ALG3-congenital disorder of glycosylation

Summary

ALG3-congenital disorder of glycosylation (MONDO:0010998) is a disease caused by ALG3 (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ALG3 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 185
• Phenotypes (HPO): 45

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		15	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

45 HPO clinical features (Orphanet curated; top 45 by frequency):

HPO ID	Term	Frequency
HP:0012379	Abnormal enzyme/coenzyme activity	Obligate (100%)
HP:0001252	Hypotonia	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0002060	Abnormal cerebral morphology	Very frequent (80-99%)
HP:0002719	Recurrent infections	Very frequent (80-99%)
HP:0011024	Abnormality of the gastrointestinal tract	Very frequent (80-99%)
HP:0011968	Feeding difficulties	Very frequent (80-99%)
HP:0000119	Abnormality of the genitourinary system	Frequent (30-79%)
HP:0000252	Microcephaly	Frequent (30-79%)
HP:0000365	Hearing impairment	Frequent (30-79%)
HP:0000366	Abnormality of the nose	Frequent (30-79%)
HP:0000377	Abnormal pinna morphology	Frequent (30-79%)
HP:0000478	Abnormality of the eye	Frequent (30-79%)
HP:0000818	Abnormality of the endocrine system	Frequent (30-79%)
HP:0000938	Osteopenia	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001410	Decreased liver function	Frequent (30-79%)
HP:0002086	Abnormality of the respiratory system	Frequent (30-79%)
HP:0002813	Abnormality of limb bone morphology	Frequent (30-79%)
HP:0030680	Abnormal cardiovascular system morphology	Frequent (30-79%)
HP:0040064	Abnormality of limbs	Frequent (30-79%)
HP:0001276	Hypertonia	Occasional (5-29%)
HP:0001285	Spastic tetraparesis	Occasional (5-29%)
HP:0001332	Dystonia	Occasional (5-29%)
HP:0001871	Abnormality of blood and blood-forming tissues	Occasional (5-29%)
HP:0003186	Inverted nipples	Occasional (5-29%)
HP:0012444	Brain atrophy	Occasional (5-29%)
HP:0045005	Neural tube defect	Occasional (5-29%)
HP:0000158	Macroglossia	Very rare (<1-4%)
HP:0000172	Abnormality of the uvula	Very rare (<1-4%)
HP:0000218	High palate	Very rare (<1-4%)
HP:0000518	Cataract	Very rare (<1-4%)
HP:0000639	Nystagmus	Very rare (<1-4%)
HP:0001010	Hypopigmentation of the skin	Very rare (<1-4%)
HP:0001305	Dandy-Walker malformation	Very rare (<1-4%)
HP:0001638	Cardiomyopathy	Very rare (<1-4%)
HP:0002079	Hypoplasia of the corpus callosum	Very rare (<1-4%)
HP:0002089	Pulmonary hypoplasia	Very rare (<1-4%)
HP:0002804	Arthrogryposis multiplex congenita	Very rare (<1-4%)
HP:0005871	Metaphyseal chondrodysplasia	Very rare (<1-4%)
HP:0009125	Lipodystrophy	Very rare (<1-4%)
HP:0012110	Hypoplasia of the pons	Very rare (<1-4%)
HP:0012157	Subcortical cerebral atrophy	Very rare (<1-4%)
HP:0012305	Coarctation of the descending aortic arch	Very rare (<1-4%)
HP:0012762	Cerebral white matter atrophy	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	ALG3-congenital disorder of glycosylation
Mondo ID	MONDO:0010998
MeSH	C535742
OMIM	601110
Orphanet	79321
DOID	DOID:0080556
NCIT	C126870
SNOMED CT	720976009
UMLS	C1832736
MedGen	322026
GARD	0009827
Is cancer (heuristic)	no

Also known as: ALG3-CDG · ALG3-CDG (CDG-Id) · ALG3-congenital disorder of glycosylation · carbohydrate deficient glycoprotein syndrome type Id · carbohydrate-deficient glycoprotein syndrome type IV (formerly) · CDG 1D · CDG syndrome type Id · CDG-Id · CDG1D · CDGId · CDGS4 (formerly) · congenital disorder of glycosylation type 1d · congenital disorder of glycosylation type Id · congenital disorder of glycosylation, type Id · mannosyltransferase 6 deficiency

Data availability: 185 ClinVar variants · 5 GenCC gene-disease records · 2 cell lines.

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 I › ALG3-congenital disorder of glycosylation

Related subtypes (27): PMM2-congenital disorder of glycosylation, developmental and epileptic encephalopathy, 36, SSR4-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

185 retrieved; paginated sample, class counts are floors:

76 uncertain significance, 51 likely benign, 17 conflicting classifications of pathogenicity, 17 pathogenic, 13 likely pathogenic, 4 pathogenic/likely pathogenic, 4 benign/likely benign, 3 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1053045	NM_005787.6(ALG3):c.1061G>A (p.Arg354His)	ALG3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1172674	NM_005787.6(ALG3):c.72G>A (p.Trp24Ter)	ALG3	Pathogenic	criteria provided, single submitter
1184848	NM_005787.6(ALG3):c.796C>T (p.Arg266Cys)	ALG3	Pathogenic	criteria provided, multiple submitters, no conflicts
1184850	NM_005787.6(ALG3):c.1154G>C (p.Arg385Thr)	ALG3	Pathogenic	no assertion criteria provided
2000151	NM_005787.6(ALG3):c.1188dup (p.Asn397fs)	ALG3	Pathogenic	criteria provided, single submitter
2127	NM_005787.6(ALG3):c.353G>A (p.Gly118Asp)	ALG3	Pathogenic	no assertion criteria provided
2128	NM_005787.6(ALG3):c.165C>T (p.Gly55=)	ALG3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2129	NM_005787.6(ALG3):c.512G>A (p.Arg171Gln)	ALG3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2131	NM_005787.6(ALG3):c.470T>A (p.Met157Lys)	ALG3	Pathogenic	no assertion criteria provided
2741374	NM_005787.6(ALG3):c.29_45dup (p.Gln16fs)	ALG3	Pathogenic	criteria provided, single submitter
2780035	NM_005787.6(ALG3):c.1188G>A (p.Trp396Ter)	ALG3	Pathogenic	criteria provided, multiple submitters, no conflicts
3251416	NM_005787.6(ALG3):c.67C>T (p.Gln23Ter)	ALG3	Pathogenic	criteria provided, single submitter
3588985	NM_005787.6(ALG3):c.116del (p.Pro39fs)	ALG3	Pathogenic	criteria provided, single submitter
3609293	NM_005787.6(ALG3):c.890_891del (p.His297fs)	ALG3	Pathogenic	criteria provided, single submitter
4706770	NM_005787.6(ALG3):c.859C>T (p.Arg287Ter)	ALG3	Pathogenic	criteria provided, single submitter
4795102	NM_005787.6(ALG3):c.606-2A>C	ALG3	Pathogenic	criteria provided, single submitter
521583	NM_005787.6(ALG3):c.991C>T (p.Gln331Ter)	ALG3	Pathogenic	criteria provided, single submitter
617476	NM_005787.6(ALG3):c.1263G>A (p.Trp421Ter)	ALG3	Pathogenic	no assertion criteria provided
617513	NM_005787.6(ALG3):c.1037A>G (p.Asn346Ser)	ALG3	Pathogenic	criteria provided, single submitter
617517	NM_005787.6(ALG3):c.163_196+3del	ALG3	Pathogenic	no assertion criteria provided
988293	NM_005787.6(ALG3):c.2T>C (p.Met1Thr)	ALG3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1184851	NM_005787.6(ALG3):c.521A>G (p.Asn174Ser)	ALG3	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1184852	NM_005787.6(ALG3):c.410_411insTGTCTTCTTGCT (p.Leu137_Leu138insValPheLeuLeu)	ALG3	Likely pathogenic	no assertion criteria provided
2734602	NM_005787.6(ALG3):c.1060C>T (p.Arg354Cys)	ALG3	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3374936	NM_005787.6(ALG3):c.444+1G>A	ALG3	Likely pathogenic	criteria provided, single submitter
3896067	NM_005787.6(ALG3):c.206T>C (p.Ile69Thr)	ALG3	Likely pathogenic	criteria provided, multiple submitters, no conflicts
4531886	NM_005787.6(ALG3):c.488G>A (p.Arg163His)	ALG3	Likely pathogenic	criteria provided, single submitter
4849462	NM_005787.6(ALG3):c.511C>T (p.Arg171Trp)	ALG3	Likely pathogenic	criteria provided, single submitter
502711	NM_005787.6(ALG3):c.444+1G>T	ALG3	Likely pathogenic	criteria provided, multiple submitters, no conflicts
617514	NM_005787.6(ALG3):c.296+4A>G	ALG3	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
ALG3	Definitive	Autosomal recessive	ALG3-congenital disorder of glycosylation	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ALG3	Orphanet:79321	ALG3-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
ALG3	HGNC:23056	ENSG00000214160	Q92685	Dol-P-Man:Man(5)GlcNAc(2)-PP-Dol alpha-1,3-mannosyltransferase	gencc,clinvar
EEF1AKMT4-ECE2	HGNC:53615	ENSG00000284917	P0DPD8	EEF1AKMT4-ECE2 readthrough transcript protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ALG3	Dol-P-Man:Man(5)GlcNAc(2)-PP-Dol alpha-1,3-mannosyltransferase	Dol-P-Man:Man(5)GlcNAc(2)-PP-Dol alpha-1,3-mannosyltransferase that operates in the biosynthetic pathway of dolichol-linked oligosaccharides, the glycan precursors employed in protein asparagine (N)-glycosylation.
EEF1AKMT4-ECE2	EEF1AKMT4-ECE2 readthrough transcript protein	Converts big endothelin-1 to endothelin-1.

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
Protease	1	18.3×	0.108
Enzyme (other)	1	6.0×	0.160

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ALG3	Enzyme (other)	yes	2.4.1.258	Glycosyltransferase_ALG3
EEF1AKMT4-ECE2	Protease	yes		Peptidase_M13, Peptidase_M13_N, Peptidase_M13_C

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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
mucosa of transverse colon	1
right lobe of liver	1
stromal cell of endometrium	1
cortical plate	1
prefrontal cortex	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ALG3	208	ubiquitous	marker	mucosa of transverse colon, stromal cell of endometrium, right lobe of liver
EEF1AKMT4-ECE2	38	ubiquitous	yes	prefrontal cortex, ventricular zone, cortical plate

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ALG3	1,320
EEF1AKMT4-ECE2	448

Structural data

PDB: 0 · AlphaFold-only: 2 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
EEF1AKMT4-ECE2	P0DPD8	91.49
ALG3	Q92685	89.05

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. Enrichment computed across 2 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective ALG3 causes CDG-1d	1	11420.0×	8e-04	ALG3
Diseases associated with N-glycosylation of proteins	1	634.4×	0.007	ALG3
Biosynthesis of the N-glycan precursor (dolichol lipid-linked oligosaccharide, LLO) and transfer to a nascent protein	1	207.6×	0.014	ALG3
Diseases of glycosylation	1	131.3×	0.017	ALG3
Diseases of metabolism	1	80.4×	0.022	ALG3
Asparagine N-linked glycosylation	1	60.1×	0.025	ALG3
Post-translational protein modification	1	19.2×	0.067	ALG3
Disease	1	13.1×	0.081	ALG3
Metabolism of proteins	1	12.4×	0.081	ALG3

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
cardioblast differentiation	1	4213.0×	0.002	EEF1AKMT4-ECE2
peptide hormone processing	1	468.1×	0.006	EEF1AKMT4-ECE2
dolichol-linked oligosaccharide biosynthetic process	1	421.3×	0.006	ALG3
protein N-linked glycosylation	1	131.7×	0.015	ALG3
protein processing	1	85.1×	0.016	EEF1AKMT4-ECE2
methylation	1	85.1×	0.016	EEF1AKMT4-ECE2
brain development	1	39.8×	0.025	EEF1AKMT4-ECE2
heart development	1	39.4×	0.025	EEF1AKMT4-ECE2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ALG3	0	0
EEF1AKMT4-ECE2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
ALG3	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ALG3	2.4.1.258	dolichyl-P-Man:Man5GlcNAc2-PP-dolichol alpha-1,3-mannosyltransferase

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

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	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	2	ALG3, EEF1AKMT4-ECE2
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ALG3	1	—
EEF1AKMT4-ECE2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.