laser Acupuncture for Meniere Disease
NCT00202397	PHASE2	COMPLETED	Effect of Riluzole as a Symptomatic Approach in Patients With Chronic Cerebellar Ataxia
NCT04674735	PHASE1	WITHDRAWN	Safety of APSLXR in Patients Presenting Vertigo of Vestibular Origin or Meniere’s Disease
NCT04990388	PHASE1/PHASE2	TERMINATED	Safety, Tolerability, and Pharmacokinetics of UX053 in Patients With Glycogen Storage Disease Type III (GSD III)
NCT02054832	Not specified	COMPLETED	Sleep and Quality of Life in Patients With Glycogen Storage Disease on Standard Versus Modified Uncooked Cornstarch
NCT02385162	Not specified	WITHDRAWN	Biomarker for Glycogen Storage Diseases (BioGlycogen)
NCT02448667	Not specified	COMPLETED	Energy Supplements to Improve Exercise Tolerance in Metabolic Myopathies
NCT02635269	Not specified	UNKNOWN	Fat and Sugar Metabolism During Exercise in Patients With Metabolic Myopathy
NCT04574830	Not specified	COMPLETED	Study to Evaluate Biomarkers and Clinical Manifestations in Individuals With Glycogen Storage Disease Type III (GSD III)
NCT05196165	Not specified	TERMINATED	Clinical Survey Study to Assess Physical Function and the Incidence of Hypoglycemia in Participants With Glycogen Storage Disease Type III
NCT06616545	Not specified	RECRUITING	French Observatory for Patients with Type 3 Glycogenosis
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
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