NGLY1

Chr 3AR

N-glycanase 1

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

NCBI Gene: 55768 ENSG00000151092 UniProt: Q96IV0 OMIM: 610661

The protein specifically deglycosylates misfolded N-linked glycoproteins in the cytoplasm to facilitate their degradation by the proteasome. Mutations cause congenital disorder of deglycosylation 1, an autosomal recessive condition with early onset developmental delay, hypotonia, seizures, and liver dysfunction. The gene is highly intolerant to loss-of-function variants, consistent with the severe phenotype observed in affected individuals.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Congenital disorder of deglycosylation 1MIM #615273

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · congenital disorder of deglycosylation 1 · 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

0.95

LOEUF

LOF

Mechanism· G2P

📖

GeneReview available — NGLY1

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?

0.95LOEUF

pLI 0.000

Z-score 1.80

OE 0.68 (0.50–0.95)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.07Z-score

OE missense 1.01 (0.92–1.11)

336 obs / 332.3 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.68 (0.50–0.95)

0≤0.351.4

Missense OE?1.01 (0.92–1.11)

0≤0.61.4

Synonymous OE?0.96

0≤1.21.6

LoF obs/exp: 26 / 38.0Missense obs/exp: 336 / 332.3Syn Z: 0.38

Background carrier burden — how many people carry a rare variant somewhere in NGLY1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 71

870 rare PASS variants

Rare truncating (LoF)

1 in 620

156 rare PASS variants

Rare synonymous (reference)

1 in 160

298 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for NGLY1. 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 99	1 in 580
South Asian	~43k	1 in 81	1 in 460
Remaining (unassigned)	~30k	1 in 55	1 in 750
European (Finnish)	~27k	1 in 390	1 in 1,000
Admixed American	~22k	1 in 65	1 in 1,100
African / African American	~21k	1 in 87	1 in 1,000
East Asian	~20k	1 in 85	1 in 950
Ashkenazi Jewish	~13k	1 in 190	1 in 950
Middle Eastern	~2,884	1 in 60	≈ 1 in 850

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.