COG4-congenital disorder of glycosylation

Summary

COG4-congenital disorder of glycosylation (MONDO:0013281) is a disease caused by COG4 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: COG4 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 201
• Phenotypes (HPO): 33

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		2	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:0012347	Abnormal protein N-linked glycosylation	Very frequent (80-99%)
HP:0012358	Abnormal protein O-linked glycosylation	Very frequent (80-99%)
HP:0000252	Microcephaly	Frequent (30-79%)
HP:0000340	Sloping forehead	Frequent (30-79%)
HP:0000639	Nystagmus	Frequent (30-79%)
HP:0000737	Irritability	Frequent (30-79%)
HP:0001251	Ataxia	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001344	Absent speech	Frequent (30-79%)
HP:0001347	Hyperreflexia	Frequent (30-79%)
HP:0001394	Cirrhosis	Frequent (30-79%)
HP:0001433	Hepatosplenomegaly	Frequent (30-79%)
HP:0001510	Growth delay	Frequent (30-79%)
HP:0001531	Failure to thrive in infancy	Frequent (30-79%)
HP:0001873	Thrombocytopenia	Frequent (30-79%)
HP:0002254	Intermittent diarrhea	Frequent (30-79%)
HP:0002509	Limb hypertonia	Frequent (30-79%)
HP:0002788	Recurrent upper respiratory tract infections	Frequent (30-79%)
HP:0002910	Elevated circulating hepatic transaminase concentration	Frequent (30-79%)
HP:0003124	Hypercholesterolemia	Frequent (30-79%)
HP:0003155	Elevated circulating alkaline phosphatase concentration	Frequent (30-79%)
HP:0003256	Abnormality of the coagulation cascade	Frequent (30-79%)
HP:0006892	Frontotemporal cerebral atrophy	Frequent (30-79%)
HP:0008935	Generalized neonatal hypotonia	Frequent (30-79%)
HP:0008936	Axial hypotonia	Frequent (30-79%)
HP:0011172	Complex febrile seizure	Frequent (30-79%)
HP:0011968	Feeding difficulties	Frequent (30-79%)
HP:0012301	Type II transferrin isoform profile	Frequent (30-79%)
HP:0100874	Thick hair	Frequent (30-79%)
HP:0002079	Hypoplasia of the corpus callosum	Occasional (5-29%)
HP:0004798	Recurrent infection of the gastrointestinal tract	Occasional (5-29%)
HP:0006583	Fatal liver failure in infancy	Occasional (5-29%)
HP:0040187	Neonatal sepsis	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	COG4-congenital disorder of glycosylation
Mondo ID	MONDO:0013281
OMIM	613489
Orphanet	263501
DOID	DOID:0070262
SNOMED CT	718751000
UMLS	C4303552
MedGen	929221
GARD	0012412
Is cancer (heuristic)	no

Also known as: carbohydrate deficient glycoprotein syndrome type IIj · CDG syndrome type IIj · CDG-IIj · CDG2J · COG4-CDG · COG4-CDG (CDG-IIj) · COG4-congenital disorder of glycosylation · congenital disorder of glycosylation type 2j · congenital disorder of glycosylation type IIj · congenital disorder of glycosylation, type IIj

Data availability: 201 ClinVar variants · 4 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 II › COG4-congenital disorder of glycosylation

Related subtypes (25): MGAT2-congenital disorder of glycosylation, leukocyte adhesion deficiency type II, SLC35A2-congenital disorder of glycosylation, SLC35A1-congenital disorder of glycosylation, MOGS-congenital disorder of glycosylation, B4GALT1-congenital disorder of glycosylation, COG7-congenital disorder of glycosylation, COG8-congenital disorder of glycosylation, COG1-congenital disorder of glycosylation, COG5-congenital disorder of glycosylation, COG6-congenital disorder of glycosylation, TMEM165-congenital disorder of glycosylation, SLC39A8-CDG, CCDC115-CDG, TMEM199-CDG, congenital disorder of glycosylation, type IIr, congenital disorder of glycosylation, type iit, congenital disorder of glycosylation, type 2v, congenital disorder of glycosylation, type IIw, congenital disorder of glycosylation, type IIq, congenital disorder of glycosylation, type IIy, congenital disorder of glycosylation, type IIz, congenital disorder of glycosylation, type IIaa, congenital disorder of glycosylation, type IIbb, congenital disorder of glycosylation, type IIcc

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

201 retrieved; paginated sample, class counts are floors:

89 uncertain significance, 59 likely benign, 14 benign, 13 pathogenic, 12 conflicting classifications of pathogenicity, 6 likely pathogenic, 5 benign/likely benign, 3 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1172782	NM_015386.3(COG4):c.1255G>T (p.Glu419Ter)	COG4	Pathogenic	criteria provided, single submitter
1454863	NM_015386.3(COG4):c.883G>T (p.Glu295Ter)	COG4	Pathogenic	criteria provided, single submitter
208568	NM_015386.3(COG4):c.529C>T (p.Arg177Ter)	COG4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2917150	NM_015386.3(COG4):c.1608del (p.Gly537fs)	COG4	Pathogenic	criteria provided, single submitter
31927	NM_015386.3(COG4):c.697G>T (p.Glu233Ter)	COG4	Pathogenic	no assertion criteria provided
31928	NM_015386.3(COG4):c.2318T>G (p.Leu773Arg)	COG4	Pathogenic	no assertion criteria provided
3652	NM_015386.3(COG4):c.2197C>T (p.Arg733Trp)	COG4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
449730	NM_015386.3(COG4):c.1546G>A (p.Gly516Arg)	COG4	Pathogenic	criteria provided, multiple submitters, no conflicts
4719224	NM_015386.3(COG4):c.1434_1435del (p.Ala480fs)	COG4	Pathogenic	criteria provided, single submitter
4726045	NM_015386.3(COG4):c.1122dup (p.Arg375fs)	COG4	Pathogenic	criteria provided, single submitter
4812006	NM_015386.3(COG4):c.1955G>A (p.Trp652Ter)	COG4	Pathogenic	criteria provided, single submitter
571433	NM_015386.3(COG4):c.6del (p.Thr3fs)	COG4	Pathogenic	criteria provided, single submitter
599648	NM_015386.3(COG4):c.1840G>T (p.Glu614Ter)	COG4	Pathogenic	criteria provided, multiple submitters, no conflicts
862921	NM_015386.3(COG4):c.599_600del (p.Lys200fs)	COG4	Pathogenic	criteria provided, single submitter
915303	NM_015386.3(COG4):c.73G>T (p.Gly25Ter)	COG4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3653	NC_000016.10:g.(70426035_70473004)_(70512433_70519648)del	LOC125177345	Pathogenic	no assertion criteria provided
1172781	NM_015386.3(COG4):c.941G>A (p.Cys314Tyr)	COG4	Likely pathogenic	criteria provided, single submitter
1518423	NM_015386.3(COG4):c.544+1G>T	COG4	Likely pathogenic	criteria provided, single submitter
3581232	NM_015386.3(COG4):c.1290C>A (p.Tyr430Ter)	COG4	Likely pathogenic	criteria provided, single submitter
4714046	NM_015386.3(COG4):c.739-1G>C	COG4	Likely pathogenic	criteria provided, single submitter
4849452	NM_015386.3(COG4):c.289C>T (p.Gln97Ter)	COG4	Likely pathogenic	criteria provided, single submitter
971970	NM_015386.3(COG4):c.369+1_369+2del	COG4	Likely pathogenic	criteria provided, single submitter
1035424	NM_015386.3(COG4):c.2041G>A (p.Gly681Ser)	COG4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
194974	NM_015386.3(COG4):c.2310C>G (p.Arg770=)	COG4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2078957	NM_015386.3(COG4):c.68G>A (p.Gly23Glu)	COG4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2646683	NM_015386.3(COG4):c.1051dup (p.Ile351fs)	COG4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
430266	NM_015386.3(COG4):c.1415G>A (p.Ser472Asn)	COG4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
569846	NM_015386.3(COG4):c.1894T>C (p.Phe632Leu)	COG4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
582178	NM_015386.3(COG4):c.539A>G (p.Lys180Arg)	COG4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
702101	NM_015386.3(COG4):c.2251G>A (p.Asp751Asn)	COG4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · 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
COG4	Definitive	Autosomal recessive	COG4-congenital disorder of glycosylation	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
COG4	Orphanet:263501	COG4-CDG
COG4	Orphanet:85172	Microcephalic osteodysplastic dysplasia, Saul-Wilson type

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
COG4	HGNC:18620	ENSG00000103051	Q9H9E3	Conserved oligomeric Golgi complex subunit 4	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
COG4	Conserved oligomeric Golgi complex subunit 4	Required for normal Golgi function.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
COG4	Other/Unknown	no		COG4_M, COG4_N, COG4

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
apex of heart	1
lower esophagus mucosa	1
mucosa of transverse colon	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
COG4	273	ubiquitous	marker	lower esophagus mucosa, mucosa of transverse colon, apex of heart

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
COG4	1,452

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
COG4	Q9H9E3	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. 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
Intra-Golgi traffic	1	259.6×	0.007	COG4
Retrograde transport at the Trans-Golgi-Network	1	219.6×	0.007	COG4
COPI-mediated anterograde transport	1	109.8×	0.009	COG4

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
retrograde transport, vesicle recycling within Golgi	1	1872.4×	0.002	COG4
retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum	1	337.0×	0.006	COG4
Golgi organization	1	133.8×	0.010	COG4
protein transport	1	43.9×	0.023	COG4

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
COG4	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
COG4	2	Binding:2

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	0
E	Difficult family or no structure, no drug	1	COG4

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)
COG4	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.