CMTM4

Summary

CMTM4 (CKLF like MARVEL transmembrane domain containing 4, HGNC:19175) is a protein-coding gene on chromosome 16q22.1-q22.3, encoding CKLF-like MARVEL transmembrane domain-containing protein 4 (Q8IZR5). Acts as a backup for CMTM6 to regulate plasma membrane expression of PD-L1/CD274, an immune inhibitory ligand critical for immune tolerance to self and antitumor immunity.

This gene belongs to the chemokine-like factor gene superfamily, a novel family that is similar to the chemokine and the transmembrane 4 superfamilies of signaling molecules. This gene is one of several chemokine-like factor genes located in a cluster on chromosome 16. Alternatively spliced transcript variants encoding different isoforms have been identified.

Source: NCBI Gene 146223 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 34 total
• MANE Select transcript: NM_181521

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19175
Approved symbol	CMTM4
Name	CKLF like MARVEL transmembrane domain containing 4
Location	16q22.1-q22.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000183723
Ensembl biotype	protein_coding
OMIM	607887
Entrez	146223

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 4 protein_coding, 1 retained_intron

ENST00000330687, ENST00000394106, ENST00000561680, ENST00000563952, ENST00000581487

RefSeq mRNA: 2 — MANE Select: NM_181521 NM_178818, NM_181521

CCDS: CCDS10817, CCDS42170

Canonical transcript exons

ENST00000394106 — 4 exons

Exon	Start	End
ENSE00001291387	66636405	66636581
ENSE00001310589	66623404	66623502
ENSE00002576005	66614750	66622222
ENSE00003903966	66696340	66696743

Expression profiles

Bgee: expression breadth ubiquitous, 249 present calls, max score 99.30.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 9.5484 / max 122.4143, expressed in 1619 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
157709	8.7566	1586
157710	0.5986	323
157708	0.1589	79
157711	0.0342	13

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	99.30	gold quality
kidney epithelium	UBERON:0004819	98.90	gold quality
corpus epididymis	UBERON:0004359	98.58	gold quality
oocyte	CL:0000023	98.43	gold quality
renal medulla	UBERON:0000362	98.41	gold quality
ileal mucosa	UBERON:0000331	97.99	gold quality
bronchial epithelial cell	CL:0002328	97.91	gold quality
caput epididymis	UBERON:0004358	97.71	gold quality
bronchus	UBERON:0002185	97.67	gold quality
endothelial cell	CL:0000115	97.27	gold quality
nasal cavity epithelium	UBERON:0005384	96.82	gold quality
lateral globus pallidus	UBERON:0002476	96.71	gold quality
medulla oblongata	UBERON:0001896	96.67	gold quality
colonic mucosa	UBERON:0000317	96.64	gold quality
Brodmann (1909) area 23	UBERON:0013554	96.53	gold quality
superior vestibular nucleus	UBERON:0007227	96.52	gold quality
mucosa of paranasal sinus	UBERON:0005030	96.38	gold quality
substantia nigra pars reticulata	UBERON:0001966	96.37	gold quality
mucosa of sigmoid colon	UBERON:0004993	96.37	gold quality
entorhinal cortex	UBERON:0002728	96.32	gold quality
subthalamic nucleus	UBERON:0001906	96.19	gold quality
substantia nigra pars compacta	UBERON:0001965	96.19	gold quality
inferior vagus X ganglion	UBERON:0005363	96.01	gold quality
pylorus	UBERON:0001166	96.00	gold quality
ventral tegmental area	UBERON:0002691	95.90	gold quality
dorsal plus ventral thalamus	UBERON:0001897	95.84	gold quality
parietal lobe	UBERON:0001872	95.79	gold quality
postcentral gyrus	UBERON:0002581	95.64	gold quality
Brodmann (1909) area 46	UBERON:0006483	95.61	gold quality
middle temporal gyrus	UBERON:0002771	95.34	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.01

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

81 targeting CMTM4, 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-4692	100.00	67.32	2066
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-LET-7A-3P	100.00	74.03	3932
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-4650-5P	99.98	64.69	999
HSA-MIR-23B-5P	99.98	66.07	587
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-205-5P	99.81	70.05	1557
HSA-MIR-374C-5P	99.80	72.06	2910
HSA-MIR-655-3P	99.80	72.19	2909
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-1299	99.77	71.24	2389
HSA-MIR-6794-5P	99.76	66.38	1048
HSA-MIR-187-5P	99.74	70.26	1404
HSA-MIR-548AU-3P	99.70	68.22	1373

Literature-anchored findings (GeneRIF, showing 15)

• 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)
• Data show that CMTM4 might be an important gene involved in cell growth and cell cycle regulation. (PMID:20213316)
• CMTM4 is downregulated and exhibits tumour-suppressor activities in clear cell renal cell carcinoma, and could be exploited as a target for clear cell renal cell carcinoma treatment. (PMID:26474560)
• CMTM6 is present at the cell surface, associates with the PD-L1 protein, reduces its ubiquitination and increases PD-L1 protein half-life; CMTM6 enhances the ability of PD-L1-expressing tumour cells to inhibit T cells; collectively, our data reveal that PD-L1 relies on CMTM6/4 to efficiently carry out its inhibitory function, and suggest potential new avenues to block this pathway (PMID:28813410)
• CMTM4 plays an important role in the turnover of membrane-bound VE-cadherin at AJs, mediating endothelial barrier function and controlling vascular sprouting. (PMID:30097810)
• The results suggest that CMTM4 plays a tumor suppressive role in colorectal cancer. (PMID:31435638)
• Pancreatic stellate cells derived exosomal miR-5703 promotes pancreatic cancer by downregulating CMTM4 and activating PI3K/Akt pathway. (PMID:32585413)
• Inhibition of CMTM4 Sensitizes Cholangiocarcinoma and Hepatocellular Carcinoma to T Cell-Mediated Antitumor Immunity Through PD-L1. (PMID:34558800)
• CircCYP24A1 hampered malignant phenotype of renal cancer carcinoma through modulating CMTM-4 expression via sponging miR-421. (PMID:35220395)
• Exosomal miR-224-5p from Colorectal Cancer Cells Promotes Malignant Transformation of Human Normal Colon Epithelial Cells by Promoting Cell Proliferation through Downregulation of CMTM4. (PMID:35814269)
• CMTM6 and CMTM4 as two novel regulators of PD-L1 modulate the tumor microenvironment. (PMID:35958549)
• Analysis of CMTM6 and CMTM4 expression as potential regulators of the PD-L1 protein and its association with prognosis in glioma cancer. (PMID:35983975)
• Prognostic significance and immune characteristics of CMTM4 in hepatocellular carcinoma. (PMID:35986302)
• CMTM4 is a subunit of the IL-17 receptor and mediates autoimmune pathology. (PMID:36271145)
• Prognostic significance of RKIP, TGM2, and CMTM4 expression in oral squamous cell carcinoma. (PMID:38363884)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	cmtm4	ENSDARG00000052020
mus_musculus	Cmtm4	ENSMUSG00000096188
rattus_norvegicus	Cmtm4	ENSRNOG00000011009
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), CMTM5 (ENSG00000166091), CMTM8 (ENSG00000170293), MAL (ENSG00000172005), CKLF (ENSG00000217555)

Protein

Protein identifiers

CKLF-like MARVEL transmembrane domain-containing protein 4 — Q8IZR5 (reviewed: Q8IZR5)

Alternative names: Chemokine-like factor superfamily member 4

All UniProt accessions (2): J3QRP2, Q8IZR5

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a backup for CMTM6 to regulate plasma membrane expression of PD-L1/CD274, an immune inhibitory ligand critical for immune tolerance to self and antitumor immunity. May protect PD-L1/CD274 from being polyubiquitinated and targeted for degradation.

Subunit / interactions. Interacts with PD-L1/CD274 and CMTM6.

Subcellular location. Membrane.

Tissue specificity. Highly expressed in testis and prostate.

Similarity. Belongs to the chemokine-like factor family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q8IZR5-1	1	yes
Q8IZR5-2	2
Q8IZR5-3	3

RefSeq proteins (2): NP_848933, NP_852662* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008253	Marvel	Domain
IPR050578	MARVEL-CKLF_proteins	Family

Pfam: PF01284

UniProt features (12 total): transmembrane region 4, splice variant 2, compositionally biased region 2, chain 1, domain 1, region of interest 1, modified residue 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8IZR5-F1	73.82	0.29

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): 194

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 116 (showing top): chr16q22, TTTGTAG_MIR520D, GTGCCTT_MIR506, NKX25_01, AACTTT_UNKNOWN, HNF1_C, HOXA4_Q2, ZHAN_MULTIPLE_MYELOMA_CD1_DN, DURCHDEWALD_SKIN_CARCINOGENESIS_DN, NUYTTEN_EZH2_TARGETS_DN, CTGAGCC_MIR24, PAX6_01, NUYTTEN_NIPP1_TARGETS_DN, SMAD4_Q6, HSF2_01

GO Biological Process (0):

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

GO Cellular Component (1): membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
binding	1
cellular anatomical structure	1

Protein interactions and networks

STRING

600 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CMTM4	CMTM1	Q8IZ96	968
CMTM4	CMTM3	Q96MX0	966
CMTM4	CKLF	Q9UBR5	963
CMTM4	CMTM2	Q8TAZ6	963
CMTM4	CMTM5	Q96DZ9	822
CMTM4	CD274	Q9NZQ7	655
CMTM4	ZC3H8	Q8N5P1	475
CMTM4	DPY19L3	Q6ZPD9	461
CMTM4	FAM168B	A1KXE4	459
CMTM4	PRPSAP1	Q14558	449
CMTM4	PPP1R3G	B7ZBB8	433
CMTM4	CMTM6	Q9NX76	427
CMTM4	CMTM7	Q96FZ5	427
CMTM4	PCOLCE2	Q9UKZ9	425
CMTM4	NLRP13	Q86W25	425

IntAct

16 interactions, top by confidence:

A	B	Type	Score
LPAR1	TMEM120B	psi-mi:“MI:0914”(association)	0.530
CD274	CMTM4	psi-mi:“MI:0914”(association)	0.500
CD274	CMTM4	psi-mi:“MI:0915”(physical association)	0.500
CMTM4	DAPK1	psi-mi:“MI:0407”(direct interaction)	0.440
CMTM4	APPL1	psi-mi:“MI:0915”(physical association)	0.370
CMTM4	MRPL2	psi-mi:“MI:0915”(physical association)	0.370
CMTM6	CMTM4	psi-mi:“MI:0914”(association)	0.350
CMTM4	CMTM6	psi-mi:“MI:0914”(association)	0.350
C5AR1	TCAF2	psi-mi:“MI:0914”(association)	0.350
VIPR2	RABGAP1L	psi-mi:“MI:0914”(association)	0.350
GCGR	GPR89A	psi-mi:“MI:0914”(association)	0.350
MFSD5	ILVBL	psi-mi:“MI:0914”(association)	0.350
SLC19A3	SNAP23	psi-mi:“MI:0914”(association)	0.350
SLC38A8	ILVBL	psi-mi:“MI:0914”(association)	0.350

BioGRID (41): CMTM4 (Affinity Capture-MS), CMTM4 (Affinity Capture-MS), CMTM4 (Affinity Capture-MS), CMTM4 (Affinity Capture-MS), CMTM4 (Affinity Capture-MS), CMTM4 (Affinity Capture-MS), CMTM4 (Affinity Capture-MS), CMTM4 (Affinity Capture-MS), CMTM4 (Affinity Capture-MS), CMTM4 (Affinity Capture-MS), CMTM4 (Affinity Capture-RNA), CMTM4 (Reconstituted Complex), CMTM4 (Affinity Capture-MS), CMTM4 (Two-hybrid), CMTM4 (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: Q5RFC1, Q8CJ61, Q8IZR5, Q9CZ69, Q9NX76, A6H7B0, Q96FZ5, Q9ESD6, Q9R1Q7

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
CMTM4	“up-regulates quantity by stabilization”	CD274	stabilization

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	25
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1001 predictions. Top by Δscore:

Variant	Effect	Δscore
16:66622218:AATAT:A	acceptor_gain	1.0000
16:66622220:TAT:T	acceptor_gain	1.0000
16:66622221:AT:A	acceptor_gain	1.0000
16:66622223:C:CC	acceptor_gain	1.0000
16:66622223:CT:C	acceptor_loss	1.0000
16:66622224:T:A	acceptor_loss	1.0000
16:66623398:GCTTA:G	donor_loss	1.0000
16:66623399:CTTA:C	donor_loss	1.0000
16:66623400:TTA:T	donor_loss	1.0000
16:66623401:TAC:T	donor_loss	1.0000
16:66623402:A:AC	donor_gain	1.0000
16:66623403:C:CC	donor_gain	1.0000
16:66623403:CCA:C	donor_gain	1.0000
16:66623499:AATC:A	acceptor_gain	1.0000
16:66623501:TC:T	acceptor_gain	1.0000
16:66623502:CC:C	acceptor_gain	1.0000
16:66623502:CCTAA:C	acceptor_loss	1.0000
16:66623503:C:CC	acceptor_gain	1.0000
16:66623504:T:C	acceptor_loss	1.0000
16:66636403:A:AC	donor_gain	1.0000
16:66636404:C:CC	donor_gain	1.0000
16:66636404:CTGT:C	donor_gain	1.0000
16:66636578:AGAT:A	acceptor_gain	1.0000
16:66636579:GAT:G	acceptor_gain	1.0000
16:66636582:C:CA	acceptor_loss	1.0000
16:66636582:C:CC	acceptor_gain	1.0000
16:66696339:CCA:C	donor_gain	1.0000
16:66622219:ATAT:A	acceptor_gain	0.9900
16:66623498:AAATC:A	acceptor_gain	0.9900
16:66623500:ATC:A	acceptor_gain	0.9900

AlphaMissense

1362 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:66636495:G:C	S91R	0.999
16:66636495:G:T	S91R	0.999
16:66636497:T:G	S91R	0.999
16:66636489:A:C	S93R	0.998
16:66636489:A:T	S93R	0.998
16:66636491:T:G	S93R	0.998
16:66622215:C:T	G157D	0.997
16:66636416:A:G	W118R	0.997
16:66636416:A:T	W118R	0.997
16:66636414:C:A	W118C	0.996
16:66636414:C:G	W118C	0.996
16:66636494:A:G	C92R	0.996
16:66636501:A:C	F89L	0.996
16:66636501:A:T	F89L	0.996
16:66636503:A:G	F89L	0.996
16:66622216:C:G	G157R	0.995
16:66636473:C:G	G99R	0.995
16:66623408:G:T	A153D	0.993
16:66636450:A:C	S106R	0.993
16:66636450:A:T	S106R	0.993
16:66636452:T:G	S106R	0.993
16:66636507:A:C	F87L	0.993
16:66636507:A:T	F87L	0.993
16:66636509:A:G	F87L	0.993
16:66696352:C:A	K58N	0.993
16:66696352:C:G	K58N	0.993
16:66636472:C:T	G99D	0.992
16:66636561:G:C	F69L	0.992
16:66636561:G:T	F69L	0.992
16:66636563:A:G	F69L	0.992

dbSNP variants (sampled 300 via entrez): RS1000003366 (16:66681778 T>A), RS1000008426 (16:66662670 C>T), RS1000038398 (16:66669814 G>A), RS1000053829 (16:66672227 GTC>G), RS1000063464 (16:66660832 G>A), RS1000115095 (16:66617915 G>A), RS1000121161 (16:66655374 A>C), RS1000182966 (16:66661696 A>C,G), RS1000200038 (16:66605063 C>A,G,T), RS1000257275 (16:66655712 T>C), RS1000279590 (16:66644701 A>C), RS1000283815 (16:66669541 C>G,T), RS1000284350 (16:66677566 C>T), RS1000394023 (16:66624426 T>C), RS1000397590 (16:66663087 C>G)

Disease associations

OMIM: gene MIM:607887 | 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

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases methylation, increases expression	2
Benzo(a)pyrene	decreases expression, increases methylation, affects methylation	2
Estradiol	increases expression, affects expression	2
Valproic Acid	affects expression, decreases expression	2
Cadmium Chloride	increases abundance, increases expression, decreases expression	2
aristolochic acid I	decreases expression	1
FR900359	decreases phosphorylation	1
sodium arsenate	increases abundance, increases expression	1
di-n-butylphosphoric acid	affects expression	1
ICG 001	increases expression	1
abrine	decreases expression	1
Sunitinib	increases expression	1
Vorinostat	decreases expression	1
Leflunomide	decreases expression	1
Acetaminophen	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	increases abundance, increases expression	1
Cadmium	increases abundance, increases expression	1
Caffeine	decreases phosphorylation	1
Coal	decreases expression, increases abundance	1
Doxorubicin	decreases expression	1
Lead	affects expression	1
Smoke	decreases expression, increases abundance	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	1
1-Methyl-4-phenylpyridinium	increases expression	1
Aflatoxin B1	increases methylation	1
Antirheumatic Agents	increases expression	1

Clinical trials (associated diseases)

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