CMC4

Summary

CMC4 (C-X9-C motif containing 4, HGNC:35428) is a protein-coding gene on chromosome Xq28, encoding Cx9C motif-containing protein 4 (P56277).

This gene was identified by involvement in some t(X;14) translocations associated with mature T-cell proliferations. This region has a complex gene structure, with a common promoter and 5’ exon spliced to two different sets of 3’ exons that encode two different proteins. This gene represents the downstream 8 kDa protein that localizes to mitochondria.

Source: NCBI Gene 100272147 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 38 total — 3 pathogenic
• MANE Select transcript: NM_001018024

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:35428
Approved symbol	CMC4
Name	C-X9-C motif containing 4
Location	Xq28
Locus type	gene with protein product
Status	Approved
Aliases	P8MTCP1, p8
Ensembl gene	ENSG00000182712
Ensembl biotype	protein_coding
OMIM	301088
Entrez	100272147

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000369479, ENST00000369484

RefSeq mRNA: 1 — MANE Select: NM_001018024 NM_001018024

CCDS: CCDS14764

Canonical transcript exons

ENST00000369484 — 3 exons

Exon	Start	End
ENSE00003490058	155063966	155064033
ENSE00003689863	155061622	155061991
ENSE00003849365	155070694	155071136

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 93.51.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 3.5982 / max 32.5109, expressed in 1477 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
201078	17.7624	1796
201080	3.5982	1477
201079	1.9939	1255
201077	0.0873	23

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right atrium auricular region	UBERON:0006631	93.51	gold quality
heart left ventricle	UBERON:0002084	93.37	gold quality
apex of heart	UBERON:0002098	92.30	gold quality
heart	UBERON:0000948	92.29	gold quality
gastrocnemius	UBERON:0001388	90.50	gold quality
muscle of leg	UBERON:0001383	90.44	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	90.34	gold quality
calcaneal tendon	UBERON:0003701	89.25	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	89.14	gold quality
substantia nigra	UBERON:0002038	88.81	gold quality
popliteal artery	UBERON:0002250	88.80	gold quality
tibial artery	UBERON:0007610	88.79	gold quality
amygdala	UBERON:0001876	88.33	gold quality
lower esophagus muscularis layer	UBERON:0035833	88.26	gold quality
lower esophagus	UBERON:0013473	88.23	gold quality
temporal lobe	UBERON:0001871	88.05	gold quality
putamen	UBERON:0001874	87.95	gold quality
hindlimb stylopod muscle	UBERON:0004252	87.89	gold quality
body of pancreas	UBERON:0001150	87.57	gold quality
left coronary artery	UBERON:0001626	87.52	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	87.49	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	87.18	gold quality
nucleus accumbens	UBERON:0001882	87.11	gold quality
descending thoracic aorta	UBERON:0002345	87.06	gold quality
muscle layer of sigmoid colon	UBERON:0035805	87.02	gold quality
right coronary artery	UBERON:0001625	87.00	gold quality
ascending aorta	UBERON:0001496	86.98	gold quality
thoracic aorta	UBERON:0001515	86.96	gold quality
caudate nucleus	UBERON:0001873	86.83	gold quality
hypothalamus	UBERON:0001898	86.71	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-MTAB-6142	no	112.27
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Cmc4	ENSMUSG00000090110
drosophila_melanogaster	CG42381	FBGN0259727

Protein

Protein identifiers

Cx9C motif-containing protein 4 — P56277 (reviewed: P56277)

Alternative names: Mature T-cell proliferation 1 neighbor protein, Mature T-cell proliferation-1 type A, Protein p8 MTCP-1

All UniProt accessions (1): P56277

UniProt curated annotations — full annotation on UniProt →

Subcellular location. Mitochondrion.

Tissue specificity. Expressed in many tissues with a relatively high level in skeletal muscle.

Disease relevance. Overexpressed in T-cell leukemia bearing a t(X;14) translocation.

Domain organisation. The twin Cx9C motifs are involved in the recognition by the mitochondrial disulfide relay system.

Miscellaneous. Shares a non-coding 5’ exon with isoform 2 which is spliced to a different set of 3’ exons encoding an unrelated protein.

Similarity. Belongs to the CMC4 family.

Isoforms (2)

UniProt ID	Names	Canonical?
P56277-1	1, Short, Type A, p8 MTCP1	yes
P56278-1	2, Long, Type B1, p13 MTCP1

RefSeq proteins (1): NP_001018024* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR009069	Cys_alpha_HP_mot_SF	Homologous_superfamily
IPR027179	CMC4	Family

Pfam: PF08991

UniProt features (14 total): helix 5, disulfide bond 3, turn 2, short sequence motif 2, chain 1, domain 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
1EI0	SOLUTION NMR
1HP8	SOLUTION NMR
2HP8	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P56277-F1	86.19	0.53

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Disulfide bonds (3): 7–38, 17–28, 39–50

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-1268020	Mitochondrial protein import

MSigDB gene sets: 68 (showing top): BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, YAO_TEMPORAL_RESPONSE_TO_PROGESTERONE_CLUSTER_1, GROSS_HYPOXIA_VIA_HIF1A_DN, GOCC_MITOCHONDRIAL_ENVELOPE, SPIELMAN_LYMPHOBLAST_EUROPEAN_VS_ASIAN_UP, MARKEY_RB1_ACUTE_LOF_UP, CONCANNON_APOPTOSIS_BY_EPOXOMICIN_DN, GOCC_ORGANELLE_ENVELOPE_LUMEN, GOCC_ORGANELLE_ENVELOPE, chrXq28, ASTON_MAJOR_DEPRESSIVE_DISORDER_UP, BOUDOUKHA_BOUND_BY_IGF2BP2, HOLLEMAN_ASPARAGINASE_RESISTANCE_ALL_DN, REACTOME_PROTEIN_LOCALIZATION, GLI1_TARGET_GENES

GO Biological Process (0):

GO Molecular Function (0):

GO Cellular Component (2): mitochondrion (GO:0005739), mitochondrial intermembrane space (GO:0005758)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Protein localization	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	1
intracellular membrane-bounded organelle	1
mitochondrial envelope	1
organelle envelope lumen	1

Protein interactions and networks

STRING

910 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CMC4	CMC2	Q9NRP2	731
CMC4	COA4	Q9NYJ1	664
CMC4	FUNDC2	Q9BWH2	594
CMC4	VBP1	P61758	479
CMC4	RNF213	Q63HN8	448
CMC4	COA7	Q96BR5	434
CMC4	COA5	Q86WW8	421
CMC4	MTCP1	P56278	410
CMC4	CLIC2	O15247	402
CMC4	FAM47C	Q5HY64	391
CMC4	CMC1	Q7Z7K0	380
CMC4	MC5R	P33032	373
CMC4	CPXCR1	Q8N123	370
CMC4	TLCD2	A6NGC4	370
CMC4	FAM9B	Q8IZU0	369

IntAct

7 interactions, top by confidence:

A	B	Type	Score
CMC4	GFER	psi-mi:“MI:0915”(physical association)	0.400
EWSR1	CMC4	psi-mi:“MI:0915”(physical association)	0.370
ORF69	PEPD	psi-mi:“MI:0914”(association)	0.350
AIFM1	NUDT19	psi-mi:“MI:2364”(proximity)	0.270
SCO1	HAX1	psi-mi:“MI:2364”(proximity)	0.270
SFXN1	HAX1	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (8): CMC4 (Affinity Capture-MS), CMC4 (Proximity Label-MS), CMC4 (Proximity Label-MS), CMC4 (Proximity Label-MS), CMC4 (Proximity Label-MS), CMC4 (Proximity Label-MS), GFER (Affinity Capture-MS), CMC4 (Affinity Capture-MS)

ESM2 similar proteins: A0A096LP55, A0A1D8PJT8, A1L243, A1L3N6, A6H767, A9ULB4, P00126, P00429, P05067, P07919, P08592, P12023, P13805, P14854, P23025, P27088, P28656, P36233, P36378, P48504, P55209, P56277, P79307, P99028, Q0P451, Q0VBY0, Q15545, Q28CA1, Q28EB4, Q2HJG8, Q4R374, Q4R5A5, Q4U0Y4, Q53CG4, Q5IS80, Q5M9I5, Q5R4D4, Q5R7L9, Q5RCT0, Q64267

Diamond homologs: A5DUN2, A6ZMQ6, B3LM82, B5RTE0, C4Y2J3, C4YIM0, C5DT65, C5E268, C5M6H7, C7GRF7, C8ZF59, G2TRJ8, P56277, Q0VBY0, Q3E7A9, Q61908, Q6C4R1

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	0
Uncertain significance	15
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
144123	GRCh38/hg38 Xq28(chrX:154984506-155098444)x1	Pathogenic
189218	GRCh37/hg19 Xq28(chrX:154124111-154564398)	Pathogenic
3235933	GRCh38/hg38 Xq28(chrX:154895862-155336084)	Pathogenic

SpliceAI

971 predictions. Top by Δscore:

Variant	Effect	Δscore
X:155061992:C:CC	acceptor_gain	1.0000
X:155064034:C:CC	acceptor_gain	1.0000
X:155061988:TTGG:T	acceptor_gain	0.9900
X:155061989:TGG:T	acceptor_gain	0.9900
X:155061989:TGGC:T	acceptor_loss	0.9900
X:155061990:GGC:G	acceptor_loss	0.9900
X:155061992:CT:C	acceptor_loss	0.9900
X:155063960:TACTA:T	donor_loss	0.9900
X:155063961:ACTAC:A	donor_loss	0.9900
X:155063963:TA:T	donor_loss	0.9900
X:155063964:AC:A	donor_loss	0.9900
X:155063965:CCT:C	donor_loss	0.9900
X:155063984:T:TA	donor_gain	0.9900
X:155064029:GAAAA:G	acceptor_gain	0.9900
X:155064032:AA:A	acceptor_gain	0.9900
X:155064033:AC:A	acceptor_loss	0.9900
X:155064034:CTAAA:C	acceptor_loss	0.9900
X:155070752:T:TA	donor_gain	0.9900
X:155070947:A:C	donor_gain	0.9900
X:155061990:GG:G	acceptor_gain	0.9800
X:155063965:C:A	donor_gain	0.9800
X:155063966:C:G	donor_loss	0.9800
X:155064031:AAA:A	acceptor_gain	0.9800
X:155064035:T:C	acceptor_loss	0.9800
X:155065636:T:C	donor_gain	0.9800
X:155070692:A:AC	donor_gain	0.9800
X:155070693:C:CC	donor_gain	0.9800
X:155070778:AAG:A	donor_gain	0.9800
X:155070962:A:AC	donor_gain	0.9800
X:155070963:C:CC	donor_gain	0.9800

AlphaMissense

437 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:155063971:A:G	L18S	0.993
X:155061967:C:G	C28S	0.988
X:155061968:A:T	C28S	0.988
X:155064004:C:G	C7S	0.985
X:155064005:A:T	C7S	0.985
X:155063983:A:G	I14T	0.983
X:155063979:C:A	Q15H	0.978
X:155063979:C:G	Q15H	0.978
X:155061968:A:G	C28R	0.976
X:155063974:C:G	C17S	0.976
X:155063975:A:T	C17S	0.976
X:155063975:A:G	C17R	0.974
X:155061901:C:G	C50S	0.973
X:155061902:A:T	C50S	0.973
X:155061937:C:G	C38S	0.972
X:155061938:A:T	C38S	0.972
X:155061902:A:G	C50R	0.971
X:155061934:C:G	C39S	0.971
X:155061935:A:T	C39S	0.971
X:155064005:A:G	C7R	0.969
X:155061946:A:G	L35P	0.965
X:155061966:A:C	C28W	0.964
X:155061901:C:T	C50Y	0.962
X:155063983:A:T	I14K	0.962
X:155064004:C:T	C7Y	0.962
X:155061934:C:T	C39Y	0.961
X:155061967:C:A	C28F	0.961
X:155064003:G:C	C7W	0.958
X:155061938:A:G	C38R	0.956
X:155061900:A:C	C50W	0.954

dbSNP variants (sampled 300 via entrez): RS1000285506 (X:155070923 A>G), RS1002504314 (X:155062154 C>T), RS1003030322 (X:155061518 T>C), RS1003621099 (X:155064347 G>T), RS1003913027 (X:155064867 A>C), RS1004271514 (X:155065139 T>C), RS1005496711 (X:155072163 A>C), RS1005913307 (X:155062719 T>C), RS1005942686 (X:155062171 A>C), RS1008812549 (X:155066925 A>G), RS1008842176 (X:155066257 T>C), RS1009200289 (X:155067052 C>T), RS1009503000 (X:155067638 T>C), RS1010516727 (X:155070832 G>A,T), RS1010880059 (X:155063840 A>G)

Disease associations

OMIM: gene MIM:301088 | disease phenotypes: MIM:300815

GenCC curated gene-disease

Mondo (2): chromosome Xq28 duplication syndrome (MONDO:0010436), megacolon (MONDO:0001273)

Orphanet (1): Proximal Xq28 duplication syndrome (Orphanet:1762)

HPO phenotypes

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

GWAS associations

0 associations (top):

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008531	Megacolon	C06.405.469.158.701
C567580	Chromosome Xq28 Duplication Syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

12 total (human), top 12 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
tris(2-butoxyethyl) phosphate	affects expression	1
monomethylarsonous acid	decreases expression	1
Arsenicals	decreases expression	1
Benzo(a)pyrene	affects methylation	1
Cadmium	increases abundance, increases expression	1
Methyl Methanesulfonate	increases expression	1
Valproic Acid	decreases methylation	1
1-Methyl-4-phenylpyridinium	increases expression	1
Cyclosporine	decreases expression	1
Aflatoxin B1	decreases methylation	1
Cadmium Chloride	increases abundance, increases expression	1
Okadaic Acid	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04340856	Not specified	COMPLETED	Retrospective, Uncontrolled Cohort Study on the Therapy of Chronic Megalon
NCT07470892	Not specified	NOT_YET_RECRUITING	Preoperative Fish Oil PN and Prognosis After Constipation Surgery