alpha-N-acetylgalactosaminidase deficiency type 1

Summary

alpha-N-acetylgalactosaminidase deficiency type 1 (MONDO:0012221) is a disease caused by NAGA (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: NAGA (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 359
• Phenotypes (HPO): 30

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		10	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

30 HPO clinical features (Orphanet curated; top 30 by frequency):

HPO ID	Term	Frequency
HP:0000365	Hearing impairment	Very frequent (80-99%)
HP:0001250	Seizure	Very frequent (80-99%)
HP:0001252	Hypotonia	Very frequent (80-99%)
HP:0001257	Spasticity	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0001324	Muscle weakness	Very frequent (80-99%)
HP:0002363	Abnormal brainstem morphology	Very frequent (80-99%)
HP:0002376	Developmental regression	Very frequent (80-99%)
HP:0003700	Generalized amyotrophy	Very frequent (80-99%)
HP:0007256	Abnormal pyramidal sign	Very frequent (80-99%)
HP:0010864	Intellectual disability, severe	Very frequent (80-99%)
HP:0100704	Cerebral visual impairment	Very frequent (80-99%)
HP:0000486	Strabismus	Frequent (30-79%)
HP:0000639	Nystagmus	Frequent (30-79%)
HP:0000648	Optic atrophy	Frequent (30-79%)
HP:0000717	Autism	Frequent (30-79%)
HP:0000763	Sensory neuropathy	Frequent (30-79%)
HP:0000962	Hyperkeratosis	Frequent (30-79%)
HP:0001009	Telangiectasia	Frequent (30-79%)
HP:0001336	Myoclonus	Frequent (30-79%)
HP:0002071	Abnormality of extrapyramidal motor function	Frequent (30-79%)
HP:0002321	Vertigo	Frequent (30-79%)
HP:0004374	Hemiplegia/hemiparesis	Frequent (30-79%)
HP:0100585	Telangiectasia of the skin	Frequent (30-79%)
HP:0001004	Lymphedema	Occasional (5-29%)
HP:0001639	Hypertrophic cardiomyopathy	Occasional (5-29%)
HP:0002240	Hepatomegaly	Occasional (5-29%)
HP:0003401	Paresthesia	Occasional (5-29%)
HP:0007360	Aplasia/Hypoplasia of the cerebellum	Occasional (5-29%)
HP:0009830	Peripheral neuropathy	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	alpha-N-acetylgalactosaminidase deficiency type 1
Mondo ID	MONDO:0012221
OMIM	609241
Orphanet	79279
DOID	DOID:0112318
ICD-11	1058486825
SNOMED CT	879937000
UMLS	C1836544
MedGen	373113
GARD	0000116
Is cancer (heuristic)	no

Also known as: alpha-N-acetylgalactosaminidase deficiency, type 1 · N-acetyl-alpha-D-galactosaminidase deficiency type III · NAGA deficiency type 1 · NAGA deficiency, type 1 · neuroaxonal dystrophy, Schindler type · Schindler disease type 1 · Schindler disease type I · Schindler disease, type III

Data availability: 359 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › developmental anomaly of metabolic origin › oligosaccharidosis › alpha-N-acetylgalactosaminidase deficiency › alpha-N-acetylgalactosaminidase deficiency type 1

Related subtypes (2): alpha-N-acetylgalactosaminidase deficiency type 2, alpha-N-acetylgalactosaminidase deficiency type 3

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

359 retrieved; paginated sample, class counts are floors:

211 likely benign, 73 uncertain significance, 26 pathogenic, 15 benign, 15 likely pathogenic, 14 conflicting classifications of pathogenicity, 3 benign/likely benign, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2714494	NM_000262.3(NAGA):c.319_322dup (p.Tyr108Ter)	LOC126863160	Pathogenic	criteria provided, single submitter
3004926	NM_000262.3(NAGA):c.157C>T (p.Gln53Ter)	LOC126863160	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3671348	NM_000262.3(NAGA):c.190C>T (p.Gln64Ter)	LOC126863160	Pathogenic	criteria provided, single submitter
2422706	NC_000022.10:g.(?42461722)(42464598_?)del	NAGA	Pathogenic	criteria provided, single submitter
2422707	NC_000022.10:g.(?42456283)(42463314_?)del	NAGA	Pathogenic	criteria provided, single submitter
2697112	NM_000262.3(NAGA):c.70C>T (p.Gln24Ter)	NAGA	Pathogenic	criteria provided, single submitter
2697961	NM_000262.3(NAGA):c.1029C>A (p.Cys343Ter)	NAGA	Pathogenic	criteria provided, single submitter
2716438	NM_000262.3(NAGA):c.354del (p.Tyr119fs)	NAGA	Pathogenic	criteria provided, single submitter
2724906	NM_000262.3(NAGA):c.665G>A (p.Trp222Ter)	NAGA	Pathogenic	criteria provided, single submitter
2725305	NM_000262.3(NAGA):c.1047T>G (p.Tyr349Ter)	NAGA	Pathogenic	criteria provided, single submitter
2731436	NM_000262.3(NAGA):c.324C>A (p.Tyr108Ter)	NAGA	Pathogenic	criteria provided, single submitter
2754823	NM_000262.3(NAGA):c.756_757del (p.Met253fs)	NAGA	Pathogenic	criteria provided, single submitter
2760723	NM_000262.3(NAGA):c.839del (p.Leu280fs)	NAGA	Pathogenic	criteria provided, single submitter
2769604	NM_000262.3(NAGA):c.968_969del (p.Leu323fs)	NAGA	Pathogenic	criteria provided, single submitter
2803545	NM_000262.3(NAGA):c.606_607del (p.Tyr202_Ser203delinsTer)	NAGA	Pathogenic	criteria provided, single submitter
2829443	NM_000262.3(NAGA):c.666G>A (p.Trp222Ter)	NAGA	Pathogenic	criteria provided, single submitter
2838630	NM_000262.3(NAGA):c.793C>T (p.Gln265Ter)	NAGA	Pathogenic	criteria provided, single submitter
2850966	NM_000262.3(NAGA):c.639dup (p.Asn214Ter)	NAGA	Pathogenic	criteria provided, single submitter
2863502	NM_000262.3(NAGA):c.402_403del (p.Leu135fs)	NAGA	Pathogenic	criteria provided, single submitter
2867375	NM_000262.3(NAGA):c.655C>T (p.Gln219Ter)	NAGA	Pathogenic	criteria provided, single submitter
2959509	NM_000262.3(NAGA):c.874C>T (p.Gln292Ter)	NAGA	Pathogenic	criteria provided, multiple submitters, no conflicts
2991771	NM_000262.3(NAGA):c.324del (p.Asp107_Tyr108insTer)	NAGA	Pathogenic	criteria provided, single submitter
3010084	NM_000262.3(NAGA):c.635G>A (p.Trp212Ter)	NAGA	Pathogenic	criteria provided, single submitter
3247580	NC_000022.10:g.(?42456283)(42466301_?)del	NAGA	Pathogenic	criteria provided, single submitter
3247591	NC_000022.10:g.(?42456908)(42459048_?)del	NAGA	Pathogenic	criteria provided, single submitter
3725146	NM_000262.3(NAGA):c.667del (p.Trp223fs)	NAGA	Pathogenic	criteria provided, single submitter
4735205	NM_000262.3(NAGA):c.913del (p.Ile305fs)	NAGA	Pathogenic	criteria provided, single submitter
947187	NM_000262.3(NAGA):c.443G>A (p.Trp148Ter)	NAGA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2839129	NM_000262.3(NAGA):c.324+1G>C	LOC126863160	Likely pathogenic	criteria provided, single submitter
566309	NM_000262.3(NAGA):c.324+1G>A	LOC126863160	Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 3 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
NAGA	Definitive	Autosomal recessive	alpha-N-acetylgalactosaminidase deficiency type 2	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NAGA	Orphanet:79279	Alpha-N-acetylgalactosaminidase deficiency type 1
NAGA	Orphanet:79280	Alpha-N-acetylgalactosaminidase deficiency type 2
NAGA	Orphanet:79281	Alpha-N-acetylgalactosaminidase deficiency type 3

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NAGA	HGNC:7631	ENSG00000198951	P17050	Alpha-N-acetylgalactosaminidase	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NAGA	Alpha-N-acetylgalactosaminidase	Removes terminal alpha-N-acetylgalactosamine residues from glycolipids and glycopeptides.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NAGA	Enzyme (other)	yes	3.2.1.49	Glyco_hydro_27/36_CS, Glyco_hydro_27, Glyco_hydro_b

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
leukocyte	1
monocyte	1
mononuclear cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NAGA	252	ubiquitous	marker	monocyte, mononuclear cell, leukocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NAGA	1,327

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NAGA	P17050	7

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
glycolipid catabolic process	1	8426.0×	5e-04	NAGA
carbohydrate catabolic process	1	3370.4×	5e-04	NAGA
glycoside catabolic process	1	2808.7×	5e-04	NAGA
oligosaccharide metabolic process	1	702.2×	0.001	NAGA

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NAGA	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
NAGA	4	Binding:4

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
NAGA	3.2.1.49	alpha-N-acetylgalactosaminidase

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	NAGA
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
NAGA	4	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.