NAGA

Summary

NAGA (alpha-N-acetylgalactosaminidase, HGNC:7631) is a protein-coding gene on chromosome 22q13.2, encoding Alpha-N-acetylgalactosaminidase (P17050). Removes terminal alpha-N-acetylgalactosamine residues from glycolipids and glycopeptides.

NAGA encodes the lysosomal enzyme alpha-N-acetylgalactosaminidase, which cleaves alpha-N-acetylgalactosaminyl moieties from glycoconjugates. Mutations in NAGA have been identified as the cause of Schindler disease types I and II (type II also known as Kanzaki disease).

Source: NCBI Gene 4668 — RefSeq curated summary.

At a glance

• Gene–disease (curated): alpha-N-acetylgalactosaminidase deficiency (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 8
• Clinical variants (ClinVar): 338 total — 24 pathogenic, 14 likely-pathogenic
• Phenotypes (HPO): 68
• Druggable target: yes
• MANE Select transcript: NM_000262

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7631
Approved symbol	NAGA
Name	alpha-N-acetylgalactosaminidase
Location	22q13.2
Locus type	gene with protein product
Status	Approved
Aliases	D22S674
Ensembl gene	ENSG00000198951
Ensembl biotype	protein_coding
OMIM	104170
Entrez	4668

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 9 protein_coding

ENST00000396398, ENST00000402937, ENST00000403363, ENST00000898671, ENST00000898672, ENST00000898673, ENST00000898674, ENST00000898675, ENST00000958241

RefSeq mRNA: 3 — MANE Select: NM_000262 NM_000262, NM_001362848, NM_001362850

CCDS: CCDS14030

Canonical transcript exons

ENST00000396398 — 9 exons

Exon	Start	End
ENSE00000656357	42060924	42061067
ENSE00000656363	42062827	42063024
ENSE00000656366	42067113	42067290
ENSE00000656371	42067765	42067936
ENSE00000880509	42068439	42068574
ENSE00001109463	42058334	42060413
ENSE00001286066	42066710	42066804
ENSE00001296419	42065738	42065899
ENSE00001370916	42070282	42070812

Expression profiles

Bgee: expression breadth ubiquitous, 252 present calls, max score 96.41.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 22.1453 / max 201.2312, expressed in 1810 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
194406	19.0182	1805
194403	1.7992	789
194405	0.8183	476
194404	0.5096	278

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	96.41	gold quality
mononuclear cell	CL:0000842	96.20	gold quality
leukocyte	CL:0000738	96.15	gold quality
granulocyte	CL:0000094	95.05	gold quality
stromal cell of endometrium	CL:0002255	91.14	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	89.69	gold quality
gall bladder	UBERON:0002110	89.48	gold quality
rectum	UBERON:0001052	89.44	gold quality
placenta	UBERON:0001987	88.86	gold quality
vermiform appendix	UBERON:0001154	87.66	gold quality
descending thoracic aorta	UBERON:0002345	87.46	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	87.42	gold quality
right coronary artery	UBERON:0001625	87.41	gold quality
blood	UBERON:0000178	87.40	gold quality
mucosa of transverse colon	UBERON:0004991	87.11	gold quality
smooth muscle tissue	UBERON:0001135	86.72	gold quality
thoracic aorta	UBERON:0001515	86.43	gold quality
ascending aorta	UBERON:0001496	86.28	gold quality
transverse colon	UBERON:0001157	86.17	gold quality
right lobe of liver	UBERON:0001114	86.05	gold quality
left coronary artery	UBERON:0001626	86.02	gold quality
right lung	UBERON:0002167	85.74	gold quality
caecum	UBERON:0001153	85.71	gold quality
coronary artery	UBERON:0001621	85.64	gold quality
left uterine tube	UBERON:0001303	85.53	gold quality
upper lobe of left lung	UBERON:0008952	85.46	gold quality
right ovary	UBERON:0002118	85.29	gold quality
small intestine Peyer’s patch	UBERON:0003454	85.29	gold quality
islet of Langerhans	UBERON:0000006	85.27	gold quality
aorta	UBERON:0000947	85.15	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	11.68
E-MTAB-3929	no	80.95

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

88 targeting NAGA, 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-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-433-3P	99.98	69.37	1203
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-221-5P	99.86	65.45	1052
HSA-MIR-8073	99.86	65.21	1118
HSA-MIR-3133	99.81	70.92	3506
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-561-3P	99.64	70.90	3647
HSA-MIR-1260A	99.61	66.67	1098

Literature-anchored findings (GeneRIF, showing 12)

• Tumor cell alpha-N-acetylgalactosaminidase activity and its involvement in GcMAF-related macrophage activation. (PMID:12062184)
• Structural analysis revealed biochemical and phenotypic differences in these Kanzaki patients with the R329Q and R329W mutation. (PMID:15619430)
• NAGA mutation p.D217N (c.649G>A) in exon 6 and mutation p.E325K (c.973G>A) in exon 8 may have roles in alpha-N-acetylgalactosaminidase deficiency with cardiomyopathy (PMID:17171432)
• Specific enzymatic activity of serum alpha-N-acetylgalactosaminidase was significantly increased in stage III melanoma patients, but not in early stages. (PMID:19394758)
• The active site of human alpha-NAGAL has anomeric selectivity for its catalytic product and the structure reveals a novel active-site rearrangement upon hexose ligand binding. (PMID:19683538)
• Use of a modified NAGA in the development of enzyme replacement therapy for Fabry disease is reported. (PMID:19853240)
• the active sites of human lysosomal enzymes alpha-galactosidase and alpha-N-acetylgalactosaminidase have interconvertible specificites (PMID:20444686)
• results demonstrate the utility of eQTL mapping in the identification of novel asthma genes and provide evidence for the importance of FADS2, NAGA, and F13A1 in the pathogenesis of asthma. (PMID:24934276)
• A Novel Homozygous Missense Variant in the NAGA Gene with Extreme Intrafamilial Phenotypic Heterogeneity. (PMID:31468281)
• A missense variant in NDUFA6 confers schizophrenia risk by affecting YY1 binding and NAGA expression. (PMID:33931730)
• Silencing of alpha-N-acetylgalactosaminidase in the gastric cancer cells amplified cell death and attenuated migration, while the multidrug resistance remained unchanged. (PMID:34816536)
• Could low alpha-N-acetylgalactosaminidase plasma concentration cause schizophrenia? (PMID:35521802)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	naga	ENSDARG00000099313
mus_musculus	Naga	ENSMUSG00000022453
rattus_norvegicus	Naga	ENSRNOG00000008064
drosophila_melanogaster	CG5731	FBGN0032192
drosophila_melanogaster	CG7997	FBGN0034117
caenorhabditis_elegans		WBGENE00011095

Paralogs (1): GLA (ENSG00000102393)

Protein

Protein identifiers

Alpha-N-acetylgalactosaminidase — P17050 (reviewed: P17050)

Alternative names: Alpha-galactosidase B

All UniProt accessions (1): P17050

UniProt curated annotations — full annotation on UniProt →

Function. Removes terminal alpha-N-acetylgalactosamine residues from glycolipids and glycopeptides. Required for the breakdown of glycolipids.

Subunit / interactions. Homodimer.

Subcellular location. Lysosome.

Disease relevance. Schindler disease (SCHIND) [MIM:609241] Form of NAGA deficiency characterized by early-onset neuroaxonal dystrophy and neurological signs (convulsion during fever, epilepsy, psychomotor retardation and hypotonia). NAGA deficiency is typically classified in three main phenotypes: NAGA deficiency type I (Schindler disease or Schindler disease type I) with severe manifestations; NAGA deficiency type II (Kanzazi disease or Schindler disease type II) which is mild; NAGA deficiency type III (Schindler disease type III) characterized by mild-to-moderate neurologic manifestations. NAGA deficiency results in the increased urinary excretion of glycopeptides and oligosaccharides containing alpha-N-acetylgalactosaminyl moieties. Inheritance is autosomal recessive. The disease is caused by variants affecting the gene represented in this entry. Kanzaki disease (KANZD) [MIM:609242] Autosomal recessive disorder characterized by late-onset, angiokeratoma corporis diffusum and mild intellectual impairment. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. Alpha-galactosidase B was first found to be an isoenzyme of alpha-galactosidases, but apparently it differs from alpha-galactosidase A in substrate specificity and is alpha-N-acetylgalactosaminidase.

Similarity. Belongs to the glycosyl hydrolase 27 family.

RefSeq proteins (3): NP_000253, NP_001349777, NP_001349779 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000111	Glyco_hydro_27/36_CS	Conserved_site
IPR002241	Glyco_hydro_27	Family
IPR013780	Glyco_hydro_b	Homologous_superfamily
IPR013785	Aldolase_TIM	Homologous_superfamily
IPR017853	GH_hydrolase_sf	Homologous_superfamily
IPR035373	Melibiase/NAGA_C	Domain

Pfam: PF16499, PF17450

Enzyme classification (BRENDA):

• EC 3.2.1.49 — alpha-N-acetylgalactosaminidase (BRENDA: 49 organisms, 88 substrates, 46 inhibitors, 70 Km, 31 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
4-NITROPHENYL ALPHA-N-ACETYLGALACTOSAMINIDE	0.0172–6.6	18
4-NITROPHENYL N-ACETYL-ALPHA-D-GALACTOSAMINIDE	0.0115–1.09	7
GALNAC-ALPHA-PNP	0.042–0.34	6
P-NITROPHENYL-ALPHA-N-ACETYLGALACTOSAMINIDE	0.23–2.4	4
2-NITROPHENYL-ALPHA-N-ACETYLGALACTOSAMINIDE	0.56–0.73	3
GALNAC-ALPHA-1,3-GALNAC-BETA-1,3-GAL-ALPHA-1,4-G	1.04–3.97	3
4-NITROPHENYL ALPHA-D-N-ACETYLGALACTOSAMINIDE	0.7–0.89	2
FORSSMAN HAPTEN	0.036–0.59	2
O-NITROPHENYL-ALPHA-N-ACETYLGALACTOSAMINIDE	1.3–2.4	2
O-NITROPHENYL-N-ACETYL-ALPHA-D-GALACTOSAMINIDE	1.58–1.62	2
P-NITROPHENYL N-ACETYL-ALPHA-D-GALACTOSAMINIDE	1.27–4.83	2
P-NITROPHENYL-N-ACETYL-ALPHA-D-GALACTOSAMINIDE	1.1–1.35	2
SERUM VITAMIN D3-BINDING PROTEIN	1.27–4.83	2
2-NITROPHENYL ALPHA-D-FUCOPYRANOSIDE	8.8	1
4-METHYLUMBELLIFERYL-ALPHA-D-GALACTOPYRANOSIDE	6.8	1

Catalyzed reactions (Rhea), 3 shown:

• a neolactoside IV(3)-alpha-GalNAc,IV(2)-alpha-Fuc-nLc4Cer(d18:1(4E)) + H2O = a neolactoside IV(2)-alpha-Fuc-nLc4Cer(d18:1(4E)) + N-acetyl-alpha-D-galactosamine (RHEA:48212)
• a globoside IV3GalNAc-Gb4Cer + H2O = N-acetyl-alpha-D-galactosamine + a globoside Gb4Cer (RHEA:48412)
• a neolactoside IV(3)-alpha-GalNAc,IV(2)-alpha-Fuc-nLc4Cer(d18:0) + H2O = a neolactoside IV(2)-alpha-Fuc-nLc4Cer(d18:0) + N-acetyl-alpha-D-galactosamine (RHEA:49304)

UniProt features (74 total): strand 21, helix 18, turn 6, glycosylation site 5, binding site 5, disulfide bond 4, sequence variant 4, sequence conflict 4, modified residue 2, active site 2, signal peptide 1, chain 1, mutagenesis site 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
4DO4	X-RAY DIFFRACTION	1.4
4DO5	X-RAY DIFFRACTION	1.51
4DO6	X-RAY DIFFRACTION	1.6
3H55	X-RAY DIFFRACTION	1.91
3H53	X-RAY DIFFRACTION	2.01
3IGU	X-RAY DIFFRACTION	2.15
3H54	X-RAY DIFFRACTION	2.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P17050-F1	96.18	0.94

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 (2): 156 (nucleophile); 217 (proton donor)

Ligand- & substrate-binding residues (5): 78–79; 154; 188; 213; 217

Post-translational modifications (2): 332, 322

Disulfide bonds (4): 38–80, 42–49, 127–158, 187–209

Glycosylation sites (5): 124, 177, 201, 359, 385

Mutagenesis-validated functional residues (1):

Position	Phenotype
201	loss of glycosylation site; no effect on enzyme activity and stability.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 325 (showing top): GOBP_OLIGOSACCHARIDE_METABOLIC_PROCESS, WANG_CLIM2_TARGETS_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_CARBOHYDRATE_DERIVATIVE_CATABOLIC_PROCESS, KEGG_LYSOSOME, GOBP_MEMBRANE_LIPID_CATABOLIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, MODULE_492, GOBP_GLYCOLIPID_CATABOLIC_PROCESS, KEGG_GLYCOSPHINGOLIPID_BIOSYNTHESIS_GLOBO_SERIES, BLALOCK_ALZHEIMERS_DISEASE_UP, GOBP_CARBOHYDRATE_METABOLIC_PROCESS, MORF_PRKDC, GOZGIT_ESR1_TARGETS_UP, GOBP_LIPID_METABOLIC_PROCESS

GO Biological Process (6): oligosaccharide metabolic process (GO:0009311), carbohydrate catabolic process (GO:0016052), glycoside catabolic process (GO:0016139), glycolipid catabolic process (GO:0019377), carbohydrate metabolic process (GO:0005975), lipid metabolic process (GO:0006629)

GO Molecular Function (6): alpha-galactosidase activity (GO:0004557), alpha-N-acetylgalactosaminidase activity (GO:0008456), protein homodimerization activity (GO:0042803), hydrolase activity, hydrolyzing O-glycosyl compounds (GO:0004553), hydrolase activity (GO:0016787), hydrolase activity, acting on glycosyl bonds (GO:0016798)

GO Cellular Component (4): cytoplasm (GO:0005737), lysosome (GO:0005764), membrane (GO:0016020), extracellular exosome (GO:0070062)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
carbohydrate metabolic process	2
primary metabolic process	2
cellular anatomical structure	2
catabolic process	1
glycoside metabolic process	1
glycosyl compound catabolic process	1
glycolipid metabolic process	1
lipid catabolic process	1
carbohydrate derivative catabolic process	1
galactosidase activity	1
hexosaminidase activity	1
identical protein binding	1
protein dimerization activity	1
hydrolase activity, acting on glycosyl bonds	1
catalytic activity	1
hydrolase activity	1
intracellular anatomical structure	1
lytic vacuole	1
extracellular vesicle	1

Protein interactions and networks

STRING

1230 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NAGA	OGA	O60502	662
NAGA	ACO2	Q99798	650
NAGA	FUCA1	P04066	582
NAGA	GUSB	P08236	529
NAGA	PHETA2	Q6ICB4	527
NAGA	MAN2B1	O00754	526
NAGA	MANBA	O00462	516
NAGA	HEXA	P06865	510
NAGA	ASAH1	Q13510	447
NAGA	AMDHD2	Q9Y303	446
NAGA	GALNS	P34059	443
NAGA	BCKDHA	P12694	436
NAGA	ANGEL1	Q9UNK9	433
NAGA	ATOSB	Q7L5A3	430
NAGA	IL2RA	P01589	424

IntAct

32 interactions, top by confidence:

A	B	Type	Score
CTSG	MANBA	psi-mi:“MI:0914”(association)	0.530
EPDR1	NAGA	psi-mi:“MI:0914”(association)	0.530
NEK4	E2F8	psi-mi:“MI:0914”(association)	0.350
TAZ	MANBA	psi-mi:“MI:0914”(association)	0.350
SLAMF1	RTCA	psi-mi:“MI:0914”(association)	0.350
CANX	HLA-A	psi-mi:“MI:0914”(association)	0.350
NUMA1	SHANK3	psi-mi:“MI:0914”(association)	0.350
NAGA	TMEM223	psi-mi:“MI:0914”(association)	0.350
IL5RA	POTEF	psi-mi:“MI:0914”(association)	0.350
TMEM87A	POTEF	psi-mi:“MI:0914”(association)	0.350
NCR3	POTEF	psi-mi:“MI:0914”(association)	0.350
LYPD4	POTEF	psi-mi:“MI:0914”(association)	0.350
EDN3	POTEF	psi-mi:“MI:0914”(association)	0.350
PCP4	A2ML1	psi-mi:“MI:0914”(association)	0.350
PRG2	QSOX1	psi-mi:“MI:0914”(association)	0.350
RLN1	MANBA	psi-mi:“MI:0914”(association)	0.350
CRLF1	MANBA	psi-mi:“MI:0914”(association)	0.350
C1QB	MANBA	psi-mi:“MI:0914”(association)	0.350
TRGV3	MANBA	psi-mi:“MI:0914”(association)	0.350
CBLN4	AGRN	psi-mi:“MI:0914”(association)	0.350
LYZL1	MAN2B1	psi-mi:“MI:0914”(association)	0.350
NXPH3	ACACB	psi-mi:“MI:0914”(association)	0.350
SIRPD	ADAM10	psi-mi:“MI:0914”(association)	0.350
KLK15	APAF1	psi-mi:“MI:0914”(association)	0.350
TAFAZZIN	BCKDK	psi-mi:“MI:0914”(association)	0.350
NAGA	ACSL4	psi-mi:“MI:0914”(association)	0.350
MAD2L1BP	NDUFS6	psi-mi:“MI:0914”(association)	0.350
BOC	ALDH1A2	psi-mi:“MI:0914”(association)	0.350
ENPP7	PDIA4	psi-mi:“MI:0914”(association)	0.350
KLHL22	TRAV18	psi-mi:“MI:0914”(association)	0.350

BioGRID (65): NAGA (Affinity Capture-MS), NAGA (Co-fractionation), NAGA (Affinity Capture-MS), NAGA (Affinity Capture-MS), NAGA (Affinity Capture-MS), EFNB3 (Affinity Capture-MS), TMEM223 (Affinity Capture-MS), MICU2 (Affinity Capture-MS), COL14A1 (Affinity Capture-MS), EPDR1 (Affinity Capture-MS), ACSL4 (Affinity Capture-MS), NXPH4 (Affinity Capture-MS), EPHA4 (Affinity Capture-MS), NAGA (Affinity Capture-MS), NAGA (Affinity Capture-MS)

ESM2 similar proteins: A1C5D3, A1CBW8, A1CCL9, A1CTM5, A1D0A3, A1D9S3, A1DDD8, A2QEJ9, A2QL72, A2R2S6, A4DA70, A7XZT2, B0Y224, B0YEK2, B8MWJ5, B8N306, B8N7Z0, D4AUH6, D4AZY1, P04824, P16278, P17050, P28351, P41945, P41946, P41947, Q03647, Q09187, Q0CPK2, Q0CVH2, Q0CVX4, Q11129, Q2UI87, Q2UJ97, Q2UT06, Q4WE86, Q4WVZ3, Q58DH9, Q5AVQ6, Q5AWB7

Diamond homologs: A1C5D3, A1D0A3, A1D9S3, A1DDD8, A2QEJ9, A2R2S6, A4DA70, A7XZT2, B0Y224, B0YEK2, B3PGJ1, B8N306, B8N7Z0, O94221, P04824, P06280, P14749, P17050, P41945, P41946, P41947, P51569, Q03647, Q09187, Q0CVX4, Q11129, Q2UI87, Q2UJ97, Q42656, Q4WE86, Q4WVZ3, Q55B10, Q58DH9, Q5AVQ6, Q5AX28, Q66H12, Q8RX86, Q8VXZ7, Q90744, Q99172

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	24
Likely pathogenic	14
Uncertain significance	94
Likely benign	163
Benign	26

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
2422706	NC_000022.10:g.(?42461722)(42464598_?)del	Pathogenic
2422707	NC_000022.10:g.(?42456283)(42463314_?)del	Pathogenic
2697112	NM_000262.3(NAGA):c.70C>T (p.Gln24Ter)	Pathogenic
2697961	NM_000262.3(NAGA):c.1029C>A (p.Cys343Ter)	Pathogenic
2716438	NM_000262.3(NAGA):c.354del (p.Tyr119fs)	Pathogenic
2724906	NM_000262.3(NAGA):c.665G>A (p.Trp222Ter)	Pathogenic
2725305	NM_000262.3(NAGA):c.1047T>G (p.Tyr349Ter)	Pathogenic
2731436	NM_000262.3(NAGA):c.324C>A (p.Tyr108Ter)	Pathogenic
2754823	NM_000262.3(NAGA):c.756_757del (p.Met253fs)	Pathogenic
2760723	NM_000262.3(NAGA):c.839del (p.Leu280fs)	Pathogenic
2769604	NM_000262.3(NAGA):c.968_969del (p.Leu323fs)	Pathogenic
2803545	NM_000262.3(NAGA):c.606_607del (p.Tyr202_Ser203delinsTer)	Pathogenic
2829443	NM_000262.3(NAGA):c.666G>A (p.Trp222Ter)	Pathogenic
2838630	NM_000262.3(NAGA):c.793C>T (p.Gln265Ter)	Pathogenic
2850966	NM_000262.3(NAGA):c.639dup (p.Asn214Ter)	Pathogenic
2863502	NM_000262.3(NAGA):c.402_403del (p.Leu135fs)	Pathogenic
2867375	NM_000262.3(NAGA):c.655C>T (p.Gln219Ter)	Pathogenic
2959509	NM_000262.3(NAGA):c.874C>T (p.Gln292Ter)	Pathogenic
2991771	NM_000262.3(NAGA):c.324del (p.Asp107_Tyr108insTer)	Pathogenic
3010084	NM_000262.3(NAGA):c.635G>A (p.Trp212Ter)	Pathogenic
3247580	NC_000022.10:g.(?42456283)(42466301_?)del	Pathogenic
3247591	NC_000022.10:g.(?42456908)(42459048_?)del	Pathogenic
3725146	NM_000262.3(NAGA):c.667del (p.Trp223fs)	Pathogenic
4735205	NM_000262.3(NAGA):c.913del (p.Ile305fs)	Pathogenic
18163	NM_000262.3(NAGA):c.985C>T (p.Arg329Trp)	Likely pathogenic
212736	NM_000262.3(NAGA):c.606C>A (p.Tyr202Ter)	Likely pathogenic
2848506	NM_000262.3(NAGA):c.16+1G>A	Likely pathogenic
2856961	NM_000262.3(NAGA):c.949_957+8del	Likely pathogenic
2903154	NM_000262.3(NAGA):c.322_324+9del	Likely pathogenic
3007394	NM_000262.3(NAGA):c.598-1G>A	Likely pathogenic

SpliceAI

2080 predictions. Top by Δscore:

Variant	Effect	Δscore
22:42060412:GCCT:G	acceptor_loss	1.0000
22:42060413:CCT:C	acceptor_loss	1.0000
22:42060414:CT:C	acceptor_loss	1.0000
22:42062823:GTAC:G	donor_loss	1.0000
22:42062826:C:CT	donor_loss	1.0000
22:42062843:C:A	donor_gain	1.0000
22:42063025:C:CC	acceptor_gain	1.0000
22:42065720:C:A	donor_gain	1.0000
22:42065729:T:TA	donor_gain	1.0000
22:42065752:T:A	donor_gain	1.0000
22:42065784:ATGT:A	donor_gain	1.0000
22:42065787:T:TA	donor_gain	1.0000
22:42066803:CC:C	acceptor_gain	1.0000
22:42066804:CC:C	acceptor_gain	1.0000
22:42067107:A:C	donor_gain	1.0000
22:42067108:CTCA:C	donor_loss	1.0000
22:42067109:TCACC:T	donor_loss	1.0000
22:42067110:CACCC:C	donor_loss	1.0000
22:42067111:A:AC	donor_gain	1.0000
22:42067111:AC:A	donor_gain	1.0000
22:42067112:C:CC	donor_gain	1.0000
22:42067112:CC:C	donor_gain	1.0000
22:42067286:TGAAC:T	acceptor_gain	1.0000
22:42067287:GAAC:G	acceptor_gain	1.0000
22:42067289:AC:A	acceptor_gain	1.0000
22:42067290:CC:C	acceptor_gain	1.0000
22:42067290:CCTGT:C	acceptor_loss	1.0000
22:42067291:C:CC	acceptor_gain	1.0000
22:42067292:T:G	acceptor_loss	1.0000
22:42067293:G:C	acceptor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000116126 (22:42069824 C>T), RS1000132200 (22:42067365 C>A), RS1000273647 (22:42070070 T>C), RS1000791587 (22:42063300 T>C), RS1001635786 (22:42063659 G>A), RS1001652568 (22:42064300 A>G), RS1001681904 (22:42064599 C>G,T), RS1001771180 (22:42070864 G>T), RS1001825192 (22:42070662 G>A), RS1001916936 (22:42058650 G>A), RS1002024382 (22:42063862 T>C), RS1002571373 (22:42069198 T>C), RS1002699415 (22:42063258 G>A), RS1003092449 (22:42060597 C>T), RS1003450532 (22:42072479 C>A)

Disease associations

OMIM: gene MIM:104170 | disease phenotypes: MIM:609241, MIM:609242, MIM:613494, MIM:617468, MIM:208150

GenCC curated gene-disease

Disease	Classification	Inheritance
alpha-N-acetylgalactosaminidase deficiency type 2	Definitive	Autosomal recessive
alpha-N-acetylgalactosaminidase deficiency type 1	Strong	Autosomal recessive
alpha-N-acetylgalactosaminidase deficiency	Strong	Autosomal recessive
alpha-N-acetylgalactosaminidase deficiency type 3	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
alpha-N-acetylgalactosaminidase deficiency	Definitive	AR

Mondo (8): alpha-N-acetylgalactosaminidase deficiency type 1 (MONDO:0012221), alpha-N-acetylgalactosaminidase deficiency type 2 (MONDO:0012222), immunodeficiency, common variable, 4 (MONDO:0013284), intellectual disability (MONDO:0001071), alpha-N-acetylgalactosaminidase deficiency (MONDO:0017779), alpha-N-acetylgalactosaminidase deficiency type 3 (MONDO:0019264), arthrogryposis multiplex congenita (MONDO:0015168), fetal akinesia deformation sequence 1 (MONDO:0100101)

Orphanet (9): Alpha-N-acetylgalactosaminidase deficiency (Orphanet:3137), Alpha-N-acetylgalactosaminidase deficiency type 1 (Orphanet:79279), Alpha-N-acetylgalactosaminidase deficiency type 3 (Orphanet:79281), Alpha-N-acetylgalactosaminidase deficiency type 2 (Orphanet:79280), OBSOLETE: Common variable immunodeficiency (Orphanet:1572), Adult-onset common variable immunodeficiency due to BAFF-receptor deficiency (Orphanet:696925), Arthrogryposis multiplex congenita (Orphanet:1037), Fetal akinesia deformation sequence (Orphanet:994), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

68 total (30 of 68 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000179	Thick lower lip vermilion
HP:0000214	Lip telangiectasia
HP:0000280	Coarse facial features
HP:0000360	Tinnitus
HP:0000365	Hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000486	Strabismus
HP:0000503	Tortuosity of conjunctival vessels
HP:0000518	Cataract
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000717	Autism
HP:0000763	Sensory neuropathy
HP:0000938	Osteopenia
HP:0000958	Dry skin
HP:0000962	Hyperkeratosis
HP:0000967	Petechiae
HP:0001004	Lymphedema
HP:0001009	Telangiectasia
HP:0001071	Angiokeratoma corporis diffusum
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001256	Mild intellectual disability
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001290	Generalized hypotonia
HP:0001324	Muscle weakness
HP:0001336	Myoclonus

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST001585_27	Breast size	5.000000e-07
GCST002539_95	Schizophrenia	2.000000e-09
GCST004364_23	Intelligence	3.000000e-10
GCST004364_5	Intelligence	3.000000e-10
GCST004521_160	Autism spectrum disorder or schizophrenia	3.000000e-08
GCST004521_244	Autism spectrum disorder or schizophrenia	4.000000e-09
GCST006803_13	Schizophrenia	2.000000e-14
GCST010002_83	Refractive error	2.000000e-27

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004337	intelligence

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3132 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, increases expression	3
sodium arsenite	affects methylation, decreases expression, increases abundance	2
Cisplatin	affects cotreatment, increases expression	2
Nickel	decreases expression, increases expression	2
Cyclosporine	decreases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	decreases expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
decabromobiphenyl ether	decreases expression	1
sodium bichromate	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cobaltous chloride	decreases expression	1
butyraldehyde	decreases expression	1
tetrabromobisphenol A	decreases expression	1
ochratoxin A	decreases expression	1
CGP 52608	affects binding, increases reaction	1
bisphenol B	increases expression	1
abrine	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, decreases expression	1
jinfukang	affects cotreatment, increases expression	1
bisphenol AF	increases expression	1
Sunitinib	decreases expression	1
Acetaminophen	increases expression	1
Air Pollutants	decreases expression	1
Air Pollutants, Occupational	decreases expression	1
Arsenic	decreases expression, increases abundance	1
Benzo(a)pyrene	affects methylation	1
Catechin	affects cotreatment, decreases expression	1
Dichlorodiphenyl Dichloroethylene	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
CHEMBL649725	Binding	Inhibition of the enzyme alpha-N-acetylgalactosaminidase from chicken liver was determined at 1 mM concentration of the compound; No inhibition	Dihydroxypyrrolidines C-linked to galactose. Total synthesis of a specific inhibitor of -mannosidases — Bioorg Med Chem Lett

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT01891422	Not specified	COMPLETED	Longitudinal Studies of the Glycoproteinoses
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study
NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD
NCT02591446	Not specified	COMPLETED	Transcranial Magnetic Stimulation Studies in Autism Spectrum Disorders
NCT02714868	Not specified	COMPLETED	Evaluation of Project TEAM (Teens Making Environmental and Activity Modifications)
NCT02721394	Not specified	UNKNOWN	FCT With Young Children With ID in the UK: A Feasibility Project V.1
NCT02746614	Not specified	COMPLETED	Psychomotor Therapy Effects in Adaptive Behavior and Motor Proficiency in Intellectual Disability