AGA

Summary

AGA (aspartylglucosaminidase, HGNC:318) is a protein-coding gene on chromosome 4q34.3, encoding N(4)-(beta-N-acetylglucosaminyl)-L-asparaginase (P20933). Cleaves the GlcNAc-Asn bond which joins oligosaccharides to the peptide of asparagine-linked glycoproteins.

This gene encodes a member of the N-terminal nucleophile (Ntn) hydrolase family of proteins. The encoded preproprotein is proteolytically processed to generate alpha and beta chains that comprise the mature enzyme. This enzyme is involved in the catabolism of N-linked oligosaccharides of glycoproteins. It cleaves asparagine from N-acetylglucosamines as one of the final steps in the lysosomal breakdown of glycoproteins. Mutations in this gene are associated with the lysosomal storage disease aspartylglycosaminuria that results in progressive neurodegeneration. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is subject to proteolytic processing.

Source: NCBI Gene 175 — RefSeq curated summary.

At a glance

• Gene–disease (curated): aspartylglucosaminuria (Definitive, ClinGen)
• GWAS associations: 8
• Clinical variants (ClinVar): 599 total — 40 pathogenic, 59 likely-pathogenic
• Phenotypes (HPO): 78
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_000027

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:318
Approved symbol	AGA
Name	aspartylglucosaminidase
Location	4q34.3
Locus type	gene with protein product
Status	Approved
Aliases	ASRG
Ensembl gene	ENSG00000038002
Ensembl biotype	protein_coding
OMIM	613228
Entrez	175

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 4 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000264595, ENST00000502310, ENST00000506853, ENST00000510635, ENST00000510955, ENST00000511231, ENST00000926431

RefSeq mRNA: 2 — MANE Select: NM_000027 NM_000027, NM_001171988

CCDS: CCDS3829

Canonical transcript exons

ENST00000264595 — 9 exons

Exon	Start	End
ENSE00002055757	177442249	177442437
ENSE00002212427	177433214	177433347
ENSE00002227706	177434382	177434489
ENSE00002233825	177436276	177436351
ENSE00002255233	177430774	177431808
ENSE00003529604	177440273	177440426
ENSE00003657899	177437405	177437519
ENSE00003680928	177438745	177438857
ENSE00003683620	177439576	177439688

Expression profiles

Bgee: expression breadth ubiquitous, 287 present calls, max score 94.06.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 16.1218 / max 160.1103, expressed in 1806 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
55058	9.9510	1785
55059	5.7481	1717
55057	0.4227	227

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
esophagus squamous epithelium	UBERON:0006920	94.06	gold quality
squamous epithelium	UBERON:0006914	92.79	gold quality
epithelium of esophagus	UBERON:0001976	92.72	gold quality
corpus epididymis	UBERON:0004359	92.45	gold quality
gingival epithelium	UBERON:0001949	92.44	gold quality
tongue squamous epithelium	UBERON:0006919	91.80	gold quality
gingiva	UBERON:0001828	91.71	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	91.40	gold quality
skin of hip	UBERON:0001554	91.27	gold quality
stromal cell of endometrium	CL:0002255	91.01	gold quality
upper leg skin	UBERON:0004262	90.72	gold quality
oral cavity	UBERON:0000167	90.71	gold quality
islet of Langerhans	UBERON:0000006	89.96	gold quality
parotid gland	UBERON:0001831	89.93	silver quality
nephron tubule	UBERON:0001231	89.92	gold quality
choroid plexus epithelium	UBERON:0003911	89.74	gold quality
cervix squamous epithelium	UBERON:0006922	89.51	silver quality
epithelium of nasopharynx	UBERON:0001951	89.41	gold quality
nasal cavity epithelium	UBERON:0005384	89.41	gold quality
nasopharynx	UBERON:0001728	89.39	gold quality
hair follicle	UBERON:0002073	89.10	gold quality
bone marrow cell	CL:0002092	89.03	gold quality
penis	UBERON:0000989	88.92	gold quality
bone marrow	UBERON:0002371	88.58	gold quality
nasal cavity mucosa	UBERON:0001826	88.39	gold quality
tonsil	UBERON:0002372	88.33	gold quality
pigmented layer of retina	UBERON:0001782	88.13	gold quality
retina	UBERON:0000966	88.11	gold quality
monocyte	CL:0000576	88.01	gold quality
mammalian vulva	UBERON:0000997	87.99	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	11.80

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): SP1, TP53

miRNA regulators (miRDB)

71 targeting AGA, 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-1252-5P	100.00	69.80	2774
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-106B-5P	99.88	74.72	2795
HSA-MIR-20A-5P	99.88	74.76	2769
HSA-MIR-20B-5P	99.88	74.01	2621
HSA-MIR-519D-3P	99.88	73.97	2607
HSA-MIR-93-5P	99.88	73.98	2606
HSA-MIR-526B-3P	99.88	74.06	2587
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-4503	99.85	71.45	1869
HSA-MIR-5010-3P	99.83	70.60	2357
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-374C-5P	99.80	72.06	2910
HSA-MIR-655-3P	99.80	72.19	2909

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 11)

• Molecular mechanism for the autoproteolytic activation of aspartylglucosaminidase. (PMID:14616088)
• A new point mutation, c.44T>G, found in a Finnish compound heterozygote causes a L15R AA substitution in the signal sequence of the AGA enzyme, affecting AGA translocation by altering a critical hydrophobic core structure in the signal sequence. (PMID:15365992)
• aspartylglucosaminidase may have a role in development of congenital disorders of glycosylation type I (PMID:16435229)
• The amino acid substitutions in aspartylglucosaminidase responsible for aspartylglucosaminuria were classified and divided in three groups. (PMID:18992224)
• Increased AGA plasma activity, although a consistent finding in congenital disorders of glycosylation patients, is not specific to this group of disorders. (PMID:19100247)
• [review] Natural killer (NK) cell tumors, subtypes of myeloid leukemias and T-cell lymphomas respond to ASNase; ovarian carcinomas and other solid tumors have been proposed as additional targets for ASNase, with a potential role for glutaminase. activity. (PMID:21854356)
• study reports 2 novel aspartylglucosaminidase gene mutations, one in Qatari twins with an early, perinatal presentation not previously described for aspartylglucosaminuria and the other in 3 Turkish children with newly diagnosed aspartylglucosaminuria and a more classical disease course (PMID:23271757)
• We show that gene-silenced cells show specifically reduced AGA activity and store globotriaosylceramide. In gene-silenced cells, release of the neurotransmitter acetylcholine is significantly reduced, demonstrating that this model may be used to study specific neuronal functions such as neurotransmitter release in Fabry disease (PMID:27471012)
• 1.8A resolution crystal structure of mature G172D mutant of a model missense GA corresponding to a Canadian aspartylglucosaminuria allele; studied the effect of its single amino acid change on substrate processing (PMID:28457719)
• Determination a 1.6 A-resolution structure of the Finnish AGU model and building of an enzyme-substrate complex to provide a structural basis for analyzing the negative effects of the point mutation on KM and kcat of the mature enzyme. (PMID:29993127)
• T99K variant of glycosylasparaginase shows a new structural mechanism of the genetic disease aspartylglucosaminuria (PMID:30901125)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	aga	ENSDARG00000004889
mus_musculus	Aga	ENSMUSG00000031521
rattus_norvegicus	Aga	ENSRNOG00000000108
drosophila_melanogaster	CG1827	FBGN0033431
drosophila_melanogaster	CG10474	FBGN0034427
drosophila_melanogaster	CG4372	FBGN0034665
caenorhabditis_elegans		WBGENE00019867

Paralogs (2): TASP1 (ENSG00000089123), ASRGL1 (ENSG00000162174)

Protein

Protein identifiers

N(4)-(beta-N-acetylglucosaminyl)-L-asparaginase — P20933 (reviewed: P20933)

Alternative names: Aspartylglucosaminidase, Glycosylasparaginase, N4-(N-acetyl-beta-glucosaminyl)-L-asparagine amidase

All UniProt accessions (3): P20933, H0Y8L9, H0Y9C7

UniProt curated annotations — full annotation on UniProt →

Function. Cleaves the GlcNAc-Asn bond which joins oligosaccharides to the peptide of asparagine-linked glycoproteins.

Subunit / interactions. Heterotetramer of two alpha and two beta chains arranged as a dimer of alpha/beta heterodimers.

Subcellular location. Lysosome.

Post-translational modifications. Cleaved into an alpha and beta chain by autocatalysis; this activates the enzyme. The N-terminal residue of the beta subunit is responsible for the nucleophile hydrolase activity. N-glycosylated.

Disease relevance. Aspartylglucosaminuria (AGU) [MIM:208400] An inborn lysosomal storage disease causing excess accumulation of glycoasparagine in the body tissues and its increased excretion in urine. Clinical features include mild to severe intellectual disability manifesting from the age of two, coarse facial features and mild connective tissue abnormalities. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the Ntn-hydrolase family.

RefSeq proteins (2): NP_000018, NP_001165459 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000246	Peptidase_T2	Family
IPR029055	Ntn_hydrolases_N	Homologous_superfamily

Pfam: PF01112

Enzyme classification (BRENDA):

• EC 3.5.1.26 — N4-(beta-N-acetylglucosaminyl)-L-asparaginase (BRENDA: 15 organisms, 71 substrates, 45 inhibitors, 33 Km, 7 kcat entries)

Substrate kinetics (BRENDA)

11 substrates with measured Km, best-characterized 11. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
N4-(BETA-N-ACETYL-D-GLUCOSAMINYL)-L-ASPARAGINE	0.09–2.5	9
L-ASPARAGINE	0.66–12.1	4
1-L-BETA-ASPARTAMIDO-(2-ACETAMIDO)-1,2-DIDEOXY-B	0.05–1	3
N4-(BETA-N-ACETYLGLUCOSAMINYL)-L-ASPARAGINE	0.09–0.26	3
1-L-BETA-ASPARTAMIDO-(2-ACETAMIDO)-1,2-DIDEOXY-B	1–14	2
2-ACETAMIDO-1-BETA-(L-ASPARTAMIDO)-1,2-DIDEOXY-D	0.143–0.444	2
2-ACETAMIDO-1-N-(4-L-ASPARTYL)-2-DEOXY-BETA-D-GL	0.4–0.64	2
L-ASPARTYL-BETA-(7-AMIDO-4-METHYLCOUMARIN)	0.0449–0.0742	2
1-L-BETA-ASPARTAMIDO-BETA-D-GALACTOSE	10.8	1
1-L-BETA-ASPARTAMIDO-BETA-D-MANNOSE	5.7	1
OVALBUMIN	0.77	1

Catalyzed reactions (Rhea), 1 shown:

• N(4)-(beta-N-acetyl-D-glucosaminyl)-L-asparagine + H2O = N-acetyl-beta-D-glucosaminylamine + L-aspartate + H(+) (RHEA:11544)

UniProt features (60 total): sequence variant 15, strand 15, helix 10, turn 5, disulfide bond 4, chain 2, sequence conflict 2, binding site 2, glycosylation site 2, signal peptide 1, active site 1, modified residue 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
1APY	X-RAY DIFFRACTION	2
1APZ	X-RAY DIFFRACTION	2.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P20933-F1	91.41	0.86

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): 206 (nucleophile)

Ligand- & substrate-binding residues (2): 234–237; 257–260

Post-translational modifications (1): 24

Disulfide bonds (4): 163–179, 286–306, 317–345, 64–69

Glycosylation sites (2): 38, 308

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-6798695	Neutrophil degranulation
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System

MSigDB gene sets: 281 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_DN, RRAGTTGT_UNKNOWN, REACTOME_INNATE_IMMUNE_SYSTEM, MODULE_169, XU_GH1_AUTOCRINE_TARGETS_UP, GOCC_SECRETORY_GRANULE, chr4q34, KEGG_LYSOSOME, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_PROTEIN_DEGLYCOSYLATION, MODULE_211, LIU_CMYB_TARGETS_UP, LIU_VMYB_TARGETS_UP, IZADPANAH_STEM_CELL_ADIPOSE_VS_BONE_UP, DEURIG_T_CELL_PROLYMPHOCYTIC_LEUKEMIA_UP

GO Biological Process (2): proteolysis (GO:0006508), protein deglycosylation (GO:0006517)

GO Molecular Function (5): N4-(beta-N-acetylglucosaminyl)-L-asparaginase activity (GO:0003948), peptidase activity (GO:0008233), protein binding (GO:0005515), hydrolase activity (GO:0016787), hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds, in linear amides (GO:0016811)

GO Cellular Component (6): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), cytoplasm (GO:0005737), lysosome (GO:0005764), endoplasmic reticulum (GO:0005783), azurophil granule lumen (GO:0035578)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Innate Immune System	1
Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
protein metabolic process	1
glycoprotein metabolic process	1
protein modification process	1
hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds, in linear amides	1
hydrolase activity	1
catalytic activity, acting on a protein	1
binding	1
catalytic activity	1
hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds	1
intracellular anatomical structure	1
lytic vacuole	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
vacuolar lumen	1
secretory granule lumen	1
azurophil granule	1

Protein interactions and networks

STRING

850 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AGA	GGCT	O75223	845
AGA	GLS	O94925	836
AGA	GGTLC3	B5MD39	797
AGA	GGT2P	P36268	768
AGA	GGT1	P19440	745
AGA	GLYAT	Q6IB77	743
AGA	RAB22A	Q9UL26	662
AGA	GUCY2C	P25092	624
AGA	CLN5	O75503	592
AGA	PPT2	Q9UMR5	585
AGA	GCG	P01275	579
AGA	TSHZ1	Q6ZSZ6	570
AGA	FETUB	Q9UGM5	560
AGA	LPAR2	Q9HBW0	550
AGA	LPA	P08519	549

IntAct

28 interactions, top by confidence:

A	B	Type	Score
FBXO6	MAN2B1	psi-mi:“MI:0914”(association)	0.640
KRTAP1-3	AGA	psi-mi:“MI:0915”(physical association)	0.560
AGA	NEFL	psi-mi:“MI:0915”(physical association)	0.560
AGA	WFS1	psi-mi:“MI:0915”(physical association)	0.560
AGA	KIF1B	psi-mi:“MI:0915”(physical association)	0.560
AGA	HBB	psi-mi:“MI:0914”(association)	0.530
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
AGA	SIL1	psi-mi:“MI:0915”(physical association)	0.400
ALB	SH3BP5	psi-mi:“MI:0914”(association)	0.350
ST14	LIPT2	psi-mi:“MI:0914”(association)	0.350
AGA	IGF2R	psi-mi:“MI:0914”(association)	0.350
MRM1	RIMOC1	psi-mi:“MI:0914”(association)	0.350
SH2D3A	A2ML1	psi-mi:“MI:0914”(association)	0.350
SARAF	A2ML1	psi-mi:“MI:0914”(association)	0.350
ATP6AP2	KLK10	psi-mi:“MI:0914”(association)	0.350
IGF2R	MANBA	psi-mi:“MI:0914”(association)	0.350
TMEM185A	AGA	psi-mi:“MI:0914”(association)	0.350
AGA	KRTAP1-3	psi-mi:“MI:0915”(physical association)	0.000
AGA		psi-mi:“MI:0915”(physical association)	0.000

BioGRID (51): AGA (Affinity Capture-MS), MOB4 (Affinity Capture-MS), HBA2 (Affinity Capture-MS), HBB (Affinity Capture-MS), IGHG1 (Affinity Capture-MS), ZER1 (Affinity Capture-MS), MOB4 (Affinity Capture-MS), HBB (Affinity Capture-MS), AGA (Affinity Capture-MS), HBA2 (Affinity Capture-MS), ZER1 (Affinity Capture-MS), AGA (Affinity Capture-MS), AADAT (Co-fractionation), ECHS1 (Co-fractionation), ECI1 (Co-fractionation)

ESM2 similar proteins: A0A3G9HHK2, A2Y6Z7, B3MJ16, B3N6Y7, B3NN96, B4GGF2, B4GHE3, B4HT15, B4I7X1, B4JVW6, B4NWI1, B4P8E0, B4QGM0, B4QHB1, O09046, O59759, P16393, P20933, P23225, P30919, P48441, Q0C8L9, Q0VCR7, Q21697, Q28XQ5, Q28Y14, Q43155, Q4R6C4, Q53WK1, Q567W6, Q5R889, Q5REF9, Q64191, Q67WN8, Q84WB7, Q8BJM7, Q8MR45, Q96HN2, Q96RQ9, Q9LY71

Diamond homologs: B3MJ16, B3N6Y7, B3NN96, B4GGF2, B4GHE3, B4HT15, B4I7X1, B4JVW6, B4NWI1, B4P8E0, B4QGM0, B4QHB1, O02467, O57971, P20933, P30362, P30919, Q21697, Q28XQ5, Q28Y14, Q47898, Q4R6C4, Q54WW4, Q56W64, Q5JHT1, Q64191, Q8MR45, Q8U4E6, Q9V262, Q9W2C3, Q9ZSD6, A3MUS8, P30364, P37595, P50287, P50288, Q4R7U8, Q5BKW9, Q6GM78, Q7CQV5

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 24 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
Neutrophil degranulation	5	7.7×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	40
Likely pathogenic	59
Uncertain significance	148
Likely benign	257
Benign	37

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1068996	NC_000004.11:g.(?178363393)(178363667_?)del	Pathogenic
1071135	NM_000027.4(AGA):c.128-2A>G	Pathogenic
1075443	NM_000027.4(AGA):c.698+1del	Pathogenic
1341346	NM_000027.4(AGA):c.202C>T (p.Gln68Ter)	Pathogenic
1351725	NM_000027.4(AGA):c.187dup (p.Met63fs)	Pathogenic
1357402	NM_000027.4(AGA):c.268dup (p.Met90fs)	Pathogenic
1446399	NM_000027.4(AGA):c.509dup (p.Asn170fs)	Pathogenic
1455592	NM_000027.4(AGA):c.519dup (p.Asp174fs)	Pathogenic
2008973	NM_000027.4(AGA):c.9del (p.Lys4fs)	Pathogenic
2029864	NM_000027.4(AGA):c.665del (p.Thr222fs)	Pathogenic
2108081	NM_000027.4(AGA):c.55del (p.Ala19fs)	Pathogenic
2109804	NM_000027.4(AGA):c.172G>T (p.Glu58Ter)	Pathogenic
219	NM_000027.4(AGA):c.488G>C (p.Cys163Ser)	Pathogenic
220	NM_000027.4(AGA):c.904G>A (p.Gly302Arg)	Pathogenic
229	NM_000027.4(AGA):c.214T>C (p.Ser72Pro)	Pathogenic
2422151	NC_000004.11:g.(?178357420)(178363667_?)del	Pathogenic
2422152	NC_000004.11:g.(?178351918)(178357515_?)del	Pathogenic
2789512	NM_000027.4(AGA):c.797dup (p.Leu267fs)	Pathogenic
291257	NM_000027.4(AGA):c.319C>T (p.Arg107Ter)	Pathogenic
3246598	NC_000004.11:g.(?178352862)(178363529_?)del	Pathogenic
3246599	NC_000004.11:g.(?178363383)(178363529_?)del	Pathogenic
3246600	NC_000004.11:g.(?178352862)(178360031_?)del	Pathogenic
3246601	NC_000004.11:g.(?178352862)(178358693_?)del	Pathogenic
3605108	NM_000027.4(AGA):c.88dup (p.Val30fs)	Pathogenic
370266	NM_000027.4(AGA):c.473G>A (p.Trp158Ter)	Pathogenic
4075196	NM_000027.4(AGA):c.108_111dup (p.Asn38Ter)	Pathogenic
4075197	NM_000027.4(AGA):c.96C>A (p.Asn32Lys)	Pathogenic
4817922	NM_000027.4(AGA):c.504G>A (p.Trp168Ter)	Pathogenic
495346	NM_000027.4(AGA):c.101_107del (p.Trp34fs)	Pathogenic
551282	NM_000027.4(AGA):c.3G>C (p.Met1Ile)	Pathogenic

SpliceAI

1348 predictions. Top by Δscore:

Variant	Effect	Δscore
4:177433209:CTTA:C	donor_loss	1.0000
4:177433210:TTA:T	donor_loss	1.0000
4:177433211:TAC:T	donor_loss	1.0000
4:177433212:A:AC	donor_gain	1.0000
4:177433212:A:T	donor_loss	1.0000
4:177433213:C:CC	donor_gain	1.0000
4:177433213:C:T	donor_loss	1.0000
4:177433345:TAG:T	acceptor_gain	1.0000
4:177433346:AG:A	acceptor_gain	1.0000
4:177433348:C:CC	acceptor_gain	1.0000
4:177433352:T:C	acceptor_gain	1.0000
4:177433352:T:TC	acceptor_gain	1.0000
4:177434525:CGAG:C	acceptor_gain	1.0000
4:177436568:C:A	donor_gain	1.0000
4:177436595:T:TA	donor_gain	1.0000
4:177437400:ATTAC:A	donor_loss	1.0000
4:177437401:TTAC:T	donor_loss	1.0000
4:177437402:TA:T	donor_loss	1.0000
4:177437403:A:AC	donor_gain	1.0000
4:177437403:A:AT	donor_loss	1.0000
4:177437404:C:A	donor_loss	1.0000
4:177437404:C:CC	donor_gain	1.0000
4:177437516:CATT:C	acceptor_gain	1.0000
4:177437517:ATT:A	acceptor_gain	1.0000
4:177437518:TT:T	acceptor_gain	1.0000
4:177437519:TC:T	acceptor_loss	1.0000
4:177437520:C:CA	acceptor_loss	1.0000
4:177437520:C:CC	acceptor_gain	1.0000
4:177437521:T:C	acceptor_loss	1.0000
4:177438739:GCATA:G	donor_loss	1.0000

AlphaMissense

2260 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:177434487:C:G	R234P	0.991
4:177440289:C:G	A89P	0.991
4:177433296:G:C	C286W	0.989
4:177433236:A:C	C306W	0.987
4:177438845:G:T	A136D	0.987
4:177439623:C:G	R116P	0.987
4:177433347:G:C	S269R	0.984
4:177433347:G:T	S269R	0.984
4:177434383:T:G	S269R	0.984
4:177436312:C:T	G221D	0.981
4:177439669:C:G	A101P	0.981
4:177433238:A:G	C306R	0.980
4:177434488:G:T	R234S	0.980
4:177434427:G:T	A254D	0.976
4:177434428:C:G	A254P	0.976
4:177433297:C:T	C286Y	0.975
4:177434452:A:C	Y246D	0.974
4:177434463:C:T	G242E	0.974
4:177440362:A:C	C64W	0.974
4:177433340:C:G	A272P	0.973
4:177438847:A:C	F135L	0.972
4:177438847:A:T	F135L	0.972
4:177438849:A:G	F135L	0.972
4:177439656:A:G	L105P	0.972
4:177436303:G:A	T224I	0.971
4:177436307:A:G	S223P	0.971
4:177438857:G:T	A132D	0.971
4:177433240:A:T	I305K	0.970
4:177434479:C:G	D237H	0.970
4:177436306:G:A	S223F	0.970

dbSNP variants (sampled 300 via entrez): RS1000375404 (4:177435896 G>C), RS1000586402 (4:177444231 T>A,G), RS1000647909 (4:177435357 T>C), RS1000665024 (4:177432850 T>A,C), RS1000716995 (4:177433313 C>A,T), RS1000998782 (4:177435666 T>A,C), RS1001103607 (4:177438871 A>G,T), RS1001161312 (4:177433759 T>C), RS1001672360 (4:177439767 C>T), RS10018500 (4:177433149 T>A), RS1002260541 (4:177442108 C>G,T), RS1002331609 (4:177444095 C>A), RS1002735937 (4:177437999 T>C), RS10027395 (4:177435590 T>A,C), RS1002819359 (4:177437704 T>G)

Disease associations

OMIM: gene MIM:613228 | disease phenotypes: MIM:208400, MIM:607842, MIM:209850

GenCC curated gene-disease

Disease	Classification	Inheritance
aspartylglucosaminuria	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
aspartylglucosaminuria	Definitive	AR

Mondo (5): aspartylglucosaminuria (MONDO:0008830), aural atresia, congenital (MONDO:0011921), autism (MONDO:0005260), intellectual disability (MONDO:0001071), neurodevelopmental disorder (MONDO:0700092)

Orphanet (2): Aspartylglucosaminuria (Orphanet:93), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

78 total (30 of 78 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000023	Inguinal hernia
HP:0000053	Macroorchidism
HP:0000154	Wide mouth
HP:0000158	Macroglossia
HP:0000164	Abnormality of the dentition
HP:0000179	Thick lower lip vermilion
HP:0000212	Gingival overgrowth
HP:0000248	Brachycephaly
HP:0000252	Microcephaly
HP:0000280	Coarse facial features
HP:0000283	Broad face
HP:0000303	Mandibular prognathia
HP:0000316	Hypertelorism
HP:0000389	Chronic otitis media
HP:0000431	Wide nasal bridge
HP:0000463	Anteverted nares
HP:0000518	Cataract
HP:0000670	Carious teeth
HP:0000708	Atypical behavior
HP:0000750	Delayed speech and language development
HP:0000768	Pectus carinatum
HP:0000926	Platyspondyly
HP:0000943	Dysostosis multiplex
HP:0001061	Acne
HP:0001071	Angiokeratoma corporis diffusum
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001257	Spasticity

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST002028_3	Serum selenium levels	3.000000e-07
GCST002157_6	Response to mTOR inhibitor (everolimus)	7.000000e-06
GCST002596_3	Colorectal cancer (calcium intake interaction)	7.000000e-07
GCST002759_30	Motion sickness	4.000000e-09
GCST004736_2	Familial hepatitis B virus-related hepatocellular carcinoma	6.000000e-06
GCST008953_1	Chromosomal aberration frequency (chromatid type)	4.000000e-07
GCST009391_849	Metabolite levels	8.000000e-06
GCST012020_5	Serum metabolite levels	4.000000e-13

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0005417	response to mTOR inhibitor
EFO:0006521	calcium intake measurement
EFO:0006928	motion sickness
EFO:0009862	chromatid-type aberration frequency
EFO:0010400	triacylglycerol 46:0 measurement

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D054880	Aspartylglucosaminuria	C16.320.565.595.100; C18.452.648.595.100
D001321	Autistic Disorder	F03.625.164.113.500
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065886	Neurodevelopmental Disorders	F03.625
C564321	Aural Atresia, Congenital (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

Binding affinities (BindingDB)

6 measured of 7 human assays (10 total across all organisms); most potent 6 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
GlcNAc-Asn analogue, 12	KI	560000 nM
GlcNAc-Asn analogue, 11	KI	640000 nM
D,L-2-Methylsuccinic acid, 5	KI	700000 nM
GlcNAc-Asn analogue, 10	KI	750000 nM
L-2-bromosuccinic acid, 4	KI	2.7e+06 nM
L-2-Chlorosuccinic acid, 3	KI	7.7e+06 nM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression	6
sodium arsenite	increases abundance, affects methylation, affects cotreatment, decreases expression	2
Arsenic	decreases expression, increases abundance, affects cotreatment	2
Cyclosporine	increases expression	2
GSK-J4	decreases expression	1
shuanghuang shengbai	decreases expression	1
dicrotophos	decreases expression	1
methylmercuric chloride	decreases expression	1
sodium arsenate	decreases expression, increases abundance	1
terbufos	decreases methylation	1
mono-(2-ethylhexyl)phthalate	decreases expression	1
cobaltous chloride	decreases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
1-UFT protocol	decreases response to substance	1
bisphenol S	affects cotreatment, increases expression	1
NSC 689534	increases expression, affects binding	1
bisphenol AF	increases expression	1
Sunitinib	decreases expression	1
Vorinostat	increases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Carbamazepine	affects expression	1
Copper	affects binding, increases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Fonofos	decreases methylation	1
Indomethacin	affects cotreatment, increases expression	1
Manganese	affects cotreatment, decreases expression, increases abundance	1
Parathion	decreases methylation	1
Phenobarbital	affects expression	1
Rotenone	increases expression	1

Cellosaurus cell lines

7 cell lines: 4 finite cell line, 3 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2R9	Abcam HEK293T AGA KO	Transformed cell line	Female
CVCL_E2QF	HEK293T AGA KO	Transformed cell line	Female
CVCL_E2QH	HEK293T AGA/SLC35A1 DKO	Transformed cell line	Female
CVCL_F606	GM03560	Finite cell line	Male
CVCL_X446	GM00568	Finite cell line	Female
CVCL_X447	GM02056	Finite cell line	Male
CVCL_X448	GM02057	Finite cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00211796	PHASE4	COMPLETED	Divalproex Sodium ER in Adult Autism
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT00409747	PHASE4	COMPLETED	Minocycline to Treat Childhood Regressive Autism
NCT00576732	PHASE4	COMPLETED	A Study of the Effectiveness and Safety of Two Doses of Risperidone in the Treatment of Children and Adolescents With Autistic Disorder
NCT00844753	PHASE4	COMPLETED	Atomoxetine, Placebo and Parent Management Training in Autism
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01098383	PHASE4	UNKNOWN	Treatment With Acetyl-Choline Esterase Inhibitors in Children With Autism Spectrum Disorders
NCT01333865	PHASE4	COMPLETED	A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders
NCT01337700	PHASE4	COMPLETED	Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism
NCT01695200	PHASE4	COMPLETED	Omega-3 Fatty Acids in Autism Spectrum Disorders
NCT02069977	PHASE4	UNKNOWN	Study to Evaluate the Efficacy and Safety of Aripiprazole
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02199925	PHASE4	UNKNOWN	An Open-Label Study to Evaluate the Efficacy of High-Dose Gammaplex in Children on the Autism Spectrum
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02255565	PHASE4	COMPLETED	Dose Response Effects of Quillivant XR in Children With ADHD and Autism: A Pilot Study
NCT02940574	PHASE4	COMPLETED	Neural and Behavioral Effects of Oxytocin in Autism Spectrum Disorders
NCT03333629	PHASE4	COMPLETED	Promoting Positive Outcomes for Individuals With ASD: Linking Early Detection, Treatment, and Long-term Outcomes
NCT03337646	PHASE4	COMPLETED	Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With ADHD and Autism
NCT03538431	PHASE4	COMPLETED	Improving Driving in Young People With Autism Spectrum Disorders
NCT03757585	PHASE4	COMPLETED	Natural Treatments for the Management of Emotional Dysregulation in Youth With Non-verbal Learning Disability (NVLD) and/or Autism Spectrum Disorders (ASD)
NCT04903353	PHASE4	COMPLETED	Pragmatic Trial Comparing Weight Gain in Children With Autism Taking Risperidone Versus Aripiprazole
NCT05063656	PHASE4	COMPLETED	Biomarker-Driven Pharmacological Treatment of Adolescents With Autism Spectrum Disorder With Gabapentin
NCT05146245	PHASE4	UNKNOWN	Safety and Pharmacokinetics of Antipsychotics in Children 2: Studying TDM in an RCT
NCT05916339	PHASE4	RECRUITING	AWARE: Management of ADHD in Autism Spectrum Disorder
NCT05954052	PHASE4	TERMINATED	A Study of Glutathione in Children With Autism Spectrum Disorder
NCT06853665	PHASE4	RECRUITING	The TEAM Study - Treatment Efficacy for Autism/Attention Using Mixed Amphetamine
NCT07054697	PHASE4	COMPLETED	Pilot-RCT With Individualized Homeopathic Treatment in the Children With Autism Spectrum Disorder
NCT07161804	PHASE4	COMPLETED	Pilot RCT Using Homeopathic Medicines in ASD
NCT07439042	PHASE4	NOT_YET_RECRUITING	Buspirone for Anxiety in Autistic Youth
NCT00036231	PHASE3	TERMINATED	Synthetic Human Secretin in Children With Autism and Gastrointestinal Dysfunction
NCT00036244	PHASE3	COMPLETED	Synthetic Human Secretin in Children With Autism
NCT00065884	PHASE3	UNKNOWN	Valproate Response in Aggressive Autistic Adolescents
NCT00065962	PHASE3	COMPLETED	Secretin for the Treatment of Autism
NCT00252603	PHASE3	COMPLETED	Galantamine Versus Placebo in Childhood Autism
NCT00346736	PHASE3	COMPLETED	Use of Acupuncture In Children With Autistic Spectrum Disorder
NCT00352248	PHASE3	COMPLETED	Randomized Controlled Trial of Acupuncture Versus Sham Acupuncture in Autistic Spectrum Disorder
NCT00352352	PHASE3	COMPLETED	Use of Acupuncture In Children With Autistic Spectrum Disorder
NCT00355329	PHASE3	COMPLETED	Randomized Control Trial of Using Tongue Acupuncture in Autistic Spectrum Disorder Using PET Scan for Clinical Correlation
NCT00498173	PHASE3	COMPLETED	Effectiveness of Atomoxetine in Treating ADHD Symptoms in Children and Adolescents With Autism
NCT00541346	PHASE3	COMPLETED	A Pilot Study of Daytrana TM in Children With Autism Co-Morbid for Attention Deficit Hyperactivity Disorder (ADHD) Symptoms