CMTM5

Summary

CMTM5 (CKLF like MARVEL transmembrane domain containing 5, HGNC:19176) is a protein-coding gene on chromosome 14q11.2, encoding CKLF-like MARVEL transmembrane domain-containing protein 5 (Q96DZ9).

This gene encodes a member of the chemokine-like factor superfamily. This family of genes encodes multi-pass membrane proteins that are similar to both the chemokine and the transmembrane 4 superfamilies of signaling molecules. The encoded protein may exhibit tumor suppressor activity. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 116173 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 49 total — 1 pathogenic
• MANE Select transcript: NM_001288746

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19176
Approved symbol	CMTM5
Name	CKLF like MARVEL transmembrane domain containing 5
Location	14q11.2
Locus type	gene with protein product
Status	Approved
Aliases	FLJ37521
Ensembl gene	ENSG00000166091
Ensembl biotype	protein_coding
OMIM	607888
Entrez	116173

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 13 protein_coding, 2 retained_intron

ENST00000339180, ENST00000342473, ENST00000359320, ENST00000382809, ENST00000397227, ENST00000553750, ENST00000555487, ENST00000555731, ENST00000649278, ENST00000882118, ENST00000882119, ENST00000882120, ENST00000882121, ENST00000882122, ENST00000928856

RefSeq mRNA: 5 — MANE Select: NM_001288746 NM_001037288, NM_001288744, NM_001288745, NM_001288746, NM_138460

CCDS: CCDS32050, CCDS73617, CCDS73618, CCDS73619, CCDS9598

Canonical transcript exons

ENST00000339180 — 6 exons

Exon	Start	End
ENSE00001099695	23378349	23378501
ENSE00001373873	23378669	23378869
ENSE00001821778	23377046	23377377
ENSE00003492422	23379031	23379123
ENSE00003587174	23379474	23379772
ENSE00003589947	23379299	23379383

Expression profiles

Bgee: expression breadth ubiquitous, 181 present calls, max score 98.99.

FANTOM5 (CAGE): breadth broad, TPM avg 3.8683 / max 434.1932, expressed in 293 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
138902	2.7952	286
138906	0.2718	72
138904	0.2604	72
138903	0.1378	63
138899	0.1237	51
138901	0.0714	25
138905	0.0642	39
138907	0.0613	38
207157	0.0414	30
138900	0.0409	27

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
C1 segment of cervical spinal cord	UBERON:0006469	98.99	gold quality
spinal cord	UBERON:0002240	98.77	gold quality
inferior vagus X ganglion	UBERON:0005363	98.29	gold quality
pons	UBERON:0000988	96.31	gold quality
substantia nigra	UBERON:0002038	96.04	gold quality
midbrain	UBERON:0001891	95.83	gold quality
subthalamic nucleus	UBERON:0001906	95.70	gold quality
right atrium auricular region	UBERON:0006631	94.92	gold quality
medulla oblongata	UBERON:0001896	94.85	gold quality
monocyte	CL:0000576	94.68	gold quality
substantia nigra pars reticulata	UBERON:0001966	94.63	gold quality
putamen	UBERON:0001874	94.11	gold quality
tibial nerve	UBERON:0001323	94.06	gold quality
corpus callosum	UBERON:0002336	93.83	gold quality
lateral globus pallidus	UBERON:0002476	93.83	gold quality
leukocyte	CL:0000738	93.79	gold quality
amygdala	UBERON:0001876	93.74	gold quality
ventral tegmental area	UBERON:0002691	93.43	gold quality
dorsal plus ventral thalamus	UBERON:0001897	93.16	gold quality
superior vestibular nucleus	UBERON:0007227	93.02	gold quality
hypothalamus	UBERON:0001898	92.78	gold quality
caudate nucleus	UBERON:0001873	92.29	gold quality
Ammon’s horn	UBERON:0001954	92.20	gold quality
cardiac atrium	UBERON:0002081	92.20	gold quality
nucleus accumbens	UBERON:0001882	91.51	gold quality
Brodmann (1909) area 9	UBERON:0013540	91.50	gold quality
prefrontal cortex	UBERON:0000451	91.10	gold quality
substantia nigra pars compacta	UBERON:0001965	90.46	gold quality
trigeminal ganglion	UBERON:0001675	90.09	gold quality
anterior cingulate cortex	UBERON:0009835	89.96	gold quality

Single-cell (SCXA)

Detected in 10 experiment(s), a significant marker in 10.

Experiment	Marker?	Max mean expression
E-MTAB-6701	yes	1934.52
E-HCAD-8	yes	948.59
E-HCAD-4	yes	48.08
E-CURD-112	yes	35.39
E-CURD-122	yes	25.06
E-MTAB-9221	yes	24.89
E-HCAD-10	yes	17.90
E-MTAB-9067	yes	10.77
E-HCAD-1	yes	7.98
E-ANND-3	yes	5.34

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

14 targeting CMTM5, 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-450A-1-3P	100.00	69.33	1837
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-3913-5P	99.78	67.26	968
HSA-MIR-6887-3P	99.66	67.83	1778
HSA-MIR-6716-5P	99.56	68.62	1244
HSA-MIR-3122	99.50	66.33	821
HSA-MIR-6513-5P	99.43	67.81	1071
HSA-MIR-4505	99.27	67.81	2678
HSA-MIR-5787	99.22	67.86	2628
HSA-MIR-6814-5P	99.03	66.68	1273
HSA-MIR-887-5P	98.82	65.90	1347
HSA-MIR-6846-5P	98.81	65.86	1121
HSA-MIR-6848-5P	98.81	65.49	1126
HSA-MIR-6852-3P	98.54	67.60	1468

Literature-anchored findings (GeneRIF, showing 19)

• Bioinformatics based on CKLF2 cDNA and protein sequences in combination with experimental validation identified CKLFSF1-8 gene clusters, between the SCY and the TM4SF gene families. The 8 family members were cloned and characterized. (PMID:12782130)
• CMTM5 exhibits tumor suppressor activities, but with frequent epigenetic inactivation in carcinoma cell lines (PMID:17908965)
• These findings verify that CMTM5-v1 inhibits the growth of CC cell lines via inducing apoptosis. (PMID:19124004)
• CMTM5 may play a role in the pancreatic cancer. (PMID:19577543)
• CMTM5-v1 might be secreted via a different vesicle-mediated secretory pathway, which will be helpful for the studies of vesicle-mediated secretion and MARVEL domain-containing proteins. (PMID:20356458)
• The expression level of cmtm5 gene is abnormally lower in the bone marrow cells from the multiple myeloma patients, and are associated with ISS stages. (PMID:20416169)
• HER2 was up regulated in prostate cancer epithelium while CMTM5 was down regulated. Overexpression of CMTM5 in PC3 cells could lower the HER2 and Cyclin D1 protein level. (PMID:20721248)
• Data suggest that CMTM5 may be involved in the pathomechanism of myeloid leukemias. (PMID:21168207)
• The reduced expression of CMTM5 correlates significantly with poorly differentiated ovarian cancer and high preoperative CA125 level. (PMID:21841490)
• In the OSCC cell lines CAL27 and GNM, the ectopic expression of CMTM5-v1 strongly inhibited cell proliferation and migration and induced apoptosis. (PMID:24721428)
• results indicate that CMTM5 is down-regulated in prostate cancer and exhibit tumor suppressor activities in androgen-independent prostate cancer cells (PMID:25387568)
• Overexpression of CMTM5 attenuated vascular endothelial cells migration and proliferation. (PMID:28457985)
• CMTM5 was down-regulated in the hepatocellular carcinoma tissues.Up-regulation of miR-10b-3p promoted the progression of the hepatocellular carcinoma cells via targeting CMTM5. (PMID:29691981)
• Re-expression of CMTM5 inhibits the proliferative activity of U266 (PMID:30704230)
• CMTM5/7 are biomarkers and prognostic factors in human breast carcinoma. (PMID:32568178)
• [Association of CMTM5 gene expression with the risk of in-stent restenosis in patients with coronary artery disease after drug-eluting stent implantation and the effects and mechanisms of CMTM5 on human vascular endothelial cells]. (PMID:33047719)
• [Association between CMTM5 gene and coronary artery disease and the relative mechanism]. (PMID:33331317)
• CMTM5 inhibits the development of prostate cancer via the EGFR/PI3K/AKT signaling pathway. (PMID:34791506)
• CMTM5 influences Hippo/YAP axis to promote ferroptosis in glioma through regulating WWP2-mediated LATS2 ubiquitination. (PMID:39166861)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
mus_musculus	Cmtm5	ENSMUSG00000040759
rattus_norvegicus	Cmtm5	ENSRNOG00000016828
caenorhabditis_elegans	F28H1.4	WBGENE00017909
caenorhabditis_elegans	F47B3.3	WBGENE00018527

Paralogs (14): CMTM1 (ENSG00000089505), CMTM6 (ENSG00000091317), PLP2 (ENSG00000102007), PLLP (ENSG00000102934), CMTM3 (ENSG00000140931), CMTM2 (ENSG00000140932), MALL (ENSG00000144063), MAL2 (ENSG00000147676), CMTM7 (ENSG00000153551), MARVELD1 (ENSG00000155254), CMTM8 (ENSG00000170293), MAL (ENSG00000172005), CMTM4 (ENSG00000183723), CKLF (ENSG00000217555)

Protein

Protein identifiers

CKLF-like MARVEL transmembrane domain-containing protein 5 — Q96DZ9 (reviewed: Q96DZ9)

Alternative names: Chemokine-like factor superfamily member 5

All UniProt accessions (2): C9JAI6, Q96DZ9

UniProt curated annotations — full annotation on UniProt →

Subcellular location. Membrane.

Tissue specificity. Highly expressed in the brain.

Similarity. Belongs to the chemokine-like factor family.

Isoforms (6)

UniProt ID	Names	Canonical?
Q96DZ9-1	1	yes
Q96DZ9-2	2
Q96DZ9-3	3
Q96DZ9-4	4
Q96DZ9-5	5
Q96DZ9-6	6

RefSeq proteins (5): NP_001032365, NP_001275673, NP_001275674, NP_001275675, NP_612469 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008253	Marvel	Domain
IPR050578	MARVEL-CKLF_proteins	Family

Pfam: PF01284

UniProt features (12 total): splice variant 5, transmembrane region 4, chain 1, sequence conflict 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96DZ9-F1	59.83	0.00

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 74 (showing top): CAGCTG_AP4_Q5, GOBP_TAXIS, GOBP_REGULATION_OF_MYOBLAST_DIFFERENTIATION, GOBP_MUSCLE_STRUCTURE_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_MYOBLAST_DIFFERENTIATION, GOBP_MYOBLAST_DIFFERENTIATION, GOMF_CYTOKINE_ACTIVITY, GOBP_NEGATIVE_REGULATION_OF_DEVELOPMENTAL_PROCESS, GOMF_SIGNALING_RECEPTOR_BINDING, WANG_TUMOR_INVASIVENESS_UP, GOMF_SIGNALING_RECEPTOR_REGULATOR_ACTIVITY, WAGSCHAL_EHMT2_TARGETS_UP, BRUINS_UVC_RESPONSE_VIA_TP53_GROUP_A, ZWANG_TRANSIENTLY_UP_BY_2ND_EGF_PULSE_ONLY, HECKER_IFNB1_TARGETS

GO Biological Process (3): chemotaxis (GO:0006935), negative regulation of myoblast differentiation (GO:0045662), signal transduction (GO:0007165)

GO Molecular Function (2): cytokine activity (GO:0005125), protein binding (GO:0005515)

GO Cellular Component (2): obsolete extracellular space (GO:0005615), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
response to chemical	1
taxis	1
myoblast differentiation	1
negative regulation of cell differentiation	1
regulation of myoblast differentiation	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
receptor ligand activity	1
binding	1
cellular anatomical structure	1

Protein interactions and networks

STRING

954 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CMTM5	CKLF	Q9UBR5	945
CMTM5	CMTM1	Q8IZ96	849
CMTM5	CMTM2	Q8TAZ6	841
CMTM5	CMTM4	Q8IZR5	822
CMTM5	CMTM7	Q96FZ5	771
CMTM5	CMTM8	Q8IZV2	749
CMTM5	CMTM6	Q9NX76	736
CMTM5	CCDC120	Q96HB5	555
CMTM5	TRIM39	Q9HCM9	461
CMTM5	TSPAN1	O60635	445
CMTM5	PLLP	Q9Y342	442
CMTM5	SLC39A2	Q9NP94	403
CMTM5	C11orf86	A6NJI1	372
CMTM5	TOR1AIP1	Q5JTV8	343
CMTM5	DRP2	Q13474	339

IntAct

162 interactions, top by confidence:

A	B	Type	Score
CMTM5	ACSF2	psi-mi:“MI:0915”(physical association)	0.740
ACSF2	CMTM5	psi-mi:“MI:0915”(physical association)	0.740
CMTM5	SHMT2	psi-mi:“MI:0915”(physical association)	0.670
CMTM5	PTPN9	psi-mi:“MI:0915”(physical association)	0.670
CMTM5	MYG1	psi-mi:“MI:0915”(physical association)	0.670
CMTM5	MCEE	psi-mi:“MI:0915”(physical association)	0.670
CMTM5	GAD1	psi-mi:“MI:0915”(physical association)	0.670
CMTM5	GLTP	psi-mi:“MI:0915”(physical association)	0.670
MYG1	CMTM5	psi-mi:“MI:0915”(physical association)	0.670
MCEE	CMTM5	psi-mi:“MI:0915”(physical association)	0.670
GLTP	CMTM5	psi-mi:“MI:0915”(physical association)	0.670
SHMT2	CMTM5	psi-mi:“MI:0915”(physical association)	0.670
CMTM5	SUCLA2	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (290): CMTM5 (Two-hybrid), CMTM5 (Two-hybrid), CMTM5 (Two-hybrid), CMTM5 (Two-hybrid), CMTM5 (Two-hybrid), CMTM5 (Two-hybrid), CMTM5 (Two-hybrid), CMTM5 (Two-hybrid), CMTM5 (Two-hybrid), CMTM5 (Two-hybrid), CMTM5 (Two-hybrid), CMTM5 (Two-hybrid), CMTM5 (Two-hybrid), CMTM5 (Two-hybrid), CMTM5 (Two-hybrid)

ESM2 similar proteins: A2VE13, A4K2N5, A4K2W1, B8BPI2, E1BY51, O09117, O09198, O35682, O62646, O88662, O89104, P21145, Q04941, Q10EJ2, Q16563, Q1RMQ3, Q28296, Q3URJ8, Q3ZBY0, Q5R6H1, Q5RAI2, Q5VXT5, Q64349, Q6DHB5, Q6GPN9, Q6P0C6, Q6P742, Q6VBQ5, Q6Y1E2, Q78S06, Q86TG1, Q86UW1, Q8BI08, Q8CJ61, Q8IZ96, Q8IZR5, Q8N2H4, Q8N8D7, Q91WN2, Q95MN6

Diamond homologs: Q04941, Q28597, Q6P742, Q6Y1E2, Q95MN6, Q96DZ9, Q99LJ5, Q9D6G9, Q9R1Q7, Q96MX0

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	40
Likely benign	3
Benign	2

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
2684714	GRCh37/hg19 14q11.2-23.1(chr14:20511673-61826023)x3	Pathogenic

SpliceAI

754 predictions. Top by Δscore:

Variant	Effect	Δscore
14:23378379:AC:A	acceptor_gain	1.0000
14:23378380:C:CA	acceptor_gain	1.0000
14:23378381:G:A	acceptor_gain	1.0000
14:23378497:GTCTG:G	donor_gain	1.0000
14:23378502:G:C	donor_loss	1.0000
14:23378502:G:GG	donor_gain	1.0000
14:23378503:T:A	donor_loss	1.0000
14:23379124:G:GG	donor_gain	1.0000
14:23379289:A:AG	acceptor_gain	1.0000
14:23379294:CACAG:C	acceptor_loss	1.0000
14:23379295:ACAGG:A	acceptor_loss	1.0000
14:23379296:CAGGT:C	acceptor_loss	1.0000
14:23379297:AGGT:A	acceptor_loss	1.0000
14:23377374:GCTG:G	donor_gain	0.9900
14:23378325:T:G	acceptor_gain	0.9900
14:23378331:ACAT:A	acceptor_gain	0.9900
14:23378332:C:G	acceptor_gain	0.9900
14:23378333:AT:A	acceptor_gain	0.9900
14:23378334:T:G	acceptor_gain	0.9900
14:23378338:C:A	acceptor_gain	0.9900
14:23378343:CTGCA:C	acceptor_loss	0.9900
14:23378344:TGCA:T	acceptor_loss	0.9900
14:23378345:GCAGG:G	acceptor_loss	0.9900
14:23378346:CA:C	acceptor_loss	0.9900
14:23378347:A:T	acceptor_loss	0.9900
14:23378348:G:A	acceptor_loss	0.9900
14:23378373:T:TA	acceptor_gain	0.9900
14:23378379:A:AG	acceptor_gain	0.9900
14:23378379:ACG:A	acceptor_gain	0.9900
14:23378380:C:G	acceptor_gain	0.9900

AlphaMissense

1439 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:23379049:A:C	S167R	0.998
14:23379051:T:A	S167R	0.998
14:23379051:T:G	S167R	0.998
14:23378373:T:C	C51R	0.997
14:23379305:G:C	G194R	0.996
14:23379074:T:A	V175D	0.994
14:23379086:C:A	A179D	0.994
14:23379116:C:A	A189D	0.994
14:23377376:T:C	L42P	0.993
14:23379119:C:A	A190D	0.993
14:23379306:G:A	G194D	0.993
14:23379336:A:T	D204V	0.993
14:23378376:T:C	F52L	0.992
14:23378377:T:C	F52S	0.992
14:23378378:C:A	F52L	0.992
14:23378378:C:G	F52L	0.992
14:23379336:A:C	D204A	0.992
14:23377336:T:C	F29L	0.991
14:23377338:C:A	F29L	0.991
14:23377338:C:G	F29L	0.991
14:23378353:T:C	L44P	0.991
14:23379121:T:C	F191L	0.991
14:23379123:T:A	F191L	0.991
14:23379123:T:G	F191L	0.991
14:23379300:T:A	V192D	0.991
14:23379302:T:C	F193L	0.991
14:23379304:T:A	F193L	0.991
14:23379304:T:G	F193L	0.991
14:23379330:C:A	A202D	0.991
14:23377374:G:C	E41D	0.990

dbSNP variants (sampled 300 via entrez): RS1000814044 (14:23379451 C>T), RS1001043779 (14:23377505 C>A,G,T), RS1001356831 (14:23377818 A>C,G,T), RS1001547261 (14:23374989 G>A,T), RS1001601004 (14:23380236 C>T), RS1001712077 (14:23380044 C>G), RS1001714143 (14:23378298 G>A,T), RS1002039817 (14:23379719 A>C,G,T), RS1003792758 (14:23376406 C>T), RS1005798206 (14:23376672 C>G,T), RS1005881617 (14:23379964 G>A), RS1006551609 (14:23377454 C>T), RS1007246736 (14:23377660 G>A), RS1008369428 (14:23377934 T>A), RS1008560924 (14:23380119 C>T)

Disease associations

OMIM: gene MIM:607888 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

19 total (human), top 19 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression	5
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
pentanal	increases expression	1
entinostat	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
clothianidin	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Carbamazepine	affects expression	1
Copper	affects cotreatment, increases expression	1
Diethylhexyl Phthalate	decreases expression	1
Doxorubicin	decreases expression	1
Triclosan	decreases expression	1
Particulate Matter	decreases expression, increases abundance	1

Clinical trials (associated diseases)

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