COMMD1

Summary

COMMD1 (copper metabolism domain containing 1, HGNC:23024) is a protein-coding gene on chromosome 2p15, encoding COMM domain-containing protein 1 (Q8N668). 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.

Enables several functions, including phosphatidylinositol-3,4-bisphosphate binding activity; phospholipid binding activity; and protein homodimerization activity. Involved in several processes, including Golgi to plasma membrane transport; negative regulation of protein localization to cell surface; and regulation of protein metabolic process. Acts upstream of or within negative regulation of NF-kappaB transcription factor activity. Located in cytosol; endosome; and nucleoplasm. Part of Cul2-RING ubiquitin ligase complex.

Source: NCBI Gene 150684 — RefSeq curated summary.

At a glance

• GWAS associations: 7
• Clinical variants (ClinVar): 29 total — 1 likely-pathogenic
• MANE Select transcript: NM_152516

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23024
Approved symbol	COMMD1
Name	copper metabolism domain containing 1
Location	2p15
Locus type	gene with protein product
Status	Approved
Aliases	MURR1, MGC27155
Ensembl gene	ENSG00000173163
Ensembl biotype	protein_coding
OMIM	607238
Entrez	150684

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 10 protein_coding, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay, 1 retained_intron

ENST00000311832, ENST00000427417, ENST00000444166, ENST00000445644, ENST00000455659, ENST00000458337, ENST00000471704, ENST00000472729, ENST00000897150, ENST00000897151, ENST00000897152, ENST00000897153, ENST00000897154, ENST00000961074

RefSeq mRNA: 4 — MANE Select: NM_152516 NM_001321781, NM_001321782, NM_001371765, NM_152516

CCDS: CCDS1869

Canonical transcript exons

ENST00000311832 — 3 exons

Exon	Start	End
ENSE00001925427	62135831	62136058
ENSE00003530303	62000701	62000982
ENSE00003936561	61905674	61905858

Expression profiles

Bgee: expression breadth ubiquitous, 261 present calls, max score 98.25.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 27.9080 / max 126.3597, expressed in 1820 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
20484	23.5488	1814
20483	4.3592	1693

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left ventricle myocardium	UBERON:0006566	98.25	gold quality
tibialis anterior	UBERON:0001385	97.80	gold quality
cardiac muscle of right atrium	UBERON:0003379	97.68	gold quality
myocardium	UBERON:0002349	97.00	gold quality
kidney epithelium	UBERON:0004819	95.88	gold quality
heart right ventricle	UBERON:0002080	95.67	gold quality
deltoid	UBERON:0001476	95.38	silver quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	95.31	gold quality
heart left ventricle	UBERON:0002084	95.15	gold quality
cardiac ventricle	UBERON:0002082	95.13	gold quality
cardiac atrium	UBERON:0002081	95.04	gold quality
biceps brachii	UBERON:0001507	94.95	gold quality
right atrium auricular region	UBERON:0006631	94.93	gold quality
vena cava	UBERON:0004087	94.91	gold quality
heart	UBERON:0000948	94.86	gold quality
upper arm skin	UBERON:0004263	94.84	gold quality
ileal mucosa	UBERON:0000331	94.82	gold quality
quadriceps femoris	UBERON:0001377	94.71	gold quality
apex of heart	UBERON:0002098	94.56	gold quality
vastus lateralis	UBERON:0001379	94.29	gold quality
muscle tissue	UBERON:0002385	94.21	gold quality
adult organism	UBERON:0007023	94.21	gold quality
right testis	UBERON:0004534	94.14	gold quality
left testis	UBERON:0004533	94.08	gold quality
hindlimb stylopod muscle	UBERON:0004252	94.03	gold quality
skeletal muscle tissue	UBERON:0001134	93.91	gold quality
testis	UBERON:0000473	93.78	gold quality
tendon of biceps brachii	UBERON:0008188	93.60	gold quality
oral cavity	UBERON:0000167	93.58	gold quality
left coronary artery	UBERON:0001626	93.37	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ARNT

miRNA regulators (miRDB)

10 targeting COMMD1, 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-6825-5P	99.96	69.81	3431
HSA-MIR-29B-2-5P	99.67	68.98	1726
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-4499	99.62	67.29	1470
HSA-MIR-7159-5P	99.53	72.12	2472
HSA-MIR-940	99.37	66.14	2064
HSA-MIR-6808-5P	99.31	66.23	2150
HSA-MIR-6893-5P	99.31	66.25	2119
HSA-MIR-194-3P	97.36	65.96	1027
HSA-MIR-4737	89.94	65.03	82

Literature-anchored findings (GeneRIF, showing 40)

• No mutations in the MURR1 gene, including the intron-exon boundaries, were identified in a total of 23 patients with non-Wilsonian hepatic copper toxicosis (PMID:12547404)
• findings reveal involvement of Murr1 in the defined pathway of hepatic biliary copper excretion, suggest a mechanism for Murr1 function in this process, and provide evidence in support of the proposed role of the MURR1 gene in hepatic copper toxicosis (PMID:12968035)
• MURR1 was detected in different tissues and cell lines; in cell lines it was found both in cytosol and membrane preparations; in some cells MURR1 was associated with a vesicular compartment diffusely localized throughout the cell (PMID:14568250)
• Murr1 is a novel regulator of delta ENaC (PMID:14645214)
• Murr1, a gene product known previously for its involvement in copper regulation, inhibits HIV-1 growth in unstimulated CD4+ T cells (PMID:14685242)
• XIAP functions through MUUR1 to regulate copper homeostasis. (PMID:14685266)
• 3 intronic base pair changes, 1 new sequence variation & 2 known polymorphisms were detected, including the GAT/GAC heterozygous state at Asn 164 in 24% of the patients. GAT/GAC heterozygosity at Asn 164 is associated with earlier onset of Wilson disease. (PMID:15205742)
• MURR1/COMMD1 functions in the nucleus by affecting the association of NF-kappaB with chromatin (PMID:15799966)
• COMMD1 is not a significant contributor to Wilson-like copper storage disorders in humans. (PMID:16283886)
• These data support the significance of COMMD protein-protein interactions and provide new mechanistic insight into the function of this protein family in NF-kappaB signalling. (PMID:16573520)
• The solution structure of the N-terminal domain of COMMD1 (N-COMMD1, residues 1-108), is presented. (PMID:17097678)
• COMMD1 accelerates the ubiquitination and degradation of NF-kappaB subunits through its interaction with a multimeric ubiquitin ligase containing Elongins B and C, Cul2 and SOCS1 (ECS(SOCS1)). (PMID:17183367)
• COMMD1 specifically binds copper as Cu(II) in 1:1 stoichiometry & does not bind other divalent metals. Fluorescence studies of single point mutants of the full-length protein revealed the involvement of M110 in addition to H134 in direct Cu(II) binding. (PMID:17309234)
• Implicate COMMD1 in the pathogenesis of Wilson’s disease and indicate that COMMD1 exerts its regulatory role in copper homeostasis through the regulation of ATP7B stability. (PMID:17919502)
• the ability to promote Lys(63)-mediated polyubiquitination of COMMD1 is a novel property of ARF independent of p53 (PMID:18305112)
• COMMD1 expression is controlled primarily by protein ubiquitination (PMID:18795889)
• COMMD1 is a scaffold protein in a distinct sub-compartment of endocytic pathway and offer first clues to its role as a regulator of structurally unrelated membrane transporters. (PMID:18940794)
• Data suggest that translocation of ATP7B takes place independently of Rab7-regulated endosomal traffic, and that Murr1 plays a role in a later step of the copper excretion pathway but is not involved in the translocation of the Wilson disease protein. (PMID:18974300)
• HSCARG plays critical roles in regulation of NF-kappaB in response to cellular redox changes by promoting ubiquitination and proteolysis of RelA or COMMD1 (PMID:19433587)
• COMMD1 has a role in conjunction with HSP90beta/HSP70 in the ubiquitin and O(2)-independent regulation of HIF-1alpha (PMID:19802386)
• These data identify a new role for COMMD1 in regulating the nuclear/nucleolar distribution of RelA (PMID:20048074)
• Elevated levels of sCLU promote prostate cancer cell survival by facilitating degradation of COMMD1 and I-kappaB, thereby activating the canonical NF-kappaB pathway. (PMID:20068069)
• report a single novel, putative mutation in COMMD1 in one Wilson disease (WD) patient with atypical features; absence of any other prospective mutations among 108 patients suggests that COMMD1 variants are not major contributors towards WD phenotypes (PMID:20550661)
• COMMD1 as a novel protein regulating SOD1 activation and associate COMMD1 function with the production of free radicals. (PMID:20595380)
• We argue that COMMD1 participates in the normal disposition of copper within the hepatocyte and we speculate about that role. (PMID:21275100)
• Data show that COMMD1 interacts with CFTR. This interaction promotes CFTR cell surface expression as assessed by biotinylation experiments in heterologously expressing cells through regulation of CFTR ubiquitination. (PMID:21483833)
• These results suggest that COMMD1 downregulates deltaENaC activity by reducing deltaENaC surface expression through promoting internalization of surface deltaENaC to an intracellular recycling pool, possibly via enhanced ubiquitination. (PMID:21741370)
• COMMD1 (copper metabolism MURR1 domain-containing protein 1) regulates Cullin RING ligases by preventing CAND1 (Cullin-associated Nedd8-dissociated protein 1) binding. (PMID:21778237)
• Clusterin and COMMD1 independently regulate degradation of the mammalian copper ATPases ATP7A and ATP7B. (PMID:22130675)
• No major role can be attributed to Atox1 and COMMD in the pathophysiology or clinical variation of Wilson disease. (PMID:22677543)
• Placental COMMD1 expression is increased in women with severe preeclampsia compared to that found in women with normal pregnancies. (PMID:23364987)
• The results indicate a role for COMMD1 in the regulation of NKCC1 membrane expression and ubiquitination. (PMID:23515529)
• The role of COMMD1 in copper metabolism and it structure and function are discussed. (PMID:23677795)
• These data demonstrate the anti-inflammatory properties of COMMD1 in bronchial epithelial cells and open new therapeutic avenues in cystic fibrosis. (PMID:23892095)
• COMMD1 expression is associated with poor prognosis in diffuse large B-cell lymphoma (PMID:24625556)
• COMMD1 is identified as a novel regulator of misfolded protein aggregation. (PMID:24691167)
• COMMD1 is acetylated by p300 and that acetylation protects COMMD1 from XIAP-mediated proteosomal degradation (PMID:25074812)
• COMMD1 is directly linked to early endosomes through its interaction with a protein complex containing CCDC22, CCDC93, and C16orf62. (PMID:25355947)
• IkappaB-alpha protein was stabilized by COMMD1, which attenuated NF-kappaB signaling during Toll-like receptor ligand and tumor necrosis factor alpha treatment and enhanced HIV-1 latency in latently HIV-1-infected cells. (PMID:25520503)
• The COMMD1 downregulation by miR-205 promotes tumor development by modulating a positive feedback loop that amplifies inflammatory- and stemness-associated properties of cancer cells. (PMID:26586569)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	commd1	ENSDARG00000031203
mus_musculus	Commd1	ENSMUSG00000051355
rattus_norvegicus	Commd1	ENSRNOG00000009281

Protein

Protein identifiers

COMM domain-containing protein 1 — Q8N668 (reviewed: Q8N668)

Alternative names: Protein Murr1

All UniProt accessions (4): Q8N668, H0Y7J4, H7C169, H7C377

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. Can modulate activity of cullin-RING E3 ubiquitin ligase (CRL) complexes by displacing CAND1; in vitro promotes CRL E3 activity and dissociates CAND1 from CUL1 and CUL2. Promotes ubiquitination of NF-kappa-B subunit RELA and its subsequent proteasomal degradation. Down-regulates NF-kappa-B activity. Involved in the regulation of membrane expression and ubiquitination of SLC12A2. Modulates Na(+) transport in epithelial cells by regulation of apical cell surface expression of amiloride-sensitive sodium channel (ENaC) subunits and by promoting their ubiquitination presumably involving NEDD4L. Promotes the localization of SCNN1D to recycling endosomes. Promotes CFTR cell surface expression through regulation of its ubiquitination. Down-regulates SOD1 activity by interfering with its homodimerization. Plays a role in copper ion homeostasis. Involved in copper-dependent ATP7A trafficking between the trans-Golgi network and vesicles in the cell periphery; the function is proposed to depend on its association within the CCC complex and cooperation with the WASH complex on early endosomes. Can bind one copper ion per monomer. May function to facilitate biliary copper excretion within hepatocytes. Binds to phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2). Involved in the regulation of HIF1A-mediated transcription; competes with ARNT/Hif-1-beta for binding to HIF1A resulting in decreased DNA binding and impaired transcriptional activation by HIF-1. Negatively regulates neuroblastoma G1/S phase cell cycle progression and cell proliferation by stimulating ubiquitination of NF-kappa-B subunit RELA and NF-kappa-B degradation in a FAM107A- and actin-dependent manner.

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 COMMD6. Interacts with VPS35L; the interaction associates the CCC complex with the retriever complex. Identified in a complex with an E3 ubiquitin ligase complex composed of TCEB1/elongin C, CUL2, SOCS1 and RBX1; in the complex interacts directly with SOCS1 and CUL2. Identified in a complex with NF-kappa-B. Interacts directly with SLC12A2. Interacts directly with ATP7B (via the N-terminal region). Interacts with ATP7A. Interacts with FAM107A; this interaction stabilizes COMMD1 in the nucleus. Interacts with CCS, CDKN2A, RELA, REL, RELB, NFKB1/p105, NFKB2/p100, NFKBIB, SCNN1D, SCNN1B, CFTR, CLU, SGK1, AKT1, CUL1, CUL2, CUL3, CUL4A, CUL4B, CUL5, CUL7, HIF1A.

Subcellular location. Nucleus. Cytoplasm. Endosome membrane. Cytoplasmic vesicle. Early endosome. Recycling endosome.

Tissue specificity. Ubiquitous. Highest expression in the liver, with lower expression in brain, lung, placenta, pancreas, small intestine, heart, skeletal muscle, kidney and placenta. Down-regulated in cancer tissues.

Post-translational modifications. Acetylated by EP300 ina stimuli-specific manner; protecting it from XIAP-mediated proteasomal degradation and required for interaction with RElA in response to stress. Ubiquitinated; undergoes both ‘Lys-63’- and ‘Lys-48’-linked polyubiquitination. Ubiquitinated by XIAP, leading to its proteasomal degradation.

Similarity. Belongs to the COMM domain-containing protein 1 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8N668-1	1	yes
Q8N668-2	2

RefSeq proteins (4): NP_001308710, NP_001308711, NP_001358694, NP_689729* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR017920	COMM	Domain
IPR033776	COMMD1_N	Domain
IPR037351	Murr1	Family

Pfam: PF07258, PF17221

UniProt features (24 total): helix 6, strand 5, binding site 3, mutagenesis site 2, region of interest 2, initiator methionine 1, chain 1, turn 1, domain 1, modified residue 1, splice variant 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
8P0W	ELECTRON MICROSCOPY	2.9
8F2R	ELECTRON MICROSCOPY	3.12
8F2U	ELECTRON MICROSCOPY	3.53
2H2M	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8N668-F1	86.58	0.62

Functional residue map

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

Ligand- & substrate-binding residues (3): 101; 110; 134

Post-translational modifications (1): 2

Mutagenesis-validated functional residues (2):

Position	Phenotype
110	reduces copper-induced fluorescence change.
134	reduces copper-induced fluorescence change.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-8951664	Neddylation

MSigDB gene sets: 266 (showing top): GOBP_NEGATIVE_REGULATION_OF_TRANSMEMBRANE_TRANSPORT, GOBP_REGULATION_OF_PROTEASOMAL_UBIQUITIN_DEPENDENT_PROTEIN_CATABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_SODIUM_ION_TRANSPORT, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_STEROL_HOMEOSTASIS, GOBP_SODIUM_ION_TRANSMEMBRANE_TRANSPORT, GOBP_POSITIVE_REGULATION_OF_INTRACELLULAR_PROTEIN_TRANSPORT, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION_TO_CELL_SURFACE, GOBP_POSITIVE_REGULATION_OF_STEROL_TRANSPORT, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_PROTEIN_LOCALIZATION_TO_CELL_PERIPHERY, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_LOCALIZATION

GO Biological Process (19): nucleotide-excision repair (GO:0006289), Golgi to plasma membrane transport (GO:0006893), protein transport (GO:0015031), positive regulation of protein ubiquitination (GO:0031398), protein destabilization (GO:0031648), obsolete negative regulation of NF-kappaB transcription factor activity (GO:0032088), regulation of proteasomal ubiquitin-dependent protein catabolic process (GO:0032434), low-density lipoprotein particle clearance (GO:0034383), protein localization to cell surface (GO:0034394), cholesterol homeostasis (GO:0042632), plasma membrane to endosome transport (GO:0048227), copper ion homeostasis (GO:0055070), negative regulation of hypoxia-inducible factor-1alpha signaling pathway (GO:1902072), negative regulation of sodium ion transmembrane transport (GO:1902306), positive regulation of cholesterol import (GO:1904109), positive regulation of endosome to plasma membrane protein transport (GO:1905751), negative regulation of protein localization to cell surface (GO:2000009), positive regulation of protein localization to cell surface (GO:2000010), regulation of plasma lipoprotein particle levels (GO:0097006)

GO Molecular Function (12): copper ion binding (GO:0005507), phosphatidylinositol-4,5-bisphosphate binding (GO:0005546), phosphatidylinositol-3,4,5-trisphosphate binding (GO:0005547), sodium channel inhibitor activity (GO:0019871), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), phosphatidylinositol-3,4-bisphosphate binding (GO:0043325), phosphatidic acid binding (GO:0070300), phosphatidylinositol-3,5-bisphosphate binding (GO:0080025), protein binding (GO:0005515), lipid binding (GO:0008289), metal ion binding (GO:0046872)

GO Cellular Component (11): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), endosome (GO:0005768), early endosome (GO:0005769), cytosol (GO:0005829), endosome membrane (GO:0010008), Cul2-RING ubiquitin ligase complex (GO:0031462), recycling endosome (GO:0055037), membrane (GO:0016020), cytoplasmic vesicle (GO:0031410)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Post-translational protein modification	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
phosphatidylinositol phosphate binding	3
phosphatidylinositol bisphosphate binding	3
endosome	3
intracellular protein localization	2
protein localization to cell surface	2
regulation of protein localization to cell surface	2
anion binding	2
binding	2
cytoplasm	2
DNA repair	1
post-Golgi vesicle-mediated transport	1
vesicle-mediated transport to the plasma membrane	1
transport	1
establishment of protein localization	1
protein ubiquitination	1
regulation of protein ubiquitination	1
positive regulation of protein modification by small protein conjugation or removal	1
regulation of protein stability	1
proteasome-mediated ubiquitin-dependent protein catabolic process	1
regulation of proteasomal protein catabolic process	1
regulation of ubiquitin-dependent protein catabolic process	1
plasma lipoprotein particle clearance	1
low-density lipoprotein particle disassembly	1
sterol homeostasis	1
vesicle-mediated transport	1
monoatomic cation homeostasis	1
inorganic ion homeostasis	1
hypoxia-inducible factor-1alpha signaling pathway	1
negative regulation of cellular response to hypoxia	1
regulation of hypoxia-inducible factor-1alpha signaling pathway	1
negative regulation of intracellular signal transduction	1
negative regulation of sodium ion transport	1
sodium ion transmembrane transport	1
regulation of sodium ion transmembrane transport	1
negative regulation of cation transmembrane transport	1
positive regulation of cholesterol transport	1
regulation of cholesterol import	1
cholesterol import	1
positive regulation of intracellular protein transport	1

Protein interactions and networks

STRING

1466 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
COMMD1	CUL2	Q13617	991
COMMD1	KAT2A	Q92830	982
COMMD1	CCDC22	O60826	950
COMMD1	KAT2B	Q92831	948
COMMD1	ATP7B	P35670	945
COMMD1	SOCS1	O15524	932
COMMD1	VPS35L	Q7Z3J2	929
COMMD1	CCDC93	Q567U6	918
COMMD1	COMMD6	Q7Z4G1	906
COMMD1	RELA	Q04206	817
COMMD1	ATOX1	O00244	813
COMMD1	COMMD9	Q9P000	733
COMMD1	VPS26C	O14972	721
COMMD1	COMMD10	Q9Y6G5	714
COMMD1	COMMD5	Q9GZQ3	674

IntAct

188 interactions, top by confidence:

A	B	Type	Score
RELA	NFKBIA	psi-mi:“MI:0914”(association)	0.980
NFKBIA	RELA	psi-mi:“MI:0914”(association)	0.980
COMMD1	CCDC22	psi-mi:“MI:0914”(association)	0.970
COMMD1	CCDC22	psi-mi:“MI:0915”(physical association)	0.970
CCDC22	COMMD1	psi-mi:“MI:0403”(colocalization)	0.970
CCDC22	COMMD1	psi-mi:“MI:0915”(physical association)	0.970
CCDC22	COMMD1	psi-mi:“MI:0914”(association)	0.970
CCDC22	CCDC93	psi-mi:“MI:0914”(association)	0.960
CCDC93	CCDC22	psi-mi:“MI:0914”(association)	0.960
CCDC22	CCDC93	psi-mi:“MI:0403”(colocalization)	0.960
CCDC22	CCDC93	psi-mi:“MI:0915”(physical association)	0.960
COMMD6	COMMD1	psi-mi:“MI:0914”(association)	0.950
COMMD6	COMMD1	psi-mi:“MI:0915”(physical association)	0.950

BioGRID (295): COMMD6 (Two-hybrid), COMMD1 (Affinity Capture-Western), COMMD1 (Affinity Capture-Western), C16orf62 (Affinity Capture-Western), CCDC93 (Affinity Capture-Western), COMMD1 (Affinity Capture-MS), COMMD1 (Affinity Capture-MS), COMMD1 (Co-fractionation), COMMD1 (Co-fractionation), COMMD1 (Co-fractionation), COMMD1 (Co-fractionation), COMMD1 (Co-fractionation), COMMD1 (Affinity Capture-MS), COMMD1 (Affinity Capture-MS), COMMD1 (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: Q2M2T5, Q8K4M5, Q8N668, Q8WMD0, Q54DR0

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
SCF-betaTRCP	“down-regulates quantity by destabilization”	COMMD1	ubiquitination
CLU	“down-regulates quantity by destabilization”	COMMD1	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 71 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
TAK1-dependent IKK and NF-kappa-B activation	5	29.5×	7e-05
SARS-CoV-1 activates/modulates innate immune responses	5	26.7×	8e-05
Activation of NF-kappaB in B cells	6	23.2×	3e-05
Dectin-1 mediated noncanonical NF-kB signaling	5	21.1×	2e-04
FCERI mediated NF-kB activation	5	15.3×	6e-04
CLEC7A (Dectin-1) signaling	5	14.0×	9e-04
Neddylation	14	13.0×	8e-10
Downstream TCR signaling	5	12.6×	1e-03

GO biological processes:

GO term	Partners	Fold	FDR
non-canonical NF-kappaB signal transduction	6	82.9×	4e-08
canonical NF-kappaB signal transduction	6	36.0×	4e-06
endocytic recycling	6	26.3×	2e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	25
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
625544	GRCh37/hg19 2p16.1-15(chr2:57445335-62733206)	Likely pathogenic

SpliceAI

2680 predictions. Top by Δscore:

Variant	Effect	Δscore
2:61905841:A:G	donor_gain	1.0000
2:61905855:TAAGG:T	donor_loss	1.0000
2:61905856:AAG:A	donor_loss	1.0000
2:61905857:AGGTA:A	donor_loss	1.0000
2:61905858:GGTA:G	donor_loss	1.0000
2:61905859:GTACT:G	donor_loss	1.0000
2:61905860:T:A	donor_loss	1.0000
2:62000687:T:A	acceptor_gain	1.0000
2:62000691:A:AG	acceptor_gain	1.0000
2:62000692:T:G	acceptor_gain	1.0000
2:62000697:A:AG	acceptor_gain	1.0000
2:62000698:T:G	acceptor_gain	1.0000
2:62000699:A:AG	acceptor_gain	1.0000
2:62000700:G:GT	acceptor_gain	1.0000
2:62000700:GT:G	acceptor_gain	1.0000
2:62000700:GTC:G	acceptor_gain	1.0000
2:62000700:GTCT:G	acceptor_gain	1.0000
2:62000700:GTCTA:G	acceptor_gain	1.0000
2:62000980:CAGG:C	donor_loss	1.0000
2:62000983:G:GA	donor_loss	1.0000
2:62000983:G:GG	donor_gain	1.0000
2:62000984:T:A	donor_loss	1.0000
2:62135825:TTCCA:T	acceptor_loss	1.0000
2:62135826:TCCAG:T	acceptor_loss	1.0000
2:62135827:CCA:C	acceptor_loss	1.0000
2:62135828:CAG:C	acceptor_loss	1.0000
2:62135829:A:AG	acceptor_gain	1.0000
2:62135829:AG:A	acceptor_gain	1.0000
2:62135829:AGG:A	acceptor_loss	1.0000
2:62135830:G:GC	acceptor_gain	1.0000

AlphaMissense

1247 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:62000812:T:A	W98R	0.997
2:62000812:T:C	W98R	0.997
2:62000743:T:C	F75L	0.994
2:62000745:C:A	F75L	0.994
2:62000745:C:G	F75L	0.994
2:62000890:T:A	W124R	0.994
2:62000890:T:C	W124R	0.994
2:62000735:T:C	L72P	0.991
2:62000753:C:A	A78D	0.988
2:62000814:G:C	W98C	0.988
2:62000814:G:T	W98C	0.988
2:62000948:C:A	A143D	0.988
2:62000813:G:C	W98S	0.986
2:62000960:T:C	L147P	0.986
2:62000747:T:C	L76S	0.985
2:62000791:G:C	A91P	0.985
2:62000721:G:A	M67I	0.983
2:62000721:G:C	M67I	0.983
2:62000721:G:T	M67I	0.983
2:62000809:T:C	F97L	0.981
2:62000811:C:A	F97L	0.981
2:62000811:C:G	F97L	0.981
2:62000763:A:C	K81N	0.980
2:62000763:A:T	K81N	0.980
2:61905820:T:C	F48L	0.979
2:61905822:C:A	F48L	0.979
2:61905822:C:G	F48L	0.979
2:62000846:T:C	L109P	0.979
2:61905854:T:C	L59P	0.975
2:62000810:T:C	F97S	0.975

dbSNP variants (sampled 300 via entrez): RS1000001739 (2:62038605 T>C), RS1000009246 (2:62129930 C>T), RS1000060279 (2:62036925 A>G), RS1000067766 (2:62046800 T>C), RS1000080777 (2:61913573 A>G), RS1000081164 (2:62087976 C>A,T), RS1000086204 (2:61956168 T>C), RS1000086338 (2:61990191 T>C), RS1000089758 (2:61886663 C>G), RS1000092101 (2:61916364 T>C), RS1000096789 (2:61996575 G>A,C), RS1000118401 (2:61960811 C>T), RS1000136841 (2:61919774 C>G), RS1000154080 (2:62098929 T>G), RS1000176176 (2:62105302 C>T)

Disease associations

OMIM: gene MIM:607238 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST004571_25	Iron status biomarkers (total iron binding capacity)	7.000000e-08
GCST004572_6	Iron status biomarkers (transferrin saturation)	7.000000e-08
GCST004602_85	Mean corpuscular volume	1.000000e-14
GCST006956_8	Erectile dysfunction	8.000000e-06
GCST008468_9	Nonalcoholic fatty liver disease	4.000000e-06
GCST008839_310	Height	2.000000e-11
GCST90013423_4	Age-related nuclear cataracts	1.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0006334	total iron binding capacity

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: other protein — COMMD proteins

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	6
Benzo(a)pyrene	decreases expression	4
bisphenol A	decreases expression, decreases methylation, increases expression	3
cupric chloride	decreases expression, decreases response to substance, affects binding, increases reaction	2
bisphenol S	increases methylation, increases expression, affects cotreatment	2
Aflatoxin B1	decreases expression, increases methylation	2
aristolochic acid I	decreases expression	1
CIGB-552 peptide	increases expression, decreases expression, decreases reaction, increases ubiquitination, increases response to substance (+1 more)	1
bisphenol F	affects cotreatment, increases expression	1
2,4,6-tribromophenol	increases expression	1
methyleugenol	decreases expression	1
decabromobiphenyl ether	decreases expression	1
arsenite	affects binding, increases reaction	1
4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone	increases expression	1
tetrabromobisphenol A	increases expression	1
isobutyl alcohol	affects cotreatment, decreases expression, increases abundance	1
benzyloxycarbonylleucyl-leucyl-leucine aldehyde	increases expression	1
tanespimycin	increases degradation, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
bisphenol B	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	increases expression	1
dorsomorphin	increases expression, affects cotreatment	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	increases expression	1
Sunitinib	decreases expression	1
Fulvestrant	increases methylation, affects cotreatment	1
Benzophenoneidum	increases expression	1
Cadmium	increases abundance, increases expression	1
Copper	increases transport, increases activity	1
Dexamethasone	increases expression, affects cotreatment	1

Clinical trials (associated diseases)

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