COMMD8

Summary

COMMD8 (COMM domain containing 8, HGNC:26036) is a protein-coding gene on chromosome 4p12, encoding COMM domain-containing protein 8 (Q9NX08). 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. It is a selective cancer dependency (DepMap: 11.4% of cell lines).

The protein encoded by this gene binds coiled-coil domain-containing protein 22 (CCDC22), and this complex can regulate the turnover of I-kappa-B and the activation of NF-kappa-B.

Source: NCBI Gene 54951 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 38 total
• Cancer dependency (DepMap): dependent in 11.4% of screened cell lines
• MANE Select transcript: NM_017845

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26036
Approved symbol	COMMD8
Name	COMM domain containing 8
Location	4p12
Locus type	gene with protein product
Status	Approved
Aliases	FLJ20502
Ensembl gene	ENSG00000169019
Ensembl biotype	protein_coding
OMIM	616656
Entrez	54951

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 5 protein_coding, 1 retained_intron

ENST00000381571, ENST00000509220, ENST00000860334, ENST00000860335, ENST00000860336, ENST00000952424

RefSeq mRNA: 2 — MANE Select: NM_017845 NM_001329668, NM_017845

CCDS: CCDS3475

Canonical transcript exons

ENST00000381571 — 5 exons

Exon	Start	End
ENSE00001122055	47456577	47456729
ENSE00001122065	47460144	47460299
ENSE00001126666	47453059	47453214
ENSE00001489158	47450787	47451665
ENSE00001606759	47463586	47463702

Expression profiles

Bgee: expression breadth ubiquitous, 281 present calls, max score 95.23.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 16.5612 / max 243.7578, expressed in 1781 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
52032	15.9750	1779
203166	0.5862	339

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
choroid plexus epithelium	UBERON:0003911	95.23	gold quality
nephron tubule	UBERON:0001231	94.86	gold quality
monocyte	CL:0000576	94.65	gold quality
renal glomerulus	UBERON:0000074	94.65	gold quality
mononuclear cell	CL:0000842	94.62	gold quality
leukocyte	CL:0000738	94.37	gold quality
skin of hip	UBERON:0001554	94.26	gold quality
metanephric glomerulus	UBERON:0004736	94.22	gold quality
oral cavity	UBERON:0000167	94.21	gold quality
upper leg skin	UBERON:0004262	94.03	gold quality
kidney epithelium	UBERON:0004819	93.37	gold quality
esophagus squamous epithelium	UBERON:0006920	93.16	gold quality
calcaneal tendon	UBERON:0003701	92.91	gold quality
metanephros	UBERON:0000081	92.01	gold quality
epithelium of nasopharynx	UBERON:0001951	91.17	gold quality
bronchial epithelial cell	CL:0002328	90.83	gold quality
jejunal mucosa	UBERON:0000399	90.81	gold quality
oocyte	CL:0000023	90.61	gold quality
pigmented layer of retina	UBERON:0001782	90.52	gold quality
epithelium of esophagus	UBERON:0001976	90.40	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	90.27	gold quality
cortex of kidney	UBERON:0001225	90.18	gold quality
adult mammalian kidney	UBERON:0000082	90.15	gold quality
palpebral conjunctiva	UBERON:0001812	90.14	gold quality
squamous epithelium	UBERON:0006914	90.07	gold quality
secondary oocyte	CL:0000655	90.06	gold quality
penis	UBERON:0000989	89.68	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	89.64	gold quality
heart right ventricle	UBERON:0002080	89.41	gold quality
kidney	UBERON:0002113	89.20	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.17
E-MTAB-7037	no	107.44

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

67 targeting COMMD8, 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-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-1-3P	99.93	72.35	1914
HSA-MIR-206	99.93	72.50	1893
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-613	99.91	71.50	1710
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-374B-5P	99.90	69.98	2734
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-7162-3P	99.89	68.16	1682
HSA-MIR-4503	99.85	71.45	1869
HSA-MIR-323A-3P	99.79	70.30	1739
HSA-MIR-26A-5P	99.78	73.52	2303
HSA-MIR-26B-5P	99.78	73.51	2305
HSA-MIR-4465	99.71	72.56	2096
HSA-MIR-3059-5P	99.70	69.93	2491
HSA-MIR-4677-5P	99.70	70.09	1940
HSA-MIR-7154-5P	99.69	70.52	1900
HSA-MIR-3177-5P	99.65	70.38	1174
HSA-MIR-7156-5P	99.64	68.81	1369
HSA-MIR-7152-5P	99.60	69.33	2094

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 11.4% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 3)

• MNX1-AS1 promoted COMMD8 expression through sponging miR-218-5p. MNX1-AS1 promoted hepatocellular carcinoma progression through activating COMMD8. (PMID:30982576)
• complex determines GRK6 specificity for chemoattractant receptors (PMID:31088898)
• Long noncoding RNA LINC00657 induced by SP1 contributes to the non-small cell lung cancer progression through targeting miR-26b-5p/COMMD8 axis. (PMID:31566716)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	commd8	ENSDARG00000028201
mus_musculus	Commd8	ENSMUSG00000029213
rattus_norvegicus	Commd8	ENSRNOG00000002320

Paralogs (2): COMMD7 (ENSG00000149600), COMMD6 (ENSG00000188243)

Protein

Protein identifiers

COMM domain-containing protein 8 — Q9NX08 (reviewed: Q9NX08)

All UniProt accessions (1): Q9NX08

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.

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 COMMD4. Interacts with RELA, RELB, NFKB1/p105. Interacts with CCDC22, CCDC93, SCNN1B, CUL1, CUL2, CUL3, CUL4A, CUL4B, CUL5.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Widely expressed with highest expression in thyroid.

Similarity. Belongs to the COMM domain-containing protein 8 family.

RefSeq proteins (2): NP_001316597, NP_060315* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR017920	COMM	Domain
IPR047155	COMMD4/6/7/8	Family
IPR047235	COMMD8	Family
IPR055184	COMMD8_HN	Domain

Pfam: PF07258, PF22838

UniProt features (17 total): helix 8, strand 3, turn 2, chain 1, domain 1, sequence variant 1, sequence conflict 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-Q9NX08-F1	87.67	0.68

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-8951664	Neddylation

MSigDB gene sets: 133 (showing top): STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, GOBP_VESICLE_MEDIATED_TRANSPORT, chr4p12, WEI_MYCN_TARGETS_WITH_E_BOX, MILI_PSEUDOPODIA_HAPTOTAXIS_UP, ROZANOV_MMP14_TARGETS_UP, USF_01, TIEN_INTESTINE_PROBIOTICS_24HR_UP, GOBP_ENDOCYTIC_RECYCLING, USF_02, GOBP_LOCALIZATION_WITHIN_MEMBRANE, ROSTY_CERVICAL_CANCER_PROLIFERATION_CLUSTER, RIGGINS_TAMOXIFEN_RESISTANCE_DN, SENESE_HDAC3_TARGETS_DN, GOCC_MEMBRANE_PROTEIN_COMPLEX

GO Biological Process (1): signal transduction (GO:0007165)

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

GO Cellular Component (4): nucleoplasm (GO:0005654), cytosol (GO:0005829), 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
cellular anatomical structure	3
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
nuclear lumen	1
cytoplasm	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1718 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
COMMD8	CCDC22	O60826	845
COMMD8	COMMD2	Q86X83	710
COMMD8	COMMD9	Q9P000	706
COMMD8	COMMD10	Q9Y6G5	636
COMMD8	COMMD5	Q9GZQ3	635
COMMD8	COMMD4	Q9H0A8	621
COMMD8	GABRB1	P18505	591
COMMD8	COMMD1	Q8N668	589
COMMD8	COMMD6	Q7Z4G1	558
COMMD8	A0A2R8Y455	A0A2R8Y455	557
COMMD8	COMMD7	Q86VX2	553
COMMD8	TIGD4	Q8IY51	539
COMMD8	COMMD3	Q9UBI1	535
COMMD8	TMEM131L	A2VDJ0	526
COMMD8	SMIM14	Q96QK8	507

IntAct

93 interactions, top by confidence:

A	B	Type	Score
CCDC22	CCDC93	psi-mi:“MI:0915”(physical association)	0.960
CCDC22	CCDC93	psi-mi:“MI:0914”(association)	0.960
COMMD1	COMMD6	psi-mi:“MI:0915”(physical association)	0.950
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
CCDC22	COMMD8	psi-mi:“MI:0915”(physical association)	0.920
COMMD1	COMMD8	psi-mi:“MI:0915”(physical association)	0.920
COMMD4	COMMD8	psi-mi:“MI:0915”(physical association)	0.880
COMMD4	COMMD8	psi-mi:“MI:0914”(association)	0.880
COMMD8	CCDC93	psi-mi:“MI:0915”(physical association)	0.850
ODAD1	HGS	psi-mi:“MI:0914”(association)	0.850
COMMD3	COMMD8	psi-mi:“MI:0915”(physical association)	0.840
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
COMMD4	VPS26C	psi-mi:“MI:0914”(association)	0.730

BioGRID (143): COMMD8 (Affinity Capture-MS), COMMD8 (Affinity Capture-MS), COMMD8 (Affinity Capture-MS), COMMD5 (Co-fractionation), COMMD8 (Co-fractionation), COMMD8 (Co-fractionation), COMMD8 (Proximity Label-MS), COMMD8 (Affinity Capture-MS), COMMD8 (Proximity Label-MS), COMMD8 (Affinity Capture-MS), COMMD8 (Affinity Capture-MS), COMMD8 (Affinity Capture-MS), COMMD8 (Affinity Capture-MS), COMMD8 (Affinity Capture-MS), COMMD4 (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: Q05AV1, Q28HC7, Q2KIY0, Q3V4B5, Q54MA5, Q7Z4G1, Q9NX08, Q54CU8, Q9CZG3

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 53 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	11	15.3×	1e-08

GO biological processes:

GO term	Partners	Fold	FDR
endocytic recycling	6	34.9×	5e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	26
Likely benign	5
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

612 predictions. Top by Δscore:

Variant	Effect	Δscore
4:47453054:AATAC:A	donor_loss	1.0000
4:47453056:TACCT:T	donor_loss	1.0000
4:47453058:C:CG	donor_loss	1.0000
4:47453210:GCAAG:G	acceptor_gain	1.0000
4:47453211:CAAG:C	acceptor_gain	1.0000
4:47453211:CAAGC:C	acceptor_gain	1.0000
4:47453212:AAG:A	acceptor_gain	1.0000
4:47453213:AG:A	acceptor_gain	1.0000
4:47453215:C:A	acceptor_loss	1.0000
4:47453215:C:CC	acceptor_gain	1.0000
4:47453217:G:C	acceptor_gain	1.0000
4:47453219:T:C	acceptor_gain	1.0000
4:47453219:T:TC	acceptor_gain	1.0000
4:47453226:C:CT	acceptor_gain	1.0000
4:47453227:A:T	acceptor_gain	1.0000
4:47456574:TA:T	donor_loss	1.0000
4:47456727:TAT:T	acceptor_gain	1.0000
4:47456730:C:CC	acceptor_gain	1.0000
4:47460143:CC:C	donor_loss	1.0000
4:47460143:CCT:C	donor_gain	1.0000
4:47460295:AGAAG:A	acceptor_gain	1.0000
4:47460296:GAAG:G	acceptor_gain	1.0000
4:47460296:GAAGC:G	acceptor_loss	1.0000
4:47460297:AAG:A	acceptor_gain	1.0000
4:47460298:AG:A	acceptor_gain	1.0000
4:47460299:GCTA:G	acceptor_loss	1.0000
4:47460300:C:CC	acceptor_gain	1.0000
4:47460300:CTAG:C	acceptor_loss	1.0000
4:47460301:T:C	acceptor_loss	1.0000
4:47460304:C:CT	acceptor_gain	1.0000

AlphaMissense

1203 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:47456588:A:G	W122R	0.995
4:47456588:A:T	W122R	0.995
4:47453087:A:G	L168P	0.991
4:47453096:A:G	L165P	0.988
4:47453162:A:G	L143P	0.987
4:47453156:A:G	L145P	0.985
4:47453200:A:C	S130R	0.982
4:47453200:A:T	S130R	0.982
4:47453202:T:G	S130R	0.982
4:47453067:C:G	A175P	0.980
4:47456586:C:A	W122C	0.978
4:47456586:C:G	W122C	0.978
4:47456661:C:A	R97S	0.977
4:47456661:C:G	R97S	0.977
4:47456602:A:G	L117P	0.975
4:47453162:A:T	L143Q	0.973
4:47453162:A:C	L143R	0.972
4:47456592:A:C	F120L	0.971
4:47456592:A:T	F120L	0.971
4:47456594:A:G	F120L	0.971
4:47456602:A:C	L117R	0.971
4:47456602:A:T	L117Q	0.971
4:47456662:C:G	R97T	0.970
4:47456593:A:G	F120S	0.965
4:47453066:G:T	A175E	0.964
4:47456662:C:A	R97M	0.962
4:47456587:C:G	W122S	0.961
4:47453156:A:T	L145Q	0.958
4:47460215:A:G	W51R	0.955
4:47460215:A:T	W51R	0.955

dbSNP variants (sampled 300 via entrez): RS1000144504 (4:47455235 C>T), RS1000145396 (4:47465548 A>G,T), RS1000405067 (4:47457341 T>C), RS1000499592 (4:47452444 T>C), RS10005092 (4:47450383 C>T), RS1000545048 (4:47461076 G>A), RS1001041262 (4:47452094 T>C), RS1001140300 (4:47458575 A>G), RS1001148155 (4:47454115 T>G), RS1001645340 (4:47456004 G>A), RS10016711 (4:47450368 A>G), RS10017614 (4:47454206 C>A,G,T), RS1001816937 (4:47462365 AG>A,AGG), RS1001843740 (4:47454583 C>G), RS1001862995 (4:47457930 T>C,G)

Disease associations

OMIM: gene MIM:616656 | 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
GCST007323_45	Risk-taking tendency (4-domain principal component model)	4.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0008579	risk-taking behaviour

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

22 total (human), top 22 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases methylation, increases expression	5
aristolochic acid I	decreases expression	1
dicrotophos	decreases expression	1
sodium arsenite	decreases expression	1
cupric chloride	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
abrine	decreases expression	1
Vorinostat	increases expression	1
Air Pollutants	increases abundance, decreases expression	1
Diethylstilbestrol	increases expression	1
Estradiol	affects expression	1
Gold	decreases expression	1
Hydrogen Peroxide	affects expression	1
Ivermectin	decreases expression	1
Quercetin	decreases expression	1
Aflatoxin B1	affects expression	1
Sodium Selenite	increases expression	1
Copper Sulfate	decreases expression	1
Lactic Acid	decreases expression	1
Particulate Matter	decreases expression, increases abundance	1

Clinical trials (associated diseases)

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