COMMD4

Summary

COMMD4 (COMM domain containing 4, HGNC:26027) is a protein-coding gene on chromosome 15q24.2, encoding COMM domain-containing protein 4 (Q9H0A8). 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 signal transduction. Located in cytosol; intracellular membrane-bounded organelle; and plasma membrane.

Source: NCBI Gene 54939 — RefSeq curated summary.

At a glance

• GWAS associations: 6
• Clinical variants (ClinVar): 52 total — 1 pathogenic
• MANE Select transcript: NM_017828

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26027
Approved symbol	COMMD4
Name	COMM domain containing 4
Location	15q24.2
Locus type	gene with protein product
Status	Approved
Aliases	FLJ20452
Ensembl gene	ENSG00000140365
Ensembl biotype	protein_coding
OMIM	616701
Entrez	54939

Gene structure

Transcript identifiers

Ensembl transcripts: 46 — 28 protein_coding, 14 retained_intron, 3 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000267935, ENST00000338995, ENST00000480484, ENST00000561662, ENST00000562310, ENST00000562610, ENST00000562789, ENST00000563220, ENST00000564068, ENST00000564587, ENST00000564815, ENST00000565517, ENST00000565834, ENST00000566230, ENST00000566843, ENST00000567023, ENST00000567195, ENST00000567377, ENST00000567399, ENST00000567720, ENST00000567935, ENST00000568034, ENST00000568301, ENST00000568877, ENST00000569245, ENST00000869634, ENST00000869635, ENST00000869636, ENST00000869637, ENST00000869638, ENST00000869639, ENST00000869640, ENST00000869641, ENST00000928185, ENST00000928186, ENST00000928187, ENST00000928188, ENST00000928189, ENST00000928190, ENST00000928191, ENST00000928192, ENST00000928193, ENST00000928194, ENST00000928195, ENST00000944821, ENST00000944822

RefSeq mRNA: 9 — MANE Select: NM_017828 NM_001284377, NM_001284378, NM_001284379, NM_001321844, NM_001321845, NM_001321846, NM_001321847, NM_001321848, NM_017828

CCDS: CCDS10277, CCDS66834, CCDS66835, CCDS73764, CCDS81909

Canonical transcript exons

ENST00000267935 — 8 exons

Exon	Start	End
ENSE00001424829	75336063	75336092
ENSE00001842777	75339965	75340273
ENSE00003463152	75339264	75339344
ENSE00003533754	75338355	75338420
ENSE00003552441	75339702	75339878
ENSE00003574027	75338646	75338685
ENSE00003585450	75338985	75339104
ENSE00003619772	75338062	75338133

Expression profiles

Bgee: expression breadth ubiquitous, 280 present calls, max score 97.71.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 11.0299 / max 69.9234, expressed in 1778 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
147798	9.2129	1751
147797	1.0864	763
147799	0.7307	434

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left testis	UBERON:0004533	97.71	gold quality
right testis	UBERON:0004534	97.59	gold quality
right adrenal gland	UBERON:0001233	97.45	gold quality
right adrenal gland cortex	UBERON:0035827	97.41	gold quality
left adrenal gland cortex	UBERON:0035825	97.24	gold quality
left adrenal gland	UBERON:0001234	97.13	gold quality
adrenal cortex	UBERON:0001235	96.89	gold quality
granulocyte	CL:0000094	96.66	gold quality
mucosa of transverse colon	UBERON:0004991	96.16	gold quality
metanephros cortex	UBERON:0010533	96.13	gold quality
apex of heart	UBERON:0002098	95.88	gold quality
adrenal gland	UBERON:0002369	95.73	gold quality
stromal cell of endometrium	CL:0002255	95.51	gold quality
testis	UBERON:0000473	95.47	gold quality
body of stomach	UBERON:0001161	95.40	gold quality
right lobe of thyroid gland	UBERON:0001119	95.11	gold quality
adenohypophysis	UBERON:0002196	95.07	gold quality
left lobe of thyroid gland	UBERON:0001120	95.01	gold quality
transverse colon	UBERON:0001157	94.70	gold quality
minor salivary gland	UBERON:0001830	94.62	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	94.57	gold quality
right lobe of liver	UBERON:0001114	94.54	gold quality
muscle layer of sigmoid colon	UBERON:0035805	94.51	gold quality
mucosa of stomach	UBERON:0001199	94.43	gold quality
endometrium epithelium	UBERON:0004811	94.42	gold quality
right uterine tube	UBERON:0001302	94.40	gold quality
ectocervix	UBERON:0012249	94.38	gold quality
lower esophagus	UBERON:0013473	94.36	gold quality
lower esophagus muscularis layer	UBERON:0035833	94.36	gold quality
left coronary artery	UBERON:0001626	94.34	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-11121	yes	289.70
E-ANND-3	yes	8.08

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

9 targeting COMMD4, 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-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-513C-5P	99.50	68.42	1730
HSA-MIR-514B-5P	99.50	68.19	1766
HSA-MIR-4316	99.37	65.75	1360
HSA-MIR-3074-5P	98.82	66.56	1414
HSA-MIR-2278	97.30	66.19	1130

Literature-anchored findings (GeneRIF, showing 2)

• Defining COMMD4 as an anti-cancer therapeutic target and prognostic factor in non-small cell lung cancer. (PMID:32439936)
• COMMD4 functions with the histone H2A-H2B dimer for the timely repair of DNA double-strand breaks. (PMID:33875784)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	commd4	ENSDARG00000061946
mus_musculus	Commd4	ENSMUSG00000032299
rattus_norvegicus	Commd4	ENSRNOG00000018671
drosophila_melanogaster	CG34039	FBGN0054039
caenorhabditis_elegans	T28F2.2	WBGENE00020901

Protein

Protein identifiers

COMM domain-containing protein 4 — Q9H0A8 (reviewed: Q9H0A8)

All UniProt accessions (7): Q9H0A8, A0A0B4J287, H3BM91, H3BPG2, H3BQF2, H3BRX0, H3BTV9

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.

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 COMMD8. Interacts with RELA, RELB, NFKB1/p105. Interacts with CCDC22, CCDC93, SCNN1B, CUL2, CUL3, CUL4A, CUL5, CUL7.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Ubiquitous.

Similarity. Belongs to the COMM domain-containing protein 4 family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9H0A8-1	1	yes
Q9H0A8-2	2
Q9H0A8-3	3

RefSeq proteins (9): NP_001271306, NP_001271307, NP_001271308, NP_001308773, NP_001308774, NP_001308775, NP_001308776, NP_001308777, NP_060298* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR017920	COMM	Domain
IPR037356	COMMD4	Family
IPR047155	COMMD4/6/7/8	Family

Pfam: PF07258, PF21672

UniProt features (16 total): helix 8, strand 3, splice variant 2, chain 1, domain 1, turn 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
9ZMZ	X-RAY DIFFRACTION	2.12
8P0W	ELECTRON MICROSCOPY	2.9
8F2R	ELECTRON MICROSCOPY	3.12
8F2U	ELECTRON MICROSCOPY	3.53

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H0A8-F1	80.85	0.08

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-8951664	Neddylation

MSigDB gene sets: 141 (showing top): MULLIGHAN_NPM1_SIGNATURE_3_UP, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_ENDOCYTIC_RECYCLING, BASAKI_YBX1_TARGETS_UP, GOBP_LOCALIZATION_WITHIN_MEMBRANE, NUYTTEN_EZH2_TARGETS_DN, MOREAUX_MULTIPLE_MYELOMA_BY_TACI_DN, GOCC_MEMBRANE_PROTEIN_COMPLEX, MORF_RAN, MULLIGHAN_MLL_SIGNATURE_1_UP, MORF_CSNK2B, MULLIGHAN_NPM1_MUTATED_SIGNATURE_1_UP, MORF_PSMC1, MORF_G22P1, REACTOME_POST_TRANSLATIONAL_PROTEIN_MODIFICATION

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

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

GO Cellular Component (4): nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886)

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	2
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
binding	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cytoplasm	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

1779 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
COMMD4	COMMD2	Q86X83	832
COMMD4	CCDC22	O60826	775
COMMD4	COMMD3	Q9UBI1	775
COMMD4	COMMD9	Q9P000	760
COMMD4	COMMD1	Q8N668	671
COMMD4	VPS26C	O14972	634
COMMD4	COMMD5	Q9GZQ3	627
COMMD4	COMMD8	Q9NX08	621
COMMD4	COMMD6	Q7Z4G1	614
COMMD4	COMMD10	Q9Y6G5	571
COMMD4	DPM3	Q9P2X0	514
COMMD4	A0A2R8Y455	A0A2R8Y455	507
COMMD4	COMMD7	Q86VX2	506
COMMD4	ACYP1	P07311	476
COMMD4	R4GMX3	R4GMX3	471

IntAct

109 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	COMMD6	psi-mi:“MI:0914”(association)	0.930
COMMD2	CCDC22	psi-mi:“MI:0914”(association)	0.930
CCDC22	COMMD4	psi-mi:“MI:0915”(physical association)	0.920
COMMD1	COMMD4	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
ODAD1	HGS	psi-mi:“MI:0914”(association)	0.850
COMMD2	COMMD4	psi-mi:“MI:0915”(physical association)	0.820
COMMD4	CCDC93	psi-mi:“MI:0915”(physical association)	0.800
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
COMMD4	VPS26C	psi-mi:“MI:0914”(association)	0.730
E2F6	WDR5	psi-mi:“MI:0914”(association)	0.730

BioGRID (195): COMMD4 (Affinity Capture-MS), COMMD4 (Affinity Capture-MS), COMMD4 (Affinity Capture-MS), COMMD4 (Affinity Capture-MS), COMMD4 (Affinity Capture-MS), COMMD2 (Affinity Capture-MS), C16orf62 (Affinity Capture-MS), CCDC93 (Affinity Capture-MS), COMMD10 (Affinity Capture-MS), TP53RK (Affinity Capture-MS), EXOSC4 (Affinity Capture-MS), COMMD7 (Affinity Capture-MS), FAM45A (Affinity Capture-MS), EXOSC2 (Affinity Capture-MS), COMMD6 (Affinity Capture-MS)

ESM2 similar proteins: A4IFQ0, A4QNE0, O09172, O75031, P41214, P48507, P48508, P48553, P50747, P54198, Q08BT5, Q0P5I8, Q13769, Q2T9Y6, Q2TBN5, Q3B7L5, Q3T0J1, Q3TLI0, Q5E9V6, Q5R812, Q5RA63, Q5RAQ5, Q61666, Q66H91, Q68FF6, Q68FX7, Q6DFV5, Q6NRL4, Q6P6Y1, Q6ZPY2, Q76JQ2, Q7L5D6, Q8BKT7, Q8JZY2, Q8K2Q0, Q8R1T1, Q8WUX9, Q91W86, Q91W96, Q920N2

Diamond homologs: Q550I8, Q5E9V6, Q9CQ02, Q9H0A8

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 64 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	13.0×	1e-07

GO biological processes:

GO term	Partners	Fold	FDR
endocytic recycling	6	28.2×	3e-05
cilium assembly	8	10.3×	2e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	34
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
58080	GRCh38/hg38 15q24.2(chr15:75336215-75658670)x3	Pathogenic

SpliceAI

1446 predictions. Top by Δscore:

Variant	Effect	Δscore
15:75338061:GA:G	acceptor_gain	1.0000
15:75338133:GGT:G	donor_gain	1.0000
15:75338135:T:G	donor_gain	1.0000
15:75338135:T:TG	donor_gain	1.0000
15:75338139:G:GG	donor_gain	1.0000
15:75338353:A:AG	acceptor_gain	1.0000
15:75338354:G:GG	acceptor_gain	1.0000
15:75338644:A:AG	acceptor_gain	1.0000
15:75338645:G:GG	acceptor_gain	1.0000
15:75338645:GT:G	acceptor_gain	1.0000
15:75338684:TGG:T	donor_loss	1.0000
15:75338685:GGT:G	donor_loss	1.0000
15:75338686:GT:G	donor_loss	1.0000
15:75338973:C:CA	acceptor_gain	1.0000
15:75339341:CGCA:C	donor_gain	1.0000
15:75339342:GCA:G	donor_gain	1.0000
15:75339342:GCAG:G	donor_gain	1.0000
15:75339343:CA:C	donor_gain	1.0000
15:75339343:CAG:C	donor_loss	1.0000
15:75339344:AGT:A	donor_loss	1.0000
15:75339345:G:GG	donor_gain	1.0000
15:75339346:TAA:T	donor_loss	1.0000
15:75339700:A:AG	acceptor_gain	1.0000
15:75339701:G:GG	acceptor_gain	1.0000
15:75339701:GTGA:G	acceptor_gain	1.0000
15:75336093:G:GG	donor_gain	0.9900
15:75336094:T:G	donor_loss	0.9900
15:75336098:GCAC:G	donor_gain	0.9900
15:75338057:TGCA:T	acceptor_loss	0.9900
15:75338058:GCA:G	acceptor_loss	0.9900

AlphaMissense

1283 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:75338065:T:C	F3L	0.999
15:75338067:C:A	F3L	0.999
15:75338067:C:G	F3L	0.999
15:75338098:T:A	W14R	0.999
15:75338098:T:C	W14R	0.999
15:75338100:G:C	W14C	0.999
15:75338100:G:T	W14C	0.999
15:75339081:T:C	L93P	0.997
15:75338066:T:C	F3S	0.996
15:75338066:T:G	F3C	0.996
15:75339096:T:C	L98P	0.996
15:75338071:T:C	F5L	0.995
15:75338073:C:A	F5L	0.995
15:75338073:C:G	F5L	0.995
15:75338091:T:G	C11W	0.995
15:75339093:G:A	G97E	0.995
15:75338089:T:C	C11R	0.994
15:75339968:T:C	L188P	0.994
15:75338065:T:G	F3V	0.993
15:75338078:G:T	G7V	0.993
15:75338090:G:A	C11Y	0.993
15:75338105:T:C	L16P	0.993
15:75339090:T:C	L96P	0.993
15:75338099:G:T	W14L	0.992
15:75339039:C:A	A79E	0.992
15:75339078:A:T	E92V	0.992
15:75339092:G:A	G97R	0.992
15:75339092:G:C	G97R	0.992
15:75338065:T:A	F3I	0.991
15:75338099:G:C	W14S	0.991

dbSNP variants (sampled 300 via entrez): RS1000233675 (15:75334743 A>C), RS1000302644 (15:75339554 C>A,G,T), RS1000694685 (15:75338291 G>C), RS1000771377 (15:75343652 T>G), RS1000890935 (15:75338466 A>C,G), RS1000967784 (15:75342917 C>G), RS1001854713 (15:75342887 T>C,G), RS1002030519 (15:75341401 G>A,T), RS1003627901 (15:75335163 A>G), RS1004184441 (15:75339786 A>C), RS1004590468 (15:75341042 G>C), RS1004644507 (15:75340831 G>A), RS1004820075 (15:75336346 G>C), RS1005089694 (15:75336518 C>A,T), RS1005334432 (15:75342631 C>T)

Disease associations

OMIM: gene MIM:616701 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST007725_8	Serum uric acid levels	1.000000e-08
GCST008790_51	Urinary albumin-to-creatinine ratio	4.000000e-16
GCST008791_10	Microalbuminuria	2.000000e-07
GCST008971_14	Urate levels	2.000000e-07
GCST008972_197	Urate levels	3.000000e-12
GCST008972_43	Urate levels	3.000000e-07

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004761	uric acid measurement
EFO:0007778	urinary albumin to creatinine ratio
EFO:0004531	urate measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression, increases abundance	2
cobaltous chloride	decreases expression	2
TAK-243	increases sumoylation	1
2,4,6-tribromophenol	decreases expression	1
methylmercuric chloride	decreases expression	1
lasiocarpine	increases expression	1
bisphenol A	affects expression	1
decabromobiphenyl ether	decreases expression	1
beta-lapachone	increases expression	1
arsenite	affects binding, increases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cypermethrin	increases expression	1
tetrabromobisphenol A	decreases expression	1
zinc chromate	decreases expression, increases abundance	1
cupric chloride	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
chromium hexavalent ion	decreases expression, increases abundance	1
K 7174	decreases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
jinfukang	increases expression	1
(+)-JQ1 compound	decreases expression	1
Sunitinib	decreases expression	1
Vorinostat	increases expression	1
Arsenic	increases abundance, increases expression	1
Catechin	affects cotreatment, decreases expression	1
Cisplatin	increases expression	1

Clinical trials (associated diseases)

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