ALG2-congenital disorder of glycosylation

Summary

ALG2-congenital disorder of glycosylation (MONDO:0011933) is a disease caused by ALG2 (GenCC Strong), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ALG2 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 305
• Phenotypes (HPO): 25

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

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

Signs & symptoms

Clinical features (HPO)

25 HPO clinical features (Orphanet curated; top 25 by frequency):

HPO ID	Term	Frequency
HP:0003642	Type I transferrin isoform profile	Very frequent (80-99%)
HP:0012379	Abnormal enzyme/coenzyme activity	Very frequent (80-99%)
HP:0000252	Microcephaly	Frequent (30-79%)
HP:0000286	Epicanthus	Frequent (30-79%)
HP:0000431	Wide nasal bridge	Frequent (30-79%)
HP:0000494	Downslanted palpebral fissures	Frequent (30-79%)
HP:0000518	Cataract	Frequent (30-79%)
HP:0000565	Esotropia	Frequent (30-79%)
HP:0000612	Iris coloboma	Frequent (30-79%)
HP:0000707	Abnormality of the nervous system	Frequent (30-79%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001928	Abnormality of coagulation	Frequent (30-79%)
HP:0001999	Abnormal facial shape	Frequent (30-79%)
HP:0002521	Hypsarrhythmia	Frequent (30-79%)
HP:0011344	Severe global developmental delay	Frequent (30-79%)
HP:0002079	Hypoplasia of the corpus callosum	Occasional (5-29%)
HP:0002240	Hepatomegaly	Occasional (5-29%)
HP:0006808	Cerebral hypomyelination	Occasional (5-29%)
HP:0006956	Dilation of lateral ventricles	Occasional (5-29%)
HP:0012469	Infantile spasms	Occasional (5-29%)
HP:0012704	Widened subarachnoid space	Occasional (5-29%)
HP:0012751	Abnormal basal ganglia MRI signal intensity	Occasional (5-29%)
HP:0030890	Hyperintensity of cerebral white matter on MRI	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	ALG2-congenital disorder of glycosylation
Mondo ID	MONDO:0011933
OMIM	607906
Orphanet	79326
DOID	DOID:0080561
UMLS	C1842836
MedGen	334618
GARD	0009836
Is cancer (heuristic)	no

Also known as: ALG2-CDG · ALG2-CDG (CDG-II) · ALG2-congenital disorder of glycosylation · carbohydrate deficient glycoprotein syndrome type Ii · carbohydrate-deficient glycoprotein syndrome type 1I · CDG 1I · CDG Ii · CDG syndrome type Ii · CDG1I · congenital disorder of glycosylation type 1i · congenital disorder of glycosylation type Ii · congenital disorder of glycosylation, type Ii · mannosyltransferase 2 deficiency

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

Disease family

An umbrella term covering 1 Mondo subtype.

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 › ALG2-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, 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

Subtypes (1): congenital myasthenic syndrome 14

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:

162 uncertain significance, 116 likely benign, 8 conflicting classifications of pathogenicity, 6 benign, 6 benign/likely benign, 4 likely pathogenic, 2 pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1676197	NM_033087.4(ALG2):c.752G>T (p.Arg251Leu)	ALG2	Pathogenic	no assertion criteria provided
2699	NM_033087.4(ALG2):c.1040del (p.Gly347fs)	ALG2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2700	NM_033087.4(ALG2):c.393G>T (p.Lys131Asn)	ALG2	Pathogenic	no assertion criteria provided
1184506	NM_033087.4(ALG2):c.176G>A (p.Cys59Tyr)	ALG2	Likely pathogenic	no assertion criteria provided
3064139	NM_033087.4(ALG2):c.216delinsTCCCC (p.Asp73fs)	ALG2	Likely pathogenic	criteria provided, single submitter
3779328	NM_033087.4(ALG2):c.814G>T (p.Glu272Ter)	ALG2	Likely pathogenic	criteria provided, single submitter
915335	NM_033087.4(ALG2):c.218_225del (p.Asp73fs)	ALG2	Likely pathogenic	criteria provided, single submitter
1041171	NM_033087.4(ALG2):c.945C>T (p.Cys315=)	ALG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2146428	NM_033087.4(ALG2):c.1133G>A (p.Arg378His)	ALG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
390397	NM_033087.4(ALG2):c.475A>G (p.Ile159Val)	ALG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
464893	NM_033087.4(ALG2):c.1055_1056delinsTGA (p.Ser352fs)	ALG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
464895	NM_033087.4(ALG2):c.348+6G>A	ALG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
856875	NM_033087.4(ALG2):c.20G>A (p.Arg7Gln)	ALG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
952342	NM_033087.4(ALG2):c.1226G>A (p.Arg409Gln)	ALG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
595205	NM_001183.6(ATP6AP1):c.43C>T (p.Arg15Trp)	ATP6AP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1000582	NM_033087.4(ALG2):c.202G>A (p.Val68Met)	ALG2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1004082	NM_033087.4(ALG2):c.703G>A (p.Glu235Lys)	ALG2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1016801	NM_033087.4(ALG2):c.30del (p.Ser11fs)	ALG2	Uncertain significance	criteria provided, single submitter
1017971	NM_033087.4(ALG2):c.389G>A (p.Arg130Gln)	ALG2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1021130	NM_033087.4(ALG2):c.1054_1055insTGA (p.Ser352delinsLeuThr)	ALG2	Uncertain significance	criteria provided, single submitter
1027185	NM_033087.4(ALG2):c.1115C>T (p.Ala372Val)	ALG2	Uncertain significance	criteria provided, single submitter
1031029	NM_033087.4(ALG2):c.1064A>G (p.His355Arg)	ALG2	Uncertain significance	criteria provided, single submitter
1035954	NM_033087.4(ALG2):c.89_114del (p.Glu30fs)	ALG2	Uncertain significance	criteria provided, single submitter
1039238	NM_033087.4(ALG2):c.1218G>C (p.Gln406His)	ALG2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1041393	NM_033087.4(ALG2):c.367G>A (p.Val123Met)	ALG2	Uncertain significance	criteria provided, single submitter
1047589	NM_033087.4(ALG2):c.434C>T (p.Thr145Ile)	ALG2	Uncertain significance	criteria provided, single submitter
1053713	NM_033087.4(ALG2):c.1156_1162del (p.Met386fs)	ALG2	Uncertain significance	criteria provided, single submitter
1059228	NM_033087.4(ALG2):c.1239A>C (p.Lys413Asn)	ALG2	Uncertain significance	criteria provided, single submitter
1062878	NM_033087.4(ALG2):c.214G>A (p.Gly72Arg)	ALG2	Uncertain significance	criteria provided, single submitter
1063273	NM_033087.4(ALG2):c.32C>T (p.Ser11Leu)	ALG2	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 3 · 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
ALG2	Strong	Autosomal recessive	congenital myasthenic syndrome 14	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ALG2	Orphanet:353327	Congenital myasthenic syndrome with glycosylation defect
ALG2	Orphanet:79326	ALG2-CDG
ATP6AP1	Orphanet:692790	ATP6AP1-CDG

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ALG2	HGNC:23159	ENSG00000119523	Q9H553	Alpha-1,3/1,6-mannosyltransferase ALG2	gencc,clinvar
ANP32B	HGNC:16677	ENSG00000136938	Q92688	Acidic leucine-rich nuclear phosphoprotein 32 family member B	clinvar
ATP6AP1	HGNC:868	ENSG00000071553	Q15904	V-type proton ATPase subunit S1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ALG2	Alpha-1,3/1,6-mannosyltransferase ALG2	Mannosyltransferase that operates in the biosynthetic pathway of dolichol-linked oligosaccharides, the glycan precursors employed in protein asparagine (N)-glycosylation.
ANP32B	Acidic leucine-rich nuclear phosphoprotein 32 family member B	Multifunctional protein that is involved in the regulation of many processes including cell proliferation, apoptosis, cell cycle progression or transcription.
ATP6AP1	V-type proton ATPase subunit S1	Accessory subunit of the proton-transporting vacuolar (V)-ATPase protein pump, which is required for luminal acidification of secretory vesicles.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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	4.0×	0.460
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ALG2	Enzyme (other)	yes	2.4.1.132	Glyco_trans_1, ALG2, Glyco_trans_4-like_N
ANP32B	Other/Unknown	no		Leu-rich_rpt, U2A’_phosphoprotein32A_C, LRR_dom_sf
ATP6AP1	Other/Unknown	no		Ac45_acc_su, VAS1_LD, VAS1/VOA1_TM

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
caput epididymis	1
corpus epididymis	1
epithelial cell of pancreas	1
cranial nerve II	1
tendon of biceps brachii	1
trabecular bone tissue	1
Brodmann (1909) area 10	1
endometrium epithelium	1
paraflocculus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ALG2	256	ubiquitous	marker	epithelial cell of pancreas, corpus epididymis, caput epididymis
ANP32B	295	ubiquitous	marker	tendon of biceps brachii, trabecular bone tissue, cranial nerve II
ATP6AP1	291	ubiquitous	marker	endometrium epithelium, Brodmann (1909) area 10, paraflocculus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ALG2	1,967
ATP6AP1	1,759
ANP32B	339

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ATP6AP1	Q15904	9
ANP32B	Q92688	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ALG2	Q9H553	91.03

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. Enrichment computed across 3 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 ALG2 causes CDG-1i	1	5710.0×	0.002	ALG2
Diseases associated with N-glycosylation of proteins	1	317.2×	0.018	ALG2
Insulin receptor recycling	1	190.3×	0.018	ATP6AP1
Transferrin endocytosis and recycling	1	184.2×	0.018	ATP6AP1
Biosynthesis of the N-glycan precursor (dolichol lipid-linked oligosaccharide, LLO) and transfer to a nascent protein	1	103.8×	0.025	ALG2
Diseases of glycosylation	1	65.6×	0.033	ALG2
Ion channel transport	1	48.0×	0.038	ATP6AP1
Diseases of metabolism	1	40.2×	0.038	ALG2
RHOA GTPase cycle	1	37.3×	0.038	ATP6AP1
Asparagine N-linked glycosylation	1	30.1×	0.043	ALG2
Post-translational protein modification	1	9.6×	0.120	ALG2
Disease	1	6.5×	0.155	ALG2
Metabolism of proteins	1	6.2×	0.155	ALG2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
obsolete regulation of cellular pH	1	1123.5×	0.007	ATP6AP1
endosome to plasma membrane protein transport	1	1123.5×	0.007	ATP6AP1
osteoclast development	1	702.2×	0.007	ATP6AP1
cellular response to increased oxygen levels	1	702.2×	0.007	ATP6AP1
Golgi lumen acidification	1	561.7×	0.007	ATP6AP1
endosomal lumen acidification	1	401.2×	0.007	ATP6AP1
intracellular pH reduction	1	401.2×	0.007	ATP6AP1
vasculature development	1	374.5×	0.007	ANP32B
synaptic vesicle lumen acidification	1	312.1×	0.007	ATP6AP1
dolichol-linked oligosaccharide biosynthetic process	1	280.9×	0.007	ALG2
ventricular system development	1	280.9×	0.007	ANP32B
positive regulation of protein export from nucleus	1	267.5×	0.007	ANP32B
vacuolar acidification	1	244.2×	0.008	ATP6AP1
lysosomal lumen acidification	1	224.7×	0.008	ATP6AP1
inner ear development	1	124.8×	0.013	ANP32B
glycoprotein biosynthetic process	1	112.3×	0.013	ALG2
proton transmembrane transport	1	104.0×	0.014	ATP6AP1
negative regulation of cell differentiation	1	95.2×	0.014	ANP32B
protein N-linked glycosylation	1	87.8×	0.014	ALG2
roof of mouth development	1	82.6×	0.014	ANP32B
intracellular iron ion homeostasis	1	81.4×	0.014	ATP6AP1
nucleosome assembly	1	46.8×	0.023	ANP32B
regulation of apoptotic process	1	27.8×	0.037	ANP32B
negative regulation of apoptotic process	1	11.6×	0.084	ANP32B

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ANP32B	1	2
ALG2	0	0
ATP6AP1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	ANP32B

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
ANP32B	9	Binding:9
ATP6AP1	7	Binding:7

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ALG2	2.4.1.132, 2.4.1.257	GDP-Man:Man1GlcNAc2-PP-dolichol alpha-1,3-mannosyltransferase, GDP-Man:Man2GlcNAc2-PP-dolichol alpha-1,6-mannosyltransferase

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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)
MOLIBRESIB	2	ANP32B

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	ANP32B
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	ALG2
E	Difficult family or no structure, no drug	1	ATP6AP1

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)
ALG2	0	—
ATP6AP1	7	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.