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): 40 total
• GTEx eGene: eQTL in 16 tissues, sQTL in 5 (q < 0.05)
• Cancer dependency (DepMap): dependent in 11.4% of screened cell lines
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.37 (unconstrained)
• 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: 8 — 6 protein_coding, 1 retained_intron, 1 nonsense_mediated_decay

MANE Select: ENST00000381571

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1, TSL 2: 1

ENST00000381571, ENST00000509220, ENST00000860334, ENST00000860335, ENST00000860336, ENST00000952424, ENST00001064747, ENST00001134076

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.

Highest expression (Bgee): choroid plexus epithelium, nephron tubule, monocyte, renal glomerulus, mononuclear cell.

Genetic regulation across tissues (GTEx eQTL / sQTL)

COMMD8 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 16 tissues and its splicing (sQTL) in 5 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 21 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Muscle Skeletal	eqtl	4.3e-13	-0.36	4:47463352:G:A
Esophagus Mucosa	eqtl	1.6e-06	-0.15	4:47473842:C:A
Cells Cultured fibroblasts	sqtl	3.1e-06	-0.23	4:47449006:A:G
Cells EBV-transformed lymphocytes	sqtl	1.4e-05	-0.62	4:47449006:A:G
Whole Blood	eqtl	7.2e-05	+0.08	4:47876962:C:CAAAT
Skin Not Sun Exposed Suprapubic	eqtl	3.7e-04	+0.09	4:47411505:G:A
Artery Tibial	eqtl	3.1e-03	+0.12	4:47512406:G:A
Esophagus Muscularis	eqtl	3.7e-03	+0.29	4:48186126:C:G
Skin Sun Exposed Lower leg	eqtl	1.0e-02	-0.34	4:47454837:C:T
Nerve Tibial	sqtl	1.0e-02	+1.02	4:47683384:G:A
Cells Cultured fibroblasts	eqtl	1.1e-02	+0.08	4:47420979:G:C
Adipose Subcutaneous	eqtl	1.7e-02	-0.16	4:47093696:G:T
Small Intestine Terminal Ileum	eqtl	2.2e-02	+0.68	4:47671608:G:T
Thyroid	eqtl	2.5e-02	-0.08	4:47333726:C:A
Adipose Visceral Omentum	eqtl	3.0e-02	+0.43	4:46998637:G:A
Cells EBV-transformed lymphocytes	eqtl	3.4e-02	-0.11	4:47414802:G:T
Artery Aorta	eqtl	4.2e-02	-0.11	4:47513172:T:G
Esophagus Mucosa	sqtl	4.7e-02	-0.73	4:46953173:T:C
Pancreas	eqtl	4.7e-02	+0.54	4:46582422:AC:A
Lung	eqtl	4.8e-02	+0.14	4:47543795:T:C

FANTOM5 promoters

2 alternative TSS:

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

Top tissues by expression

showing 100 of 288 tissues 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
rectum	UBERON:0001052	89.19	gold quality
islet of Langerhans	UBERON:0000006	89.12	gold quality
metanephros cortex	UBERON:0010533	89.04	gold quality
tibia	UBERON:0000979	88.98	gold quality
vermiform appendix	UBERON:0001154	88.59	gold quality
gingiva	UBERON:0001828	88.42	gold quality
esophagus mucosa	UBERON:0002469	88.36	gold quality
lymph node	UBERON:0000029	88.32	gold quality
granulocyte	CL:0000094	88.30	gold quality
parietal pleura	UBERON:0002400	88.25	gold quality
ileal mucosa	UBERON:0000331	88.03	gold quality
pleura	UBERON:0000977	87.98	gold quality
gingival epithelium	UBERON:0001949	87.95	gold quality
adrenal tissue	UBERON:0018303	87.89	gold quality
duodenum	UBERON:0002114	87.69	gold quality
epithelium of bronchus	UBERON:0002031	87.58	gold quality
germinal epithelium of ovary	UBERON:0001304	87.32	gold quality
visceral pleura	UBERON:0002401	87.18	gold quality
corpus epididymis	UBERON:0004359	87.10	gold quality
hair follicle	UBERON:0002073	87.09	gold quality
bronchus	UBERON:0002185	86.98	gold quality
heart left ventricle	UBERON:0002084	86.94	gold quality
cardiac ventricle	UBERON:0002082	86.86	gold quality
bone marrow	UBERON:0002371	86.73	gold quality
colonic mucosa	UBERON:0000317	86.71	gold quality
placenta	UBERON:0001987	86.70	gold quality
descending thoracic aorta	UBERON:0002345	86.44	gold quality
thoracic aorta	UBERON:0001515	86.35	gold quality
ascending aorta	UBERON:0001496	86.32	gold quality
caecum	UBERON:0001153	86.28	gold quality
gall bladder	UBERON:0002110	86.25	gold quality
amniotic fluid	UBERON:0000173	86.17	gold quality
heart	UBERON:0000948	86.17	gold quality
right adrenal gland cortex	UBERON:0035827	86.06	gold quality
adenohypophysis	UBERON:0002196	86.05	gold quality
jejunum	UBERON:0002115	85.96	gold quality
right adrenal gland	UBERON:0001233	85.89	gold quality
mucosa of transverse colon	UBERON:0004991	85.85	gold quality
left coronary artery	UBERON:0001626	85.77	gold quality
esophagus	UBERON:0001043	85.76	gold quality
mucosa of sigmoid colon	UBERON:0004993	85.62	gold quality
mucosa of paranasal sinus	UBERON:0005030	85.56	gold quality
blood vessel layer	UBERON:0004797	85.44	gold quality
nucleus accumbens	UBERON:0001882	85.19	gold quality
smooth muscle tissue	UBERON:0001135	85.18	gold quality
right atrium auricular region	UBERON:0006631	85.18	gold quality
endometrium	UBERON:0001295	85.02	gold quality
caudate nucleus	UBERON:0001873	84.97	gold quality
left adrenal gland	UBERON:0001234	84.88	gold quality
coronary artery	UBERON:0001621	84.81	gold quality
aorta	UBERON:0000947	84.74	gold quality
pituitary gland	UBERON:0000007	84.73	gold quality
synovial joint	UBERON:0002217	84.72	gold quality
cardiac atrium	UBERON:0002081	84.67	gold quality
pancreas	UBERON:0001264	84.64	gold quality
myocardium	UBERON:0002349	84.47	gold quality
testis	UBERON:0000473	84.43	gold quality
sperm	CL:0000019	84.33	gold quality
superficial temporal artery	UBERON:0001614	84.33	gold quality
spleen	UBERON:0002106	84.26	gold quality
adrenal gland	UBERON:0002369	84.25	gold quality
left adrenal gland cortex	UBERON:0035825	84.13	gold quality
upper arm skin	UBERON:0004263	84.07	gold quality
nasal cavity mucosa	UBERON:0001826	84.04	gold quality
hypothalamus	UBERON:0001898	84.01	gold quality
adipose tissue	UBERON:0001013	83.95	gold quality
left testis	UBERON:0004533	83.92	gold quality
renal medulla	UBERON:0000362	83.90	gold quality
cranial nerve II	UBERON:0000941	83.90	gold quality
caput epididymis	UBERON:0004358	83.90	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

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Hippocampal formation	tissue	77.1
Cerebral cortex	tissue	72.2	medium
Retrosplenial and cingulate cortex	tissue	72.2
Prefrontal cortex	tissue	70.1
Motor cortex	tissue	68.7
Entorhinal cortex	tissue	66.9
Retrosplenial cortex	tissue	65.6
Occipital cortex	tissue	62.2
Insular cortex	tissue	61.9
Hypothalamus	tissue	61.2
Temporal cortex	tissue	61.1
Somatosensory cortex	tissue	59.9
Septum	tissue	59.2
Amygdala	tissue	55.4
Pons	tissue	53.5
Ventral forebrain	tissue	52.9
Periaqueductal gray	tissue	48.8
Thalamus	tissue	48.7
Basal ganglia	tissue	45.5	high
Midbrain	tissue	45.5
Substantia nigra	tissue	43.8
Kidney	tissue	42.2	medium
Corpus callosum	tissue	42.2
Medulla oblongata	tissue	41.8
Spinal cord	tissue	40.0
Putamen	tissue	35.3
Olfactory bulb	tissue	34.3
Superior colliculi	tissue	32.2
Cerebellum	tissue	31.1	high
Lymph node	tissue	28.4	medium
Heart muscle	tissue	25.4	high
Parathyroid gland	tissue	25.2	low
Tonsil	tissue	23.8	high
Esophagus	tissue	22.7	medium
Testis	tissue	22.5	medium
Epididymis	tissue	21.4	high
Thymus	tissue	20.2
Bone marrow	tissue	20.2	medium
Thyroid gland	tissue	19.9	medium
Appendix	tissue	19.2	medium
Placenta	tissue	17.9	medium
Small intestine	tissue	17.9	medium
Duodenum	tissue	17.3	medium
Spleen	tissue	17.0	medium
Rectum	tissue	16.9	medium
Skin 1	tissue	16.6	high
Colon	tissue	16.6	medium
Urinary bladder	tissue	15.8	medium
Adrenal gland	tissue	14.7	medium
Choroid plexus	tissue	14.1
Smooth muscle	tissue	14.0	low
Stomach 1	tissue	13.5	medium
Caudate putamen	tissue	13.3
Gallbladder	tissue	12.9	medium
Breast	tissue	12.7	high
Frontal cortex	tissue	12.7
Lung	tissue	12.7	medium
Pituitary gland	tissue	12.6
Adipose tissue	tissue	12.6	low
Retina	tissue	12.5

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Subiculum (77.1), Dorsal hippocampus (75.5), Ventral hippocampus (75.5), White matter (42.2), Dorsal spinal cord (40.0).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

Targeting COMMD8 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 67 miRNAs:

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

gnomAD constraint: pLI 8.56e-05, LOEUF 1.37, missense Z -0.307 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000381571 — one region, missense o/e 1.03. DepMap (CRISPR cell-line fitness): dependent in 11.4% of screened cell lines.

Most-dependent cell lines (DepMap gene-effect, lower = stronger; ≤ −0.5 shown): KYAE-1 (-1.121), HuNS1 (-1.104), NCI-H211 (-1.013), DOK (-0.968), Hs 695T (-0.965), YD-38 (-0.929), MAVER-1 (-0.929), LS 180 (-0.901), KLE (-0.879), UPMD1 (-0.879), NB-4 (-0.858), CAL-72 (-0.835), SCCOHT-1 (-0.828), SNU-81 (-0.817), SKN-3 (-0.817).

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)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1343485) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 11 distinct phenotype terms.

Mouse phenotype (MP)	Records
decreased IgM level	1
decreased follicular B cell number	1
abnormal follicular B cell physiology	1
decreased mature B cell number	1
abnormal spleen B cell follicle morphology	1
decreased spleen germinal center number	1
decreased IgG1 level	1
decreased IgG2b level	1
decreased IgG3 level	1
decreased IgG2c level	1
abnormal plasmablast number	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Bos taurus	Q2KIY0	88.2%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
MIR8053	ncRNA	102467004
CORIN	protein-coding	10699
ATP10D	protein-coding	57205
GABRB1	protein-coding	2560
COX7B2	protein-coding	170712
GABRA4	protein-coding	2557

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 (18 total): helix 9, strand 3, turn 2, chain 1, domain 1, sequence variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

3 structures by resolution:

PDB	Title	Method	Resolution (Å)
8P0W	Structure of the human Commander complex COMMD ring	ELECTRON MICROSCOPY	2.9
8F2R	Human CCC complex	ELECTRON MICROSCOPY	3.12
8F2U	Human CCC complex	ELECTRON MICROSCOPY	3.53

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NX08-F1	87.67	0.68

Human Protein Atlas

Protein class: Predicted intracellular proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): cytosol; nucleoplasm

Antibody reliability (HPA): IH approved · IF supported

Function

Pathways and Gene Ontology

Reactome pathways

1 curated (TAS) of 3; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

3 pathways:

ID	Pathway	Evidence
R-HSA-8951664	Neddylation	curated
R-HSA-392499	Metabolism of proteins	—
R-HSA-597592	Post-translational protein modification	—

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 (3): DNA-templated transcription (GO:0006351), signal transduction (GO:0007165), endocytic recycling (GO:0032456)

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

GO Cellular Component (7): nucleoplasm (GO:0005654), cytosol (GO:0005829), endosome membrane (GO:0010008), protein-containing complex (GO:0032991), nucleus (GO:0005634), cytoplasm (GO:0005737), endoplasmic reticulum membrane (GO:0005789)

Reactome top-level categories

2 top-level categories:

Category	Pathways
Post-translational protein modification	1
Metabolism of proteins	1

GO top-level categories

23 GO namespaces:

Category	Terms
cellular anatomical structure	3
gene expression	1
RNA biosynthetic process	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
endosomal transport	1
vesicle-mediated transport to the plasma membrane	1
RNA polymerase II-specific DNA-binding transcription factor binding	1
binding	1
nuclear lumen	1
cytoplasm	1
endosome	1
cytoplasmic vesicle membrane	1
bounding membrane of organelle	1
cellular_component	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 3 of 12 annotations. The rest are phylogenetic / computational / electronic (IEA).

3 experimentally-supported GO terms:

GO term	NS	Evidence
cytosol	CC	direct assay
nucleoplasm	CC	direct assay
protein-containing complex	CC	direct assay

Protein interactions and networks

STRING

showing 15 of 1,087 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
COMMD8	COMMD5	Q9GZQ3	781
COMMD8	COMMD4	Q9H0A8	773
COMMD8	COMMD2	Q86X83	772
COMMD8	COMMD3	Q9UBI1	771
COMMD8	COMMD6	Q7Z4G1	739
COMMD8	COMMD9	Q9P000	723
COMMD8	CCDC22	O60826	717
COMMD8	COMMD10	Q9Y6G5	697
COMMD8	COMMD1	Q8N668	675
COMMD8	CCDC93	Q567U6	671
COMMD8	COMMD7	Q86VX2	643
COMMD8	A0A2R8Y455	A0A2R8Y455	643
COMMD8	DENND10	Q8TCE6	627
COMMD8	VPS35L	Q7Z3J2	600
COMMD8	GABRB1	P18505	542

IntAct

Human interaction partners of COMMD8 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

13 partners by confidence:

Partner	Interaction type	MIscore	Records
CCDC22	physical association	0.920	1
COMMD1	physical association	0.920	1
COMMD4	physical association	0.880	9
CCDC93	physical association	0.850	1
COMMD3	physical association	0.840	1
COMMD6	association	0.730	1
VPS26C	association	0.640	4
ZNF474	physical association	0.560	3
AKR1C1	physical association	0.370	1
TMX2	physical association	0.370	1
CUL1	association	0.350	1
NFKB1	association	0.350	1
NDUFA4L2	physical association	0.000	1

BioGRID (143 interactions; top human partners by supporting records): COMMD3 (Affinity Capture-MS; 7 records), CCDC22 (Affinity Capture-MS; 6 records), COMMD1 (Affinity Capture-MS; 6 records), COMMD2 (Co-fractionation; 6 records), COMMD4 (Affinity Capture-MS; 5 records), CCDC93 (Affinity Capture-MS; 4 records), COMMD10 (Affinity Capture-MS; 4 records), COMMD6 (Affinity Capture-MS; 4 records), VPS29 (Affinity Capture-MS; 4 records), C16orf62 (Affinity Capture-MS; 3 records), CCDC151 (Affinity Capture-MS; 3 records), COMMD5 (Co-fractionation; 3 records), COMMD7 (Affinity Capture-MS; 3 records), E2F6 (Affinity Capture-MS; 3 records), TFDP1 (Affinity Capture-MS; 3 records)

Protein complexes (CORUM) (4)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

4 complexes by size:

Complex	Subunits	Members
CCC-Wash (WASH1, FAM21C) complex	15	COMMD3, COMMD4, CCDC22, COMMD1, COMMD8, WASHC1, WASHC2C, CCDC93, COMMD10, COMMD2, COMMD5, COMMD7, COMMD6, COMMD9, VPS35L
CCC complex	13	COMMD2, COMMD3, COMMD6, COMMD8, VPS35L, CCDC93, COMMD1, COMMD10, COMMD4, COMMD5, COMMD7, COMMD9, CCDC22
CCDC22-COMMD8-CUL1 complex	3	CUL1, CCDC22, COMMD8
Ubiquitin E3 ligase (CCDC22, COMMD8, CUL3)	3	CCDC22, COMMD8, CUL3

Disease & clinical

Genetic variants

Variant evidence for COMMD8: 40 ClinVar records (0 pathogenic / likely pathogenic); 1 GWAS association.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	28
Likely benign	5
Benign	0

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 34 predictions of 387):

Position(s)	Effect	Δscore	Sites
4:47453057–47453058	donor_loss	1.0000	4
4:47453215–47453216	acceptor_loss	1.0000	5
4:47453217–47453219	acceptor_gain	1.0000	2
4:47453227	acceptor_gain	1.0000
4:47456575–47456576	donor_loss	1.0000	5
4:47460142–47460143	donor_loss	1.0000	5
4:47460300–47460301	acceptor_loss	1.0000	5
4:47460305	acceptor_gain	1.0000
4:47463584–47463585	donor_loss	1.0000	5
4:47451667	acceptor_gain	0.9900

AlphaMissense

244 missense substitutions predicted likely pathogenic (of 1,203 scored), across 85 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
F120	8	0.823	0.971
W122	7	0.955	0.995
R97	7	0.853	0.977
D119	7	0.829	0.904
D131	7	0.816	0.926
E159	7	0.781	0.880
D29	7	0.751	0.829
D121	7	0.727	0.785
M160	6	0.887	0.947
S130	6	0.885	0.982
W46	6	0.844	0.950
W51	6	0.840	0.955
H25	6	0.713	0.759
K125	5	0.747	0.828
P139	5	0.709	0.849
K183	4	0.835	0.887
C93	4	0.763	0.887
S161	4	0.697	0.739
L143	3	0.977	0.987
L117	3	0.972	0.975

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

3 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	3.09e-06
Colon Adenocarcinoma (validation)	favorable	5.91e-06
Liver Hepatocellular Carcinoma (TCGA)	unfavorable	3.43e-05

Disease associations

OMIM: gene MIM:616656 | disease phenotypes:

GWAS associations

1 associations:

Study	Trait	p-value
GCST007323_101	Risk-taking tendency (4-domain principal component model)	4e-8

EFO canonical traits (from GWAS)

1 canonical traits:

EFO ID	Trait name
EFO:0008579	risk-taking behaviour

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases methylation, increases expression, affects 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	decreases expression, increases abundance	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)

Via MONDO — disease-level, not drug-specific.