EDEM3

Summary

EDEM3 (ER degradation enhancing alpha-mannosidase like protein 3, HGNC:16787) is a protein-coding gene on chromosome 1q25.3, encoding ER degradation-enhancing alpha-mannosidase-like protein 3 (Q9BZQ6). Involved in endoplasmic reticulum-associated degradation (ERAD).

Quality control in the endoplasmic reticulum (ER) ensures that only properly folded proteins are retained in the cell through recognition and degradation of misfolded or unassembled proteins. EDEM3 belongs to a group of proteins that accelerate degradation of misfolded glycoproteins in the ER (Hirao et al., 2006 [PubMed 16431915]).

Source: NCBI Gene 80267 — RefSeq curated summary.

At a glance

• Gene–disease (curated): congenital disorder of glycosylation, type 2v (Strong, ClinGen)
• GWAS associations: 13
• Clinical variants (ClinVar): 157 total — 14 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 36
• MANE Select transcript: NM_025191

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16787
Approved symbol	EDEM3
Name	ER degradation enhancing alpha-mannosidase like protein 3
Location	1q25.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000116406
Ensembl biotype	protein_coding
OMIM	610214
Entrez	80267

Gene structure

Transcript identifiers

Ensembl transcripts: 24 — 13 protein_coding, 8 retained_intron, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000318130, ENST00000367512, ENST00000439962, ENST00000466392, ENST00000466606, ENST00000474725, ENST00000685249, ENST00000685596, ENST00000686047, ENST00000686225, ENST00000687113, ENST00000687397, ENST00000689766, ENST00000689946, ENST00000690028, ENST00000692170, ENST00000692182, ENST00000693477, ENST00000902843, ENST00000902844, ENST00000902845, ENST00000902846, ENST00000902847, ENST00000951032

RefSeq mRNA: 2 — MANE Select: NM_025191 NM_001319960, NM_025191

CCDS: CCDS1363, CCDS91128

Canonical transcript exons

ENST00000318130 — 20 exons

Exon	Start	End
ENSE00000790719	184708153	184708344
ENSE00000790720	184710394	184710547
ENSE00000790723	184716888	184717012
ENSE00000790724	184717540	184717623
ENSE00000790726	184719443	184719568
ENSE00000790727	184721289	184721386
ENSE00000822908	184712433	184712598
ENSE00001030398	184711723	184711877
ENSE00001218809	184719162	184719245
ENSE00001342527	184749547	184749592
ENSE00001380524	184690237	184694472
ENSE00001444841	184754489	184754858
ENSE00003477413	184723751	184723856
ENSE00003493303	184702811	184702996
ENSE00003526753	184737611	184737711
ENSE00003532244	184737025	184737064
ENSE00003601227	184732837	184732990
ENSE00003606082	184706643	184706808
ENSE00003637402	184734531	184734643
ENSE00003643810	184726255	184726389

Expression profiles

Bgee: expression breadth ubiquitous, 280 present calls, max score 96.12.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 14.9681 / max 699.1161, expressed in 1801 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
16270	11.2167	1790
16269	2.5011	756
16268	0.9174	589
16267	0.3329	179

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pylorus	UBERON:0001166	96.12	gold quality
mucosa of sigmoid colon	UBERON:0004993	95.17	gold quality
jejunal mucosa	UBERON:0000399	94.98	gold quality
colonic mucosa	UBERON:0000317	94.61	gold quality
mucosa of paranasal sinus	UBERON:0005030	92.69	gold quality
trabecular bone tissue	UBERON:0002483	92.32	gold quality
islet of Langerhans	UBERON:0000006	92.17	gold quality
stromal cell of endometrium	CL:0002255	92.13	gold quality
cardia of stomach	UBERON:0001162	92.12	gold quality
body of pancreas	UBERON:0001150	92.02	gold quality
adrenal tissue	UBERON:0018303	91.94	gold quality
rectum	UBERON:0001052	91.65	gold quality
bronchial epithelial cell	CL:0002328	91.55	gold quality
lower lobe of lung	UBERON:0008949	91.49	gold quality
pericardium	UBERON:0002407	91.23	gold quality
calcaneal tendon	UBERON:0003701	91.18	gold quality
pancreas	UBERON:0001264	91.11	gold quality
bone marrow cell	CL:0002092	90.99	gold quality
jejunum	UBERON:0002115	90.99	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	90.70	gold quality
skin of hip	UBERON:0001554	90.53	gold quality
superior surface of tongue	UBERON:0007371	90.08	gold quality
colonic epithelium	UBERON:0000397	90.06	gold quality
oral cavity	UBERON:0000167	89.61	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	89.49	gold quality
bone marrow	UBERON:0002371	89.40	gold quality
superficial temporal artery	UBERON:0001614	89.19	gold quality
placenta	UBERON:0001987	89.14	gold quality
corpus callosum	UBERON:0002336	89.10	gold quality
stomach	UBERON:0000945	88.57	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-CURD-11	no	445.39
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

208 targeting EDEM3, 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-3646	100.00	73.56	5283
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821

Literature-anchored findings (GeneRIF, showing 7)

• The data corroborated herein suggest that besides ER residents, EDEM3 interacts also with proteins involved in the ERAD cargo recognition and targeting to degradation translocation into the cytosol, including UBA1 and UBA2 ubiquitinating enzymes. In addition, the results indicate that this network of EDEM3 interactors is highly sensitive to interfering with early ER N-glycan processing. (PMID:28366632)
• the mannose-trimming activity of EDEM3 toward the model misfolded substrate, the glycoprotein T-cell receptor alpha locus (TCRalpha), was reconstituted only when ERp46 had established a covalent interaction with EDEM3 (PMID:29784879)
• IL8 and EDEM3 gene expression ratio indicates peripheral blood mononuclear cell (PBMC) quality. (PMID:30496732)
• EDEM3 Domains Cooperate to Perform Its Overall Cell Functioning. (PMID:33671632)
• Bi-allelic variants in the ER quality-control mannosidase gene EDEM3 cause a congenital disorder of glycosylation. (PMID:34143952)
• Purified EDEM3 or EDEM1 alone produces determinant oligosaccharide structures from M8B in mammalian glycoprotein ERAD. (PMID:34698634)
• Pro-Survival Factor EDEM3 Confers Therapy Resistance in Prostate Cancer. (PMID:35897761)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	edem3	ENSDARG00000074129
mus_musculus	Edem3	ENSMUSG00000043019
rattus_norvegicus	Edem3	ENSRNOG00000028358
drosophila_melanogaster	Edem2	FBGN0032480
drosophila_melanogaster	alpha-Man-Ic	FBGN0051202
drosophila_melanogaster	alpha-Man-Ia	FBGN0259170
caenorhabditis_elegans		WBGENE00008258
caenorhabditis_elegans		WBGENE00013919

Paralogs (6): EDEM2 (ENSG00000088298), MAN1A1 (ENSG00000111885), MAN1C1 (ENSG00000117643), EDEM1 (ENSG00000134109), MAN1B1 (ENSG00000177239), MAN1A2 (ENSG00000198162)

Protein

Protein identifiers

ER degradation-enhancing alpha-mannosidase-like protein 3 — Q9BZQ6 (reviewed: Q9BZQ6)

Alternative names: Alpha-1,2-mannosidase EDEM3

All UniProt accessions (9): Q9BZQ6, A0A8I5KR65, A0A8I5KSQ8, A0A8I5KTR7, A0A8I5KU04, A0A8I5KVE6, A0A8I5KWI4, A0A8J8YX80, H0Y498

UniProt curated annotations — full annotation on UniProt →

Function. Involved in endoplasmic reticulum-associated degradation (ERAD). Accelerates the glycoprotein ERAD by proteasomes, by catalyzing mannose trimming from Man8GlcNAc2 to Man7GlcNAc2 in the N-glycans. May also participate in mannose trimming from all glycoproteins and not just misfolded ones targeted to ERAD. May have alpha 1,2-mannosidase activity.

Subcellular location. Endoplasmic reticulum lumen.

Disease relevance. Congenital disorder of glycosylation 2V (CDG2V) [MIM:619493] A form of congenital disorder of glycosylation, a genetically heterogeneous group of multisystem disorders caused by a defect in glycoprotein biosynthesis and characterized by under-glycosylated serum glycoproteins. Congenital disorders of glycosylation result in a wide variety of clinical features, such as defects in the nervous system development, psychomotor retardation, dysmorphic features, hypotonia, coagulation disorders, and immunodeficiency. The broad spectrum of features reflects the critical role of N-glycoproteins during embryonic development, differentiation, and maintenance of cell functions. CDG2V is an autosomal recessive form characterized by neurodevelopmental delay and variable facial dysmorphic features. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Contains a protease-associated domain (PA) of unknown function.

Pathway. Protein modification; protein glycosylation.

Similarity. Belongs to the glycosyl hydrolase 47 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9BZQ6-1	1	yes
Q9BZQ6-2	2

RefSeq proteins (2): NP_001306889, NP_079467* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001382	Glyco_hydro_47	Family
IPR003137	PA_domain	Domain
IPR012341	6hp_glycosidase-like_sf	Homologous_superfamily
IPR036026	Seven-hairpin_glycosidases	Homologous_superfamily
IPR037322	EDEM3_PA	Domain
IPR044674	EDEM1/2/3	Family
IPR046450	PA_dom_sf	Homologous_superfamily

Pfam: PF01532, PF02225

Catalyzed reactions (Rhea), 2 shown:

• N(4)-(alpha-D-Man-(1->2)-alpha-D-Man-(1->2)-alpha-D-Man-(1->3)-[alpha-D-Man-(1->2)-alpha-D-Man-(1->3)-[alpha-D-Man-(1->2)-alpha-D-Man-(1->6)]-alpha-D-Man-(1->6)]-beta-D-Man-(1->4)-beta-D-GlcNAc-(1->4)-beta-D-GlcNAc)-L-asparaginyl-[protein] (N-glucan mannose isomer 9A1,2,3B1,2,3) + 4 H2O = N(4)-(alpha-D-Man-(1->3)-[alpha-D-Man-(1->3)-[alpha-D-Man-(1->6)]-alpha-D-Man-(1->6)]-beta-D-Man-(1->4)-beta-D-GlcNAc-(1->4)-beta-D-GlcNAc)-L-asparaginyl-[protein] (N-glucan mannose isomer 5A1,2) + 4 beta-D-mannose (RHEA:56008)
• N(4)-(alpha-D-Man-(1->2)-alpha-D-Man-(1->2)-alpha-D-Man-(1->3)-[alpha-D-Man-(1->3)-[alpha-D-Man-(1->2)-alpha-D-Man-(1->6)]-alpha-D-Man-(1->6)]-beta-D-Man-(1->4)-beta-D-GlcNAc-(1->4)-beta-D-GlcNAc)-L-asparaginyl-[protein] (N-glucan mannose isomer 8A1,2,3B1,3) + 3 H2O = N(4)-(alpha-D-Man-(1->3)-[alpha-D-Man-(1->3)-[alpha-D-Man-(1->6)]-alpha-D-Man-(1->6)]-beta-D-Man-(1->4)-beta-D-GlcNAc-(1->4)-beta-D-GlcNAc)-L-asparaginyl-[protein] (N-glucan mannose isomer 5A1,2) + 3 beta-D-mannose (RHEA:56028)

UniProt features (29 total): glycosylation site 7, sequence variant 5, active site 4, compositionally biased region 3, splice variant 2, sequence conflict 2, signal peptide 1, chain 1, binding site 1, domain 1, region of interest 1, short sequence motif 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BZQ6-F1	78.50	0.54

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 (4): 387 (proton donor); 405; 146 (proton donor); 293

Ligand- & substrate-binding residues (1): 491

Glycosylation sites (7): 118, 195, 504, 511, 810, 814, 900

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-901032	ER Quality Control Compartment (ERQC)

MSigDB gene sets: 322 (showing top): GOBP_RESPONSE_TO_NITROGEN_COMPOUND, TTTGTAG_MIR520D, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GTCTACC_MIR379, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_CATABOLIC_PROCESS, MITSIADES_RESPONSE_TO_APLIDIN_DN, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_CELLULAR_RESPONSE_TO_TOPOLOGICALLY_INCORRECT_PROTEIN, OSWALD_HEMATOPOIETIC_STEM_CELL_IN_COLLAGEN_GEL_UP, GOBP_CARBOHYDRATE_METABOLIC_PROCESS, AAAGACA_MIR511, GOBP_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, BOYAULT_LIVER_CANCER_SUBCLASS_G1_UP

GO Biological Process (10): carbohydrate metabolic process (GO:0005975), endoplasmic reticulum unfolded protein response (GO:0030968), ERAD pathway (GO:0036503), ubiquitin-dependent glycoprotein ERAD pathway (GO:0097466), endoplasmic reticulum mannose trimming (GO:1904380), obsolete mannoprotein catabolic process (GO:0006058), obsolete protein glycosylation (GO:0006486), response to unfolded protein (GO:0006986), glycoprotein metabolic process (GO:0009100), mannose trimming involved in glycoprotein ERAD pathway (GO:1904382)

GO Molecular Function (5): mannosyl-oligosaccharide 1,2-alpha-mannosidase activity (GO:0004571), calcium ion binding (GO:0005509), hydrolase activity (GO:0016787), hydrolase activity, acting on glycosyl bonds (GO:0016798), metal ion binding (GO:0046872)

GO Cellular Component (4): endoplasmic reticulum (GO:0005783), endoplasmic reticulum lumen (GO:0005788), membrane (GO:0016020), endoplasmic reticulum quality control compartment (GO:0044322)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Calnexin/calreticulin cycle	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
response to endoplasmic reticulum stress	2
protein alpha-1,2-demannosylation	2
endoplasmic reticulum	2
cellular anatomical structure	2
primary metabolic process	1
cellular response to unfolded protein	1
intracellular signal transduction	1
proteasomal protein catabolic process	1
response to chemical	1
glycoprotein catabolic process	1
ERAD pathway	1
response to glycoprotein	1
endoplasmic reticulum quality control compartment	1
response to topologically incorrect protein	1
protein metabolic process	1
carbohydrate derivative metabolic process	1
protein deglycosylation involved in glycoprotein catabolic process	1
ubiquitin-dependent glycoprotein ERAD pathway	1
mannosyl-oligosaccharide mannosidase activity	1
metal ion binding	1
catalytic activity	1
hydrolase activity	1
cation binding	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
intracellular organelle lumen	1

Protein interactions and networks

STRING

1028 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EDEM3	OS9	Q13438	823
EDEM3	MAN2A1	Q16706	817
EDEM3	SEL1L	Q9UBV2	782
EDEM3	SERPINA1	P01009	720
EDEM3	CALR	P27797	718
EDEM3	ERLEC1	Q96DZ1	714
EDEM3	UFD1	Q92890	637
EDEM3	TXNDC11	Q6PKC3	630
EDEM3	UGGT1	Q9NYU2	620
EDEM3	DNAJB9	Q9UBS3	617
EDEM3	MAN2C1	Q9NTJ4	603
EDEM3	XBP1	P17861	587
EDEM3	DNAJC3	Q13217	578
EDEM3	HSP90B1	P14625	576
EDEM3	DNAJC10	Q8IXB1	549

IntAct

74 interactions, top by confidence:

A	B	Type	Score
DEFA1	MANBA	psi-mi:“MI:0914”(association)	0.530
OS9	AGRN	psi-mi:“MI:0914”(association)	0.530
ANGPTL7	TCP1	psi-mi:“MI:0914”(association)	0.530
	PLOD2	psi-mi:“MI:0914”(association)	0.530
ALOXE3	HSPA8	psi-mi:“MI:0914”(association)	0.530
CD70	METTL15	psi-mi:“MI:0914”(association)	0.530
PBXIP1	KCNN4	psi-mi:“MI:0914”(association)	0.530
ANKRD22	ESYT2	psi-mi:“MI:0914”(association)	0.530
Zwint	NDC80	psi-mi:“MI:0915”(physical association)	0.400
LRPPRC	HSPA8	psi-mi:“MI:0914”(association)	0.350
	HAX1	psi-mi:“MI:0914”(association)	0.350
RIPK4	VWA8	psi-mi:“MI:0914”(association)	0.350
M	NPEPPSL1	psi-mi:“MI:0914”(association)	0.350
M2	IPO5	psi-mi:“MI:0914”(association)	0.350
NUDCD1	TUBAL3	psi-mi:“MI:0914”(association)	0.350
NUDCD1	DNAJB2	psi-mi:“MI:0914”(association)	0.350
ALOXE3	HSPD1	psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
	PLOD2	psi-mi:“MI:0914”(association)	0.350
ATG16L1	ESYT2	psi-mi:“MI:0914”(association)	0.350
P2RY10	POTEF	psi-mi:“MI:0914”(association)	0.350
LLCFC1	POTEF	psi-mi:“MI:0914”(association)	0.350
CEACAM8	PRRT4	psi-mi:“MI:0914”(association)	0.350
GPIHBP1	SAC3D1	psi-mi:“MI:0914”(association)	0.350
LGI1	APAF1	psi-mi:“MI:0914”(association)	0.350

BioGRID (150): EDEM3 (Affinity Capture-MS), EDEM3 (Affinity Capture-MS), SEL1L (Affinity Capture-Western), EDEM3 (Affinity Capture-Western), EDEM3 (Affinity Capture-MS), EDEM3 (Affinity Capture-MS), EDEM3 (Affinity Capture-MS), EDEM3 (Affinity Capture-MS), HSPB1 (Affinity Capture-MS), STT3A (Affinity Capture-MS), SAE1 (Affinity Capture-MS), KIAA0368 (Affinity Capture-MS), EDEM2 (Affinity Capture-MS), ERP29 (Affinity Capture-MS), MOGS (Affinity Capture-MS)

ESM2 similar proteins: A2AJ15, B2GUY0, O02773, O18498, O60476, P32906, P33908, P39098, P45700, P45701, P53624, Q08463, Q10471, Q18788, Q1L8D2, Q2HXL6, Q49A17, Q5EA41, Q5GF25, Q5RFJ6, Q6GQB9, Q6NXH2, Q6P9S7, Q6PB93, Q6WV16, Q80VA0, Q86SF2, Q86SR1, Q8BJT9, Q8H116, Q8J0Q0, Q8K1B9, Q8N428, Q925R7, Q925U4, Q92611, Q93Y37, Q9BV94, Q9BZQ6, Q9C512

Diamond homologs: A1CP08, A1D1W1, A2AJ15, A2QAS2, B0XMT4, B2GUY0, B8N417, D4AV26, E9CXX8, O02773, O18498, O60476, O94726, P31723, P32906, P33908, P39098, P45700, P45701, P53624, Q0D076, Q12563, Q18788, Q2HXL6, Q2ULB2, Q4WRZ5, Q6GQB9, Q8BJT9, Q8H116, Q8J0Q0, Q925U4, Q92611, Q93Y37, Q9BV94, Q9BZQ6, Q9C512, Q9FG93, Q9NR34, Q9P7C3, Q9SXC9

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 103 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	14	5.6×	4e-05

GO biological processes:

GO term	Partners	Fold	FDR
ERAD pathway	7	14.8×	3e-04
protein folding	7	8.4×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	14
Likely pathogenic	3
Uncertain significance	116
Likely benign	5
Benign	2

Top pathogenic / likely-pathogenic (17)

Variant ID	HGVS	Classification
1210133	NM_025191.4(EDEM3):c.1859del (p.Ile620fs)	Pathogenic
1210134	NM_025191.4(EDEM3):c.2001dup (p.Ala668fs)	Pathogenic
1210135	NM_025191.4(EDEM3):c.1369del (p.Arg457fs)	Pathogenic
1210136	NM_025191.4(EDEM3):c.940A>T (p.Arg314Ter)	Pathogenic
1210137	NM_025191.4(EDEM3):c.853+1G>T	Pathogenic
1210138	NM_025191.4(EDEM3):c.1407T>A (p.Tyr469Ter)	Pathogenic
1210139	NM_025191.4(EDEM3):c.1382_1385del (p.Phe461fs)	Pathogenic
1210140	NM_025191.4(EDEM3):c.182A>G (p.Asp61Gly)	Pathogenic
1210141	NM_025191.4(EDEM3):c.1366G>A (p.Asp456Asn)	Pathogenic
2639631	NM_025191.4(EDEM3):c.1942C>T (p.Arg648Ter)	Pathogenic
2639636	NM_025191.4(EDEM3):c.346-1G>A	Pathogenic
3382610	NM_025191.4(EDEM3):c.848del (p.Arg283fs)	Pathogenic
4279255	GRCh37/hg19 1q25.3(chr1:184628432-184938385)x1	Pathogenic
4845475	NM_025191.4(EDEM3):c.1998del (p.Pro667fs)	Pathogenic
1803729	NM_025191.4(EDEM3):c.1090del (p.Asp364fs)	Likely pathogenic
3767979	NM_025191.4(EDEM3):c.793C>T (p.Arg265Ter)	Likely pathogenic
599481	NM_025191.4(EDEM3):c.1204T>G (p.Leu402Val)	Likely pathogenic

SpliceAI

3841 predictions. Top by Δscore:

Variant	Effect	Δscore
1:184702806:CTTAC:C	donor_loss	1.0000
1:184702808:TA:T	donor_loss	1.0000
1:184702809:A:AC	donor_gain	1.0000
1:184702809:AC:A	donor_gain	1.0000
1:184702810:C:A	donor_loss	1.0000
1:184702810:C:CC	donor_gain	1.0000
1:184702810:CC:C	donor_gain	1.0000
1:184702810:CCT:C	donor_gain	1.0000
1:184702810:CCTCG:C	donor_gain	1.0000
1:184702841:CTT:C	donor_gain	1.0000
1:184702842:TTC:T	donor_gain	1.0000
1:184702843:TCT:T	donor_gain	1.0000
1:184702849:T:TA	donor_gain	1.0000
1:184706639:TTACC:T	donor_loss	1.0000
1:184706640:TA:T	donor_loss	1.0000
1:184706641:A:AC	donor_gain	1.0000
1:184706641:AC:A	donor_gain	1.0000
1:184706641:ACCA:A	donor_loss	1.0000
1:184706642:C:A	donor_loss	1.0000
1:184706642:C:CA	donor_gain	1.0000
1:184706642:CC:C	donor_gain	1.0000
1:184706642:CCA:C	donor_gain	1.0000
1:184706642:CCAA:C	donor_gain	1.0000
1:184706642:CCAAT:C	donor_gain	1.0000
1:184706804:CTTGT:C	acceptor_gain	1.0000
1:184706805:TTGT:T	acceptor_gain	1.0000
1:184706805:TTGTC:T	acceptor_loss	1.0000
1:184706806:TGT:T	acceptor_gain	1.0000
1:184706807:GT:G	acceptor_gain	1.0000
1:184706808:TC:T	acceptor_loss	1.0000

AlphaMissense

6202 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:184702896:G:C	F768L	1.000
1:184702896:G:T	F768L	1.000
1:184702898:A:G	F768L	1.000
1:184702951:A:C	M750R	1.000
1:184702951:A:G	M750T	1.000
1:184702956:G:C	F748L	1.000
1:184702956:G:T	F748L	1.000
1:184702957:A:C	F748C	1.000
1:184702957:A:G	F748S	1.000
1:184702958:A:G	F748L	1.000
1:184706648:A:T	V733D	1.000
1:184706657:C:T	G730D	1.000
1:184706684:C:G	R721P	1.000
1:184706688:C:G	A720P	1.000
1:184706689:C:A	K719N	1.000
1:184706689:C:G	K719N	1.000
1:184706698:A:C	F716L	1.000
1:184706698:A:T	F716L	1.000
1:184706699:A:C	F716C	1.000
1:184706699:A:G	F716S	1.000
1:184706700:A:G	F716L	1.000
1:184706705:C:G	C714S	1.000
1:184706706:A:G	C714R	1.000
1:184706706:A:T	C714S	1.000
1:184706768:C:G	C693S	1.000
1:184706769:A:T	C693S	1.000
1:184708178:C:T	G671E	1.000
1:184708179:C:A	G671W	1.000
1:184708180:A:C	F670L	1.000
1:184708180:A:T	F670L	1.000

dbSNP variants (sampled 300 via entrez): RS1000063763 (1:184735482 G>T), RS1000096989 (1:184692004 T>C), RS1000126681 (1:184691741 A>T), RS1000135027 (1:184738100 T>C), RS1000149178 (1:184705379 T>A), RS1000280721 (1:184707087 T>C), RS1000304035 (1:184738345 A>C), RS1000338506 (1:184721495 A>G), RS1000399088 (1:184698716 C>A), RS1000400784 (1:184713657 G>T), RS1000434974 (1:184735266 C>A), RS1000461127 (1:184715858 A>G,T), RS1000507437 (1:184737727 T>A,C), RS1000507883 (1:184719207 A>G), RS1000603275 (1:184751163 T>C)

Disease associations

OMIM: gene MIM:610214 | disease phenotypes: MIM:619493

GenCC curated gene-disease

Disease	Classification	Inheritance
congenital disorder of glycosylation, type 2v	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
congenital disorder of glycosylation, type 2v	Strong	AR

Mondo (2): congenital disorder of glycosylation, type 2v (MONDO:0030423), congenital disorder of glycosylation (MONDO:0015286)

Orphanet (2): EDEM3-CDG (Orphanet:695783), Congenital disorder of glycosylation (Orphanet:137)

HPO phenotypes

36 total (30 of 36 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000034	Hydrocele testis
HP:0000175	Cleft palate
HP:0000218	High palate
HP:0000219	Thin upper lip vermilion
HP:0000278	Retrognathia
HP:0000286	Epicanthus
HP:0000316	Hypertelorism
HP:0000322	Short philtrum
HP:0000369	Low-set ears
HP:0000391	Thickened helices
HP:0000411	Protruding ear
HP:0000414	Bulbous nose
HP:0000430	Underdeveloped nasal alae
HP:0000431	Wide nasal bridge
HP:0000483	Astigmatism
HP:0000486	Strabismus
HP:0000490	Deeply set eye
HP:0000494	Downslanted palpebral fissures
HP:0000508	Ptosis
HP:0000629	Periorbital fullness
HP:0001052	Nevus flammeus
HP:0001249	Intellectual disability
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001762	Talipes equinovarus
HP:0002020	Gastroesophageal reflux
HP:0002162	Low posterior hairline
HP:0002280	Enlarged cisterna magna
HP:0003593	Infantile onset

GWAS associations

13 associations (top):

Study	Trait	p-value
GCST001762_705	Obesity-related traits	6.000000e-06
GCST002463_9	Systemic lupus erythematosus	2.000000e-13
GCST008058_73	Estimated glomerular filtration rate	5.000000e-24
GCST008059_62	Estimated glomerular filtration rate	2.000000e-24
GCST008790_5	Urinary albumin-to-creatinine ratio	3.000000e-10
GCST008794_20	Urinary albumin-to-creatinine ratio	3.000000e-10
GCST009391_687	Metabolite levels	6.000000e-06
GCST009640_8	Urinary albumin-to-creatinine ratio	1.000000e-09
GCST010145_7	Cerebrospinal fluid immune biomarker levels	1.000000e-08
GCST010988_263	Adult body size	6.000000e-09
GCST010989_187	Body size at age 10	2.000000e-16
GCST90013406_85	Liver enzyme levels (alkaline phosphatase)	6.000000e-31
GCST90020029_1016	Waist circumference adjusted for body mass index	2.000000e-08

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0005106	body composition measurement
EFO:0007778	urinary albumin to creatinine ratio
EFO:0008529	kynurenine measurement
EFO:0010596	monocyte chemotactic protein 1 measurement
EFO:0009819	comparative body size at age 10, self-reported
EFO:0004533	alkaline phosphatase measurement
EFO:0007789	BMI-adjusted waist circumference

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D018981	Congenital Disorders of Glycosylation	C16.320.565.202.125; C18.452.648.202.125

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

50 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects cotreatment, decreases expression, increases expression	3
Valproic Acid	increases expression	3
Cyclosporine	increases expression	3
Endosulfan	increases expression	2
Gold	decreases expression, affects binding	2
Hydrogen Peroxide	affects expression, increases expression	2
2,4,6-tribromophenol	decreases expression	1
lasiocarpine	decreases expression	1
decabromobiphenyl ether	increases expression	1
sodium arsenite	decreases expression	1
tetrabromobisphenol A	increases expression	1
nickel chloride	decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
Huang Qi	affects cotreatment, decreases expression, decreases reaction, increases expression	1
nickel sulfate	decreases expression	1
beta-methylcholine	affects expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
Coptidis rhizoma extract	affects cotreatment, decreases expression, decreases reaction, increases expression	1
abrine	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	increases expression	1
pentabrominated diphenyl ether 100	increases expression	1
Centella asiatica extract	affects cotreatment, decreases expression, decreases reaction, increases expression	1
enzalutamide	decreases expression	1
jinfukang	decreases expression	1
Sugars	decreases expression, decreases reaction, increases expression, affects cotreatment	1
Resveratrol	affects cotreatment, increases expression	1
Acetaminophen	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT07572825	PHASE1	NOT_YET_RECRUITING	Assessing the Safety and Tolerability of NMN in DHDDS-CDG
NCT02089789	Not specified	RECRUITING	Clinical and Basic Investigations Into Known and Suspected Congenital Disorders of Glycosylation
NCT02503267	Not specified	UNKNOWN	Incidence and Consequences of Disorders of Glycosylation in Patients With Conotruncal and Septal Heart Defects
NCT02955264	Not specified	COMPLETED	Using D-Galactose as a Food Supplement in Congenital Disorders of Glycosylation
NCT03250728	Not specified	COMPLETED	Role of the Endothelium in Stroke-like Episode Among CDG Patients
NCT03560570	Not specified	COMPLETED	Study of Hemostasis in Patients With Congenital Disorder of Glycosylation
NCT04198987	Not specified	COMPLETED	Dietary Monosaccharide Supplementation in Patients With Congenital Disorders of Glycosylation
NCT04199000	Not specified	RECRUITING	Clinical and Basic Investigations Into Congenital Disorders of Glycosylation
NCT04201067	Not specified	COMPLETED	Large-Scale Metabolomic Profiling for the Diagnosis of Inborn Errors of Metabolism