COMMD5

Summary

COMMD5 (COMM domain containing 5, HGNC:17902) is a protein-coding gene on chromosome 8q24.3, encoding COMM domain-containing protein 5 (Q9GZQ3). 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 proximal tubule morphogenesis. Located in cytosol and nucleoplasm.

Source: NCBI Gene 28991 — RefSeq curated summary.

At a glance

• GWAS associations: 6
• Clinical variants (ClinVar): 134 total
• MANE Select transcript: NM_014066

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17902
Approved symbol	COMMD5
Name	COMM domain containing 5
Location	8q24.3
Locus type	gene with protein product
Status	Approved
Aliases	HT002, FLJ13008, HCaRG
Ensembl gene	ENSG00000170619
Ensembl biotype	protein_coding
OMIM	608216
Entrez	28991

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 12 protein_coding, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000305103, ENST00000402718, ENST00000450361, ENST00000529143, ENST00000530332, ENST00000533270, ENST00000543949, ENST00000851064, ENST00000877942, ENST00000877943, ENST00000877944, ENST00000932218, ENST00000961494, ENST00000961495

RefSeq mRNA: 4 — MANE Select: NM_014066 NM_001081003, NM_001081004, NM_001287237, NM_014066

CCDS: CCDS6436

Canonical transcript exons

ENST00000305103 — 2 exons

Exon	Start	End
ENSE00001341053	144852839	144853048
ENSE00002193746	144850176	144851395

Expression profiles

Bgee: expression breadth ubiquitous, 227 present calls, max score 91.12.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 14.9157 / max 80.8629, expressed in 1806 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
95724	9.8582	1772
95725	3.8269	1308
95726	1.2306	779

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	91.12	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	90.58	gold quality
colonic epithelium	UBERON:0000397	89.88	gold quality
mucosa of transverse colon	UBERON:0004991	88.94	gold quality
leukocyte	CL:0000738	88.71	gold quality
monocyte	CL:0000576	88.59	gold quality
apex of heart	UBERON:0002098	88.56	gold quality
right adrenal gland cortex	UBERON:0035827	88.43	gold quality
right adrenal gland	UBERON:0001233	88.29	gold quality
left adrenal gland	UBERON:0001234	88.21	gold quality
left adrenal gland cortex	UBERON:0035825	87.90	gold quality
lower esophagus mucosa	UBERON:0035834	87.47	gold quality
prefrontal cortex	UBERON:0000451	87.01	gold quality
thoracic aorta	UBERON:0001515	86.95	gold quality
left coronary artery	UBERON:0001626	86.88	gold quality
ascending aorta	UBERON:0001496	86.87	gold quality
right hemisphere of cerebellum	UBERON:0014890	86.82	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	86.80	gold quality
cerebellar hemisphere	UBERON:0002245	86.75	gold quality
right coronary artery	UBERON:0001625	86.73	gold quality
cerebellar cortex	UBERON:0002129	86.61	gold quality
stromal cell of endometrium	CL:0002255	86.56	gold quality
adrenal cortex	UBERON:0001235	86.55	gold quality
lower esophagus muscularis layer	UBERON:0035833	86.50	gold quality
lower esophagus	UBERON:0013473	86.49	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	86.47	gold quality
gastrocnemius	UBERON:0001388	86.41	gold quality
spleen	UBERON:0002106	86.40	gold quality
descending thoracic aorta	UBERON:0002345	86.40	gold quality
adrenal gland	UBERON:0002369	86.23	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.31

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

26 targeting COMMD5, 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-5196-5P	100.00	67.98	2761
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-3714	99.71	70.74	2671
HSA-MIR-3618	99.69	68.57	1012
HSA-MIR-1283	99.69	72.42	3009
HSA-MIR-298	99.63	67.56	1916
HSA-MIR-365A-3P	99.43	70.02	836
HSA-MIR-365B-3P	99.43	70.02	836
HSA-MIR-130A-5P	99.33	70.26	2623
HSA-MIR-3199	99.17	65.19	696
HSA-MIR-8052	99.17	65.01	719
HSA-MIR-4801	98.96	69.42	2096
HSA-MIR-1227-5P	98.65	65.32	1549
HSA-MIR-4731-3P	98.56	68.60	1860
HSA-MIR-1910-3P	98.44	67.51	1695
HSA-MIR-1304-3P	98.29	66.44	1207
HSA-MIR-6511A-5P	98.13	67.47	1770
HSA-MIR-214-5P	97.34	66.50	617
HSA-MIR-6736-3P	96.98	65.22	1342
HSA-MIR-4440	90.29	63.67	61

Literature-anchored findings (GeneRIF, showing 6)

• The gene for human HCaRG is located on chromosome 8q24.3. (PMID:11871861)
• The up-regulation of HCaRG may be one of the mechanisms underlying the chemopreventive effect of rosiglitazone in gastric cancer. (PMID:18949406)
• HCaRG accelerates repair of renal proximal tubules by modulating cell proliferation of resident tubular epithelial cells and by facilitating redifferentiation. (PMID:21921141)
• the hypertension-related, calcium-regulated gene (HCaRG/COMMD5) is involved in renal repair. (PMID:24515317)
• COMMD5 participates in long-range endosome transport, including epidermal growth factor receptor (EGFR) recycling, and provides the strength to deform and assist the scission of vesicles into sorting endosomes. (PMID:30021164)
• COMMD5 Inhibits Malignant Behavior of Renal Cancer Cells. (PMID:34083270)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	commd5	ENSDARG00000029660
mus_musculus	Commd5	ENSMUSG00000055041
rattus_norvegicus	Commd5	ENSRNOG00000004484
drosophila_melanogaster	LSm-4	FBGN0067622

Protein

Protein identifiers

COMM domain-containing protein 5 — Q9GZQ3 (reviewed: Q9GZQ3)

Alternative names: Hypertension-related calcium-regulated gene protein

All UniProt accessions (3): Q9GZQ3, E9PJE4, H0YEQ6

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. Negatively regulates cell proliferation. Negatively regulates cell cycle G2/M phase transition probably by transactivating p21/CDKN1A through the p53/TP53-independent signaling pathway. Involved in kidney proximal tubule morphogenesis. 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 COMMD10. Interacts (via COMM domain) with COMMD1 (via COMM domain). Interacts with RELA, RELB, NFKB1/p105. Interacts with CCDC22, CCDC93, SCNN1B, CUL2, CUL3, CUL4A, CUL4B, CUL7.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Highly expressed in heart, stomach, jejunum, kidney, liver, and adrenal gland. Expression was generally higher in adult organs than in fetal tissues, particularly in heart, kidney, and liver.

Similarity. Belongs to the COMM domain-containing protein 5 family.

RefSeq proteins (4): NP_001074472, NP_001074473, NP_001274166, NP_054785* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR017920	COMM	Domain
IPR037357	COMMD5	Family

Pfam: PF07258, PF21672

UniProt features (21 total): helix 10, strand 3, sequence variant 2, initiator methionine 1, chain 1, turn 1, domain 1, modified residue 1, sequence conflict 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
8P0W	ELECTRON MICROSCOPY	2.9
8F2R	ELECTRON MICROSCOPY	3.12
8ESD	X-RAY DIFFRACTION	3.33
8F2U	ELECTRON MICROSCOPY	3.53

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9GZQ3-F1	84.49	0.61

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): 2

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-8951664	Neddylation

MSigDB gene sets: 103 (showing top): GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_DN, GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_DN, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, RACCACAR_AML_Q6, GOBP_VESICLE_MEDIATED_TRANSPORT, GARY_CD5_TARGETS_DN, GOBP_ENDOCYTIC_RECYCLING, GOBP_LOCALIZATION_WITHIN_MEMBRANE, GOCC_MEMBRANE_PROTEIN_COMPLEX, SCGGAAGY_ELK1_02, MGGAAGTG_GABP_B, NIKOLSKY_BREAST_CANCER_8Q23_Q24_AMPLICON, VECCHI_GASTRIC_CANCER_EARLY_UP, REACTOME_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, JOHNSTONE_PARVB_TARGETS_2_DN

GO Biological Process (0):

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

GO Cellular Component (4): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytosol (GO:0005829), 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
binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cytoplasm	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1351 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
COMMD5	COMMD9	Q9P000	774
COMMD5	COMMD10	Q9Y6G5	728
COMMD5	COMMD2	Q86X83	711
COMMD5	A0A2R8Y455	A0A2R8Y455	700
COMMD5	COMMD7	Q86VX2	699
COMMD5	COMMD1	Q8N668	674
COMMD5	TIGD5	Q53EQ6	658
COMMD5	COMMD6	Q7Z4G1	650
COMMD5	COMMD8	Q9NX08	635
COMMD5	COMMD4	Q9H0A8	627
COMMD5	CCDC93	Q567U6	566
COMMD5	PYCR3	Q53H96	559
COMMD5	COMMD3	Q9UBI1	538
COMMD5	ZNF517	Q6ZMY9	530
COMMD5	MOCS2	O96007	528

IntAct

87 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
COMMD9	CCDC22	psi-mi:“MI:0914”(association)	0.940
COMMD10	CCDC22	psi-mi:“MI:0914”(association)	0.940
COMMD5	CCDC22	psi-mi:“MI:0915”(physical association)	0.930
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
COMMD5	COMMD10	psi-mi:“MI:0915”(physical association)	0.870
ODAD1	HGS	psi-mi:“MI:0914”(association)	0.850
COMMD1	COMMD5	psi-mi:“MI:0915”(physical association)	0.830
COMMD5	CCDC93	psi-mi:“MI:0915”(physical association)	0.800
CCDC22	VPS26C	psi-mi:“MI:0914”(association)	0.790
VPS26C	CCDC22	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
VPS35L	VPS26C	psi-mi:“MI:0914”(association)	0.730

BioGRID (85): COMMD5 (Affinity Capture-MS), COMMD5 (Affinity Capture-MS), COMMD1 (Co-fractionation), COMMD5 (Co-fractionation), COMMD5 (Co-fractionation), COMMD5 (Co-fractionation), COMMD5 (Co-fractionation), COMMD5 (Affinity Capture-MS), COMMD5 (Affinity Capture-MS), COMMD5 (Affinity Capture-MS), COMMD5 (Affinity Capture-MS), COMMD5 (Affinity Capture-MS), COMMD5 (Affinity Capture-MS), COMMD5 (Affinity Capture-MS), COMMD5 (Affinity Capture-MS)

ESM2 similar proteins: A0JN53, A5PK26, O43299, O75064, O94812, O95248, O95382, P0DX19, Q15027, Q15628, Q17RN3, Q1M161, Q2KI74, Q2VPK5, Q3SYU1, Q3T1I9, Q3U0V2, Q3V3V9, Q5E9K1, Q6IUP3, Q6P5E6, Q6P9Q4, Q6ZNJ1, Q6ZQA0, Q7YS91, Q80TE0, Q80TT2, Q80UW5, Q8BG94, Q8C3S2, Q8K2Z4, Q8NAA4, Q8R395, Q8R5F8, Q8TE68, Q924T7, Q96EP0, Q96FC9, Q96KV7, Q9BWH6

Diamond homologs: Q5E9K1, Q86IW8, Q8R395, Q9ERR2, Q9GZQ3

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
COMMD5	“up-regulates activity”	RHOA
RAB5A	“up-regulates activity”	COMMD5	binding
COMMD5	“up-regulates quantity”	EGFR	relocalization
COMMD5	up-regulates	Actin_cytoskeleton_reorganization

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 40 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	10	17.6×	2e-08

GO biological processes:

GO term	Partners	Fold	FDR
endocytic recycling	6	44.6×	8e-07

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	123
Likely benign	7
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

814 predictions. Top by Δscore:

Variant	Effect	Δscore
8:144841349:TTTCA:T	acceptor_loss	0.9900
8:144841350:TTCAG:T	acceptor_loss	0.9900
8:144841352:CA:C	acceptor_loss	0.9900
8:144841353:A:AC	acceptor_loss	0.9900
8:144841353:A:AG	acceptor_gain	0.9900
8:144841354:G:GG	acceptor_gain	0.9900
8:144841354:G:GT	acceptor_loss	0.9900
8:144852635:C:A	donor_gain	0.9900
8:144851393:TGCC:T	acceptor_loss	0.9800
8:144851396:C:CA	acceptor_loss	0.9800
8:144851396:C:CC	acceptor_gain	0.9800
8:144851397:T:G	acceptor_loss	0.9800
8:144852634:T:TA	donor_gain	0.9700
8:144851393:TGC:T	acceptor_gain	0.9600
8:144851401:G:GC	acceptor_gain	0.9600
8:144852954:TC:T	donor_gain	0.9600
8:144852955:CC:C	donor_gain	0.9600
8:144851391:GATGC:G	acceptor_gain	0.9500
8:144851394:GC:G	acceptor_gain	0.9500
8:144851395:CC:C	acceptor_gain	0.9500
8:144852600:CTCCT:C	donor_gain	0.9500
8:144852601:TCCTT:T	donor_gain	0.9500
8:144852602:CCTTC:C	donor_gain	0.9500
8:144852605:TC:T	donor_gain	0.9400
8:144852679:T:TA	donor_gain	0.9400
8:144851392:ATGC:A	acceptor_gain	0.9300
8:144851401:G:C	acceptor_gain	0.9300
8:144852586:C:CT	donor_gain	0.9300
8:144852837:A:AC	donor_gain	0.9300
8:144852838:C:CC	donor_gain	0.9300

AlphaMissense

1440 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:144850870:A:G	W157R	0.991
8:144850870:A:T	W157R	0.991
8:144850812:A:T	V176D	0.979
8:144850851:A:T	I163N	0.973
8:144850749:A:G	F197S	0.972
8:144850740:A:G	L200P	0.971
8:144850866:C:G	R158P	0.970
8:144850851:A:G	I163T	0.969
8:144850868:C:A	W157C	0.962
8:144850868:C:G	W157C	0.962
8:144850851:A:C	I163S	0.961
8:144850748:G:C	F197L	0.960
8:144850748:G:T	F197L	0.960
8:144850750:A:G	F197L	0.960
8:144850869:C:G	W157S	0.953
8:144850764:A:T	V192D	0.942
8:144850725:G:T	A205D	0.932
8:144850740:A:C	L200R	0.931
8:144850737:C:G	R201P	0.927
8:144850716:A:G	L208P	0.924
8:144850800:A:G	L180P	0.923
8:144850946:A:C	F131L	0.920
8:144850946:A:T	F131L	0.920
8:144850948:A:G	F131L	0.920
8:144850806:A:T	M178K	0.919
8:144850857:A:T	V161E	0.917
8:144850749:A:C	F197C	0.916
8:144851076:C:T	G88D	0.912
8:144850806:A:C	M178R	0.908
8:144850726:C:G	A205P	0.904

dbSNP variants (sampled 300 via entrez): RS1000025187 (8:144839454 G>A), RS1000078481 (8:144839663 G>A), RS1000119752 (8:144838619 G>C), RS1000338509 (8:144844275 C>A,T), RS1000767357 (8:144847567 T>C), RS1000783426 (8:144850697 C>T), RS1000798496 (8:144847244 T>C), RS1001010064 (8:144838464 C>G,T), RS1001017319 (8:144841909 C>T), RS1001316431 (8:144851955 T>C), RS1001338858 (8:144846692 GGGA>G), RS1001449274 (8:144849954 C>T), RS1001512186 (8:144842106 C>T), RS1001612858 (8:144845038 T>G), RS1001668068 (8:144838297 C>T)

Disease associations

OMIM: gene MIM:608216 | 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
GCST006879_12	Blood metabolite levels	4.000000e-10
GCST006879_13	Blood metabolite levels	2.000000e-09
GCST006879_14	Blood metabolite levels	2.000000e-11
GCST006879_5	Blood metabolite levels	2.000000e-12
GCST007005_3	Logical memory (immediate recall) in normal cognition	5.000000e-07
GCST007005_4	Logical memory (immediate recall) in normal cognition	2.000000e-07

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004874	memory performance

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

18 total (human), top 18 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
triphenyl phosphate	affects expression	1
bisphenol A	decreases methylation	1
sodium arsenite	increases expression	1
cupric chloride	decreases expression	1
abrine	increases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	decreases expression, decreases reaction	1
Rosiglitazone	increases expression	1
Vehicle Emissions	decreases expression, decreases reaction	1
Doxorubicin	decreases expression	1
Smoke	decreases expression	1
Thiram	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Tunicamycin	increases expression	1
Valproic Acid	increases expression	1
Aflatoxin B1	increases methylation	1
Cadmium Chloride	increases expression, increases methylation	1
Particulate Matter	decreases expression, decreases reaction	1
Magnetite Nanoparticles	increases expression	1

Clinical trials (associated diseases)

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