congenital disorder of glycosylation type I

Summary

congenital disorder of glycosylation type I (MONDO:0005500) is a disease (an umbrella term covering 28 Mondo subtypes) caused by PMM2 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: PMM2 (GenCC Definitive)
• Umbrella term: 28 Mondo subtypes
• Cohort genes: 2
• ClinVar variants: 2

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital disorder of glycosylation type I
Mondo ID	MONDO:0005500
EFO	EFO:0005545
OMIM	212065
DOID	DOID:0050570
UMLS	C4700504
MedGen	1684618
GARD	0024196
Is cancer (heuristic)	no

Also known as: congenital disorders of glycosylation, type I

Data availability: 2 ClinVar variants · 1 GenCC gene-disease record.

Disease family

An umbrella term covering 28 Mondo subtypes.

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 I

Related subtypes (24): congenital disorder of glycosylation type II, Larsen-like syndrome, B3GAT3 type, Ehlers-Danlos syndrome, musculocontractural type, temtamy preaxial brachydactyly syndrome, progressive myoclonic epilepsy type 3, autosomal recessive limb-girdle muscular dystrophy type 2P, seizures-scoliosis-macrocephaly syndrome, disorder of protein N-glycosylation, disorder of protein O-glycosylation, inborn disorder of glycosphingolipid and glycosylphosphatidylinositol anchor glycosylation, disorder of multiple glycosylation, XYLT1-congenital disorder of glycosylation, congenital muscular dystrophy with intellectual disability, congenital disorder of glycosylation syndrome type 4, congenital disorder of glycosylation with defective fucosylation, SLC10A7-congenital disorder of glycosylation, ALG14-congenital disorder of glycosylation, B3GALT6-congenital disorder of glycosylation, A4GALT-congenital disorder of glycosylation, FAM20B-congenital disorder of glycosylation, ALG10-congenital disorder of glycosylation, congenital disorder of glycosylation, type Ibb, congenital disorder of glycosylation, type Iw, autosomal dominant, congenital disorder of glycosylation, type 1DD

Subtypes (28): PMM2-congenital disorder of glycosylation, developmental and epileptic encephalopathy, 36, SSR4-congenital disorder of glycosylation, ALG3-congenital disorder of glycosylation, MPI-congenital disorder of glycosylation, ALG6-congenital disorder of glycosylation 1C, ALG12-congenital disorder of glycosylation, ALG2-congenital disorder of glycosylation, DPAGT1-congenital disorder of glycosylation, ALG8-congenital disorder of glycosylation, ALG1-congenital disorder of glycosylation, ALG9-congenital disorder of glycosylation, congenital disorder of glycosylation type 1E, MPDU1-congenital disorder of glycosylation, DK1-congenital disorder of glycosylation, RFT1-congenital disorder of glycosylation, SRD5A3-congenital disorder of glycosylation, DPM3-congenital disorder of glycosylation, ALG11-congenital disorder of glycosylation, DDOST-congenital disorder of glycosylation, PGM1-congenital disorder of glycosylation, congenital muscular dystrophy with intellectual disability and severe epilepsy, STT3A-congenital disorder of glycosylation, STT3B-congenital disorder of glycosylation, developmental and epileptic encephalopathy, 50, congenital disorder of glycosylation, type IAA, congenital disorder of glycosylation, type ICC, SSR3-CDG

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

2 retrieved; paginated sample, class counts are floors:

1 pathogenic/likely pathogenic, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
224118	NM_019109.5(ALG1):c.1187+3A>G	ALG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
7706	NM_000303.3(PMM2):c.422G>A (p.Arg141His)	PMM2	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 2 · 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
PMM2	Definitive	Autosomal recessive	congenital disorder of glycosylation type I	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PMM2	Orphanet:79318	PMM2-CDG
ALG1	Orphanet:79327	ALG1-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
PMM2	HGNC:9115	ENSG00000140650	O15305	Phosphomannomutase 2	gencc,clinvar
ALG1	HGNC:18294	ENSG00000033011	Q9BT22	Chitobiosyldiphosphodolichol beta-mannosyltransferase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PMM2	Phosphomannomutase 2	Involved in the synthesis of the GDP-mannose and dolichol-phosphate-mannose required for a number of critical mannosyl transfer reactions.
ALG1	Chitobiosyldiphosphodolichol beta-mannosyltransferase	Mannosyltransferase that operates in the biosynthetic pathway of dolichol-linked oligosaccharides, the glycan precursors employed in protein asparagine (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)
PMM2	Enzyme (other)	yes	5.4.2.8	PMM, HAD-SF_hydro_IIB, HAD_sf
ALG1	Enzyme (other)	yes	2.4.1.142	Glyco_trans_1, ALG1-like

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
body of pancreas	2
calcaneal tendon	1
rectum	1
buccal mucosa cell	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PMM2	139	ubiquitous	marker	body of pancreas, calcaneal tendon, rectum
ALG1	185	ubiquitous	marker	stromal cell of endometrium, buccal mucosa cell, body of pancreas

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ALG1	2,187
PMM2	2,002

Intra-cohort edges

A	B	Sources
ALG1	PMM2	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PMM2	O15305	7

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ALG1	Q9BT22	93.24

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. 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 PMM2 causes PMM2-CDG	1	5710.0×	1e-03	PMM2
Defective ALG1 causes CDG-1k	1	5710.0×	1e-03	ALG1
Synthesis of GDP-mannose	1	951.7×	0.004	PMM2
Diseases associated with N-glycosylation of proteins	1	317.2×	0.009	ALG1
Biosynthesis of the N-glycan precursor (dolichol lipid-linked oligosaccharide, LLO) and transfer to a nascent protein	1	103.8×	0.021	ALG1
Diseases of glycosylation	1	65.6×	0.028	ALG1
Diseases of metabolism	1	40.2×	0.039	ALG1
Asparagine N-linked glycosylation	1	30.1×	0.045	ALG1
Post-translational protein modification	1	9.6×	0.124	ALG1
Disease	1	6.5×	0.155	ALG1
Metabolism of proteins	1	6.2×	0.155	ALG1

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
protein N-linked glycosylation	2	263.3×	1e-04	PMM2, ALG1
obsolete GDP-D-mannose biosynthetic process from fructose-6-phosphate	1	4213.0×	8e-04	PMM2
obsolete GDP-mannose biosynthetic process from mannose	1	2808.7×	8e-04	PMM2
GDP-mannose biosynthetic process	1	1404.3×	0.001	PMM2
mannose metabolic process	1	1053.2×	0.001	PMM2
dolichol-linked oligosaccharide biosynthetic process	1	421.3×	0.003	ALG1
glycoprotein biosynthetic process	1	168.5×	0.006	PMM2

Therapeutics

Drug target analysis

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

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
PMM2	1	3
ALG1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
EBSELEN	3	PMM2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
PMM2	3	Binding:3
ALG1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PMM2	5.4.2.8	phosphomannomutase
ALG1	2.4.1.142	chitobiosyldiphosphodolichol beta-mannosyltransferase

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

1 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)
EBSELEN	3	PMM2

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	1	PMM2
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	ALG1
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ALG1	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.