COG6

Summary

COG6 (component of oligomeric golgi complex 6, HGNC:18621) is a protein-coding gene on chromosome 13q14.11, encoding Conserved oligomeric Golgi complex subunit 6 (Q9Y2V7). Required for normal Golgi function. It is a selective cancer dependency (DepMap: 19.7% of cell lines).

This gene encodes a subunit of the conserved oligomeric Golgi complex that is required for maintaining normal structure and activity of the Golgi apparatus. The encoded protein is organized with conserved oligomeric Golgi complex components 5, 7 and 8 into a sub-complex referred to as lobe B. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 57511 — RefSeq curated summary.

At a glance

• Gene–disease (curated): COG6-congenital disorder of glycosylation (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 27
• Clinical variants (ClinVar): 455 total — 18 pathogenic, 16 likely-pathogenic
• Phenotypes (HPO): 64
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 19.7% of screened cell lines
• MANE Select transcript: NM_020751

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18621
Approved symbol	COG6
Name	component of oligomeric golgi complex 6
Location	13q14.11
Locus type	gene with protein product
Status	Approved
Aliases	COD2, KIAA1134
Ensembl gene	ENSG00000133103
Ensembl biotype	protein_coding
OMIM	606977
Entrez	57511

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 12 protein_coding, 5 nonsense_mediated_decay, 4 protein_coding_CDS_not_defined

ENST00000356576, ENST00000416691, ENST00000422759, ENST00000455146, ENST00000460701, ENST00000465775, ENST00000536488, ENST00000537156, ENST00000542266, ENST00000543790, ENST00000543804, ENST00000630730, ENST00000866285, ENST00000866286, ENST00000866287, ENST00000866288, ENST00000919967, ENST00000950571, ENST00000950572, ENST00000950573, ENST00000950574

RefSeq mRNA: 2 — MANE Select: NM_020751 NM_001145079, NM_020751

CCDS: CCDS45042, CCDS9370

Canonical transcript exons

ENST00000455146 — 19 exons

Exon	Start	End
ENSE00001934927	39750946	39752628
ENSE00003478470	39682171	39682264
ENSE00003520605	39687503	39687631
ENSE00003537288	39679975	39680045
ENSE00003544206	39694634	39694725
ENSE00003554166	39665096	39665154
ENSE00003586799	39677468	39677579
ENSE00003630811	39724508	39724561
ENSE00003631796	39659364	39659507
ENSE00003632693	39723333	39723440
ENSE00003632706	39660810	39660881
ENSE00003636690	39687708	39687799
ENSE00003637918	39679538	39679620
ENSE00003651291	39727469	39727548
ENSE00003661651	39719660	39719827
ENSE00003676543	39699501	39699618
ENSE00003679526	39689760	39689824
ENSE00003688014	39719236	39719367
ENSE00003770097	39655662	39655879

Expression profiles

Bgee: expression breadth ubiquitous, 254 present calls, max score 95.30.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 19.3128 / max 191.2846, expressed in 1798 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
134819	18.9414	1797
134820	0.2928	121
134821	0.0787	18

Top tissues by expression

256 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	95.30	gold quality
tibia	UBERON:0000979	95.27	gold quality
calcaneal tendon	UBERON:0003701	93.70	gold quality
epithelial cell of pancreas	CL:0000083	92.77	gold quality
islet of Langerhans	UBERON:0000006	90.72	gold quality
palpebral conjunctiva	UBERON:0001812	90.66	gold quality
oocyte	CL:0000023	90.65	gold quality
esophagus squamous epithelium	UBERON:0006920	90.06	gold quality
adrenal tissue	UBERON:0018303	89.54	gold quality
tendon	UBERON:0000043	89.23	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	88.99	gold quality
stromal cell of endometrium	CL:0002255	88.89	gold quality
mucosa of paranasal sinus	UBERON:0005030	88.65	gold quality
bronchial epithelial cell	CL:0002328	88.50	gold quality
ileal mucosa	UBERON:0000331	88.49	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	88.48	gold quality
corpus callosum	UBERON:0002336	88.46	gold quality
pancreas	UBERON:0001264	88.38	gold quality
colonic epithelium	UBERON:0000397	88.09	gold quality
bronchus	UBERON:0002185	88.08	gold quality
epithelium of nasopharynx	UBERON:0001951	87.41	gold quality
body of pancreas	UBERON:0001150	87.22	gold quality
skin of hip	UBERON:0001554	87.20	gold quality
pigmented layer of retina	UBERON:0001782	87.08	gold quality
germinal epithelium of ovary	UBERON:0001304	86.97	gold quality
bone marrow cell	CL:0002092	86.92	gold quality
upper leg skin	UBERON:0004262	86.91	gold quality
layer of synovial tissue	UBERON:0007616	86.89	gold quality
placenta	UBERON:0001987	86.85	gold quality
decidua	UBERON:0002450	86.76	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.83

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

120 targeting COG6, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-3682-5P	99.93	67.97	1163

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 19.7% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 13)

• This paper reports a new congenital disorder caused by mutations in the human COG8 gene and describes the affect this mutation has on the other COG components. (PMID:17331980)
• COG directly and positively regulates endosome-to-TGN retrograde transport by specific and direct interaction with the t-SNARE Stx6 via its Cog6 subunit. (PMID:21807881)
• COG6 rs9548934C–>T polymorphism is associated with lower risk of premature coronary artery disease, especially in female subjects and subjects with lower serum lipid levels. (PMID:22883088)
• COG6 interaction with SNARE proteins via universal SNARE-binding motif of COG6 is important for Golgi complex intergrity. (PMID:23057818)
• data implicate COG6 in the pathogenesis of a novel hypohidrotic disorder in humans that is distinct from congenital disorders of glycosylation. (PMID:23606727)
• Targeted silencing of components of lobe B of the COG complex, namely COG5, COG6, COG7 and COG8, inhibited HIV-1 replication (PMID:25179963)
• Our findings implicate COG6 rs9548934C–>T genotypes and circulating miRNA-1 phenotype in modulating the occurrence and major adverse cardiovascular events of coronary artery disease. (PMID:25197382)
• The aim of this study was to investigate whether the HCP5, TNIP1, TNFAIP3, SPATA2 and COG6 genes were genetic risk factors for psoriasis in Chinese population. (PMID:25264125)
• study presents 7 additional patients with 4 novel COG6 mutations; genotype-phenotype correlation can be discerned ranging from deep intronic mutations found in Shaheen syndrome as the mildest form to loss-of-function mutations leading to early lethal congenital disorders of glycosylation phenotypes (PMID:26260076)
• COG6 is a novel shared risk locus for rheumatoid arthritis and systemic lupus erythematosus. (PMID:27193031)
• Ptahogenic compound heterozygous variants of the COG6 gene were identified in a neonatal patient. (PMID:29709711)
• COG6-CDG: Expanding the phenotype with emphasis on glycosylation defects involved in the causation of male disorders of sex development. (PMID:32683677)
• Disorder of sex development associated with a novel homozygous nonsense mutation in COG6 expands the phenotypic spectrum of COG6-CDG. (PMID:33394555)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	cog6	ENSDARG00000103149
mus_musculus	Cog6	ENSMUSG00000027742
rattus_norvegicus	Cog6	ENSRNOG00000013660
drosophila_melanogaster	Cog6	FBGN0033401
caenorhabditis_elegans		WBGENE00019481

Protein

Protein identifiers

Conserved oligomeric Golgi complex subunit 6 — Q9Y2V7 (reviewed: Q9Y2V7)

Alternative names: Component of oligomeric Golgi complex 6

All UniProt accessions (5): A0A140VJG7, Q9Y2V7, F5GX38, F5GX76, H0YGX8

UniProt curated annotations — full annotation on UniProt →

Function. Required for normal Golgi function.

Subunit / interactions. Component of the conserved oligomeric Golgi complex which is composed of eight different subunits and is required for normal Golgi morphology and localization.

Subcellular location. Golgi apparatus membrane.

Disease relevance. Congenital disorder of glycosylation 2L (CDG2L) [MIM:614576] A multisystem disorder caused by a defect in glycoprotein biosynthesis and characterized by under-glycosylated serum glycoproteins. Congenital disorders of glycosylation result in a wide variety of clinical features, such as defects in 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. Clinical features of CDG2L include neonatal intractable focal seizures, vomiting, loss of consciousness, intracranial bleeding due to vitamin K deficiency, and death in infancy. The disease is caused by variants affecting the gene represented in this entry. Shaheen syndrome (SHNS) [MIM:615328] An autosomal recessive syndrome characterized by severe intellectual disability, hypohidrosis, dental enamel hypoplasia, and hyperkeratosis of the palms and soles. Some may develop mild microcephaly. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Similarity. Belongs to the COG6 family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9Y2V7-1	1	yes
Q9Y2V7-2	2
Q9Y2V7-4	4

RefSeq proteins (2): NP_001138551, NP_065802* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR010490	COG6	Family
IPR048368	COG6_N	Domain
IPR048369	COG6_C	Domain

Pfam: PF06419, PF20653

UniProt features (12 total): sequence variant 5, splice variant 4, sequence conflict 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y2V7-F1	86.62	0.58

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-6807878	COPI-mediated anterograde transport
R-HSA-6811438	Intra-Golgi traffic
R-HSA-6811440	Retrograde transport at the Trans-Golgi-Network

MSigDB gene sets: 275 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_UP, TGCGCANK_UNKNOWN, KYNG_DNA_DAMAGE_DN, GOBP_VESICLE_MEDIATED_TRANSPORT, REACTOME_MEMBRANE_TRAFFICKING, GOBP_INTRA_GOLGI_VESICLE_MEDIATED_TRANSPORT, GOCC_TRANS_GOLGI_NETWORK, WANG_LMO4_TARGETS_DN, PETRETTO_HEART_MASS_QTL_CIS_DN, GOBP_ENDOMEMBRANE_SYSTEM_ORGANIZATION, chr13q14, GOBP_GOLGI_ORGANIZATION, GOCC_GOLGI_TRANSPORT_COMPLEX, GOCC_TRANS_GOLGI_NETWORK_MEMBRANE, GOCC_ORGANELLE_SUBCOMPARTMENT

GO Biological Process (5): retrograde transport, vesicle recycling within Golgi (GO:0000301), intra-Golgi vesicle-mediated transport (GO:0006891), Golgi organization (GO:0007030), protein transport (GO:0015031), obsolete glycosylation (GO:0070085)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (5): Golgi membrane (GO:0000139), COG complex (GO:0017119), trans-Golgi network membrane (GO:0032588), Golgi apparatus (GO:0005794), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Intra-Golgi and retrograde Golgi-to-ER traffic	2
ER to Golgi Anterograde Transport	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
Golgi apparatus	2
intra-Golgi vesicle-mediated transport	1
Golgi vesicle transport	1
organelle organization	1
endomembrane system organization	1
transport	1
intracellular protein localization	1
establishment of protein localization	1
binding	1
bounding membrane of organelle	1
vesicle tethering complex	1
trans-Golgi network	1
organelle membrane	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1752 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
COG6	COG8	Q96MW5	990
COG6	COG2	Q14746	986
COG6	COG7	P83436	982
COG6	COG5	Q9UP83	979
COG6	COG1	Q8WTW3	976
COG6	COG3	Q96JB2	968
COG6	COG4	Q9H9E3	961
COG6	SNAP29	O95721	795
COG6	STX6	O43752	792
COG6	STX5	Q13190	783
COG6	GOSR2	O14653	778
COG6	VPS52	Q8N1B4	758
COG6	EXOC7	Q9UPT5	723
COG6	EXOC3	O60645	670
COG6	VPS53	Q5VIR6	667

IntAct

316 interactions, top by confidence:

A	B	Type	Score
BCL10	COG6	psi-mi:“MI:0915”(physical association)	0.700
FAM90A1	COG6	psi-mi:“MI:0915”(physical association)	0.700
SCNM1	COG6	psi-mi:“MI:0915”(physical association)	0.700
CCHCR1	COG6	psi-mi:“MI:0915”(physical association)	0.700
ZBTB16	COG6	psi-mi:“MI:0915”(physical association)	0.700
RAB6B	COG6	psi-mi:“MI:0915”(physical association)	0.700
NTAQ1	COG6	psi-mi:“MI:0915”(physical association)	0.700
ARHGEF5	COG6	psi-mi:“MI:0915”(physical association)	0.700
COG6	BCL10	psi-mi:“MI:0915”(physical association)	0.700
COG6	SCNM1	psi-mi:“MI:0915”(physical association)	0.700
COG6	ZBTB16	psi-mi:“MI:0915”(physical association)	0.700
COG6	ARHGEF5	psi-mi:“MI:0915”(physical association)	0.700
COG6	WASHC3	psi-mi:“MI:0915”(physical association)	0.670
IFT57	IFT56	psi-mi:“MI:0914”(association)	0.640
SCN2B	EXOC5	psi-mi:“MI:0914”(association)	0.640
COMMD8	VPS26C	psi-mi:“MI:0914”(association)	0.640
VSIG1	TTI1	psi-mi:“MI:0914”(association)	0.640
COG3	COG7	psi-mi:“MI:0914”(association)	0.640

BioGRID (268): COG6 (Affinity Capture-MS), COG6 (Affinity Capture-MS), COG6 (Affinity Capture-MS), COG6 (Affinity Capture-MS), COG6 (Affinity Capture-MS), COG6 (Affinity Capture-MS), COG6 (Affinity Capture-MS), COG6 (Affinity Capture-MS), COG1 (Co-fractionation), COG6 (Co-fractionation), COG6 (Co-fractionation), COG6 (Co-fractionation), COG6 (Co-fractionation), COG7 (Co-fractionation), COG6 (Synthetic Lethality)

ESM2 similar proteins: A1A4I4, A2SXS5, A6QQ47, B2DCZ9, O00255, O08908, O55166, O75146, O88559, P70268, Q0P5I0, Q0VCR8, Q155U0, Q16512, Q29RB1, Q2KJ58, Q3MHG0, Q3MII6, Q3SZI7, Q3UVL4, Q4V9Y0, Q505L3, Q5R7R6, Q5TJF0, Q5ZJ25, Q63433, Q63788, Q68FF6, Q68FP9, Q69Z89, Q6PB44, Q6ZT62, Q865S3, Q8BI71, Q8BZQ7, Q8C190, Q8C754, Q8N1B4, Q8R1U1, Q8R3I3

Diamond homologs: A1CU89, A1DNX2, A2QLL1, A4QUK5, A6R6L9, A7ERK2, C8V7C6, Q0CSR3, Q0UYL3, Q1E6R9, Q2HH52, Q2UUV3, Q3SZI7, Q4WLS7, Q68FP9, Q7S4D8, Q8R3I3, Q9Y2V7, P0CM80, P0CM81, Q54CT0, Q6NMI3, Q9V564

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
COG6	“form complex”	“COG tethering complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 105 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Intra-Golgi traffic	6	25.5×	6e-05
Nuclear Pore Complex (NPC) Disassembly	5	25.3×	4e-04
Retrograde transport at the Trans-Golgi-Network	5	18.0×	1e-03
snRNP Assembly	5	17.3×	1e-03
ISG15 antiviral mechanism	5	12.3×	1e-03
Regulation of HSF1-mediated heat shock response	5	11.4×	2e-03
Assembly of the pre-replicative complex	5	11.4×	2e-03
COPI-mediated anterograde transport	6	10.8×	1e-03

GO biological processes:

GO term	Partners	Fold	FDR
retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum	5	19.1×	1e-03
Golgi organization	6	9.1×	6e-03
protein transport	11	5.5×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

455 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	18
Likely pathogenic	16
Uncertain significance	198
Likely benign	95
Benign	81

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1454276	NM_020751.3(COG6):c.252del (p.Ala85fs)	Pathogenic
193438	NM_020751.3(COG6):c.112A>T (p.Lys38Ter)	Pathogenic
194109	NM_020751.3(COG6):c.1075-1G>T	Pathogenic
2203823	NM_020751.3(COG6):c.651_654del (p.Leu217fs)	Pathogenic
2498080	NM_020751.3(COG6):c.1672C>T (p.Gln558Ter)	Pathogenic
2498081	NM_020751.3(COG6):c.153+392A>G	Pathogenic
2576959	NM_020751.3(COG6):c.1884T>G (p.Tyr628Ter)	Pathogenic
30628	NM_020751.3(COG6):c.1646G>T (p.Gly549Val)	Pathogenic
4755703	NM_020751.3(COG6):c.984_994del (p.Leu329fs)	Pathogenic
4783322	NM_020751.3(COG6):c.1078C>T (p.Arg360Ter)	Pathogenic
4791614	NM_020751.3(COG6):c.686G>A (p.Trp229Ter)	Pathogenic
4820287	NM_020751.3(COG6):c.248del (p.Ser83fs)	Pathogenic
4845389	NM_020751.3(COG6):c.1009+1G>T	Pathogenic
487578	NM_020751.3(COG6):c.388C>T (p.Gln130Ter)	Pathogenic
493007	NM_020751.3(COG6):c.511C>T (p.Arg171Ter)	Pathogenic
493010	NM_020751.3(COG6):c.1239dup (p.Phe414fs)	Pathogenic
688225	GRCh37/hg19 13q14.11(chr13:40329397-40380244)x1	Pathogenic
816813	NM_020751.3(COG6):c.726del (p.Cys242fs)	Pathogenic
1346002	NM_020751.3(COG6):c.1585-2A>G	Likely pathogenic
1678040	NM_020751.3(COG6):c.1062C>A (p.Cys354Ter)	Likely pathogenic
1690777	NM_020751.3(COG6):c.181del (p.Ser61fs)	Likely pathogenic
2136197	NM_020751.3(COG6):c.298-1G>A	Likely pathogenic
2219419	NM_020751.3(COG6):c.1166+1G>A	Likely pathogenic
2439180	NM_020751.3(COG6):c.789-1G>T	Likely pathogenic
2633023	NM_020751.3(COG6):c.1060del (p.Cys354fs)	Likely pathogenic
3065602	NM_020751.3(COG6):c.1826+2T>C	Likely pathogenic
3341068	NM_020751.3(COG6):c.691C>T (p.Gln231Ter)	Likely pathogenic
3344756	NM_020751.3(COG6):c.906_907delinsA (p.His302fs)	Likely pathogenic
3779114	NM_020751.3(COG6):c.182C>G (p.Ser61Ter)	Likely pathogenic
4278444	NM_020751.3(COG6):c.695-8T>G	Likely pathogenic

SpliceAI

3637 predictions. Top by Δscore:

Variant	Effect	Δscore
13:39655876:CAAGG:C	donor_loss	1.0000
13:39655877:AAG:A	donor_loss	1.0000
13:39655878:AGGTA:A	donor_loss	1.0000
13:39655879:GGTAA:G	donor_loss	1.0000
13:39655880:G:GA	donor_loss	1.0000
13:39659358:GTATA:G	acceptor_loss	1.0000
13:39659359:TATA:T	acceptor_loss	1.0000
13:39659361:T:G	acceptor_gain	1.0000
13:39659361:TA:T	acceptor_loss	1.0000
13:39659362:A:AT	acceptor_loss	1.0000
13:39659363:G:A	acceptor_loss	1.0000
13:39659363:GGA:G	acceptor_gain	1.0000
13:39659412:A:AG	acceptor_gain	1.0000
13:39659413:G:GG	acceptor_gain	1.0000
13:39659496:G:GT	donor_gain	1.0000
13:39659504:GGAG:G	donor_gain	1.0000
13:39659505:GAGG:G	donor_gain	1.0000
13:39659508:G:GA	donor_loss	1.0000
13:39659508:G:GG	donor_gain	1.0000
13:39660805:TTCA:T	acceptor_loss	1.0000
13:39660806:TCA:T	acceptor_loss	1.0000
13:39660807:CAG:C	acceptor_loss	1.0000
13:39660808:A:AG	acceptor_gain	1.0000
13:39660808:AG:A	acceptor_gain	1.0000
13:39660808:AGG:A	acceptor_loss	1.0000
13:39660809:G:GT	acceptor_gain	1.0000
13:39660809:GG:G	acceptor_gain	1.0000
13:39660809:GGA:G	acceptor_gain	1.0000
13:39660809:GGAA:G	acceptor_gain	1.0000
13:39660809:GGAAC:G	acceptor_gain	1.0000

AlphaMissense

4306 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
13:39659434:T:C	L75S	0.999
13:39660877:T:C	L122P	0.999
13:39687568:T:C	L285P	0.999
13:39687736:C:G	H316D	0.999
13:39694706:T:C	F383L	0.999
13:39694708:T:A	F383L	0.999
13:39694708:T:G	F383L	0.999
13:39659380:T:C	L57P	0.998
13:39659425:G:C	R72P	0.998
13:39659429:A:C	R73S	0.998
13:39659429:A:T	R73S	0.998
13:39660814:T:C	L101P	0.998
13:39665099:G:C	A125P	0.998
13:39687564:G:C	A284P	0.998
13:39687728:C:A	A313D	0.998
13:39687730:T:A	W314R	0.998
13:39687730:T:C	W314R	0.998
13:39694698:T:C	L380P	0.998
13:39719709:C:A	A489D	0.998
13:39723355:T:C	L536P	0.998
13:39655842:T:C	L39P	0.997
13:39659389:T:C	L60P	0.997
13:39659411:T:A	N67K	0.997
13:39659411:T:G	N67K	0.997
13:39659424:C:G	R72G	0.997
13:39659428:G:C	R73T	0.997
13:39665142:T:C	L139P	0.997
13:39679593:T:C	L199P	0.997
13:39682240:T:C	L255P	0.997
13:39687568:T:A	L285H	0.997

dbSNP variants (sampled 300 via entrez): RS1000023030 (13:39749898 A>G), RS1000038891 (13:39770649 A>C), RS1000059859 (13:39659622 A>G), RS1000064012 (13:39671090 G>A), RS1000067478 (13:39765761 A>G), RS1000072608 (13:39766127 G>A,T), RS1000110570 (13:39721522 A>G), RS1000132402 (13:39669445 C>A), RS1000132800 (13:39665457 T>A), RS1000164141 (13:39682332 G>A,T), RS1000165424 (13:39665026 T>G), RS1000166046 (13:39724679 A>G), RS1000171882 (13:39752841 G>A), RS1000179197 (13:39709251 G>A,C), RS1000179808 (13:39720440 A>G,T)

Disease associations

OMIM: gene MIM:606977 | disease phenotypes: MIM:614576, MIM:615328, MIM:616268

GenCC curated gene-disease

Disease	Classification	Inheritance
COG6-congenital disorder of glycosylation	Strong	Autosomal recessive
hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
COG6-congenital disorder of glycosylation	Definitive	AR

Mondo (4): COG6-congenital disorder of glycosylation (MONDO:0013810), hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome (MONDO:0014131), intellectual disability (MONDO:0001071), autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome (MONDO:0014558)

Orphanet (4): Hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome (Orphanet:363523), COG6-CGD (Orphanet:464443), KAT6-related intellectual disability-craniofacial anomalies-cardiac defects syndrome (Orphanet:457193), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

64 total (30 of 64 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000114	Proximal tubulopathy
HP:0000122	Unilateral renal agenesis
HP:0000238	Hydrocephalus
HP:0000252	Microcephaly
HP:0000278	Retrognathia
HP:0000286	Epicanthus
HP:0000455	Broad nasal tip
HP:0000648	Optic atrophy
HP:0000670	Carious teeth
HP:0000750	Delayed speech and language development
HP:0000958	Dry skin
HP:0000962	Hyperkeratosis
HP:0000966	Hypohidrosis
HP:0000972	Palmoplantar hyperkeratosis
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001263	Global developmental delay
HP:0001272	Cerebellar atrophy
HP:0001290	Generalized hypotonia
HP:0001385	Hip dysplasia
HP:0001394	Cirrhosis
HP:0001396	Cholestasis
HP:0001508	Failure to thrive
HP:0001510	Growth delay
HP:0001511	Intrauterine growth retardation
HP:0001522	Death in infancy
HP:0001629	Ventricular septal defect
HP:0001631	Atrial septal defect
HP:0001643	Patent ductus arteriosus

GWAS associations

27 associations (top):

Study	Trait	p-value
GCST000173_1	Psoriasis	2.000000e-06
GCST002318_13	Rheumatoid arthritis	3.000000e-11
GCST002318_68	Rheumatoid arthritis	2.000000e-12
GCST002541_94	Menarche (age at onset)	2.000000e-11
GCST002874_27	Psoriasis	5.000000e-08
GCST002874_31	Psoriasis	3.000000e-08
GCST003620_1	Systemic lupus erythematosus or rheumatoid arthritis	3.000000e-13
GCST004482_28	Peripheral arterial disease (traffic-related air pollution interaction)	7.000000e-06
GCST004600_10	Eosinophil percentage of white cells	2.000000e-12
GCST004606_74	Eosinophil count	1.000000e-11
GCST004617_147	Eosinophil percentage of granulocytes	2.000000e-10
GCST004623_62	Neutrophil percentage of granulocytes	2.000000e-09
GCST004624_149	Sum eosinophil basophil counts	1.000000e-10
GCST005528_26	Juvenile idiopathic arthritis (oligoarticular or rheumatoid factor-negative polyarticular)	5.000000e-08
GCST005531_79	Multiple sclerosis	2.000000e-06
GCST005568_53	Rheumatoid arthritis (ACPA-positive)	5.000000e-06
GCST006048_31	Rheumatoid arthritis (ACPA-positive)	5.000000e-09
GCST006959_151	Rheumatoid arthritis	2.000000e-12
GCST006959_61	Rheumatoid arthritis	8.000000e-11
GCST007798_153	Asthma	1.000000e-07
GCST007799_35	Asthma (adult onset)	4.000000e-09
GCST008839_441	Height	5.000000e-16
GCST009597_209	Multiple sclerosis	2.000000e-07
GCST009798_42	Asthma	4.000000e-09
GCST010042_6	Asthma	6.000000e-10
GCST90002381_67	Eosinophil count	5.000000e-32
GCST90002382_203	Eosinophil percentage of white cells	7.000000e-34

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0004703	age at menarche
EFO:0007908	traffic air pollution measurement
EFO:0007991	eosinophil percentage of leukocytes
EFO:0004842	eosinophil count
EFO:0007996	eosinophil percentage of granulocytes
EFO:0007994	neutrophil percentage of granulocytes
EFO:0005090	basophil count
EFO:1002011	adult onset asthma

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4105962 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

2 potent at pChembl≥5 of 3 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.57	Kd	269.1	nM	CHEMBL3752910
6.57	ED50	269.1	nM	CHEMBL3752910

PubChem BioAssay actives

1 with measured affinity, of 6 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148108: Binding affinity to human COG6 incubated for 45 mins by Kinobead based pull down assay	kd	0.2691	uM

CTD chemical–gene interactions

35 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases abundance, increases expression	2
Hydrogen Peroxide	affects expression, increases expression	2
Particulate Matter	decreases expression, increases abundance, increases expression	2
aristolochic acid I	decreases expression	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases methylation	1
arsenite	decreases reaction, affects binding	1
tetrabromobisphenol A	increases expression	1
potassium chromate(VI)	decreases expression, affects cotreatment	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
perfluorooctane sulfonic acid	increases expression	1
K 7174	increases expression	1
ICG 001	decreases expression	1
abrine	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	increases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	increases abundance, decreases expression	1
Arsenic	increases abundance, increases expression	1
Vehicle Emissions	increases abundance, increases expression	1
Cisplatin	decreases expression	1
Coumestrol	decreases expression	1
Methyl Methanesulfonate	increases expression	1
Plant Extracts	affects cotreatment, increases expression	1
Quercetin	decreases expression	1
Tetrachlorodibenzodioxin	decreases expression	1
Dronabinol	decreases expression	1
Tunicamycin	increases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4012604	Binding	Binding affinity to COG6 in human INA-6 cells after 3 hrs by nanoLC-MS/MS method	Ugi Reaction-Derived α-Acyl Aminocarboxamides Bind to Phosphatidylinositol 3-Kinase-Related Kinases, Inhibit HSF1-Dependent Heat Shock Response, and Induce Apoptosis in Multiple Myeloma Cells. — J Med Chem

Clinical trials (associated diseases)

197 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study
NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD
NCT02591446	Not specified	COMPLETED	Transcranial Magnetic Stimulation Studies in Autism Spectrum Disorders
NCT02714868	Not specified	COMPLETED	Evaluation of Project TEAM (Teens Making Environmental and Activity Modifications)
NCT02721394	Not specified	UNKNOWN	FCT With Young Children With ID in the UK: A Feasibility Project V.1
NCT02746614	Not specified	COMPLETED	Psychomotor Therapy Effects in Adaptive Behavior and Motor Proficiency in Intellectual Disability
NCT02836405	Not specified	COMPLETED	TMS for the Investigation of Brain Plasticity in Autism Spectrum Disorders