NGLY1

Chr 3AR

N-glycanase 1

Also known as: CDDG, CDG1V, PNG-1, PNG1, PNGase

NCBI Gene: 55768ENSG00000151092UniProt: Q96IV0

This gene encodes an enzyme that catalyzes hydrolysis of an N(4)-(acetyl-beta-D-glucosaminyl) asparagine residue to N-acetyl-beta-D-glucosaminylamine and a peptide containing an aspartate residue. The encoded enzyme may play a role in the proteasome-mediated degradation of misfolded glycoproteins. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Feb 2009]

Primary Disease Associations & Inheritance

Congenital disorder of deglycosylation 1MIM #615273
AR
958
ClinVar variants
66
Pathogenic / LP
0.00
pLI score
1
Active trials
Clinical Summary— NGLY1
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
66 Pathogenic / Likely Pathogenic· 162 VUS of 958 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

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.
0.95LOEUF
pLI 0.000
Z-score 1.80
OE 0.68 (0.50–0.95)
Tolerant

Typical tolerance to LoF variation

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.
-0.07Z-score
OE missense 1.01 (0.92–1.11)
336 obs / 332.3 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.0.68 (0.50–0.95)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.01 (0.92–1.11)
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.0.96
0≤1.21.6
LoF obs/exp: 26 / 38.0Missense obs/exp: 336 / 332.3Syn Z: 0.38

ClinVar Variant Classifications

958 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic47
Likely Pathogenic19
VUS162
Likely Benign234
Benign21
Conflicting4
47
Pathogenic
19
Likely Pathogenic
162
VUS
234
Likely Benign
21
Benign
4
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
22
1
24
0
47
Likely Pathogenic
12
2
5
0
19
VUS
3
144
13
2
162
Likely Benign
0
3
97
134
234
Benign
0
0
21
0
21
Conflicting
—4
Total37150160136487

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

View in ClinVar →

Protein Context — Lollipop Plot

NGLY1 · protein map & ClinVar variants

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

Gene2Phenotype Curations

NGLY1-related congenital disorder of deglycosylation

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. DisordersEye
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
N-GLYCANASE 1; NGLY1
MIM #610661 · *

Congenital disorder of deglycosylation 1

MIM #615273

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Impaired catabolism of free oligosaccharides due to MAN2C1 variants causes a neurodevelopmental disorder.
Maia N et al.·Am J Hum Genet
2022Case report
AP3B1 facilitates PDIA3/ERP57 function to regulate rabies virus glycoprotein selective degradation and viral entry.
Zhang Y et al.·Autophagy
2024
NGLY1 deficiency: Novel variants and literature review.
Kariminejad A et al.·Eur J Med Genet
2021Review
NGLY1 deficiency: estimated incidence, clinical features, and genotypic spectrum from the NGLY1 Registry.
Stanclift CR et al.·Orphanet J Rare Dis
2022
Mitochondrial function requires NGLY1.
Kong J et al.·Mitochondrion
2018
Comparative proteomics reveals elevated CCN2 in NGLY1-deficient cells.
Hetz R et al.·Biochem Biophys Res Commun
2022
NGLY1 deficiency: a prospective natural history study.
Tong S et al.·Hum Mol Genet
2023Natural history
Delineating the epilepsy phenotype of NGLY1 deficiency.
Levy RJ et al.·J Inherit Metab Dis
2022
Structural and Functional Characterization of N-Glycanase-1 Pathogenic Variants.
Banning A et al.·Cells
2025Functional
Novel NGLY1 gene variants in Chinese children with global developmental delay, microcephaly, hypotonia, hypertransaminasemia, alacrimia, and feeding difficulty.
Abuduxikuer K et al.·J Hum Genet
2020Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Erratum: [Erratum] Tofacitinib Improves Motor Symptoms in Parkinsonism Associated with a Heterozygous NGLY1 Variant and Autoimmune Disease.
Reina-Llompart N et al.·Eur J Case Rep Intern Med
2025🔓 Open Access
Structural characterization and insights into the formation of N-acetylglucosaminylasparagine and its derivatives in NGLY1-deficient models and patients.
Hirayama H et al.·Glycobiology
2025Cohort
Tofacitinib Improves Motor Symptoms in Parkinsonism Associated with a Heterozygous NGLY1 Variant and Autoimmune Disease.
Reina-Llompart N et al.·Eur J Case Rep Intern Med
2025🔓 Open Access
AAV9-mediated NGLY1 gene replacement suppresses non-epileptic convulsions in Ngly1-/- rats.
Asahina M et al.·Biochem Biophys Res Commun
2025
NGLY1 as an Emerging Critical Modulator for Neurodevelopment and Pathogenesis in the Brain.
Zhang H et al.·Int J Mol Sci
2025🔓 Open Access
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
NGLY1 Deficiency

Safety and Efficacy of GS-100 Gene Therapy in Patients With NGLY1 Deficiency

RECRUITING
NCT06199531Phase PHASE1, PHASE2Grace Science, LLCStarted 2024-02-13
GS-100

External Resources

Links to major genomics databases and tools