ALG1-congenital disorder of glycosylation

Summary

ALG1-congenital disorder of glycosylation (MONDO:0012052) is a disease caused by ALG1 (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ALG1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 873
• Phenotypes (HPO): 33

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		57	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

33 HPO clinical features (Orphanet curated; top 33 by frequency):

HPO ID	Term	Frequency
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001250	Seizure	Very frequent (80-99%)
HP:0001252	Hypotonia	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0000253	Progressive microcephaly	Frequent (30-79%)
HP:0000478	Abnormality of the eye	Frequent (30-79%)
HP:0000486	Strabismus	Frequent (30-79%)
HP:0000924	Abnormality of the skeletal system	Frequent (30-79%)
HP:0001256	Intellectual disability, mild	Frequent (30-79%)
HP:0001871	Abnormality of blood and blood-forming tissues	Frequent (30-79%)
HP:0001999	Abnormal facial shape	Frequent (30-79%)
HP:0002028	Chronic diarrhea	Frequent (30-79%)
HP:0002650	Scoliosis	Frequent (30-79%)
HP:0003073	Hypoalbuminemia	Frequent (30-79%)
HP:0011024	Abnormality of the gastrointestinal tract	Frequent (30-79%)
HP:0011344	Severe global developmental delay	Frequent (30-79%)
HP:0410263	Brain imaging abnormality	Frequent (30-79%)
HP:0000077	Abnormality of the kidney	Occasional (5-29%)
HP:0000083	Renal insufficiency	Occasional (5-29%)
HP:0000100	Nephrotic syndrome	Occasional (5-29%)
HP:0000639	Nystagmus	Occasional (5-29%)
HP:0001272	Cerebellar atrophy	Occasional (5-29%)
HP:0001376	Limitation of joint mobility	Occasional (5-29%)
HP:0001410	Decreased liver function	Occasional (5-29%)
HP:0001627	Abnormal heart morphology	Occasional (5-29%)
HP:0001638	Cardiomyopathy	Occasional (5-29%)
HP:0002059	Cerebral atrophy	Occasional (5-29%)
HP:0002243	Protein-losing enteropathy	Occasional (5-29%)
HP:0002719	Recurrent infections	Occasional (5-29%)
HP:0002721	Immunodeficiency	Occasional (5-29%)
HP:0002808	Kyphosis	Occasional (5-29%)
HP:0002878	Respiratory failure	Occasional (5-29%)
HP:0100806	Sepsis	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	ALG1-congenital disorder of glycosylation
Mondo ID	MONDO:0012052
MeSH	C535749
OMIM	608540
Orphanet	79327
DOID	DOID:0080563
SNOMED CT	720941007
UMLS	C2931005
MedGen	419308
GARD	0009838
Is cancer (heuristic)	no

Also known as: ALG1-CDG · ALG1-CDG (CDG-Ik) · ALG1-congenital disorder of glycosylation · carbohydrate deficient glycoprotein syndrome type Ik · CDG 1K · CDG syndrome type Ik · CDG-Ik · CDG1K · congenital disorder of glycosylation type 1k · congenital disorder of glycosylation type Ik · congenital disorder of glycosylation, type Ik · mannosyltransferase 1 deficiency

Data availability: 873 ClinVar variants · 5 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 I › ALG1-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, ALG8-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

600 retrieved; paginated sample, class counts are floors:

311 likely benign, 189 uncertain significance, 35 pathogenic, 21 conflicting classifications of pathogenicity, 17 likely pathogenic, 15 benign, 7 pathogenic/likely pathogenic, 5 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1179118	GRCh37/hg19 16p13.3(chr16:5129043-5129828)	ALG1	Pathogenic	no assertion criteria provided
1179164	GRCh37/hg19 16p13.3(chr16:5121789-5133778)	ALG1	Pathogenic	no assertion criteria provided
1323043	NM_019109.5(ALG1):c.1073-2A>G	ALG1	Pathogenic	criteria provided, single submitter
1323051	NM_019109.5(ALG1):c.791_804del (p.Asp264fs)	ALG1	Pathogenic	criteria provided, single submitter
1323877	NM_019109.5(ALG1):c.339C>G (p.Tyr113Ter)	ALG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1393773	NC_000016.9:g.(?5121851)(5134882_?)del	ALG1	Pathogenic	criteria provided, single submitter
1400583	NM_019109.5(ALG1):c.398_399insCA (p.Gly134fs)	ALG1	Pathogenic	criteria provided, single submitter
1416621	NM_019109.5(ALG1):c.309C>G (p.Tyr103Ter)	ALG1	Pathogenic	criteria provided, single submitter
1421067	NM_019109.5(ALG1):c.711_726del (p.Gly238fs)	ALG1	Pathogenic	criteria provided, single submitter
1454830	NM_019109.5(ALG1):c.598C>T (p.Arg200Ter)	ALG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1457013	NM_019109.5(ALG1):c.621G>A (p.Trp207Ter)	ALG1	Pathogenic	criteria provided, single submitter
1458147	NM_019109.5(ALG1):c.1182C>G (p.Phe394Leu)	ALG1	Pathogenic	criteria provided, single submitter
1522448	NC_000016.9:g.(?5125369)(5134882_?)del	ALG1	Pathogenic	criteria provided, single submitter
1702670	NM_019109.5(ALG1):c.295C>T (p.Arg99Ter)	ALG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
193419	NM_019109.5(ALG1):c.15C>A (p.Cys5Ter)	ALG1	Pathogenic	criteria provided, multiple submitters, no conflicts
194107	NM_019109.5(ALG1):c.1188-2A>G	ALG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1994449	NM_019109.5(ALG1):c.235C>T (p.Gln79Ter)	ALG1	Pathogenic	criteria provided, single submitter
2095499	NM_019109.5(ALG1):c.710del (p.Leu237fs)	ALG1	Pathogenic	criteria provided, single submitter
2103963	NM_019109.5(ALG1):c.1255C>T (p.Gln419Ter)	ALG1	Pathogenic	criteria provided, single submitter
2115837	NM_019109.5(ALG1):c.486dup (p.Ile163fs)	ALG1	Pathogenic	criteria provided, single submitter
2183419	NM_019109.5(ALG1):c.740_740+5delinsTGTAGA	ALG1	Pathogenic	criteria provided, single submitter
224118	NM_019109.5(ALG1):c.1187+3A>G	ALG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2426514	NC_000016.9:g.(?5121851)(5125557_?)del	ALG1	Pathogenic	criteria provided, single submitter
2442437	NM_019109.5(ALG1):c.1095_1098del (p.Leu366fs)	ALG1	Pathogenic	criteria provided, multiple submitters, no conflicts
2697122	NM_019109.5(ALG1):c.645C>G (p.Tyr215Ter)	ALG1	Pathogenic	criteria provided, single submitter
2698916	NM_019109.5(ALG1):c.875del (p.Phe292fs)	ALG1	Pathogenic	criteria provided, single submitter
2698923	NM_019109.5(ALG1):c.301_302dup (p.Gln102fs)	ALG1	Pathogenic	criteria provided, single submitter
2706806	NM_019109.5(ALG1):c.1263+2T>C	ALG1	Pathogenic	criteria provided, single submitter
2736317	NM_019109.5(ALG1):c.1263G>A (p.Gln421=)	ALG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2748116	NM_019109.5(ALG1):c.87_91del (p.Arg30fs)	ALG1	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
ALG1	Definitive	Autosomal recessive	ALG1-congenital disorder of glycosylation	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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
ALG1	HGNC:18294	ENSG00000033011	Q9BT22	Chitobiosyldiphosphodolichol beta-mannosyltransferase	gencc,clinvar
EEF2KMT	HGNC:32221	ENSG00000118894	Q96G04	Protein-lysine N-methyltransferase EEF2KMT	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ALG1	Chitobiosyldiphosphodolichol beta-mannosyltransferase	Mannosyltransferase that operates in the biosynthetic pathway of dolichol-linked oligosaccharides, the glycan precursors employed in protein asparagine (N)-glycosylation.
EEF2KMT	Protein-lysine N-methyltransferase EEF2KMT	Catalyzes the trimethylation of eukaryotic elongation factor 2 (EEF2) on ‘Lys-525’.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ALG1	Enzyme (other)	yes	2.4.1.142	Glyco_trans_1, ALG1-like
EEF2KMT	Other/Unknown	no		Methyltransf_16, SAM-dependent_MTases_sf, FAM86_N

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	1
buccal mucosa cell	1
stromal cell of endometrium	1
male germ line stem cell (sensu Vertebrata) in testis	1
mucosa of transverse colon	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ALG1	185	ubiquitous	marker	stromal cell of endometrium, buccal mucosa cell, body of pancreas
EEF2KMT	182	broad	marker	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, mucosa of transverse colon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ALG1	2,187
EEF2KMT	455

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
EEF2KMT	Q96G04	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ALG1	Q9BT22	93.24

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. 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 ALG1 causes CDG-1k	1	5710.0×	0.002	ALG1
Protein methylation	1	335.9×	0.011	EEF2KMT
Diseases associated with N-glycosylation of proteins	1	317.2×	0.011	ALG1
Biosynthesis of the N-glycan precursor (dolichol lipid-linked oligosaccharide, LLO) and transfer to a nascent protein	1	103.8×	0.024	ALG1
Diseases of glycosylation	1	65.6×	0.030	ALG1
Diseases of metabolism	1	40.2×	0.041	ALG1
Asparagine N-linked glycosylation	1	30.1×	0.047	ALG1
Post-translational protein modification	1	9.6×	0.127	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
peptidyl-lysine trimethylation	1	1404.3×	0.002	EEF2KMT
dolichol-linked oligosaccharide biosynthetic process	1	421.3×	0.004	ALG1
protein N-linked glycosylation	1	131.7×	0.008	ALG1

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
ALG1	0	0
EEF2KMT	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
ALG1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
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

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	ALG1
E	Difficult family or no structure, no drug	1	EEF2KMT

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)
ALG1	1	—
EEF2KMT	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.