NAGPA

Chr 16

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

Also known as: APAA, UCE

NCBI Gene: 51172ENSG00000103174UniProt: Q9UK23

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]

170
ClinVar variants
26
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— NAGPA
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
26 Pathogenic / Likely Pathogenic· 114 VUS of 170 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
-1.37Z-score
OE missense 1.22 (1.12–1.33)
377 obs / 309.3 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.90 (0.63–1.32)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.22 (1.12–1.33)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.39
0≤1.21.6
LoF obs/exp: 19 / 21.2Missense obs/exp: 377 / 309.3Syn Z: -3.61

ClinVar Variant Classifications

170 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic26
VUS114
Likely Benign20
Benign9
Conflicting1
26
Pathogenic
114
VUS
20
Likely Benign
9
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
26
0
26
Likely Pathogenic
0
0
0
0
0
VUS
1
102
11
0
114
Likely Benign
0
7
2
11
20
Benign
0
3
2
4
9
Conflicting
—1
Total11124115170

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

View in ClinVar →

Protein Context — Lollipop Plot

NAGPA · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
LYSET/TMEM251- a novel key component of the mannose 6-phosphate pathway.
Qiao W et al.·Autophagy
2023
A role for inherited metabolic deficits in persistent developmental stuttering.
Kang C et al.·Mol Genet Metab
2012Review
Variants in GNPTAB, GNPTG and NAGPA genes are associated with stutterers.
Kazemi N et al.·Gene
2018
Genetic analyses of a large consanguineous south Indian family reveal novel variants in NAGPA and four hitherto unreported genes in developmental stuttering.
Nandhini Devi G et al.·Ann Hum Genet
2025
Mucolipidosis types II and III and non-syndromic stuttering are associated with different variants in the same genes.
Raza MH et al.·Eur J Hum Genet
2016
Identification of a shared genetic risk locus for Kawasaki disease and immunoglobulin A vasculitis by a cross-phenotype meta-analysis.
Carmona EG et al.·Rheumatology (Oxford)
2022
Analysis of mannose 6-phosphate uncovering enzyme mutations associated with persistent stuttering.
Lee WS et al.·J Biol Chem
2011
Association between Rare Variants in AP4E1, a Component of Intracellular Trafficking, and Persistent Stuttering.
Raza MH et al.·Am J Hum Genet
2015
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools