MGAT2-congenital disorder of glycosylation

Summary

MGAT2-congenital disorder of glycosylation (MONDO:0008908) is a disease caused by MGAT2 (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: MGAT2 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 112
• Phenotypes (HPO): 57

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		13	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

57 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0001999	Abnormal facial shape	Very frequent (80-99%)
HP:0003655	Reduced activity of N-acetylglucosaminyltransferase II	Very frequent (80-99%)
HP:0000253	Progressive microcephaly	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001252	Hypotonia	Frequent (30-79%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0000358	Posteriorly rotated ears	Occasional (5-29%)
HP:0000194	Open mouth	Occasional (5-29%)
HP:0000268	Dolichocephaly	Occasional (5-29%)
HP:0000316	Hypertelorism	Occasional (5-29%)
HP:0000363	Abnormality of earlobe	Occasional (5-29%)
HP:0000395	Prominent antihelix	Occasional (5-29%)
HP:0000444	Convex nasal ridge	Occasional (5-29%)
HP:0000494	Downslanted palpebral fissures	Occasional (5-29%)
HP:0000527	Long eyelashes	Occasional (5-29%)
HP:0000678	Dental crowding	Occasional (5-29%)
HP:0000767	Pectus excavatum	Occasional (5-29%)
HP:0000818	Abnormality of the endocrine system	Occasional (5-29%)
HP:0000938	Osteopenia	Occasional (5-29%)
HP:0001007	Hirsutism	Occasional (5-29%)
HP:0001156	Brachydactyly	Occasional (5-29%)
HP:0001290	Generalized hypotonia	Occasional (5-29%)
HP:0001627	Abnormal heart morphology	Occasional (5-29%)
HP:0001629	Ventricular septal defect	Occasional (5-29%)
HP:0001643	Patent ductus arteriosus	Occasional (5-29%)
HP:0001789	Hydrops fetalis	Occasional (5-29%)
HP:0001892	Abnormal bleeding	Occasional (5-29%)
HP:0001929	Reduced factor XI activity	Occasional (5-29%)
HP:0001965	Abnormality of the scalp	Occasional (5-29%)
HP:0002020	Gastroesophageal reflux	Occasional (5-29%)
HP:0002098	Respiratory distress	Occasional (5-29%)
HP:0002521	Hypsarrhythmia	Occasional (5-29%)
HP:0002557	Hypoplastic nipples	Occasional (5-29%)
HP:0002578	Gastroparesis	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0002808	Kyphosis	Occasional (5-29%)
HP:0003186	Inverted nipples	Occasional (5-29%)
HP:0003347	Impaired lymphocyte transformation with phytohemagglutinin	Occasional (5-29%)
HP:0003540	Impaired platelet aggregation	Occasional (5-29%)
HP:0004313	Decreased circulating antibody level	Occasional (5-29%)
HP:0004315	Decreased circulating IgG level	Occasional (5-29%)
HP:0005387	Combined immunodeficiency	Occasional (5-29%)
HP:0009765	Low hanging columella	Occasional (5-29%)
HP:0010990	Abnormality of the common coagulation pathway	Occasional (5-29%)
HP:0011471	Gastrostomy tube feeding in infancy	Occasional (5-29%)
HP:0011675	Arrhythmia	Occasional (5-29%)
HP:0011968	Feeding difficulties	Occasional (5-29%)
HP:0012171	Stereotypical hand wringing	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	MGAT2-congenital disorder of glycosylation
Mondo ID	MONDO:0008908
MeSH	C535752
OMIM	212066
Orphanet	79329
DOID	DOID:0070253
SNOMED CT	724142005
UMLS	C2931008
MedGen	443956
GARD	0009828
Is cancer (heuristic)	no

Also known as: carbohydrate deficient glycoprotein syndrome type IIa · carbohydrate-deficient glycoprotein syndrome type 2 · carbohydrate-deficient glycoprotein syndrome, type II, formerly; CDGS2, formerly · CDG 2A · CDG syndrome type IIa · CDG-IIa · CDG2A · CDGS2 · congenital disorder of glycosylation type 2a · congenital disorder of glycosylation type IIa · congenital disorder of glycosylation, type IIa · mental retardation, Growth retardation, prominent columella, and open mouth · MGAT2-CDG · MGAT2-CDG (CDG-IIa) · N-acetylglucosaminyltransferase 2 deficiency

Data availability: 112 ClinVar variants · 6 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › congenital disorder of glycosylation › congenital disorder of glycosylation type II › MGAT2-congenital disorder of glycosylation

Related subtypes (25): leukocyte adhesion deficiency type II, SLC35A2-congenital disorder of glycosylation, SLC35A1-congenital disorder of glycosylation, MOGS-congenital disorder of glycosylation, B4GALT1-congenital disorder of glycosylation, COG7-congenital disorder of glycosylation, COG8-congenital disorder of glycosylation, COG1-congenital disorder of glycosylation, COG4-congenital disorder of glycosylation, COG5-congenital disorder of glycosylation, COG6-congenital disorder of glycosylation, TMEM165-congenital disorder of glycosylation, SLC39A8-CDG, CCDC115-CDG, TMEM199-CDG, congenital disorder of glycosylation, type IIr, congenital disorder of glycosylation, type iit, congenital disorder of glycosylation, type 2v, congenital disorder of glycosylation, type IIw, congenital disorder of glycosylation, type IIq, congenital disorder of glycosylation, type IIy, congenital disorder of glycosylation, type IIz, congenital disorder of glycosylation, type IIaa, congenital disorder of glycosylation, type IIbb, congenital disorder of glycosylation, type IIcc

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

112 retrieved; paginated sample, class counts are floors:

78 uncertain significance, 11 likely benign, 6 conflicting classifications of pathogenicity, 6 pathogenic, 4 benign, 4 benign/likely benign, 3 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
617657	NM_002408.4(MGAT2):c.753dup (p.Ala252fs)	MGAT2	Pathogenic	no assertion criteria provided
617658	NM_002408.4(MGAT2):c.91C>T (p.Gln31Ter)	MGAT2	Pathogenic	no assertion criteria provided
617661	NM_002408.4(MGAT2):c.799G>C (p.Asp267His)	MGAT2	Pathogenic	no assertion criteria provided
6990	NM_002408.4(MGAT2):c.785A>G (p.His262Arg)	MGAT2	Pathogenic	no assertion criteria provided
6991	NM_002408.4(MGAT2):c.952A>G (p.Asn318Asp)	MGAT2	Pathogenic	no assertion criteria provided
6992	NM_002408.4(MGAT2):c.1017T>A (p.Cys339Ter)	MGAT2	Pathogenic	no assertion criteria provided
30270	NM_002408.4(MGAT2):c.711G>C (p.Lys237Asn)	MGAT2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3061920	NM_002408.4(MGAT2):c.1085G>A (p.Trp362Ter)	MGAT2	Likely pathogenic	criteria provided, single submitter
3065025	NM_002408.4(MGAT2):c.1199_1202del (p.Asn400fs)	MGAT2	Likely pathogenic	criteria provided, single submitter
313241	NM_002408.4(MGAT2):c.-443C>T	LOC130055539	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
218607	NM_002408.4(MGAT2):c.99G>T (p.Lys33Asn)	MGAT2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
313254	NM_002408.4(MGAT2):c.63C>T (p.Gly21=)	MGAT2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
313258	NM_002408.4(MGAT2):c.1233A>T (p.Leu411=)	MGAT2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
389347	NM_002408.4(MGAT2):c.1023T>C (p.Tyr341=)	MGAT2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
702828	NM_002408.4(MGAT2):c.229C>T (p.Pro77Ser)	MGAT2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
313239	NM_002408.4(MGAT2):c.-455C>T	LOC130055539	Uncertain significance	criteria provided, single submitter
313240	NM_002408.4(MGAT2):c.-446C>G	LOC130055539	Uncertain significance	criteria provided, single submitter
880736	NM_002408.3(MGAT2):c.-495C>T	LOC130055539	Uncertain significance	criteria provided, single submitter
880737	NM_002408.3(MGAT2):c.-494C>T	LOC130055539	Uncertain significance	criteria provided, single submitter
1017445	NM_002408.4(MGAT2):c.206A>G (p.Asn69Ser)	MGAT2	Uncertain significance	criteria provided, single submitter
1029594	NM_002408.4(MGAT2):c.509G>A (p.Cys170Tyr)	MGAT2	Uncertain significance	criteria provided, single submitter
1033505	NM_002408.4(MGAT2):c.327G>T (p.Lys109Asn)	MGAT2	Uncertain significance	criteria provided, single submitter
1045858	NM_002408.4(MGAT2):c.275G>T (p.Arg92Leu)	MGAT2	Uncertain significance	criteria provided, single submitter
1053082	NM_002408.4(MGAT2):c.544C>G (p.Gln182Glu)	MGAT2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1353108	NM_002408.4(MGAT2):c.315G>T (p.Arg105Ser)	MGAT2	Uncertain significance	criteria provided, single submitter
1378923	NM_002408.4(MGAT2):c.766C>G (p.Leu256Val)	MGAT2	Uncertain significance	criteria provided, single submitter
1390797	NM_002408.4(MGAT2):c.263C>G (p.Thr88Arg)	MGAT2	Uncertain significance	criteria provided, single submitter
1943697	NM_002408.4(MGAT2):c.848G>A (p.Cys283Tyr)	MGAT2	Uncertain significance	criteria provided, single submitter
1951756	NM_002408.4(MGAT2):c.814T>C (p.Phe272Leu)	MGAT2	Uncertain significance	criteria provided, single submitter
1969918	NM_002408.4(MGAT2):c.1262C>T (p.Ala421Val)	MGAT2	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
MGAT2	Definitive	Autosomal recessive	MGAT2-congenital disorder of glycosylation	6
MOGAT2	Definitive	Autosomal recessive	MGAT2-congenital disorder of glycosylation	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MGAT2	Orphanet:79329	MGAT2-CDG

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MOGAT2	HGNC:23248	ENSG00000166391	Q3SYC2	2-acylglycerol O-acyltransferase 2	gencc,clinvar
MGAT2	HGNC:7045	ENSG00000168282	Q10469	Alpha-1,6-mannosyl-glycoprotein 2-beta-N-acetylglucosaminyltransferase	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MOGAT2	2-acylglycerol O-acyltransferase 2	Involved in glycerolipid synthesis and lipid metabolism.
MGAT2	Alpha-1,6-mannosyl-glycoprotein 2-beta-N-acetylglucosaminyltransferase	Plays an essential role in protein N-glycosylation.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	2	12.0×	0.007

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MOGAT2	Enzyme (other)	yes	2.3.1.22	DAGAT
MGAT2	Enzyme (other)	yes	2.4.1.143	GlcNAc_II, Nucleotide-diphossugar_trans

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
ileal mucosa	1
mucosa of transverse colon	1
right lobe of liver	1
colonic mucosa	1
jejunal mucosa	1
mucosa of sigmoid colon	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MOGAT2	90	tissue_specific	marker	ileal mucosa, mucosa of transverse colon, right lobe of liver
MGAT2	278	ubiquitous	marker	jejunal mucosa, mucosa of sigmoid colon, colonic mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MOGAT2	1,248
MGAT2	647

Structural data

PDB: 1 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MGAT2	Q10469	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MOGAT2	Q3SYC2	94.86

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 22. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective MGAT2 causes CDG-2a	1	5710.0×	0.004	MGAT2
Reactions specific to the complex N-glycan synthesis pathway	1	571.0×	0.013	MGAT2
Triglyceride biosynthesis	1	335.9×	0.013	MOGAT2
Triglyceride metabolism	1	335.9×	0.013	MOGAT2
Diseases associated with N-glycosylation of proteins	1	317.2×	0.013	MGAT2
N-glycan antennae elongation in the medial/trans-Golgi	1	285.5×	0.013	MGAT2
Translation of Structural Proteins	1	203.9×	0.015	MGAT2
Late SARS-CoV-2 Infection Events	1	146.4×	0.018	MGAT2
Maturation of spike protein	1	132.8×	0.018	MGAT2
Diseases of glycosylation	1	65.6×	0.033	MGAT2
Transport to the Golgi and subsequent modification	1	51.4×	0.039	MGAT2
Diseases of metabolism	1	40.2×	0.042	MGAT2
SARS-CoV-2 Infection	1	40.2×	0.042	MGAT2
Asparagine N-linked glycosylation	1	30.1×	0.052	MGAT2
SARS-CoV Infections	1	27.7×	0.052	MGAT2
Metabolism of lipids	1	15.8×	0.083	MOGAT2
Viral Infection Pathways	1	15.4×	0.083	MGAT2
Infectious disease	1	12.4×	0.096	MGAT2
Post-translational protein modification	1	9.6×	0.118	MGAT2
Disease	1	6.5×	0.162	MGAT2
Metabolism of proteins	1	6.2×	0.163	MGAT2
Metabolism	1	5.8×	0.165	MOGAT2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
diacylglycerol biosynthetic process	1	936.2×	0.004	MOGAT2
monoacylglycerol biosynthetic process	1	766.0×	0.004	MOGAT2
intestinal absorption	1	601.9×	0.004	MOGAT2
glycerol metabolic process	1	561.7×	0.004	MOGAT2
triglyceride biosynthetic process	1	366.4×	0.004	MOGAT2
obsolete protein N-linked glycosylation via asparagine	1	337.0×	0.004	MGAT2
oligosaccharide biosynthetic process	1	324.1×	0.004	MGAT2
viral protein processing	1	271.8×	0.004	MGAT2
protein N-linked glycosylation	1	131.7×	0.008	MGAT2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 2 · Undrugged: 0

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MGAT2	2	1
MOGAT2	1	1

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BMS-986172	1	MGAT2, MOGAT2
BMS-963272	1	MGAT2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
MGAT2	32	Binding:32
MOGAT2	11	Binding:11

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MOGAT2	2.3.1.22	2-acylglycerol O-acyltransferase
MGAT2	2.4.1.143	alpha-1,6-mannosyl-glycoprotein 2-beta-N-acetylglucosaminyltransferase

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

2 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
BMS-986172	1	MGAT2, MOGAT2
BMS-963272	1	MGAT2

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	2	MOGAT2, MGAT2
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

0 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Clinical trials & evidence

Clinical trials

Clinical trials: 0.