COMMD6

Summary

COMMD6 (COMM domain containing 6, HGNC:24015) is a protein-coding gene on chromosome 13q22.2, encoding COMM domain-containing protein 6 (Q7Z4G1). 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.

COMMD6 belongs to a family of NF-kappa-B (see RELA; MIM 164014)-inhibiting proteins characterized by the presence of a COMM domain (see COMMD1; MIM 607238) (de Bie et al., 2006 [PubMed 16573520]).

Source: NCBI Gene 170622 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 27 total
• MANE Select transcript: NM_203495

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24015
Approved symbol	COMMD6
Name	COMM domain containing 6
Location	13q22.2
Locus type	gene with protein product
Status	Approved
Aliases	Acrg
Ensembl gene	ENSG00000188243
Ensembl biotype	protein_coding
OMIM	612377
Entrez	170622

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 7 protein_coding, 4 protein_coding_CDS_not_defined, 3 retained_intron, 1 nonsense_mediated_decay

ENST00000355801, ENST00000377612, ENST00000377615, ENST00000377619, ENST00000460675, ENST00000464050, ENST00000471682, ENST00000477377, ENST00000483290, ENST00000486516, ENST00000497707, ENST00000626103, ENST00000682242, ENST00000915457, ENST00000968746

RefSeq mRNA: 5 — MANE Select: NM_203495 NM_001287392, NM_001287393, NM_001287394, NM_203495, NM_203497

CCDS: CCDS9451, CCDS9452

Canonical transcript exons

ENST00000682242 — 4 exons

Exon	Start	End
ENSE00003611577	75530114	75530266
ENSE00003668456	75537764	75537841
ENSE00003680104	75537664	75537675
ENSE00003917991	75525214	75526639

Expression profiles

Bgee: expression breadth ubiquitous, 255 present calls, max score 99.57.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 137.7653 / max 1828.3224, expressed in 1820 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
137651	136.9083	1819
137652	0.8569	446

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
upper arm skin	UBERON:0004263	99.57	gold quality
ganglionic eminence	UBERON:0004023	99.45	gold quality
left ovary	UBERON:0002119	99.37	gold quality
right adrenal gland cortex	UBERON:0035827	99.30	gold quality
right adrenal gland	UBERON:0001233	99.28	gold quality
kidney epithelium	UBERON:0004819	99.28	gold quality
right ovary	UBERON:0002118	99.24	gold quality
muscle layer of sigmoid colon	UBERON:0035805	99.21	gold quality
calcaneal tendon	UBERON:0003701	99.19	gold quality
granulocyte	CL:0000094	99.18	gold quality
adrenal cortex	UBERON:0001235	99.17	gold quality
body of uterus	UBERON:0009853	99.16	gold quality
left adrenal gland cortex	UBERON:0035825	99.16	gold quality
endocervix	UBERON:0000458	99.14	gold quality
left adrenal gland	UBERON:0001234	99.14	gold quality
ventricular zone	UBERON:0003053	99.10	gold quality
myometrium	UBERON:0001296	99.08	gold quality
ileal mucosa	UBERON:0000331	99.05	gold quality
lower esophagus muscularis layer	UBERON:0035833	99.05	gold quality
lymph node	UBERON:0000029	99.04	gold quality
lower esophagus	UBERON:0013473	99.04	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	99.03	gold quality
left uterine tube	UBERON:0001303	99.01	gold quality
cortical plate	UBERON:0005343	98.99	gold quality
popliteal artery	UBERON:0002250	98.98	gold quality
tibial artery	UBERON:0007610	98.98	gold quality
ovary	UBERON:0000992	98.95	gold quality
fundus of stomach	UBERON:0001160	98.95	gold quality
adrenal gland	UBERON:0002369	98.95	gold quality
ectocervix	UBERON:0012249	98.95	gold quality

Single-cell (SCXA)

Detected in 12 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-GEOD-125970	yes	40.80
E-CURD-88	yes	33.25
E-ANND-3	yes	13.60
E-MTAB-10042	yes	12.05
E-MTAB-10596	no	952.05
E-GEOD-111727	no	438.44
E-GEOD-124858	no	409.34
E-HCAD-4	no	100.27
E-HCAD-8	no	46.05
E-HCAD-1	no	30.19
E-CURD-46	no	26.69
E-MTAB-6701	no	14.46

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

76 targeting COMMD6, 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-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-23B-5P	99.98	66.07	587
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-23A-5P	99.94	65.39	468
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-374B-5P	99.90	69.98	2734
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-106B-5P	99.88	74.72	2795
HSA-MIR-20A-5P	99.88	74.76	2769
HSA-MIR-20B-5P	99.88	74.01	2621
HSA-MIR-519D-3P	99.88	73.97	2607
HSA-MIR-526B-3P	99.88	74.06	2587
HSA-MIR-93-5P	99.88	73.98	2606
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-5003-3P	99.85	69.29	2517
HSA-MIR-576-5P	99.84	70.46	2582

Literature-anchored findings (GeneRIF, showing 2)

• 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)
• COMMD6 expression was widely observed in human tissues. COMMD6 may modulate the ubiquitination and degradation of NF-kappaB subunits and regulate ribonucleoprotein and spliceosome complex biogenesis in tumours. COMMD6 expression is increased in some cancers, and decreased in others, implying that different mechanisms are involved in the regulation of COMMD6 expression in the development of human tissues. (PMID:31523056)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	commd6	ENSDARG00000074204
mus_musculus	Commd6	ENSMUSG00000075486
rattus_norvegicus	Commd6	ENSRNOG00000038012

Paralogs (2): COMMD7 (ENSG00000149600), COMMD8 (ENSG00000169019)

Protein

Protein identifiers

COMM domain-containing protein 6 — Q7Z4G1 (reviewed: Q7Z4G1)

All UniProt accessions (3): B0QZ40, Q7Z4G1, H7C607

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. Down-regulates activation of NF-kappa-B. Inhibits TNF-induced NFKB1 activation.

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 COMMD1. May form a homodimer with isoform 1. Interacts with RELA, RELB, NFKB1/p105. Does not interact with NFKBIB. Interacts with CCDC22, CCDC93, SCNN1B, CUL4A.

Subcellular location. Nucleus. Cytoplasm.

Tissue specificity. Ubiquitous. Expressed in brain, heart, skeletal muscle, lung, pancreas, liver, kidney, small intestine and placenta.

Similarity. Belongs to the COMM domain-containing protein 6 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q7Z4G1-1	1	yes
Q7Z4G1-2	2

RefSeq proteins (5): NP_001274321, NP_001274322, NP_001274323, NP_987091, NP_987093 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR017920	COMM	Domain
IPR047155	COMMD4/6/7/8	Family

Pfam: PF07258

UniProt features (13 total): helix 3, strand 3, mutagenesis site 2, chain 1, domain 1, modified residue 1, splice variant 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-Q7Z4G1-F1	85.37	0.57

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 (1): 1

Mutagenesis-validated functional residues (2):

Position	Phenotype
24	does not abolish homodimerization and interaction with commd1. does not abolish repression of tnf-induced nfkb1 activati
41	does not abolish homodimerization and interaction with commd1. does not abolish repression of tnf-induced nfkb1 activati

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-8951664	Neddylation

MSigDB gene sets: 143 (showing top): GOBP_VESICLE_MEDIATED_TRANSPORT, HEIDENBLAD_AMPLICON_8Q24_DN, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_1, GGAANCGGAANY_UNKNOWN, NAKAMURA_TUMOR_ZONE_PERIPHERAL_VS_CENTRAL_DN, GOBP_ENDOCYTIC_RECYCLING, GOBP_LOCALIZATION_WITHIN_MEMBRANE, NKX3A_01, KYNG_RESPONSE_TO_H2O2, NUYTTEN_EZH2_TARGETS_DN, GOCC_MEMBRANE_PROTEIN_COMPLEX, SCGGAAGY_ELK1_02, GOMF_NF_KAPPAB_BINDING, GOMF_TRANSCRIPTION_FACTOR_BINDING, REACTOME_POST_TRANSLATIONAL_PROTEIN_MODIFICATION

GO Biological Process (2): signal transduction (GO:0007165), obsolete negative regulation of NF-kappaB transcription factor activity (GO:0032088)

GO Molecular Function (2): NF-kappaB binding (GO:0051059), protein binding (GO:0005515)

GO Cellular Component (2): nucleus (GO:0005634), cytoplasm (GO:0005737)

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
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
RNA polymerase II-specific DNA-binding transcription factor binding	1
binding	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1164 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
COMMD6	COMMD1	Q8N668	906
COMMD6	LMO7	Q8WWI1	864
COMMD6	UCHL3	P15374	821
COMMD6	COMMD9	Q9P000	780
COMMD6	CCDC22	O60826	730
COMMD6	COMMD2	Q86X83	726
COMMD6	VIL1	P09327	720
COMMD6	COMMD10	Q9Y6G5	718
COMMD6	VPS35L	Q7Z3J2	713
COMMD6	CCDC93	Q567U6	708
COMMD6	COMMD5	Q9GZQ3	650
COMMD6	COMMD3	Q9UBI1	642
COMMD6	COMMD4	Q9H0A8	614
COMMD6	EDNRB	P24530	578
COMMD6	COMMD8	Q9NX08	558

IntAct

89 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
COMMD6	COMMD1	psi-mi:“MI:0914”(association)	0.950
COMMD6	COMMD1	psi-mi:“MI:0915”(physical association)	0.950
COMMD1	COMMD6	psi-mi:“MI:0915”(physical association)	0.950
COMMD1	COMMD6	psi-mi:“MI:0914”(association)	0.950
COMMD9	CCDC22	psi-mi:“MI:0914”(association)	0.940
COMMD10	CCDC22	psi-mi:“MI:0914”(association)	0.940
COMMD6	CCDC22	psi-mi:“MI:0914”(association)	0.930
COMMD6	CCDC22	psi-mi:“MI:0915”(physical association)	0.930
CCDC22	COMMD6	psi-mi:“MI:0914”(association)	0.930
ODAD1	HGS	psi-mi:“MI:0914”(association)	0.850
COMMD6	COMMD9	psi-mi:“MI:0915”(physical association)	0.840
CCDC93	COMMD6	psi-mi:“MI:0914”(association)	0.820
COMMD6	CCDC93	psi-mi:“MI:0915”(physical association)	0.820
CCDC22	VPS26C	psi-mi:“MI:0914”(association)	0.790

BioGRID (138): COMMD6 (Two-hybrid), COMMD6 (Affinity Capture-RNA), COMMD6 (Affinity Capture-Western), COMMD6 (Affinity Capture-MS), COMMD6 (Affinity Capture-MS), COMMD6 (Affinity Capture-MS), COMMD6 (Affinity Capture-RNA), COMMD6 (Co-fractionation), COMMD6 (Co-fractionation), COMMD6 (Proximity Label-MS), COMMD6 (Affinity Capture-MS), COMMD6 (Affinity Capture-MS), COMMD6 (Affinity Capture-MS), COMMD6 (Affinity Capture-Western), COMMD1 (Affinity Capture-MS)

ESM2 similar proteins: A8IU92, F1QH17, O22969, O43502, O60879, O88984, O95453, P00860, P09057, P11926, P14019, P24480, P27117, P27118, P27119, P27120, P31949, P50543, P52865, P58797, P69341, Q1RMS5, Q2KIY0, Q3UFY7, Q3V4B5, Q5EBF1, Q5R752, Q5RBU4, Q5RC51, Q5ZHS3, Q5ZID6, Q5ZIZ4, Q68EQ9, Q6AYP7, Q6B345, Q6DKB0, Q6INE8, Q6NYY9, Q6P4W8, Q7Z4G1

Diamond homologs: Q05AV1, Q28HC7, Q2KIY0, Q3V4B5, Q54MA5, Q7Z4G1, Q9NX08

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 43 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
Neddylation	9	14.7×	1e-06

GO biological processes:

GO term	Partners	Fold	FDR
endocytic recycling	6	41.1×	1e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	9
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

742 predictions. Top by Δscore:

Variant	Effect	Δscore
13:75526636:AATT:A	acceptor_gain	1.0000
13:75526638:TT:T	acceptor_gain	1.0000
13:75526640:C:CC	acceptor_gain	1.0000
13:75526641:T:C	acceptor_loss	1.0000
13:75537762:A:AC	donor_gain	1.0000
13:75537763:C:CC	donor_gain	1.0000
13:75537763:CAT:C	donor_gain	1.0000
13:75526635:AAATT:A	acceptor_gain	0.9900
13:75526637:ATT:A	acceptor_gain	0.9900
13:75534633:T:TC	acceptor_gain	0.9900
13:75537773:AGCAT:A	donor_gain	0.9900
13:75537774:G:C	donor_gain	0.9900
13:75537756:GAACT:G	donor_loss	0.9800
13:75537757:AACTC:A	donor_loss	0.9800
13:75537758:ACTC:A	donor_loss	0.9800
13:75537759:CT:C	donor_loss	0.9800
13:75537760:TCAC:T	donor_loss	0.9800
13:75537761:CA:C	donor_loss	0.9800
13:75537763:C:CA	donor_loss	0.9800
13:75526636:AATTC:A	acceptor_gain	0.9700
13:75526637:ATTCT:A	acceptor_gain	0.9700
13:75526638:TTC:T	acceptor_gain	0.9700
13:75526639:TCT:T	acceptor_gain	0.9700
13:75526640:CTG:C	acceptor_gain	0.9700
13:75537755:GGAAC:G	donor_loss	0.9700
13:75526641:T:A	acceptor_gain	0.9600
13:75530188:C:CC	acceptor_gain	0.9600
13:75537743:T:A	donor_gain	0.9600
13:75537763:CA:C	donor_gain	0.9600
13:75537773:AG:A	donor_gain	0.9600

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000081218 (13:75530615 C>G), RS1000103111 (13:75548287 A>G), RS1000249633 (13:75530052 C>A,T), RS1000371811 (13:75536044 C>A,T), RS1000536226 (13:75530932 T>C), RS1000600234 (13:75529809 C>T), RS1000789681 (13:75550079 A>T), RS1000830205 (13:75546461 A>G), RS1000841894 (13:75550288 C>A), RS1001010485 (13:75525985 A>C), RS1001058102 (13:75540136 A>C,T), RS1001111393 (13:75546840 T>C), RS1001405710 (13:75540276 A>T), RS1001427980 (13:75547267 G>T), RS1001547688 (13:75535887 C>T)

Disease associations

OMIM: gene MIM:612377 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST001977_1	Diabetic retinopathy	7.000000e-06
GCST005996_40	Red blood cell count	9.000000e-09
GCST009391_243	Metabolite levels	3.000000e-06
GCST90000025_1052	Appendicular lean mass	4.000000e-09

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004305	erythrocyte count
EFO:0010494	guanosine diphosphate measurement
EFO:0004980	appendicular lean mass

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases abundance	2
Air Pollutants	decreases expression, increases abundance	2
Smoke	decreases expression, increases abundance	2
bisphenol F	affects cotreatment, increases expression	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
trichostatin A	affects expression	1
arsenite	affects binding, increases reaction	1
cupric chloride	decreases expression	1
pentanal	decreases expression	1
chloropicrin	affects expression	1
bisphenol S	affects cotreatment, increases expression	1
Irinotecan	increases expression	1
Temozolomide	decreases expression	1
Sunitinib	increases expression	1
Arsenic	decreases expression, increases abundance	1
Coal	decreases expression, increases abundance	1
Dexamethasone	affects cotreatment, increases expression	1
Doxorubicin	increases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Estradiol	decreases expression	1
Hydralazine	affects cotreatment, increases expression	1
Indomethacin	affects cotreatment, increases expression	1
Ivermectin	decreases expression	1
Tetrachlorodibenzodioxin	affects expression	1
Tretinoin	decreases expression	1
Valproic Acid	affects cotreatment, increases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression	1
Okadaic Acid	decreases expression	1
Lactic Acid	decreases expression	1

Clinical trials (associated diseases)

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