ALG8-congenital disorder of glycosylation

Summary

ALG8-congenital disorder of glycosylation (MONDO:0011969) is a disease caused by ALG8 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ALG8 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 305
• Phenotypes (HPO): 48

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)

48 HPO clinical features (Orphanet curated; top 48 by frequency):

HPO ID	Term	Frequency
HP:0000707	Abnormality of the nervous system	Very frequent (80-99%)
HP:0001252	Hypotonia	Very frequent (80-99%)
HP:0001999	Abnormal facial shape	Very frequent (80-99%)
HP:0000478	Abnormality of the eye	Frequent (30-79%)
HP:0000518	Cataract	Frequent (30-79%)
HP:0000969	Edema	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001541	Ascites	Frequent (30-79%)
HP:0001622	Premature birth	Frequent (30-79%)
HP:0001789	Hydrops fetalis	Frequent (30-79%)
HP:0001873	Thrombocytopenia	Frequent (30-79%)
HP:0002902	Hyponatremia	Frequent (30-79%)
HP:0002910	Elevated circulating hepatic transaminase concentration	Frequent (30-79%)
HP:0003256	Abnormality of the coagulation cascade	Frequent (30-79%)
HP:0003642	Type I transferrin isoform profile	Frequent (30-79%)
HP:0011024	Abnormality of the gastrointestinal tract	Frequent (30-79%)
HP:0011121	Abnormal skin morphology	Frequent (30-79%)
HP:0000158	Macroglossia	Occasional (5-29%)
HP:0000316	Hypertelorism	Occasional (5-29%)
HP:0000369	Low-set ears	Occasional (5-29%)
HP:0000488	Retinopathy	Occasional (5-29%)
HP:0000639	Nystagmus	Occasional (5-29%)
HP:0000648	Optic atrophy	Occasional (5-29%)
HP:0000973	Cutis laxa	Occasional (5-29%)
HP:0001001	Abnormality of subcutaneous fat tissue	Occasional (5-29%)
HP:0001156	Brachydactyly	Occasional (5-29%)
HP:0001251	Ataxia	Occasional (5-29%)
HP:0001508	Failure to thrive	Occasional (5-29%)
HP:0001511	Intrauterine growth retardation	Occasional (5-29%)
HP:0001518	Small for gestational age	Occasional (5-29%)
HP:0001562	Oligohydramnios	Occasional (5-29%)
HP:0001762	Talipes equinovarus	Occasional (5-29%)
HP:0001903	Anemia	Occasional (5-29%)
HP:0001929	Reduced factor XI activity	Occasional (5-29%)
HP:0001976	Reduced antithrombin III activity	Occasional (5-29%)
HP:0002013	Vomiting	Occasional (5-29%)
HP:0002014	Diarrhea	Occasional (5-29%)
HP:0002079	Hypoplasia of the corpus callosum	Occasional (5-29%)
HP:0002119	Ventriculomegaly	Occasional (5-29%)
HP:0002120	Cerebral cortical atrophy	Occasional (5-29%)
HP:0002352	Leukoencephalopathy	Occasional (5-29%)
HP:0002415	Leukodystrophy	Occasional (5-29%)
HP:0003186	Inverted nipples	Occasional (5-29%)
HP:0005543	Reduced protein C activity	Occasional (5-29%)
HP:0011968	Feeding difficulties	Occasional (5-29%)
HP:0012385	Camptodactyly	Occasional (5-29%)
HP:0100678	Premature skin wrinkling	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	ALG8-congenital disorder of glycosylation
Mondo ID	MONDO:0011969
MeSH	C535746
OMIM	608104
Orphanet	79325
DOID	DOID:0080560
SNOMED CT	720977000
UMLS	C2931002
MedGen	419692
GARD	0009834
Is cancer (heuristic)	no

Also known as: ALG8-CDG · ALG8-CDG (CDG-Ih) · ALG8-congenital disorder of glycosylation · carbohydrate deficient glycoprotein syndrome type Ih · CDG 1H · CDG syndrome type Ih · CDG-Ih · CDG1H · congenital disorder of glycosylation type 1h · congenital disorder of glycosylation type Ih · congenital disorder of glycosylation, type Ih · glucosyltransferase 2 deficiency

Data availability: 305 ClinVar variants · 5 GenCC gene-disease records · 1 cell line.

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 › ALG8-congenital disorder of glycosylation

Related subtypes (27): 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, 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

305 retrieved; paginated sample, class counts are floors:

155 uncertain significance, 62 likely benign, 28 likely pathogenic, 22 conflicting classifications of pathogenicity, 12 pathogenic, 10 pathogenic/likely pathogenic, 9 benign, 7 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1064698	NM_024079.5(ALG8):c.479A>T (p.His160Leu)	ALG8	Pathogenic	no assertion criteria provided
1342864	NM_024079.5(ALG8):c.1219_1220del (p.Leu407fs)	ALG8	Pathogenic	no assertion criteria provided
1406714	NM_024079.5(ALG8):c.802C>T (p.Arg268Ter)	ALG8	Pathogenic	criteria provided, single submitter
1437904	NM_024079.5(ALG8):c.802del (p.Arg268fs)	ALG8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2015614	NM_024079.5(ALG8):c.141_144del (p.His48fs)	ALG8	Pathogenic	criteria provided, single submitter
2123918	NM_024079.5(ALG8):c.259C>T (p.Gln87Ter)	ALG8	Pathogenic	criteria provided, single submitter
2230523	NM_024079.5(ALG8):c.309dup (p.Leu104fs)	ALG8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2506353	NM_024079.5(ALG8):c.272del (p.Asn91fs)	ALG8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2558	NM_024079.5(ALG8):c.413del (p.Thr138fs)	ALG8	Pathogenic	no assertion criteria provided
2560	NM_024079.5(ALG8):c.96-2A>G	ALG8	Pathogenic	no assertion criteria provided
2561	NM_024079.5(ALG8):c.139A>C (p.Thr47Pro)	ALG8	Pathogenic	criteria provided, single submitter
280116	NM_024079.5(ALG8):c.1090C>T (p.Arg364Ter)	ALG8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2977771	NM_024079.5(ALG8):c.1353dup (p.Glu452fs)	ALG8	Pathogenic	criteria provided, single submitter
2982294	NM_024079.5(ALG8):c.824del (p.Gly275fs)	ALG8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3244664	NC_000011.9:g.(?77850520)(77850634_?)del	ALG8	Pathogenic	criteria provided, single submitter
3574056	NM_024079.5(ALG8):c.740T>G (p.Leu247Ter)	ALG8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3693026	NM_024079.5(ALG8):c.1098_1101del (p.Thr367fs)	ALG8	Pathogenic	criteria provided, single submitter
492977	NM_024079.5(ALG8):c.535C>T (p.Arg179Ter)	ALG8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
854540	NM_024079.5(ALG8):c.761dup (p.Pro255fs)	ALG8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
956334	NM_024079.5(ALG8):c.981dup (p.Val328fs)	ALG8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
96090	NM_024079.5(ALG8):c.121C>T (p.Arg41Ter)	ALG8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
96091	NM_024079.5(ALG8):c.122G>A (p.Arg41Gln)	ALG8	Pathogenic	criteria provided, multiple submitters, no conflicts
1328207	NM_024079.5(ALG8):c.685C>T (p.Arg229Ter)	ALG8	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1344961	NM_024079.5(ALG8):c.95+1G>A	ALG8	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2118558	NM_024079.5(ALG8):c.174+2del	ALG8	Likely pathogenic	criteria provided, single submitter
2562	NM_024079.5(ALG8):c.673+4A>G	ALG8	Likely pathogenic	criteria provided, single submitter
2563	NM_024079.5(ALG8):c.824G>A (p.Gly275Asp)	ALG8	Likely pathogenic	criteria provided, single submitter
2628603	NM_024079.5(ALG8):c.777+1G>A	ALG8	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2683953	NM_024079.5(ALG8):c.544C>T (p.Gln182Ter)	ALG8	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2796277	NM_024079.5(ALG8):c.368+1G>A	ALG8	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · 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
ALG8	Definitive	Autosomal recessive	ALG8-congenital disorder of glycosylation	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ALG8	Orphanet:2924	Isolated polycystic liver disease
ALG8	Orphanet:79325	ALG8-CDG

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ALG8	HGNC:23161	ENSG00000159063	Q9BVK2	Dolichyl pyrophosphate Glc1Man9GlcNAc2 alpha-1,3-glucosyltransferase	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ALG8	Dolichyl pyrophosphate Glc1Man9GlcNAc2 alpha-1,3-glucosyltransferase	Dolichyl pyrophosphate Glc1Man9GlcNAc2 alpha-1,3-glucosyltransferase that operates in the biosynthetic pathway of dolichol-linked oligosaccharides, the glycan precursors employed in protein asparagine (N)-glycosylation.

Protein-family classification

Druggable: 1 · 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)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ALG8	Enzyme (other)	yes	2.4.1.265	Glyco_trans_ALG6/ALG8

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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
left testis	1
right testis	1
testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ALG8	282	ubiquitous	marker	right testis, left testis, testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ALG8	1,010

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ALG8	Q9BVK2	92.07

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. Enrichment computed across 1 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 ALG8 causes CDG-1h	1	11420.0×	8e-04	ALG8
Diseases associated with N-glycosylation of proteins	1	634.4×	0.007	ALG8
Biosynthesis of the N-glycan precursor (dolichol lipid-linked oligosaccharide, LLO) and transfer to a nascent protein	1	207.6×	0.014	ALG8
Diseases of glycosylation	1	131.3×	0.017	ALG8
Diseases of metabolism	1	80.4×	0.022	ALG8
Asparagine N-linked glycosylation	1	60.1×	0.025	ALG8
Post-translational protein modification	1	19.2×	0.067	ALG8
Disease	1	13.1×	0.081	ALG8
Metabolism of proteins	1	12.4×	0.081	ALG8

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
dolichol-linked oligosaccharide biosynthetic process	1	842.6×	0.002	ALG8
obsolete protein N-linked glycosylation via asparagine	1	674.1×	0.002	ALG8
protein N-linked glycosylation	1	263.3×	0.004	ALG8

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 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
ALG8	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
ALG8	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ALG8	2.4.1.265	dolichyl-P-Glc:Glc1Man9GlcNAc2-PP-dolichol alpha-1,3-glucosyltransferase

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	1	ALG8
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)
ALG8	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.