alpha-N-acetylgalactosaminidase deficiency type 2

Summary

alpha-N-acetylgalactosaminidase deficiency type 2 (MONDO:0012222) is a disease caused by NAGA (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: NAGA (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 71
• Phenotypes (HPO): 18

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)

18 HPO clinical features (Orphanet curated; top 18 by frequency):

HPO ID	Term	Frequency
HP:0000214	Lip telangiectasia	Very frequent (80-99%)
HP:0000962	Hyperkeratosis	Very frequent (80-99%)
HP:0001071	Angiokeratoma corporis diffusum	Very frequent (80-99%)
HP:0001256	Intellectual disability, mild	Very frequent (80-99%)
HP:0001482	Subcutaneous nodule	Very frequent (80-99%)
HP:0002321	Vertigo	Very frequent (80-99%)
HP:0007428	Telangiectasia of the oral mucosa	Very frequent (80-99%)
HP:0100585	Telangiectasia of the skin	Very frequent (80-99%)
HP:0200034	Papule	Very frequent (80-99%)
HP:0000280	Coarse facial features	Frequent (30-79%)
HP:0000360	Tinnitus	Frequent (30-79%)
HP:0000365	Hearing impairment	Frequent (30-79%)
HP:0001004	Lymphedema	Frequent (30-79%)
HP:0001640	Cardiomegaly	Frequent (30-79%)
HP:0005280	Depressed nasal bridge	Frequent (30-79%)
HP:0007759	Opacification of the corneal stroma	Frequent (30-79%)
HP:0009830	Peripheral neuropathy	Frequent (30-79%)
HP:0012471	Thick vermilion border	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	alpha-N-acetylgalactosaminidase deficiency type 2
Mondo ID	MONDO:0012222
OMIM	609242
Orphanet	79280
DOID	DOID:0112319
ICD-11	266505438
SNOMED CT	880065001
UMLS	C1836522
MedGen	324539
GARD	0009161
Is cancer (heuristic)	no

Also known as: adult-onset Alpha-N-acetylgalactosaminidase deficiency · Alpha-N-acetylgalactosaminidase deficiency adult onset · Kanzaki disease · NAGA deficiency type 2 · Schindler disease type 2

Data availability: 71 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 2

Related subtypes (2): alpha-N-acetylgalactosaminidase deficiency type 1, 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

71 retrieved; paginated sample, class counts are floors:

29 uncertain significance, 13 conflicting classifications of pathogenicity, 13 benign, 7 likely pathogenic, 4 likely benign, 3 benign/likely benign, 1 pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
18164	NM_000262.3(NAGA):c.577G>T (p.Glu193Ter)	LOC126863160	Pathogenic	no assertion criteria provided
3004926	NM_000262.3(NAGA):c.157C>T (p.Gln53Ter)	LOC126863160	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
566309	NM_000262.3(NAGA):c.324+1G>A	LOC126863160	Likely pathogenic	criteria provided, multiple submitters, no conflicts
18163	NM_000262.3(NAGA):c.985C>T (p.Arg329Trp)	NAGA	Likely pathogenic	criteria provided, single submitter
212736	NM_000262.3(NAGA):c.606C>A (p.Tyr202Ter)	NAGA	Likely pathogenic	criteria provided, single submitter
3588101	NM_000262.3(NAGA):c.1113dup (p.Tyr372fs)	NAGA	Likely pathogenic	criteria provided, single submitter
3588102	NM_000262.3(NAGA):c.1101+1G>A	NAGA	Likely pathogenic	criteria provided, single submitter
3588103	NM_000262.3(NAGA):c.567G>A (p.Trp189Ter)	NAGA	Likely pathogenic	criteria provided, single submitter
932122	NM_000262.3(NAGA):c.759+1_759+8del	NAGA	Likely pathogenic	criteria provided, multiple submitters, no conflicts
18165	NM_000262.3(NAGA):c.479C>G (p.Ser160Cys)	LOC126863160	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
341912	NM_000262.3(NAGA):c.280G>A (p.Asp94Asn)	LOC126863160	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
782072	NM_000262.3(NAGA):c.482C>T (p.Thr161Ile)	LOC126863160	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
899381	NM_000262.3(NAGA):c.582C>T (p.Gly194=)	LOC126863160	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
18162	NM_000262.3(NAGA):c.973G>A (p.Glu325Lys)	NAGA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
18166	NM_000262.3(NAGA):c.986G>A (p.Arg329Gln)	NAGA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
341905	NM_000262.3(NAGA):c.993G>T (p.Leu331=)	NAGA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
341910	NM_000262.3(NAGA):c.549C>T (p.Ile183=)	NAGA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
341911	NM_000262.3(NAGA):c.406G>A (p.Asp136Asn)	NAGA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
719610	NM_000262.3(NAGA):c.1209C>T (p.Ile403=)	NAGA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
738828	NM_000262.3(NAGA):c.618G>A (p.Ala206=)	NAGA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
899383	NM_000262.3(NAGA):c.486C>G (p.Pro162=)	NAGA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
903167	NM_000262.3(NAGA):c.12G>A (p.Lys4=)	NAGA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
341915	NM_000262.3(NAGA):c.19C>T (p.Leu7Phe)	LOC126863160	Uncertain significance	criteria provided, single submitter
341918	NM_000262.3(NAGA):c.-306C>A	LOC130067582	Uncertain significance	criteria provided, single submitter
1389560	NM_000262.3(NAGA):c.646G>A (p.Asp216Asn)	NAGA	Uncertain significance	criteria provided, multiple submitters, no conflicts
341890	NM_000262.3(NAGA):c.*1501C>G	NAGA	Uncertain significance	criteria provided, single submitter
341892	NM_000262.3(NAGA):c.*1299C>T	NAGA	Uncertain significance	criteria provided, single submitter
341893	NM_000262.3(NAGA):c.*1252T>C	NAGA	Uncertain significance	criteria provided, single submitter
341894	NM_000262.3(NAGA):c.*1090G>A	NAGA	Uncertain significance	criteria provided, single submitter
341896	NM_000262.3(NAGA):c.*926C>G	NAGA	Uncertain significance	criteria provided, single submitter

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.