COMMD3

Summary

COMMD3 (COMM domain containing 3, HGNC:23332) is a protein-coding gene on chromosome 10p12.2, encoding COMM domain-containing protein 3 (Q9UBI1). Scaffold protein in the commander complex that is essential for endosomal recycling of transmembrane cargos; the commander complex is composed of the CCC subcomplex and the retriever subcomplex.

Predicted to be involved in sodium ion transport. Predicted to be located in extracellular region and ficolin-1-rich granule lumen.

Source: NCBI Gene 23412 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 9 total
• MANE Select transcript: NM_012071

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23332
Approved symbol	COMMD3
Name	COMM domain containing 3
Location	10p12.2
Locus type	gene with protein product
Status	Approved
Aliases	BUP
Ensembl gene	ENSG00000148444
Ensembl biotype	protein_coding
OMIM	616700
Entrez	23412

Gene structure

Transcript identifiers

Ensembl transcripts: 20 — 10 protein_coding, 6 retained_intron, 3 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000376836, ENST00000444869, ENST00000448361, ENST00000456711, ENST00000463688, ENST00000468179, ENST00000468469, ENST00000470045, ENST00000471350, ENST00000472610, ENST00000472673, ENST00000479958, ENST00000483684, ENST00000496071, ENST00000602574, ENST00000860458, ENST00000860459, ENST00000860460, ENST00000860461, ENST00000964928

RefSeq mRNA: 1 — MANE Select: NM_012071 NM_012071

CCDS: CCDS7137

Canonical transcript exons

ENST00000376836 — 8 exons

Exon	Start	End
ENSE00001822108	22316388	22316556
ENSE00003496732	22317884	22317995
ENSE00003555854	22318272	22318306
ENSE00003558432	22318806	22318862
ENSE00003611347	22318959	22319018
ENSE00003620155	22319939	22320306
ENSE00003620718	22318105	22318168
ENSE00003623512	22318653	22318713

Expression profiles

Bgee: expression breadth ubiquitous, 287 present calls, max score 97.92.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0299 / max 4.2606, expressed in 14 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
104230	62.2653	1826
104234	0.0299	14

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
diaphragm	UBERON:0001103	97.92	gold quality
body of pancreas	UBERON:0001150	97.48	gold quality
triceps brachii	UBERON:0001509	97.13	gold quality
parotid gland	UBERON:0001831	97.08	gold quality
cortical plate	UBERON:0005343	97.02	gold quality
left ventricle myocardium	UBERON:0006566	96.92	gold quality
thymus	UBERON:0002370	96.64	gold quality
heart right ventricle	UBERON:0002080	96.58	gold quality
biceps brachii	UBERON:0001507	96.54	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	96.47	gold quality
monocyte	CL:0000576	96.46	gold quality
mononuclear cell	CL:0000842	96.43	gold quality
heart left ventricle	UBERON:0002084	96.41	gold quality
olfactory bulb	UBERON:0002264	96.41	silver quality
cardiac ventricle	UBERON:0002082	96.40	gold quality
right atrium auricular region	UBERON:0006631	96.37	gold quality
left testis	UBERON:0004533	96.36	gold quality
myocardium	UBERON:0002349	96.34	gold quality
cardiac atrium	UBERON:0002081	96.31	gold quality
adenohypophysis	UBERON:0002196	96.30	gold quality
vastus lateralis	UBERON:0001379	96.28	gold quality
leukocyte	CL:0000738	96.27	gold quality
right testis	UBERON:0004534	96.25	gold quality
quadriceps femoris	UBERON:0001377	96.22	gold quality
gluteal muscle	UBERON:0002000	96.19	gold quality
heart	UBERON:0000948	96.17	gold quality
superficial temporal artery	UBERON:0001614	96.10	gold quality
pituitary gland	UBERON:0000007	96.08	gold quality
pancreas	UBERON:0001264	96.07	gold quality
calcaneal tendon	UBERON:0003701	96.05	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-CURD-46	yes	33.70
E-ANND-3	yes	19.51
E-GEOD-36552	no	39.91

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

19 targeting COMMD3, 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-4267	99.96	66.53	2368
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-605-3P	99.88	69.22	1833
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-3059-5P	99.70	69.93	2491
HSA-MIR-6833-5P	99.50	68.93	1161
HSA-MIR-29B-1-5P	98.86	68.35	1364
HSA-MIR-6794-3P	98.76	66.99	894
HSA-MIR-4520-3P	98.75	66.55	963
HSA-MIR-6780A-3P	98.42	67.49	1518
HSA-MIR-138-1-3P	98.25	67.89	867
HSA-MIR-12126	98.09	64.82	637
HSA-MIR-6881-3P	98.04	68.24	1777
HSA-MIR-506-5P	98.02	67.41	1065
HSA-MIR-7111-3P	97.80	66.75	1467
HSA-MIR-4790-3P	96.63	67.08	806

Literature-anchored findings (GeneRIF, showing 6)

• complex determines GRK6 specificity for chemoattractant receptors (PMID:31088898)
• Data show that COMMD3 level is elevated in prostate cancer cell models, PDX models, and metastases. A positive correlation between increased COMMD3 expression and disease recurrence and poor survival was found. COMMD3 drives proliferation of normal cells and promotes migration/invasiveness of neoplastic cells. COMMD3:BMI1 fusion protein and COMMD3 regulate C-MYC transcription and C-MYC downstream pathway. (PMID:31467179)
• Transcriptional analysis of the expression, prognostic value and immune infiltration activities of the COMMD protein family in hepatocellular carcinoma. (PMID:34493238)
• Syntaxin 12 and COMMD3 are new factors that function with VPS33B in the biogenesis of platelet alpha-granules. (PMID:34905616)
• COMMD3-Mediated Endosomal Trafficking of HER2 Inhibits the Progression of Ovarian Carcinoma. (PMID:36445330)
• COMMD3 loss drives invasive breast cancer growth by modulating copper homeostasis. (PMID:37072858)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	commd3	ENSDARG00000045402
mus_musculus	Commd3	ENSMUSG00000051154
rattus_norvegicus	Commd3	ENSRNOG00000016383
drosophila_melanogaster	CG12106	FBGN0030100

Protein

Protein identifiers

COMM domain-containing protein 3 — Q9UBI1 (reviewed: Q9UBI1)

Alternative names: Protein Bup, Protein PIL

All UniProt accessions (6): Q9UBI1, H0Y4E5, H0Y4W0, H0Y6Z9, R4GN06, R4GNF2

UniProt curated annotations — full annotation on UniProt →

Function. Scaffold protein in the commander complex that is essential for endosomal recycling of transmembrane cargos; the commander complex is composed of the CCC subcomplex and the retriever subcomplex. May modulate activity of cullin-RING E3 ubiquitin ligase (CRL) complexes. May down-regulate activation of NF-kappa-B. Modulates Na(+) transport in epithelial cells by regulation of apical cell surface expression of amiloride-sensitive sodium channel (ENaC) subunits.

Subunit / interactions. Component of the commander complex consisting of the CCC subcomplex and the retriever subcomplex. Component of the CCC (COMMD/CCDC22/CCDC93) subcomplex consisting of COMMD1, COMMD2, COMMD3, COMMD4, COMMD5, COMMD6, COMMD7, COMMD8, COMMD9, COMMD10, CCDC22 and CCDC93; within the complex forms a heterodimer with COMMD2. Interacts with NFKB1/p105. Interacts with CCDC22, CCDC93, SCNN1B, CUL3, CUL4A, CUL4B, CUL5.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Widely expressed with highest expression in thymus.

Similarity. Belongs to the COMM domain-containing protein 3 family.

RefSeq proteins (1): NP_036203* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR017920	COMM	Domain
IPR037355	COMMD3	Family

Pfam: PF07258, PF21672

UniProt features (15 total): helix 6, strand 3, turn 3, chain 1, domain 1, sequence variant 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
8P0W	ELECTRON MICROSCOPY	2.9
8F2R	ELECTRON MICROSCOPY	3.12
8F2U	ELECTRON MICROSCOPY	3.53

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UBI1-F1	86.84	0.63

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-6798695	Neutrophil degranulation
R-HSA-8951664	Neddylation

MSigDB gene sets: 178 (showing top): REACTOME_INNATE_IMMUNE_SYSTEM, BENPORATH_ES_WITH_H3K27ME3, GOCC_SECRETORY_GRANULE, TGACCTY_ERR1_Q2, GOBP_VESICLE_MEDIATED_TRANSPORT, CAGCTG_AP4_Q5, GOBP_MONOATOMIC_CATION_TRANSPORT, USF_01, TGACATY_UNKNOWN, ZHOU_INFLAMMATORY_RESPONSE_LIVE_DN, AACTTT_UNKNOWN, BENPORATH_NOS_TARGETS, GOBP_ENDOCYTIC_RECYCLING, USF_02, GOBP_LOCALIZATION_WITHIN_MEMBRANE

GO Biological Process (2): sodium ion transport (GO:0006814), monoatomic ion transport (GO:0006811)

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

GO Cellular Component (4): extracellular region (GO:0005576), nucleus (GO:0005634), ficolin-1-rich granule lumen (GO:1904813), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Innate Immune System	1
Post-translational protein modification	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
metal ion transport	1
transport	1
binding	1
intracellular membrane-bounded organelle	1
intracellular organelle lumen	1
ficolin-1-rich granule	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

791 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
COMMD3	COMMD2	Q86X83	858
COMMD3	COMMD4	Q9H0A8	775
COMMD3	CCDC22	O60826	726
COMMD3	COMMD9	Q9P000	665
COMMD3	COMMD6	Q7Z4G1	642
COMMD3	COMMD1	Q8N668	636
COMMD3	COMMD10	Q9Y6G5	626
COMMD3	COMMD5	Q9GZQ3	538
COMMD3	COMMD8	Q9NX08	535
COMMD3	CCDC93	Q567U6	525
COMMD3	A0A2R8Y455	A0A2R8Y455	524
COMMD3	COMMD7	Q86VX2	523
COMMD3	VPS26C	O14972	469
COMMD3	VPS35L	Q7Z3J2	468
COMMD3	WDR81	Q562E7	428

IntAct

219 interactions, top by confidence:

A	B	Type	Score
COMMD1	CCDC22	psi-mi:“MI:0914”(association)	0.970
CCDC22	CCDC93	psi-mi:“MI:0915”(physical association)	0.960
CCDC22	CCDC93	psi-mi:“MI:0914”(association)	0.960
COMMD1	COMMD6	psi-mi:“MI:0914”(association)	0.950
COMMD1	COMMD6	psi-mi:“MI:0915”(physical association)	0.950
CCDC22	COMMD3	psi-mi:“MI:0915”(physical association)	0.930
CCDC22	COMMD6	psi-mi:“MI:0914”(association)	0.930
COMMD2	CCDC22	psi-mi:“MI:0914”(association)	0.930
COMMD5	CCDC22	psi-mi:“MI:0914”(association)	0.930
COMMD2	COMMD3	psi-mi:“MI:0915”(physical association)	0.900
COMMD3	COMMD1	psi-mi:“MI:0915”(physical association)	0.880
COMMD4	COMMD8	psi-mi:“MI:0914”(association)	0.880
COMMD3	CCDC93	psi-mi:“MI:0915”(physical association)	0.850
ODAD1	HGS	psi-mi:“MI:0914”(association)	0.850
COMMD2	COMMD4	psi-mi:“MI:0915”(physical association)	0.820
CCDC22	VPS26C	psi-mi:“MI:0914”(association)	0.790
VPS29	VPS26C	psi-mi:“MI:0914”(association)	0.760
COMMD1	VPS26C	psi-mi:“MI:0914”(association)	0.730
COMMD8	COMMD6	psi-mi:“MI:0914”(association)	0.730
VPS35L	VPS26C	psi-mi:“MI:0914”(association)	0.730

BioGRID (157): COMMD3 (Affinity Capture-RNA), COMMD3 (Affinity Capture-MS), COMMD3 (Affinity Capture-MS), COMMD3 (Affinity Capture-MS), COMMD3 (Affinity Capture-MS), COMMD3 (Affinity Capture-MS), COMMD2 (Affinity Capture-MS), C16orf62 (Affinity Capture-MS), CCDC93 (Affinity Capture-MS), COMMD10 (Affinity Capture-MS), COMMD4 (Affinity Capture-MS), COMMD7 (Affinity Capture-MS), FAM45A (Affinity Capture-MS), DSCR3 (Affinity Capture-MS), COMMD6 (Affinity Capture-MS)

ESM2 similar proteins: A4FUC9, A8MT19, B0BM28, B0BN28, F1S5L4, F2Z461, F4I735, P0DM65, P97564, Q05AV1, Q08BZ4, Q0V7M7, Q0WVH0, Q1LXZ7, Q28HC7, Q2M2T5, Q3MHX1, Q3SYG4, Q3SZ76, Q550I8, Q5GJ77, Q5ZJC7, Q61586, Q63829, Q68F70, Q6DJJ6, Q6P5U7, Q6P9U3, Q6PBQ2, Q7M6Y6, Q7Z745, Q811G0, Q86VX2, Q8BG94, Q8BWR8, Q8CIM8, Q8HXG3, Q8IUC4, Q8N668, Q8R395

Diamond homologs: Q3SZ76, Q54QK4, Q63829, Q6P9U3, Q9UBI1

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 147 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
Assembly and cell surface presentation of NMDA receptors	8	22.1×	4e-07
Neurexins and neuroligins	9	19.3×	3e-07
Protein-protein interactions at synapses	6	17.3×	1e-04
Neddylation	10	5.2×	1e-03

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	7	30.4×	2e-06
protein localization to synapse	5	28.6×	1e-04
receptor clustering	6	27.9×	1e-05
Golgi to plasma membrane transport	6	25.1×	2e-05
regulation of postsynaptic membrane neurotransmitter receptor levels	5	18.5×	9e-04
endocytic recycling	8	16.0×	1e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	8
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1395 predictions. Top by Δscore:

Variant	Effect	Δscore
10:22316552:GTTAG:G	donor_gain	1.0000
10:22316553:TTAGG:T	donor_loss	1.0000
10:22316555:AGG:A	donor_loss	1.0000
10:22316556:GGT:G	donor_loss	1.0000
10:22316557:G:GA	donor_loss	1.0000
10:22316557:G:GG	donor_gain	1.0000
10:22316558:T:G	donor_loss	1.0000
10:22318441:T:G	donor_gain	1.0000
10:22317882:A:AG	acceptor_gain	0.9900
10:22317883:G:GG	acceptor_gain	0.9900
10:22320096:G:GG	donor_gain	0.9900
10:22316657:G:GT	donor_gain	0.9800
10:22317991:CTAAG:C	donor_loss	0.9800
10:22317992:TAAGG:T	donor_loss	0.9800
10:22317993:AAGG:A	donor_loss	0.9800
10:22317994:AGGT:A	donor_loss	0.9800
10:22317995:GGT:G	donor_loss	0.9800
10:22317996:GTACA:G	donor_loss	0.9800
10:22317997:T:A	donor_loss	0.9800
10:22318437:G:GT	donor_gain	0.9800
10:22320083:G:GT	donor_gain	0.9800
10:22316428:CGGAG:C	acceptor_gain	0.9700
10:22318103:A:AG	acceptor_gain	0.9700
10:22318104:G:GG	acceptor_gain	0.9700
10:22318423:C:T	donor_gain	0.9700
10:22320095:A:AG	donor_gain	0.9700
10:22317992:TAAG:T	donor_loss	0.9600
10:22317994:AGG:A	donor_loss	0.9600
10:22317996:G:A	donor_loss	0.9600
10:22318873:A:G	donor_gain	0.9600

AlphaMissense

1280 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:22318690:T:A	W130R	0.995
10:22318690:T:C	W130R	0.995
10:22319955:T:C	L182P	0.989
10:22319014:T:C	L175S	0.988
10:22319963:G:C	A185P	0.987
10:22319964:C:A	A185D	0.985
10:22317953:T:A	I70K	0.983
10:22317961:G:C	A73P	0.980
10:22318998:T:C	C170R	0.978
10:22318839:T:G	Y149D	0.975
10:22319955:T:A	L182H	0.974
10:22318676:T:A	I125K	0.968
10:22319000:C:G	C170W	0.968
10:22318692:G:C	W130C	0.967
10:22318692:G:T	W130C	0.967
10:22319943:T:C	L178S	0.965
10:22318993:T:C	F168S	0.964
10:22317937:G:C	A65P	0.963
10:22317953:T:G	I70R	0.961
10:22318163:T:G	Y104D	0.960
10:22318992:T:C	F168L	0.960
10:22318994:T:A	F168L	0.960
10:22318994:T:G	F168L	0.960
10:22319955:T:G	L182R	0.956
10:22316445:G:C	G10R	0.954
10:22319959:A:C	K183N	0.953
10:22319959:A:T	K183N	0.953
10:22318676:T:G	I125R	0.952
10:22318685:T:A	V128D	0.950
10:22318691:G:C	W130S	0.950

dbSNP variants (sampled 300 via entrez): RS1000809035 (10:22316383 G>T), RS1000814650 (10:22319566 T>A,C), RS1001331160 (10:22315745 A>G), RS1001679281 (10:22316064 C>T), RS1002276831 (10:22314658 C>T), RS1002421016 (10:22317381 ATGAC>A), RS1002885087 (10:22317090 A>G), RS1003022707 (10:22319636 A>G), RS1004371621 (10:22317431 A>G), RS1004425405 (10:22317130 A>G), RS1004708112 (10:22316245 G>A,T), RS1005374085 (10:22318855 G>C), RS1005641475 (10:22315160 T>C), RS1005795402 (10:22315420 T>C), RS1006943275 (10:22319554 A>AT)

Disease associations

OMIM: gene MIM:616700 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST004093_34	Prostate-specific antigen levels	1.000000e-14

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases methylation, increases expression	5
Tobacco Smoke Pollution	decreases expression	2
dicrotophos	decreases expression	1
beta-lapachone	increases expression	1
methylparaben	increases expression	1
sodium arsenite	decreases expression	1
potassium chromate(VI)	decreases expression	1
cupric chloride	decreases expression	1
nickel sulfate	decreases expression	1
1-nitropyrene	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Decitabine	affects expression	1
Vorinostat	increases expression	1
Acetaminophen	decreases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Carbamazepine	affects expression	1
Cisplatin	affects expression	1
Dimethyl Sulfoxide	decreases expression	1
Estradiol	decreases expression	1
Ivermectin	decreases expression	1
Plant Extracts	affects cotreatment, increases expression	1
Selenium	decreases expression	1
Smoke	decreases expression	1
Tretinoin	increases expression	1
Vitamin E	decreases expression	1
Aflatoxin B1	decreases methylation	1
Copper Sulfate	decreases expression	1

Clinical trials (associated diseases)

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