NGLY1

Summary

NGLY1 (N-glycanase 1, HGNC:17646) is a protein-coding gene on chromosome 3p24.2, encoding Peptide-N(4)-(N-acetyl-beta-glucosaminyl)asparagine amidase (Q96IV0). Specifically deglycosylates the denatured form of N-linked glycoproteins in the cytoplasm and assists their proteasome-mediated degradation. It is a selective cancer dependency (DepMap: 11.0% of cell lines).

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.

Source: NCBI Gene 55768 — RefSeq curated summary.

At a glance

• Gene–disease (curated): congenital disorder of deglycosylation 1 (Definitive, ClinGen) — +1 more curated relationship
• Clinical variants (ClinVar): 936 total — 88 pathogenic, 32 likely-pathogenic
• Phenotypes (HPO): 148
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 11.0% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_018297

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17646
Approved symbol	NGLY1
Name	N-glycanase 1
Location	3p24.2
Locus type	gene with protein product
Status	Approved
Aliases	FLJ11005, PNG1, PNG-1
Ensembl gene	ENSG00000151092
Ensembl biotype	protein_coding
OMIM	610661
Entrez	55768

Gene structure

Transcript identifiers

Ensembl transcripts: 39 — 26 protein_coding, 5 protein_coding_CDS_not_defined, 4 nonsense_mediated_decay, 4 retained_intron

ENST00000280699, ENST00000280700, ENST00000308710, ENST00000396649, ENST00000417874, ENST00000427041, ENST00000428257, ENST00000461491, ENST00000463611, ENST00000467224, ENST00000474611, ENST00000478991, ENST00000489271, ENST00000493324, ENST00000496726, ENST00000674841, ENST00000675178, ENST00000675217, ENST00000675234, ENST00000675680, ENST00000676225, ENST00000877202, ENST00000877203, ENST00000877204, ENST00000877205, ENST00000877206, ENST00000877207, ENST00000929484, ENST00000929485, ENST00000929486, ENST00000929487, ENST00000942729, ENST00000942730, ENST00000942731, ENST00000942732, ENST00000942733, ENST00000942734, ENST00000942735, ENST00000942736

RefSeq mRNA: 4 — MANE Select: NM_018297 NM_001145293, NM_001145294, NM_001145295, NM_018297

CCDS: CCDS33719, CCDS46777, CCDS46778, CCDS46779

Canonical transcript exons

ENST00000280700 — 12 exons

Exon	Start	End
ENSE00001874898	25783260	25783443
ENSE00001880312	25718944	25719635
ENSE00003468734	25778574	25778688
ENSE00003470446	25732319	25732483
ENSE00003479047	25736004	25736149
ENSE00003486730	25733872	25733982
ENSE00003489534	25751098	25751263
ENSE00003499908	25739577	25739799
ENSE00003570332	25720014	25720191
ENSE00003589640	25764066	25764311
ENSE00003625006	25737334	25737455
ENSE00003653007	25729133	25729318

Expression profiles

Bgee: expression breadth ubiquitous, 290 present calls, max score 97.87.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 23.4787 / max 237.3726, expressed in 1810 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
41507	14.9245	1799
41508	8.5179	1738
41506	0.0363	14

Top tissues by expression

292 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
sperm	CL:0000019	97.87	gold quality
male germ cell	CL:0000015	96.34	gold quality
right testis	UBERON:0004534	95.53	gold quality
left testis	UBERON:0004533	95.51	gold quality
secondary oocyte	CL:0000655	95.14	gold quality
bone marrow cell	CL:0002092	94.93	gold quality
testis	UBERON:0000473	94.92	gold quality
cartilage tissue	UBERON:0002418	94.84	gold quality
biceps brachii	UBERON:0001507	94.77	gold quality
tendon of biceps brachii	UBERON:0008188	94.68	gold quality
bone marrow	UBERON:0002371	94.35	gold quality
bone element	UBERON:0001474	94.16	gold quality
gastrocnemius	UBERON:0001388	94.15	gold quality
gluteal muscle	UBERON:0002000	94.10	gold quality
tibia	UBERON:0000979	94.08	gold quality
deltoid	UBERON:0001476	94.04	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	93.88	gold quality
muscle of leg	UBERON:0001383	93.79	gold quality
trabecular bone tissue	UBERON:0002483	93.60	gold quality
muscle organ	UBERON:0001630	93.53	gold quality
skeletal muscle organ	UBERON:0014892	93.53	gold quality
vastus lateralis	UBERON:0001379	93.11	gold quality
skeletal muscle tissue	UBERON:0001134	93.03	gold quality
esophagus squamous epithelium	UBERON:0006920	93.03	gold quality
hindlimb stylopod muscle	UBERON:0004252	92.82	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	92.79	gold quality
granulocyte	CL:0000094	92.75	gold quality
triceps brachii	UBERON:0001509	92.66	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	92.62	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	92.38	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	15.44
E-MTAB-6678	yes	4.41

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

42 targeting NGLY1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3134	100.00	66.43	777
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-374B-5P	99.90	69.98	2734
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-4760-5P	99.80	69.88	1619
HSA-MIR-548AJ-5P	99.78	71.12	3085
HSA-MIR-548F-5P	99.78	71.02	3093
HSA-MIR-548G-5P	99.78	71.12	3085
HSA-MIR-548X-5P	99.78	71.12	3085
HSA-MIR-7154-5P	99.69	70.52	1900
HSA-MIR-8061	99.63	69.44	1411
HSA-MIR-4328	99.57	71.06	4094
HSA-MIR-154-3P	99.50	70.05	831
HSA-MIR-487A-3P	99.50	69.95	840
HSA-MIR-582-5P	99.47	70.79	2635
HSA-MIR-889-5P	99.41	68.75	1025
HSA-MIR-3140-5P	99.39	69.04	1136
HSA-MIR-2115-3P	99.31	69.68	2026
HSA-MIR-16-2-3P	99.29	70.60	1954
HSA-MIR-195-3P	99.29	70.61	1954
HSA-MIR-329-5P	99.27	68.11	1597

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 11.0% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 27)

• Describes the function of Yeast PNG1 and identifies similar proteins in mouse, human, D. melanogaster, C. elegans, and S. pombe. (PMID:10831608)
• the PUB domain functions as a p97 binding module in human peptide N-glycanase (PMID:16807242)
• generation of an HLA-A*0201-associated epitope from tyrosinase with deamidation of Asn to Asp is dependent on glycosylation in the endoplasmic reticulum (ER), and subsequent deglycosylation by peptide-N-glycanase in the cytosol (PMID:17015730)
• As the generation of the bulk of fOS is unaffected by co-down regulation of Ngly1p and Engase1p, alternative quantitatively important mechanisms must underlie the liberation of these fOS from either LLO or glycoproteins during protein N-glycosylation. (PMID:20668520)
• PNGase-PUB serves not only as p97-binding module but also as a possible activator of HR23 in endoplasmic reticulum-associated degradation mechanisms. (PMID:22575648)
• Data indicate that N-glycanase 1 (NGLY1) deficiency is a novel autosomal recessive disorder of the endoplasmic reticulum-associated degradation pathway associated with neurological dysfunction, abnormal tear production, and liver disease. (PMID:24651605)
• NGLY1 mutation causes neuromotor impairment, intellectual disability, and neuropathy (PMID:25220016)
• This review summarizes the research history of cytoplasmic PNGase. (PMID:25398991)
• The patients with NGLY1 deficiency show developmental delay, seizures, peripheral neuropathy, abnormal liver function and alacrima. (PMID:25900930)
• Our prospective phenotyping expands the clinical spectrum of NGLY1-CDDG, offers prognostic information, and provides baseline data for evaluating therapeutic interventions (PMID:27388694)
• Across these distinct evolutionary models of cytosolic NGLY1 deficiency, a consistent disruption of mitochondrial physiology was present involving modestly reduced mitochondrial content with more pronounced impairment of mitochondrial membrane potential, increased mitochondrial matrix oxidant burden, and reduced cellular respiratory capacity. (PMID:28750948)
• N-Glycanase 1 Transcriptionally Regulates Aquaporins Independent of Its Enzymatic Activity. (PMID:31875565)
• Variants in NGLY1 lead to intellectual disability, myoclonus epilepsy, sensorimotor axonal polyneuropathy and mitochondrial dysfunction. (PMID:31957011)
• Novel NGLY1 gene variants in Chinese children with global developmental delay, microcephaly, hypotonia, hypertransaminasemia, alacrimia, and feeding difficulty. (PMID:31965062)
• Loss of N-Glycanase 1 Alters Transcriptional and Translational Regulation in K562 Cell Lines. (PMID:32265286)
• Congenital disorder of deglycosylation associated with N-glycanse 1 deficiency", trans “Wrodzone zaburzenie deglikozylacji zwiazane z deficytem N-glikanazy 1. (PMID:33320481)
• NGLY1 deficiency: Novel variants and literature review. (PMID:33497766)
• Ever-expanding NGLY1 biology. (PMID:34969094)
• Ferroptosis regulation by the NGLY1/NFE2L1 pathway. (PMID:35271393)
• Deficiency of N-glycanase 1 perturbs neurogenesis and cerebral development modeled by human organoids. (PMID:35322011)
• Comprehensive Analysis of the Structure and Function of Peptide:N-Glycanase 1 and Relationship with Congenital Disorder of Deglycosylation. (PMID:35565658)
• N-glycoproteomics reveals distinct glycosylation alterations in NGLY1-deficient patient-derived dermal fibroblasts. (PMID:36102038)
• Comparative proteomics reveals elevated CCN2 in NGLY1-deficient cells. (PMID:36209585)
• NGLY1 deficiency: estimated incidence, clinical features, and genotypic spectrum from the NGLY1 Registry. (PMID:36528660)
• NGLY1 mutations cause protein aggregation in human neurons. (PMID:38039131)
• Ocular features of NGLY1 deficiency from a prospective longitudinal cohort. (PMID:38697387)
• Structural basis of sugar recognition by SCF[FBS2] ubiquitin ligase involved in NGLY1 deficiency. (PMID:39171510)

Cross-species orthologs

17 orthologs

Organism	Symbol	Gene ID
danio_rerio	ngly1	ENSDARG00000003205
mus_musculus	Ngly1	ENSMUSG00000021785
rattus_norvegicus	Ngly1	ENSRNOG00000006143
drosophila_melanogaster	Pngl	FBGN0033050
caenorhabditis_elegans	C17D12.3	WBGENE00007638
caenorhabditis_elegans	png-1	WBGENE00010160
caenorhabditis_elegans	W04G5.4	WBGENE00012265
caenorhabditis_elegans	W04G5.5	WBGENE00012266
caenorhabditis_elegans	W04G5.9	WBGENE00012269
caenorhabditis_elegans	C17D12.3	WBGENE00012945
caenorhabditis_elegans		WBGENE00015434
caenorhabditis_elegans		WBGENE00015435
caenorhabditis_elegans		WBGENE00015879
caenorhabditis_elegans		WBGENE00018052
caenorhabditis_elegans		WBGENE00020609
caenorhabditis_elegans		WBGENE00020611
caenorhabditis_elegans		WBGENE00021743

Protein

Protein identifiers

Peptide-N(4)-(N-acetyl-beta-glucosaminyl)asparagine amidase — Q96IV0 (reviewed: Q96IV0)

Alternative names: N-glycanase 1, Peptide:N-glycanase

All UniProt accessions (9): Q96IV0, A0A0C4DFP4, A0A6Q8PF23, A0A6Q8PFQ1, A0A6Q8PGC8, A0A6Q8PHH7, A0A6Q8PHJ3, C9JU75, H0Y2P2

UniProt curated annotations — full annotation on UniProt →

Function. Specifically deglycosylates the denatured form of N-linked glycoproteins in the cytoplasm and assists their proteasome-mediated degradation. Cleaves the beta-aspartyl-glucosamine (GlcNAc) of the glycan and the amide side chain of Asn, converting Asn to Asp. Prefers proteins containing high-mannose over those bearing complex type oligosaccharides. Can recognize misfolded proteins in the endoplasmic reticulum that are exported to the cytosol to be destroyed and deglycosylate them, while it has no activity toward native proteins. Deglycosylation is a prerequisite for subsequent proteasome-mediated degradation of some, but not all, misfolded glycoproteins.

Subunit / interactions. Component of a complex required to couple retrotranslocation, ubiquitination and deglycosylation composed of NGLY1, SAKS1, AMFR, VCP and RAD23B. Interacts with the proteasome components RAD23B and PSMC1. Interacts with directly with VCP. Interacts with DERL1, bringing it close to the endoplasmic reticulum membrane. Interacts with SAKS1.

Subcellular location. Cytoplasm.

Disease relevance. Congenital disorder of deglycosylation 1 (CDDG1) [MIM:615273] An autosomal recessive multisystem disorder characterized by developmental delay, hypotonia, abnormal involuntary movements and alacrima or poor tear production. Other features include microcephaly, intractable seizures, abnormal eye movements and evidence of liver dysfunction, probably due to cytoplasmic accumulation of storage material in vacuoles. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Inhibited by Z-VAD-fmk, a well-known caspase inhibitor, which inhibits enzyme activity through covalent binding of the carbohydrate to the single Cys-306 residue.

Cofactor. Binds 1 zinc ion per subunit.

Domain organisation. The PUB domain mediates the interaction with VCP.

Miscellaneous. In case of infection by cytomegaloviruses, it is not essential for degradation of MHC class I heavy chains.

Similarity. Belongs to the transglutaminase-like superfamily. PNGase family.

Isoforms (5)

UniProt ID	Names	Canonical?
Q96IV0-1	1	yes
Q96IV0-2	2
Q96IV0-3	3
Q96IV0-4	4
Q96IV0-5	5

RefSeq proteins (4): NP_001138765, NP_001138766, NP_001138767, NP_060767* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002931	Transglutaminase-like	Domain
IPR006588	Peptide_N_glycanase_PAW_dom	Domain
IPR008979	Galactose-bd-like_sf	Homologous_superfamily
IPR018997	PUB_domain	Domain
IPR036339	PUB-like_dom_sf	Homologous_superfamily
IPR038680	PAW_sf	Homologous_superfamily
IPR038765	Papain-like_cys_pep_sf	Homologous_superfamily
IPR050883	PNGase	Family

Pfam: PF01841, PF04721, PF09409

Enzyme classification (BRENDA):

• EC 3.5.1.52 — peptide-N4-(N-acetyl-beta-glucosaminyl)asparagine amidase (BRENDA: 26 organisms, 155 substrates, 72 inhibitors, 9 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

6 substrates with measured Km, best-characterized 6. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
FETUIN GLYCOPEPTIDE	0.114–1.46	3
BROMELAIN UNDECAPEPTIDE	2–2.3	2
ASIALO FETUIN GLYCOPEPTIDE I	0.2	1
ASIOLO-OVOMUCOID GLYCOPEPTIDE	0.871	1
BETA-ASPARTYLGLYCOSYLAMINE	1	1
BROMELAIN GLYCOPEPTIDE	4	1

UniProt features (31 total): helix 6, splice variant 5, binding site 4, active site 3, modified residue 2, domain 2, sequence variant 2, strand 2, initiator methionine 1, chain 1, turn 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
2CCQ	X-RAY DIFFRACTION	1.6
2CM0	X-RAY DIFFRACTION	1.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96IV0-F1	86.57	0.70

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (3): 309 (nucleophile); 336; 353

Ligand- & substrate-binding residues (4): 253; 283; 286; 250

Post-translational modifications (2): 2, 137

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-532668	N-glycan trimming in the ER and Calnexin/Calreticulin cycle

MSigDB gene sets: 458 (showing top): GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_CATABOLIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_BMP_SIGNALING_PATHWAY, GOBP_PROTEIN_MATURATION, GOBP_REGULATION_OF_TRANSMEMBRANE_RECEPTOR_PROTEIN_SERINE_THREONINE_KINASE_SIGNALING_PATHWAY, INGRAM_SHH_TARGETS_UP, GOBP_PROTEIN_FOLDING, GOBP_RESPONSE_TO_BMP, DOUGLAS_BMI1_TARGETS_DN, GOBP_RESPONSE_TO_GROWTH_FACTOR, LASTOWSKA_NEUROBLASTOMA_COPY_NUMBER_DN, GOBP_REGULATION_OF_BMP_SIGNALING_PATHWAY, WANG_RESPONSE_TO_FORSKOLIN_UP

GO Biological Process (3): protein folding (GO:0006457), glycoprotein catabolic process (GO:0006516), positive regulation of BMP signaling pathway (GO:0030513)

GO Molecular Function (4): peptide-N4-(N-acetyl-beta-glucosaminyl)asparagine amidase activity (GO:0000224), metal ion binding (GO:0046872), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (3): nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Asparagine N-linked glycosylation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
cellular process	1
protein maturation	1
glycoprotein metabolic process	1
protein catabolic process	1
carbohydrate derivative catabolic process	1
BMP signaling pathway	1
regulation of BMP signaling pathway	1
positive regulation of transmembrane receptor protein serine/threonine kinase signaling pathway	1
hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds, in linear amides	1
cation binding	1
binding	1
catalytic activity	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cytoplasm	1

Protein interactions and networks

STRING

1164 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NGLY1	OTULIN	Q96BN8	810
NGLY1	ENGASE	Q8NFI3	788
NGLY1	VCP	P55072	751
NGLY1	DDI2	Q5TDH0	722
NGLY1	NFE2L1	Q14494	664
NGLY1	NPLOC4	Q8TAT6	655
NGLY1	AMFR	P26442	633
NGLY1	DDI1	Q8WTU0	595
NGLY1	MAN2C1	Q9NTJ4	591
NGLY1	UBE4A	Q14139	571
NGLY1	XPC	Q01831	559
NGLY1	RAD23B	P54727	540
NGLY1	UFD1	Q92890	536
NGLY1	UBE4B	O95155	533
NGLY1	UBA2	Q9UBT2	514

IntAct

162 interactions, top by confidence:

A	B	Type	Score
RAD23B	NGLY1	psi-mi:“MI:0915”(physical association)	0.940
NGLY1	RAD23B	psi-mi:“MI:0915”(physical association)	0.940
NGLY1	RAD23B	psi-mi:“MI:0914”(association)	0.940
NGLY1	RAD23A	psi-mi:“MI:0915”(physical association)	0.830
RAD23A	NGLY1	psi-mi:“MI:0915”(physical association)	0.830
NGLY1	UBXN2B	psi-mi:“MI:0915”(physical association)	0.780
NGLY1	TRAFD1	psi-mi:“MI:0915”(physical association)	0.780
TRIM54	NGLY1	psi-mi:“MI:0915”(physical association)	0.780
NGLY1	UBQLN1	psi-mi:“MI:0915”(physical association)	0.780
UBXN2B	NGLY1	psi-mi:“MI:0915”(physical association)	0.780
UBQLN1	NGLY1	psi-mi:“MI:0915”(physical association)	0.780
TRAFD1	NGLY1	psi-mi:“MI:0915”(physical association)	0.780
NGLY1	TRIM54	psi-mi:“MI:0915”(physical association)	0.780

BioGRID (116): NGLY1 (Two-hybrid), NGLY1 (Two-hybrid), NGLY1 (Two-hybrid), NGLY1 (Two-hybrid), TRIM54 (Two-hybrid), GUCD1 (Two-hybrid), UBXN2B (Two-hybrid), NGLY1 (Affinity Capture-MS), RAD23B (Affinity Capture-MS), VCP (Affinity Capture-MS), NGLY1 (Reconstituted Complex), NGLY1 (Affinity Capture-MS), NGLY1 (Affinity Capture-MS), RAD23B (Co-fractionation), NGLY1 (Affinity Capture-MS)

ESM2 similar proteins: A0A0R4IB93, A0JMU5, A1A4L5, A2PYH4, A2RUV5, B3M1E1, B3P4N5, B4GZ20, B4HJC0, B4KA23, B4LVS8, B4NKI9, B4PVH6, B4QVW6, B6DMK2, D3Z4R1, O75417, O93530, O94830, Q07G10, Q0P5B2, Q15326, Q28ES8, Q29B63, Q4KLT3, Q4R6F3, Q5M8E6, Q5ZIJ9, Q5ZJM3, Q6GQ76, Q6NRS1, Q6NTR1, Q6P1Q9, Q6ZPR6, Q7ZU90, Q80Y20, Q84MA1, Q8BMK1, Q8BYH3, Q8MNT9

Diamond homologs: O74739, Q02890, Q28YQ7, Q2UPS5, Q4IR87, Q4R6F3, Q4WHW1, Q503I8, Q59Q38, Q5B6P3, Q5WNE3, Q5XI55, Q5ZJM3, Q6BNI6, Q6CAX5, Q6CLZ6, Q6FRU8, Q75D29, Q7F0R1, Q7KRR5, Q7SI01, Q8J2R3, Q96IV0, Q9FGY9, Q9JI78, Q9TW67, Q9ZU93, Q8WTJ4, A2YIW7, C9K7C5, G4NFB7, O14463, O17486, O22022, O64394, O64432, O65049, O84544, O94504, O96952

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
VCP	“up-regulates activity”	NGLY1	binding
UBXN1	“up-regulates activity”	NGLY1	binding
NGLY1	“up-regulates activity”	RAD23B	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 121 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Neutrophil degranulation	12	3.6×	7e-03

GO biological processes:

GO term	Partners	Fold	FDR
ERAD pathway	9	14.7×	8e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

936 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	88
Likely pathogenic	32
Uncertain significance	333
Likely benign	388
Benign	37

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1069924	NM_018297.4(NGLY1):c.1449del (p.Cys484fs)	Pathogenic
1070987	NM_018297.4(NGLY1):c.1771C>T (p.Gln591Ter)	Pathogenic
1070999	NM_018297.4(NGLY1):c.999C>A (p.Tyr333Ter)	Pathogenic
1071020	NC_000003.11:g.(?25760931)(25831376_?)del	Pathogenic
1073150	NM_018297.4(NGLY1):c.1748G>A (p.Trp583Ter)	Pathogenic
1076851	NM_018297.4(NGLY1):c.1515del (p.Arg506fs)	Pathogenic
1184978	NM_018297.4(NGLY1):c.571C>T (p.Gln191Ter)	Pathogenic
126422	NM_018297.4(NGLY1):c.1370dup (p.Arg458fs)	Pathogenic
126423	NM_018297.4(NGLY1):c.1202GAA[1] (p.Arg402del)	Pathogenic
126424	NM_018297.4(NGLY1):c.1624C>T (p.Arg542Ter)	Pathogenic
1375055	NM_018297.4(NGLY1):c.1551G>A (p.Trp517Ter)	Pathogenic
1392868	NM_018297.4(NGLY1):c.997dup (p.Tyr333fs)	Pathogenic
1396095	NM_018297.4(NGLY1):c.-18GCCCGCTGGCGCTCAAGCATGGCGGCGGCGGC[3] (p.Leu6fs)	Pathogenic
1415810	NM_018297.4(NGLY1):c.1431_1435del (p.Lys477fs)	Pathogenic
1431487	NM_018297.4(NGLY1):c.948_949insTTTTTTTTTTTTTTTTTTTTNNNNNNNNNNGACCTCGTGATCCGCCCGCCTCGGCCTCCCAAAGTGCTGGGATTACAGGCGTGAGCCACCGCGCCCGGCCGGGCCAATTGTTTT (p.Thr317delinsPhePhePhePhePhePheXaaXaaXaaXaaAspLeuValIleArgProProArgProProLysValLeuGlyLeuGlnAlaTer)	Pathogenic
1454942	NM_018297.4(NGLY1):c.1474C>T (p.Gln492Ter)	Pathogenic
1456986	NM_018297.4(NGLY1):c.1168C>T (p.Arg390Ter)	Pathogenic
1458545	NM_018297.4(NGLY1):c.904_905del (p.Leu302fs)	Pathogenic
1700109	NM_018297.4(NGLY1):c.710T>C (p.Phe237Ser)	Pathogenic
1703511	NM_018297.4(NGLY1):c.781dup (p.Asp261fs)	Pathogenic
1955467	NM_018297.4(NGLY1):c.14_15insGCCCGCTGGCGCTCAAGCATGGCGGCGGCGGCGGC (p.Leu6fs)	Pathogenic
2015044	NM_018297.4(NGLY1):c.1882del (p.Gln628fs)	Pathogenic
2067984	NM_018297.4(NGLY1):c.1736del (p.Gly579fs)	Pathogenic
2132011	NM_018297.4(NGLY1):c.236del (p.Gly79fs)	Pathogenic
221577	NM_018297.4(NGLY1):c.1604G>A (p.Trp535Ter)	Pathogenic
221579	NM_018297.4(NGLY1):c.347C>G (p.Ser116Ter)	Pathogenic
221581	NM_018297.4(NGLY1):c.730T>C (p.Trp244Arg)	Pathogenic
221584	NM_018297.4(NGLY1):c.881+5G>T	Pathogenic
2287190	NM_018297.4(NGLY1):c.1756C>T (p.Arg586Ter)	Pathogenic
2506033	NM_018297.4(NGLY1):c.376C>T (p.Gln126Ter)	Pathogenic

SpliceAI

2903 predictions. Top by Δscore:

Variant	Effect	Δscore
3:25719636:C:CC	acceptor_gain	1.0000
3:25733866:CCATA:C	donor_loss	1.0000
3:25733867:CATA:C	donor_loss	1.0000
3:25733868:ATAC:A	donor_loss	1.0000
3:25733869:TAC:T	donor_loss	1.0000
3:25733870:A:C	donor_loss	1.0000
3:25733871:CCTG:C	donor_gain	1.0000
3:25733915:TTA:T	donor_gain	1.0000
3:25733979:CTAC:C	acceptor_gain	1.0000
3:25733980:TAC:T	acceptor_gain	1.0000
3:25733981:AC:A	acceptor_gain	1.0000
3:25733982:CC:C	acceptor_gain	1.0000
3:25733983:C:CC	acceptor_gain	1.0000
3:25733989:CAAA:C	acceptor_gain	1.0000
3:25733990:A:T	acceptor_gain	1.0000
3:25736008:T:C	donor_gain	1.0000
3:25736043:G:A	donor_gain	1.0000
3:25736049:T:TA	donor_gain	1.0000
3:25736146:TGGT:T	acceptor_gain	1.0000
3:25739477:TATTT:T	acceptor_gain	1.0000
3:25751140:T:TA	donor_gain	1.0000
3:25751154:TGG:T	donor_gain	1.0000
3:25751259:GCAAC:G	acceptor_gain	1.0000
3:25751260:CAAC:C	acceptor_gain	1.0000
3:25751260:CAACC:C	acceptor_gain	1.0000
3:25751261:AAC:A	acceptor_gain	1.0000
3:25751261:AACC:A	acceptor_loss	1.0000
3:25751262:AC:A	acceptor_gain	1.0000
3:25751263:CC:C	acceptor_gain	1.0000
3:25751264:C:CC	acceptor_gain	1.0000

AlphaMissense

4275 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:25764298:A:G	L87P	1.000
3:25778580:A:C	F80L	1.000
3:25778580:A:T	F80L	1.000
3:25778581:A:G	F80S	1.000
3:25778582:A:G	F80L	1.000
3:25783275:G:T	A39D	1.000
3:25736108:A:G	W349R	0.999
3:25736108:A:T	W349R	0.999
3:25764253:C:G	R102P	0.999
3:25778587:A:C	M78R	0.999
3:25778587:A:T	M78K	0.999
3:25778596:A:G	L75S	0.999
3:25778600:A:G	C74R	0.999
3:25778626:A:G	L65P	0.999
3:25778659:A:C	I54S	0.999
3:25778659:A:G	I54T	0.999
3:25778659:A:T	I54N	0.999
3:25783266:A:T	I42N	0.999
3:25783276:C:G	A39P	0.999
3:25783287:A:G	L35P	0.999
3:25764265:A:G	L98P	0.998
3:25778581:A:C	F80C	0.998
3:25778608:G:T	A71D	0.998
3:25778612:C:G	G70R	0.998
3:25778612:C:T	G70R	0.998
3:25778626:A:T	L65H	0.998
3:25778637:A:C	F61L	0.998
3:25778637:A:T	F61L	0.998
3:25778638:A:G	F61S	0.998
3:25778639:A:G	F61L	0.998

dbSNP variants (sampled 300 via entrez): RS1000067094 (3:25752789 G>A), RS1000076449 (3:25786604 C>G), RS1000107184 (3:25722574 T>C,G), RS1000151871 (3:25751100 T>C,G), RS1000155374 (3:25770356 C>G,T), RS1000208192 (3:25770712 C>G), RS1000223310 (3:25762049 A>C), RS1000274542 (3:25772769 C>T), RS1000290296 (3:25789420 G>A,C,T), RS1000312874 (3:25753428 T>C), RS1000339911 (3:25762144 TAGTTTTAACCAAAAAAAAAAA>T), RS1000360704 (3:25747728 C>A,T), RS1000412496 (3:25789812 C>T), RS1000431293 (3:25765239 T>C,G), RS1000470789 (3:25741278 A>G)

Disease associations

OMIM: gene MIM:610661 | disease phenotypes: MIM:615273, MIM:615524

GenCC curated gene-disease

Disease	Classification	Inheritance
congenital disorder of deglycosylation 1	Definitive	Autosomal recessive
NGLY1-deficiency	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
congenital disorder of deglycosylation 1	Definitive	AR

Mondo (9): congenital disorder of deglycosylation (MONDO:0031376), congenital disorder of deglycosylation 1 (MONDO:0800044), microphthalmia, syndromic 12 (MONDO:0014229), intellectual disability (MONDO:0001071), epilepsy (MONDO:0005027), peripheral neuropathy (MONDO:0005244), fetal growth restriction (MONDO:0005030), lactic acidosis (MONDO:0006040), (MONDO:0014109)

Orphanet (4): Alacrimia-choreoathetosis-liver dysfunction syndrome (Orphanet:404454), Matthew-Wood syndrome (Orphanet:2470), Microphthalmia-motor delay-language delay-brain anomalies-diaphragmatic hernia syndrome (Orphanet:689829), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

148 total (30 of 148 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000194	Open mouth
HP:0000248	Brachycephaly
HP:0000252	Microcephaly
HP:0000275	Narrow face
HP:0000297	Facial hypotonia
HP:0000307	Pointed chin
HP:0000316	Hypertelorism
HP:0000350	Small forehead
HP:0000369	Low-set ears
HP:0000463	Anteverted nares
HP:0000486	Strabismus
HP:0000508	Ptosis
HP:0000522	Alacrima
HP:0000543	Optic disc pallor
HP:0000548	Cone/cone-rod dystrophy
HP:0000559	Corneal scarring
HP:0000577	Exotropia
HP:0000580	Pigmentary retinopathy
HP:0000633	Decreased lacrimation
HP:0000648	Optic atrophy
HP:0000657	Oculomotor apraxia
HP:0000711	Restlessness
HP:0000939	Osteoporosis
HP:0000954	Single transverse palmar crease
HP:0000970	Anhidrosis
HP:0000975	Hyperhidrosis
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia

GWAS associations

0 associations (top):

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D000140	Acidosis, Lactic	C18.452.076.176.180
D004827	Epilepsy	C10.228.140.490
D005317	Fetal Growth Retardation	C12.050.703.277.370; C16.300.390; C23.550.393.450
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523429 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 175,245 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1554	DACTINOMYCIN	4	175,245

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression	3
sodium arsenite	affects binding, increases reaction, increases expression	2
Cyclosporine	increases expression	2
aristolochic acid I	increases expression	1
dicrotophos	decreases expression	1
methylmercuric chloride	increases expression	1
beta-lapachone	increases expression	1
cobaltous chloride	increases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
beta-methylcholine	affects expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
benzyloxycarbonylleucyl-leucyl-leucine aldehyde	increases reaction, affects binding	1
CGP 52608	affects binding, increases reaction	1
K 7174	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Acetaminophen	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Benzo(a)pyrene	affects methylation	1
Carbamazepine	affects expression	1
Estradiol	affects cotreatment, decreases expression	1
Colforsin	increases expression	1
Plant Extracts	increases expression, affects cotreatment	1
Progesterone	affects cotreatment, decreases expression	1
Quercetin	decreases expression	1
Testosterone	increases expression	1
Metribolone	increases expression	1
Aflatoxin B1	decreases methylation	1
Particulate Matter	increases abundance, increases expression	1

ChEMBL screening assays

9 unique, capped per target: 9 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4432926	Binding	Binding affinity to recombinant hexa-histidine-tagged human full-length N-GLY1 catalytic domain expressed in Escherichia coli BL21 (DE3) assessed as change in melting temperature by thermal shift assay	Novel small molecule binders of human N-glycanase 1, a key player in the endoplasmic reticulum associated degradation pathway. — Bioorg Med Chem

Cellosaurus cell lines

69 cell lines: 27 transformed cell line, 21 finite cell line, 15 induced pluripotent stem cell, 6 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A8RE	TRNDi018-A	Induced pluripotent stem cell	Male
CVCL_A8RF	TRNDi018-B	Induced pluripotent stem cell	Male
CVCL_A8RG	TRNDi018-C	Induced pluripotent stem cell	Male
CVCL_A8RH	TRNDi018-D	Induced pluripotent stem cell	Male
CVCL_B5GI	TRNDi010-D	Induced pluripotent stem cell	Female
CVCL_B5GJ	TRNDi010-D-1	Induced pluripotent stem cell	Female
CVCL_B5GK	TRNDi010-D-2	Induced pluripotent stem cell	Female
CVCL_BX22	GM25330	Transformed cell line	Male
CVCL_BX23	GM25331	Transformed cell line	Female
CVCL_BX24	GM25340	Transformed cell line	Male

Clinical trials (associated diseases)

200 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT06199531	PHASE3	ACTIVE_NOT_RECRUITING	Safety and Efficacy of GS-100 Gene Therapy in Patients With NGLY1 Deficiency
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT05402345	PHASE2	ACTIVE_NOT_RECRUITING	A Study of GlcNAc on Tear Production in NGLY1-CDDG
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT06122766	Not specified	COMPLETED	NGLY1 Natural History
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study
NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD
NCT02591446	Not specified	COMPLETED	Transcranial Magnetic Stimulation Studies in Autism Spectrum Disorders
NCT02714868	Not specified	COMPLETED	Evaluation of Project TEAM (Teens Making Environmental and Activity Modifications)