COPB2

Summary

COPB2 (coat protein complex I subunit beta 2, HGNC:2232) is a protein-coding gene on chromosome 3q23, encoding Coatomer subunit beta’ (P35606). The coatomer is a cytosolic protein complex that binds to dilysine motifs and reversibly associates with Golgi non-clathrin-coated vesicles, which further mediate biosynthetic protein transport from the ER, via the Golgi up to the trans Golgi network. It is a common-essential gene (DepMap: required in 100.0% of cancer cell lines).

The Golgi coatomer complex (see MIM 601924) constitutes the coat of nonclathrin-coated vesicles and is essential for Golgi budding and vesicular trafficking. It consists of 7 protein subunits, including COPB2.

Source: NCBI Gene 9276 — RefSeq curated summary.

At a glance

• Gene–disease (curated): osteoporosis, childhood- or juvenile-onset, with developmental delay (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 3
• Clinical variants (ClinVar): 240 total — 6 pathogenic, 5 likely-pathogenic
• Phenotypes (HPO): 42
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 100.0% of screened cell lines (common-essential)
• MANE Select transcript: NM_004766

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2232
Approved symbol	COPB2
Name	coat protein complex I subunit beta 2
Location	3q23
Locus type	gene with protein product
Status	Approved
Aliases	beta’-COP, betaprime-COP
Ensembl gene	ENSG00000184432
Ensembl biotype	protein_coding
OMIM	606990
Entrez	9276

Gene structure

Transcript identifiers

Ensembl transcripts: 31 — 23 protein_coding, 3 retained_intron, 3 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000333188, ENST00000502734, ENST00000503326, ENST00000504295, ENST00000507777, ENST00000510181, ENST00000510491, ENST00000512153, ENST00000512242, ENST00000512309, ENST00000513274, ENST00000514508, ENST00000515006, ENST00000676700, ENST00000677073, ENST00000677309, ENST00000677601, ENST00000677882, ENST00000870961, ENST00000870962, ENST00000870963, ENST00000870964, ENST00000870965, ENST00000870966, ENST00000938173, ENST00000938174, ENST00000964704, ENST00000964705, ENST00000964706, ENST00000964707, ENST00000964708

RefSeq mRNA: 2 — MANE Select: NM_004766 NM_001410834, NM_004766

CCDS: CCDS3108, CCDS93395

Canonical transcript exons

ENST00000333188 — 22 exons

Exon	Start	End
ENSE00001292150	139367015	139367145
ENSE00001295512	139359270	139359362
ENSE00001297520	139358744	139358812
ENSE00001298231	139369261	139369367
ENSE00001299000	139371723	139371833
ENSE00001299534	139374489	139374588
ENSE00001303156	139373213	139373412
ENSE00001305773	139362407	139362517
ENSE00001311447	139368145	139368288
ENSE00001311819	139358200	139358271
ENSE00001312873	139366568	139366775
ENSE00001315090	139358998	139359178
ENSE00001317539	139369456	139369544
ENSE00001323326	139373666	139373808
ENSE00001329013	139361081	139361295
ENSE00002033749	139357406	139357958
ENSE00002035761	139389548	139389647
ENSE00003602709	139378041	139378189
ENSE00003603825	139383298	139383435
ENSE00003631384	139375468	139375614
ENSE00003672340	139379380	139379466
ENSE00003790980	139379047	139379173

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 98.71.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 79.5290 / max 1794.9435, expressed in 1825 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
44788	70.5594	1824
44787	5.8888	1659
44786	3.0808	1384

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
parotid gland	UBERON:0001831	98.71	gold quality
stromal cell of endometrium	CL:0002255	98.27	gold quality
type B pancreatic cell	CL:0000169	97.80	gold quality
oral cavity	UBERON:0000167	97.60	gold quality
body of pancreas	UBERON:0001150	97.59	gold quality
islet of Langerhans	UBERON:0000006	97.57	gold quality
mucosa of sigmoid colon	UBERON:0004993	97.46	gold quality
bronchial epithelial cell	CL:0002328	97.42	gold quality
smooth muscle tissue	UBERON:0001135	97.30	gold quality
calcaneal tendon	UBERON:0003701	97.08	gold quality
colonic mucosa	UBERON:0000317	97.07	gold quality
rectum	UBERON:0001052	97.04	gold quality
adrenal tissue	UBERON:0018303	96.96	gold quality
seminal vesicle	UBERON:0000998	96.86	gold quality
corpus epididymis	UBERON:0004359	96.76	gold quality
mucosa of paranasal sinus	UBERON:0005030	96.76	gold quality
pancreas	UBERON:0001264	96.73	gold quality
jejunal mucosa	UBERON:0000399	96.72	gold quality
epithelium of bronchus	UBERON:0002031	96.67	gold quality
bronchus	UBERON:0002185	96.59	gold quality
endometrium	UBERON:0001295	96.43	gold quality
tendon	UBERON:0000043	96.38	gold quality
tendon of biceps brachii	UBERON:0008188	96.31	gold quality
adenohypophysis	UBERON:0002196	96.30	gold quality
pituitary gland	UBERON:0000007	96.19	gold quality
duodenum	UBERON:0002114	96.18	gold quality
gall bladder	UBERON:0002110	96.10	gold quality
saliva-secreting gland	UBERON:0001044	96.03	gold quality
tibia	UBERON:0000979	95.97	gold quality
trabecular bone tissue	UBERON:0002483	95.95	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-7303	no	157.06
E-CURD-88	no	3.65
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

23 targeting COPB2, 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-5011-5P	100.00	83.46	5820
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-MIR-8062	99.88	68.43	995
HSA-MIR-4694-3P	99.79	69.53	2640
HSA-MIR-10393-3P	99.72	66.56	961
HSA-MIR-6801-5P	99.72	66.50	981
HSA-MIR-7157-5P	99.66	69.33	1829
HSA-MIR-4310	99.59	68.84	2527
HSA-MIR-330-3P	99.41	69.95	2521
HSA-MIR-4318	99.38	66.94	1505
HSA-MIR-4641	99.28	66.64	744
HSA-MIR-329-5P	99.27	68.11	1597
HSA-MIR-12135	98.99	70.26	1814
HSA-MIR-4712-3P	98.52	65.39	822
HSA-MIR-4296	96.35	63.55	1233
HSA-MIR-4265	96.18	64.68	557
HSA-MIR-4322	96.18	64.85	539
HSA-MIR-601	95.98	67.59	421

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 100.0% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 20)

• Golgi organization depends on mutually interacting domains in betaCOP and p115, suggesting that vesicle tethering at the Golgi involves p115 binding to the COPI coat (PMID:18434597)
• these data suggest that beta-COP plays a critical role in the forward transport of TREK1 channel to the plasma membrane. (PMID:20362547)
• COPB2 significantly promoted PC-3 cell proliferation and colony formation through the cell cycle and apoptosis pathway. COPB2 showed a clinical correlation and may serve as a biomarker for the detection for prostate cancer. (PMID:27986120)
• High expression of COPB2 was found in prostate cancer tissue and was related to poor overall survival based on a public dataset. Cell proliferation was significantly inhibited in COPB2-knockdown CWR22RV1 cells, as demonstrated by CCK8 and colony formation assays. (PMID:29129687)
• COPB2 is highly expressed in cholangiocellular carcinoma cell lines. (PMID:29509246)
• The increased expression of COPB2 was significantly correlated with the progression of lung adenocarcinoma. (PMID:29674272)
• Knockdown of ERC1, RAB4B, COPA, and COPB2, caused profound loss of virus production. (PMID:29946045)
• Study demonstrated that COPB2 was highly expressed in human gastric cancer cell lines, and knockdown suppressed colony formation and promoted cell apoptosis via inhibiting the RTK signaling and its downstream signaling cascade molecules. (PMID:30968146)
• COPB2 is up-regulated in breast cancer and plays a vital role in the metastasis via N-cadherin and Vimentin. (PMID:31119859)
• BMSCs-derived exosome miR-4461 downregulated COPB2 expression and inhibited HCT116 and SW480 cells migration and invasion (PMID:31631786)
• High expression of COPB2 predicts adverse outcomes: A potential therapeutic target for glioma. (PMID:31710183)
• Upregulation of the Coatomer Protein Complex Subunit beta 2 (COPB2) Gene Targets microRNA-335-3p in NCI-H1975 Lung Adenocarcinoma Cells to Promote Cell Proliferation and Migration. (PMID:32004259)
• MiR-216a-3p regulates the proliferation, apoptosis, migration, and invasion of lung cancer cells via targeting COPB2. (PMID:32619135)
• COPB2 gene silencing inhibits colorectal cancer cell proliferation and induces apoptosis via the JNK/c-Jun signaling pathway. (PMID:33211699)
• COPB2: A Novel Prognostic Biomarker That Affects Progression of HCC. (PMID:33824874)
• COPB2: a transport protein with multifaceted roles in cancer development and progression. (PMID:34101128)
• COPB2 loss of function causes a coatopathy with osteoporosis and developmental delay. (PMID:34450031)
• An Integrative Pan-Cancer Analysis of the Oncogenic Role of COPB2 in Human Tumors. (PMID:34676262)
• Comprehensive analysis reveals COPB2 and RYK associated with tumor stages of larynx squamous cell carcinoma. (PMID:35715770)
• beta-COP Suppresses the Surface Expression of the TREK2. (PMID:37296621)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	copb2	ENSDARG00000038743
mus_musculus	Copb2	ENSMUSG00000032458
rattus_norvegicus	Copb2	ENSRNOG00000060723
drosophila_melanogaster	beta’COP	FBGN0025724
caenorhabditis_elegans		WBGENE00270321

Paralogs (1): COPA (ENSG00000122218)

Protein

Protein identifiers

Coatomer subunit beta’ — P35606 (reviewed: P35606)

Alternative names: Beta’-coat protein, p102

All UniProt accessions (12): A0A7I2V258, A0A7I2V3G0, A0A7I2V526, A0A7I2YQF9, D6R997, P35606, D6RBG7, D6RBT6, D6RBZ7, D6RCL6, H0Y938, H0YAC7

UniProt curated annotations — full annotation on UniProt →

Function. The coatomer is a cytosolic protein complex that binds to dilysine motifs and reversibly associates with Golgi non-clathrin-coated vesicles, which further mediate biosynthetic protein transport from the ER, via the Golgi up to the trans Golgi network. Coatomer complex is required for budding from Golgi membranes, and is essential for the retrograde Golgi-to-ER transport of dilysine-tagged proteins. In mammals, the coatomer can only be recruited by membranes associated to ADP-ribosylation factors (ARFs), which are small GTP-binding proteins; the complex also influences the Golgi structural integrity, as well as the processing, activity, and endocytic recycling of LDL receptors. This coatomer complex protein, essential for Golgi budding and vesicular trafficking, is a selective binding protein (RACK) for protein kinase C, epsilon type. It binds to Golgi membranes in a GTP-dependent manner.

Subunit / interactions. Oligomeric complex that consists of at least the alpha, beta, beta’, gamma, delta, epsilon and zeta subunits. Probably interacts with PEX11A. Interacts with SCYL1. Interacts with JAGN1.

Subcellular location. Cytoplasm. Cytosol. Golgi apparatus membrane. Cytoplasmic vesicle. COPI-coated vesicle membrane.

Disease relevance. Microcephaly 19, primary, autosomal recessive (MCPH19) [MIM:617800] A form of microcephaly, a disease defined as a head circumference more than 3 standard deviations below the age, sex and ethnically matched mean. Brain weight is markedly reduced and the cerebral cortex is disproportionately small. MCPH19 affected individuals manifest severe developmental delay, failure to thrive, cortical blindness, and spasticity. Brain imaging show a simplified gyral pattern, thin corpus callosum, slight ventricular dilation, and delayed myelination. The disease may be caused by variants affecting the gene represented in this entry. Osteoporosis, childhood- or juvenile-onset, with developmental delay (OPDD) [MIM:619884] An autosomal dominant disorder characterized by decreased bone mass and deterioration of bone microarchitecture, fragile bones, recurrent fractures following minor trauma, and developmental delay of variable severity. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the WD repeat COPB2 family.

Isoforms (2)

UniProt ID	Names	Canonical?
P35606-1	1	yes
P35606-2	2

RefSeq proteins (2): NP_001397763, NP_004757* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001680	WD40_rpt	Repeat
IPR006692	Beta-prop_COPA/B_2nd	Domain
IPR015943	WD40/YVTN_repeat-like_dom_sf	Homologous_superfamily
IPR016453	COPB2	Family
IPR020472	WD40_PAC1	Repeat
IPR036322	WD40_repeat_dom_sf	Homologous_superfamily
IPR050844	Coatomer_complex_subunit	Family
IPR056176	TPR_COPA_B	Domain

Pfam: PF00400, PF04053, PF23953

UniProt features (82 total): strand 55, turn 10, repeat 6, modified residue 3, helix 2, initiator methionine 1, chain 1, splice variant 1, sequence variant 1, region of interest 1, coiled-coil region 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
8D41	X-RAY DIFFRACTION	2
8D30	X-RAY DIFFRACTION	2.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P35606-F1	86.75	0.61

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (3): 627, 859, 861

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-6807878	COPI-mediated anterograde transport
R-HSA-6811434	COPI-dependent Golgi-to-ER retrograde traffic

MSigDB gene sets: 221 (showing top): YAGI_AML_WITH_INV_16_TRANSLOCATION, MORF_RAB5A, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, MODULE_563, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_DN, GRAESSMANN_RESPONSE_TO_MC_AND_SERUM_DEPRIVATION_DN, KYNG_DNA_DAMAGE_DN, GOBP_VESICLE_MEDIATED_TRANSPORT, REACTOME_MEMBRANE_TRAFFICKING, MORF_PSMC2, GOBP_INTRA_GOLGI_VESICLE_MEDIATED_TRANSPORT, OUELLET_OVARIAN_CANCER_INVASIVE_VS_LMP_UP, GOBP_ENDOPLASMIC_RETICULUM_TO_GOLGI_VESICLE_MEDIATED_TRANSPORT, GOCC_COATED_VESICLE, RHODES_CANCER_META_SIGNATURE

GO Biological Process (6): intracellular protein transport (GO:0006886), endoplasmic reticulum to Golgi vesicle-mediated transport (GO:0006888), retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum (GO:0006890), intra-Golgi vesicle-mediated transport (GO:0006891), protein transport (GO:0015031), vesicle-mediated transport (GO:0016192)

GO Molecular Function (2): structural molecule activity (GO:0005198), protein binding (GO:0005515)

GO Cellular Component (11): Golgi membrane (GO:0000139), endoplasmic reticulum membrane (GO:0005789), cytosol (GO:0005829), COPI vesicle coat (GO:0030126), transport vesicle (GO:0030133), cytoplasm (GO:0005737), Golgi apparatus (GO:0005794), membrane (GO:0016020), membrane coat (GO:0030117), COPI-coated vesicle membrane (GO:0030663), cytoplasmic vesicle (GO:0031410)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
ER to Golgi Anterograde Transport	1
Golgi-to-ER retrograde transport	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	5
Golgi vesicle transport	3
cellular anatomical structure	3
intracellular protein localization	2
intracellular transport	2
transport	2
Golgi apparatus	2
endomembrane system	2
protein transport	1
intercellular transport	1
establishment of protein localization	1
cellular process	1
molecular_function	1
binding	1
bounding membrane of organelle	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
vesicle coat	1
COPI-coated vesicle membrane	1
cytoplasmic vesicle	1
intracellular anatomical structure	1
intracellular membrane-bounded organelle	1
coated membrane	1
membrane protein complex	1
COPI-coated vesicle	1
Golgi-associated vesicle membrane	1
coated vesicle membrane	1
intracellular vesicle	1

Protein interactions and networks

STRING

2256 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
COPB2	ARCN1	P48444	999
COPB2	COPE	O14579	999
COPB2	COPZ1	P61923	999
COPB2	COPB1	P53618	998
COPB2	COPG1	Q9Y678	993
COPB2	COPA	P53621	979
COPB2	COPG2	Q9UBF2	909
COPB2	MRPS22	P82650	790
COPB2	CLTCL1	P53675	676
COPB2	GOLPH3	Q9H4A6	666
COPB2	LMAN1	P49257	657
COPB2	SEC13	P55735	649
COPB2	PRKCE	Q02156	648
COPB2	CLTC	Q00610	627
COPB2	FOXL2	P58012	593

IntAct

209 interactions, top by confidence:

A	B	Type	Score
RINT1	NBAS	psi-mi:“MI:0914”(association)	0.830
COPG1	COPB2	psi-mi:“MI:0914”(association)	0.730
ZW10	NBAS	psi-mi:“MI:0914”(association)	0.720
NBAS	ZW10	psi-mi:“MI:0914”(association)	0.720
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
COPB2	NFKB1	psi-mi:“MI:0915”(physical association)	0.690
SPTLC1	SPTLC2	psi-mi:“MI:0914”(association)	0.680
COPG1	COPE	psi-mi:“MI:0914”(association)	0.640
NFKB1	NFKBIE	psi-mi:“MI:2364”(proximity)	0.600
CANX	PGRMC1	psi-mi:“MI:0914”(association)	0.570
INSR	PIK3R2	psi-mi:“MI:2364”(proximity)	0.570
COPB2	PUS1	psi-mi:“MI:0915”(physical association)	0.560
Copa	COPE	psi-mi:“MI:0915”(physical association)	0.560
	XPO1	psi-mi:“MI:0914”(association)	0.530
PPM1G	COPE	psi-mi:“MI:0914”(association)	0.530
TMED9	COPB2	psi-mi:“MI:0914”(association)	0.530

BioGRID (517): COPB2 (Affinity Capture-MS), COPB2 (Affinity Capture-MS), COPB2 (Affinity Capture-MS), COPB2 (Affinity Capture-RNA), COPA (Co-fractionation), COPB1 (Co-fractionation), COPB2 (Co-fractionation), COPB2 (Co-fractionation), COPG1 (Co-fractionation), COPZ1 (Co-fractionation), TUBB (Co-fractionation), TUBB4B (Co-fractionation), COPB2 (Affinity Capture-MS), COPB2 (Affinity Capture-MS), COPB2 (Proximity Label-MS)

ESM2 similar proteins: A0A1L8EXB5, A4QNE6, A8WGF4, C1BK83, O35142, O43684, O55029, P35605, P35606, Q17QU5, Q1JP79, Q1JQB2, Q29RH4, Q29RZ9, Q3UGF1, Q4FZW5, Q4R4I8, Q561Y0, Q5I0B4, Q5M7F6, Q5MNZ6, Q5R664, Q5RB58, Q5U4Y8, Q5VQ78, Q6GNF1, Q6NWV3, Q6PA72, Q6TGU2, Q803V5, Q8AVT9, Q8BGF3, Q8IWZ6, Q8K2G4, Q8L828, Q8NEZ3, Q8VE80, Q92747, Q96J01, Q96MX6

Diamond homologs: A0CH87, A0DB19, A8QB65, A8XL02, B0W517, B3MJV8, B3N534, B4GT01, B4HWV6, B4JPT9, B4LS78, B4P116, B4Q9T6, B7PY76, B8AP31, O35142, O55029, P35605, P35606, P91343, Q17BB0, Q20168, Q29KQ0, Q40687, Q4R4I8, Q54YD8, Q5BJ90, Q5R664, Q5VQ78, Q5XGE2, Q6H8D5, Q6H8D6, Q6NX08, Q7QJ33, Q9C827, Q9CAA0, Q9SU78, Q9VKQ3, Q9VLN1, Q9ZUN8

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 199 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
Regulation of CDH1 posttranslational processing and trafficking to plasma membrane	6	15.0×	9e-04
SPOP-mediated proteasomal degradation of PD-L1(CD274)	6	10.2×	4e-03
COPI-dependent Golgi-to-ER retrograde traffic	12	9.9×	2e-06
COPI-mediated anterograde transport	9	7.4×	9e-04

GO biological processes:

GO term	Partners	Fold	FDR
zinc ion transmembrane transport	7	29.3×	2e-06
retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum	11	22.1×	3e-09
intra-Golgi vesicle-mediated transport	6	18.8×	2e-04
intracellular zinc ion homeostasis	5	14.3×	5e-03
endoplasmic reticulum to Golgi vesicle-mediated transport	10	8.1×	2e-04
cell surface receptor protein tyrosine kinase signaling pathway	7	7.2×	9e-03
intracellular protein transport	11	4.2×	1e-02

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	5
Uncertain significance	118
Likely benign	58
Benign	14

Top pathogenic / likely-pathogenic (11)

Variant ID	HGVS	Classification
1686975	NM_004766.3(COPB2):c.1206-2A>G	Pathogenic
1686976	NM_004766.3(COPB2):c.247dup (p.Val83fs)	Pathogenic
3370487	NM_004766.3(COPB2):c.660_661del (p.Val222fs)	Pathogenic
433554	Single allele	Pathogenic
446713	NM_004766.3(COPB2):c.760C>T (p.Arg254Cys)	Pathogenic
4839260	NM_004766.2(COPB2):c.2554dupG	Pathogenic
2431662	NM_004766.3(COPB2):c.1266dup (p.Ser423fs)	Likely pathogenic
3777199	NM_004766.3(COPB2):c.1478_1480delinsCCCTTCT (p.Glu493fs)	Likely pathogenic
4293146	NM_004766.3(COPB2):c.1401+2T>A	Likely pathogenic
4531876	NM_004766.3(COPB2):c.1666dup (p.His556fs)	Likely pathogenic
4538598	NM_004766.3(COPB2):c.181C>T (p.Arg61Ter)	Likely pathogenic

SpliceAI

2691 predictions. Top by Δscore:

Variant	Effect	Δscore
3:139355674:A:AG	acceptor_gain	1.0000
3:139355678:TCA:T	acceptor_loss	1.0000
3:139355679:CA:C	acceptor_loss	1.0000
3:139355680:A:AG	acceptor_gain	1.0000
3:139355680:AG:A	acceptor_loss	1.0000
3:139355681:G:GT	acceptor_gain	1.0000
3:139355681:GA:G	acceptor_gain	1.0000
3:139355681:GAA:G	acceptor_gain	1.0000
3:139355681:GAAT:G	acceptor_gain	1.0000
3:139355681:GAATC:G	acceptor_gain	1.0000
3:139355787:CAAGG:C	donor_loss	1.0000
3:139355788:AAGG:A	donor_loss	1.0000
3:139355789:AGGTA:A	donor_loss	1.0000
3:139355791:GTAA:G	donor_loss	1.0000
3:139355792:T:A	donor_loss	1.0000
3:139357957:CT:C	acceptor_gain	1.0000
3:139358198:A:AC	donor_gain	1.0000
3:139358199:C:CC	donor_gain	1.0000
3:139358199:C:CG	donor_loss	1.0000
3:139358268:GTTC:G	acceptor_gain	1.0000
3:139358268:GTTCC:G	acceptor_loss	1.0000
3:139358269:TTC:T	acceptor_gain	1.0000
3:139358269:TTCCT:T	acceptor_loss	1.0000
3:139358270:TC:T	acceptor_gain	1.0000
3:139358270:TCC:T	acceptor_loss	1.0000
3:139358271:CC:C	acceptor_gain	1.0000
3:139358271:CCTG:C	acceptor_loss	1.0000
3:139358272:C:CC	acceptor_gain	1.0000
3:139358273:T:G	acceptor_loss	1.0000
3:139358279:C:CT	acceptor_gain	1.0000

AlphaMissense

5987 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:139359116:G:T	A789D	1.000
3:139359119:A:T	L788H	1.000
3:139359165:A:G	W773R	1.000
3:139359165:A:T	W773R	1.000
3:139361222:A:G	L690P	1.000
3:139362460:C:G	A648P	1.000
3:139362462:A:G	L647P	1.000
3:139367106:A:G	W529R	1.000
3:139367106:A:T	W529R	1.000
3:139368282:A:G	W470R	1.000
3:139368282:A:T	W470R	1.000
3:139369286:C:G	R459P	1.000
3:139371740:C:A	W396C	1.000
3:139371740:C:G	W396C	1.000
3:139371742:A:G	W396R	1.000
3:139371742:A:T	W396R	1.000
3:139371756:G:T	A391D	1.000
3:139371762:C:T	G389E	1.000
3:139371764:A:C	F388L	1.000
3:139371764:A:T	F388L	1.000
3:139371766:A:G	F388L	1.000
3:139371770:C:A	K386N	1.000
3:139371770:C:G	K386N	1.000
3:139371772:T:C	K386E	1.000
3:139371776:T:A	R384S	1.000
3:139371776:T:G	R384S	1.000
3:139371777:C:A	R384I	1.000
3:139371777:C:G	R384T	1.000
3:139371816:C:A	G371V	1.000
3:139371816:C:T	G371D	1.000

dbSNP variants (sampled 300 via entrez): RS1000206429 (3:139373191 G>A), RS1000420759 (3:139387674 T>C), RS1000485443 (3:139358139 C>G,T), RS1000544578 (3:139388558 TTAAGA>T), RS1000993236 (3:139379345 G>A), RS1001098453 (3:139386812 T>C,G), RS1001243335 (3:139386398 G>A), RS1001290629 (3:139387042 T>A,C), RS1001384043 (3:139364237 T>C), RS1001398451 (3:139359386 C>A,G,T), RS1001508683 (3:139358114 T>C), RS1001702123 (3:139379744 C>A), RS1001796573 (3:139384841 C>T), RS1001805235 (3:139364557 TCTA>T), RS1001870047 (3:139373112 A>C,T)

Disease associations

OMIM: gene MIM:606990 | disease phenotypes: MIM:617800, MIM:619884, MIM:110100

GenCC curated gene-disease

Disease	Classification	Inheritance
osteoporosis, childhood- or juvenile-onset, with developmental delay	Strong	Autosomal dominant
autosomal recessive primary microcephaly	Supportive	Autosomal recessive
microcephaly 19, primary, autosomal recessive	Limited	Autosomal recessive

Mondo (4): microcephaly 19, primary, autosomal recessive (MONDO:0054716), osteoporosis, childhood- or juvenile-onset, with developmental delay (MONDO:0859253), blepharophimosis, ptosis, and epicanthus inversus syndrome (MONDO:0007201), autosomal recessive primary microcephaly (MONDO:0016660)

Orphanet (1): Blepharophimosis-ptosis-epicanthus inversus syndrome (Orphanet:126)

HPO phenotypes

42 total (30 of 42 shown, HPO-id order):

HPO	Term
HP:0000002	Abnormality of body height
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000076	Vesicoureteral reflux
HP:0000122	Unilateral renal agenesis
HP:0000219	Thin upper lip vermilion
HP:0000252	Microcephaly
HP:0000340	Sloping forehead
HP:0000582	Upslanted palpebral fissure
HP:0000938	Osteopenia
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001274	Agenesis of corpus callosum
HP:0001302	Pachygyria
HP:0001347	Hyperreflexia
HP:0001510	Growth delay
HP:0001531	Failure to thrive in infancy
HP:0001622	Premature birth
HP:0002079	Hypoplasia of the corpus callosum
HP:0002119	Ventriculomegaly
HP:0002136	Broad-based gait
HP:0002188	Delayed CNS myelination
HP:0002282	Gray matter heterotopia
HP:0002540	Inability to walk
HP:0002757	Recurrent fractures
HP:0003103	Abnormal cortical bone morphology
HP:0003577	Congenital onset
HP:0003593	Infantile onset

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST001456_1	Kawasaki disease	8.000000e-06
GCST005116_22	Male-pattern baldness	1.000000e-15
GCST005116_23	Male-pattern baldness	2.000000e-21

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
C579935	Autosomal Recessive Primary Microcephaly (supp.)
C562419	Blepharophimosis, Ptosis, and Epicanthus Inversus (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066912 (SINGLE PROTEIN)

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

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.77	Kd	17.06	nM	CHEMBL3752910
7.77	ED50	17.06	nM	CHEMBL3752910
6.54	Kd	290.7	nM	CHEMBL5653589
6.54	ED50	290.7	nM	CHEMBL5653589

PubChem BioAssay actives

2 with measured affinity, of 4 total; 2 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	2148116: Binding affinity to human COPB2 incubated for 45 mins by Kinobead based pull down assay	kd	0.0171	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148116: Binding affinity to human COPB2 incubated for 45 mins by Kinobead based pull down assay	kd	0.2907	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol S	affects cotreatment, increases methylation, increases expression, affects expression	3
bisphenol A	increases expression, decreases expression	2
sodium arsenite	decreases expression, increases expression	2
Fulvestrant	affects cotreatment, increases methylation, decreases expression	2
Valproic Acid	affects expression, increases expression	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
dicrotophos	decreases expression	1
deoxynivalenol	decreases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, decreases expression, affects localization	1
salinomycin	decreases expression	1
beta-lapachone	decreases expression	1
afimoxifene	decreases expression	1
bicalutamide	increases expression	1
bisphenol B	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
picoxystrobin	increases expression	1
bisphenol AF	increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Arsenic Trioxide	increases expression	1
Air Pollutants	affects expression, increases abundance	1
Air Pollutants, Occupational	decreases expression	1
Atrazine	increases expression	1
Caffeine	increases phosphorylation	1
Cisplatin	decreases expression	1
Diazinon	increases methylation	1
Estradiol	increases expression	1
Furaldehyde	affects cotreatment, decreases expression, affects localization, increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651158	Binding	Binding affinity to human COPB2 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

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