COG8

protein-coding

component of oligomeric golgi complex 8, the group of Components of oligomeric golgi complex

Gene summary

This gene encodes a protein that is a component of the conserved oligomeric Golgi (COG) complex, a multiprotein complex that plays a structural role in the Golgi apparatus, and is involved in intracellular membrane trafficking and glycoprotein modification. Mutations in this gene cause congenital disorder of glycosylation, type IIh, a disease that is characterized by under-glycosylated serum proteins, and whose symptoms include severe psychomotor retardation, failure to thrive, seizures, and dairy and wheat product intolerance. [provided by RefSeq, Jul 2008]

MANE transcript

NM_032382.5

Inheritance

ClinVar variants

P:18U:139B:86

Top phenotype

Congenital disorder of glycosylation, type IIh

gnomAD constraint

pLI —, LoF o/e 0.75

Max pathogenic AF

—

Genomic locus

chr16:69,320,140-69,339,583

External References & Databases

Ensembl (ENSG00000213380)

Transcript & Mutation Effects

hg38 • Region Span ~19.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

COG8-congenital disorder of glycosylationMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0012635

Submitter: Ambry Genetics

COG8-congenital disorder of glycosylationSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012635

Submitter: Orphanet

COG8-congenital disorder of glycosylationSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012635

Submitter: Labcorp Genetics (formerly Invitae)

COG8-congenital disorder of glycosylationDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012635

Submitter: ClinGen

*COG8* was first reported in relation to autosomal recessive COG8-congenital disorder of glycosylation in 2007 (Foulquier, F. et al., PMID: 17220172). These multisystem disorders present with a wide variety of clinical features, such as disorders of the nervous system development, psychomotor retardation, dysmorphic features, hypotonia, coagulation disorders, and immunodeficiency. The broad spectrum of features reflects the critical role of glycosylation during embryonic development, differentiation, and maintenance of cell functions. Clinical characteristics for autosomal recessive COG8-congenital disorder of glycosylation include but are not limited to encephalopathy, hypotonia, pseudoptosis, decreased reflexes, intubation and ventilation. Eleven variants (missense, in-frame indel, nonsense, frameshift) that have been reported in nine probands in four publications (PMIDs: 30690882, 28619360, 17331980, 17220172) and five ClinVar records (SCV006081080.1, SCV005880064.2, SCV002767931.1, SCV001525055.1, SCV001150962.37) are included in this curation. CDGs are a family of inherited diseases caused by a defect in protein glycosylation pathways, some sharing the COG8-enabled trafficking pathway. They are often characterized by mis-glycosylated serum proteins, ranging from missing entire chains to terminal sugars. *COG8* specifically is missing terminal sugars. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by expression studies and in vitro functional assays (PMIDs: 23865579, 16051600, 17904886). Functional alterations in non-patient cells showed depletion of Cog8 markedly affected the compact organization of the Golgi apparatus in HeLa cells. Electron microscopy analysis further exposed a dilation of Golgi cisternae and accumulation of vesicles in the vicinity of the Golgi, which possibly represent vesicles that failed to fuse with the Golgi membranes. These results are consistent with previous studies in which vesiculated Golgi membranes and swollen Golgi cisternae were observed in CDG-derived Cog8-deficient fibroblasts from patient cells. Protein interactions showed Cog8 associates stably with both Cog5–7 and Cog1– 4 subcomplexes. Cog8 helps assemble the Cog1– 4 and Cog5–7 subcomplexes into the complete COG complex. Acute and short-term deficiency of Cog8 may lead to tethering defects. In summary, there is definitive evidence supporting the relationship between *COG8* and autosomal recessive COG8-congenital disorder of glycosylation. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen CDG GCEP on the meeting date March 2, 2026 (SOP Version 12).

COG8-congenital disorder of glycosylationDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012635

Submitter: G2P

Clinical Genomic Database (CGD)

Congenital disorder of glycosylation, type IIhAR

Manifestation: Biochemical; Hematologic; Neurologic

Intervention: Hematologic

Rationale: Awareness of coagulopathies may be beneficial in terms of medical management, especially in situations such as surgery

Comments: Hepatic-metabolized agents should be avoided

Refs: 17220172; 17331980; 20301507; 30690882

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to COG8 variants in ClinVar

5 Conditions Cataloged

COG8-congenital disorder of glycosylationTotal: 149

Inborn genetic diseasesTotal: 99

not specifiedTotal: 86

not providedTotal: 70

COG8-related disorderTotal: 10

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_032382.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			7 clinvar	65 clinvar		72
missense			130 clinvar	21 clinvar		151
nonsense	1 clinvar	5 clinvar	1 clinvar			7
start loss						0
frameshift	3 clinvar	5 clinvar	1 clinvar			9
splice donor/acceptor (+/-2bp)	1 clinvar	3 clinvar				4
Total	5	13	139	86	0	243

Highest pathogenic variant AF is 0.000095461015

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 15 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_032382.5	RefSeq	NP_115758.3	5	MANE Select
ENST00000306875.10	Ensembl	ENSP00000305459.6	5	MANE Select
NM_001374871.1	RefSeq	NP_001361800.1	4	Standard
NM_001379261.1	RefSeq	NP_001366190.1	6	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Vesicle-mediated transport
Membrane Trafficking
Post-translational protein modification
Metabolism of proteins
Transport to the Golgi and subsequent modification

Biological Process

endoplasmic reticulum to Golgi vesicle-mediated transport
intra-Golgi vesicle-mediated transport
protein transport

Molecular Function

protein binding

Cellular Component

Golgi membrane
Golgi apparatus
membrane
Golgi transport complex
trans-Golgi network membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000306875
Coding exons: 5
Length: 19528
Individuals with no LoFs: 125661
Homozygous LoFs: 0
Heterozygous LoFs: 86
Defined: 125747
p: 0.000342

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.0937	375	370	1.01	0.0000214	3934
Missense (PolyPhen)		108	100.17	1.0782		1101
Synonymous	-1.35	181	159	1.14	0.00000882	1325
Loss of Function	1.09	16	21.4	0.746	0.00000110	219

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00085	0.00080	rare
Latino/Admixed American	0.00061	0.00061	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00022	0.00022	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00028	0.00026	rare
South Asian	0.00043	0.00042	rare
Other	0.00066	0.00065	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Required for normal Golgi function. {ECO:0000250}.;
Disease: DISEASE: Congenital disorder of glycosylation 2H (CDG2H) [MIM:611182]: CDGs are a family of severe inherited diseases caused by a defect in protein N-glycosylation. They are characterized by under-glycosylated serum proteins. These multisystem disorders present with a wide variety of clinical features, such as disorders of the nervous system development, psychomotor retardation, dysmorphic features, hypotonia, coagulation disorders, and immunodeficiency. The broad spectrum of features reflects the critical role of N-glycoproteins during embryonic development, differentiation, and maintenance of cell functions. {ECO:0000269|PubMed:17331980}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.110

Intolerance Scores

LoFtool: 0.723
RVIS EVS: -0.22
RVIS percentile EVS: 37.54

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.917

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium