NAGA

Chr 22AR

alpha-N-acetylgalactosaminidase

Also known as: D22S674, GALB

NCBI Gene: 4668 ENSG00000198951 UniProt: P17050 OMIM: 104170

The protein removes terminal alpha-N-acetylgalactosamine residues from glycolipids and glycopeptides in lysosomes, functioning as a critical enzyme for glycolipid breakdown. Mutations cause Schindler disease (types I, II, and III) and Kanzaki disease, with type I presenting as severe infantile neuroaxonal dystrophy and type II (Kanzaki disease) manifesting as a milder adult-onset angiokeratoma disorder. These conditions follow autosomal recessive inheritance.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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). [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Kanzaki diseaseMIM #609242

Schindler disease, type IMIM #609241

Schindler disease, type IIIMIM #609241

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · alpha-N-acetylgalactosaminidase deficiency · AR · ClinGen 2022

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

—

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.30

LOEUF

LOF

Mechanism· G2P

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.30LOEUF

pLI 0.000

Z-score 0.51

OE 0.88 (0.61–1.30)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.17Z-score

OE missense 0.97 (0.87–1.08)

237 obs / 244.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.88 (0.61–1.30)

0≤0.351.4

Missense OE?0.97 (0.87–1.08)

0≤0.61.4

Synonymous OE?0.88

0≤1.21.6

LoF obs/exp: 18 / 20.5Missense obs/exp: 237 / 244.5Syn Z: 0.90

Background carrier burden — how many people carry a rare variant somewhere in NAGA?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 94

521 rare PASS variants

Rare truncating (LoF)

1 in 1,800

105 rare PASS variants

Rare synonymous (reference)

1 in 190

189 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for NAGA. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 110	1 in 1,800
South Asian	~43k	1 in 110	1 in 720
Remaining (unassigned)	~30k	1 in 83	1 in 2,000
European (Finnish)	~27k	1 in 210	≈ 1 in 8,800
Admixed American	~22k	1 in 98	1 in 1,300
African / African American	~21k	1 in 95	1 in 3,000
East Asian	~20k	1 in 74	1 in 1,800
Ashkenazi Jewish	~13k	1 in 380	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 81	≈ 1 in 2,900

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.