AGA

Chr 4AR

aspartylglucosaminidase

Also known as: AGU, ASRG, GA

NCBI Gene: 175 ENSG00000038002 UniProt: P20933 OMIM: 613228

This gene encodes aspartylglucosaminidase, a lysosomal enzyme that cleaves asparagine from N-acetylglucosamine residues during the breakdown of asparagine-linked glycoproteins. Mutations cause aspartylglucosaminuria, an autosomal recessive lysosomal storage disorder characterized by progressive neurodegeneration. The gene is not highly constrained against loss-of-function variants (pLI ~0), which is consistent with its recessive inheritance pattern where heterozygous carriers are typically unaffected.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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. [provided by RefSeq, Nov 2015]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

AspartylglucosaminuriaMIM #208400

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · aspartylglucosaminuria · 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

1235

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.04

LOEUF

LOF

Mechanism· G2P

📖

GeneReview available — AGA

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.04LOEUF

pLI 0.000

Z-score 1.43

OE 0.63 (0.40–1.04)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.45Z-score

OE missense 1.09 (0.97–1.22)

214 obs / 196.4 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.63 (0.40–1.04)

0≤0.351.4

Missense OE?1.09 (0.97–1.22)

0≤0.61.4

Synonymous OE?0.92

0≤1.21.6

LoF obs/exp: 11 / 17.4Missense obs/exp: 214 / 196.4Syn Z: 0.50

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

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 90

470 rare PASS variants

Rare truncating (LoF)

1 in 1,700

84 rare PASS variants

Rare synonymous (reference)

1 in 220

152 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for AGA. 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 140	1 in 1,800
South Asian	~43k	1 in 100	1 in 600
Remaining (unassigned)	~30k	1 in 82	1 in 5,000
European (Finnish)	~27k	1 in 610	1 in 2,400
Admixed American	~22k	1 in 130	1 in 1,000
African / African American	~21k	1 in 170	1 in 1,400
East Asian	~20k	1 in 190	1 in 2,800
Ashkenazi Jewish	~13k	1 in 260	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 110	none seen

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.

Exome coverage (gnomAD): All 9 coding exons well covered in gnomAD exomes and genomes.? see exons ↓