NAGPA

Chr 16

N-acetylglucosamine-1-phosphodiester alpha-N-acetylglucosaminidase

Also known as: APAA, UCE

NCBI Gene: 51172 ENSG00000103174 UniProt: Q9UK23 OMIM: 607985

This enzyme catalyzes the second step in forming mannose 6-phosphate targeting signals on lysosomal enzymes by removing N-acetylglucosamine residues from specific sugar moieties. Mutations cause developmental stuttering, with inheritance pattern not clearly established from available data. The gene shows minimal constraint against loss-of-function variants (pLI near zero, LOEUF 1.32), suggesting tolerance to reduced gene dosage.

OMIM ResearchSummary from RefSeq, UniProt

Hydrolases are transported to lysosomes after binding to mannose 6-phosphate receptors in the trans-Golgi network. This gene encodes the enzyme that catalyzes the second step in the formation of the mannose 6-phosphate recognition marker on lysosomal hydrolases. Commonly known as 'uncovering enzyme' or UCE, this enzyme removes N-acetyl-D-glucosamine (GlcNAc) residues from GlcNAc-alpha-P-mannose moieties and thereby produces the recognition marker. The encoded preproprotein is proteolytically processed by furin to generate the mature enzyme, a homotetramer of two disulfide-linked homodimers. Mutations in this gene are associated with developmental stuttering in human patients. [provided by RefSeq, Oct 2015]

OMIM ResearchGenerating clinical summary…

LOEUF 1.32

Clinical Summary— NAGPA

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

104 VUS of 161 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.32LOEUF

pLI 0.000

Z-score 0.43

OE 0.90 (0.63–1.32)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-1.37Z-score

OE missense 1.22 (1.12–1.33)

377 obs / 309.3 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.90 (0.63–1.32)

0≤0.351.4

Missense OE?1.22 (1.12–1.33)

0≤0.61.4

Synonymous OE?1.39

0≤1.21.6

LoF obs/exp: 19 / 21.2Missense obs/exp: 377 / 309.3Syn Z: -3.61

ClinVar Variant Classifications

161 submitted variants in ClinVar

ClinVar

Classification Summary

VUS104

Likely Benign19

Benign9

Conflicting1

104

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	0	0	0	0
VUS	1	103	0	0	104
Likely Benign	0	7	1	11	19
Benign	0	3	2	4	9
Conflicting	—				1
Total	1	113	3	15	133

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

27 pathogenic / likely-pathogenic (of 40) ClinVar copy-number / structural variants overlap NAGPA — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →