TMEM223

Summary

TMEM223 (transmembrane protein 223, HGNC:28464) is a protein-coding gene on chromosome 11q12.3, encoding Transmembrane protein 223 (A0PJW6). Mitochondrial ribosome-associated protein involved in the first steps of cytochrome c oxidase complex (complex IV) biogenesis.

Enables mitochondrial ribosome binding activity. Involved in mitochondrial cytochrome c oxidase assembly. Located in mitochondrion. Is active in mitochondrial inner membrane.

Source: NCBI Gene 79064 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 47 total
• MANE Select transcript: NM_001080501

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28464
Approved symbol	TMEM223
Name	transmembrane protein 223
Location	11q12.3
Locus type	gene with protein product
Status	Approved
Aliases	MGC3196, Mrx15
Ensembl gene	ENSG00000168569
Ensembl biotype	protein_coding
OMIM	620434
Entrez	79064

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 4 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000307366, ENST00000525631, ENST00000527073, ENST00000528367, ENST00000913614

RefSeq mRNA: 1 — MANE Select: NM_001080501 NM_001080501

CCDS: CCDS44628

Canonical transcript exons

ENST00000307366 — 2 exons

Exon	Start	End
ENSE00001141945	62791679	62792006
ENSE00001141951	62789971	62790915

Expression profiles

Bgee: expression breadth ubiquitous, 161 present calls, max score 90.46.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 18.7648 / max 75.8520, expressed in 1773 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
120234	18.7648	1773

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of transverse colon	UBERON:0004991	90.46	gold quality
apex of heart	UBERON:0002098	89.59	gold quality
right adrenal gland	UBERON:0001233	88.73	gold quality
left adrenal gland cortex	UBERON:0035825	88.55	gold quality
granulocyte	CL:0000094	88.48	gold quality
left adrenal gland	UBERON:0001234	88.38	gold quality
right adrenal gland cortex	UBERON:0035827	87.91	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	87.42	gold quality
heart left ventricle	UBERON:0002084	87.12	gold quality
metanephros cortex	UBERON:0010533	86.64	gold quality
body of pancreas	UBERON:0001150	86.28	gold quality
right lobe of liver	UBERON:0001114	86.19	gold quality
right frontal lobe	UBERON:0002810	86.08	gold quality
right atrium auricular region	UBERON:0006631	86.05	gold quality
Brodmann (1909) area 9	UBERON:0013540	85.98	gold quality
transverse colon	UBERON:0001157	85.90	gold quality
body of stomach	UBERON:0001161	85.75	gold quality
cardiac ventricle	UBERON:0002082	85.55	gold quality
anterior cingulate cortex	UBERON:0009835	85.29	gold quality
hindlimb stylopod muscle	UBERON:0004252	85.19	gold quality
adrenal cortex	UBERON:0001235	85.08	gold quality
cardiac atrium	UBERON:0002081	84.90	gold quality
right lobe of thyroid gland	UBERON:0001119	84.80	gold quality
adenohypophysis	UBERON:0002196	84.71	gold quality
adrenal gland	UBERON:0002369	84.64	gold quality
muscle of leg	UBERON:0001383	84.56	gold quality
gastrocnemius	UBERON:0001388	84.49	gold quality
small intestine Peyer’s patch	UBERON:0003454	84.42	gold quality
minor salivary gland	UBERON:0001830	84.39	gold quality
left lobe of thyroid gland	UBERON:0001120	84.12	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.52

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

12 targeting TMEM223, 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-5193	100.00	67.26	1744
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-4328	99.57	71.06	4094
HSA-MIR-569	99.42	66.32	1009
HSA-MIR-4263	99.18	69.25	2236
HSA-MIR-4725-5P	98.67	65.42	628
HSA-MIR-504-5P	98.67	65.40	631
HSA-MIR-432-5P	98.00	68.13	989
HSA-MIR-10398-5P	97.12	64.94	1051
HSA-MIR-4448	97.04	66.22	752
HSA-MIR-1236-5P	96.62	66.38	856

Literature-anchored findings (GeneRIF, showing 1)

• Defining the interactome of the human mitochondrial ribosome identifies SMIM4 and TMEM223 as respiratory chain assembly factors. (PMID:34969438)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	tmem223	ENSDARG00000069494
mus_musculus	Tmem223	ENSMUSG00000117924
rattus_norvegicus	Tmem223	ENSRNOG00000019266
drosophila_melanogaster	CG12935	FBGN0033547

Protein

Protein identifiers

Transmembrane protein 223 — A0PJW6 (reviewed: A0PJW6)

All UniProt accessions (3): A0PJW6, G5EA27, H0YCK4

UniProt curated annotations — full annotation on UniProt →

Function. Mitochondrial ribosome-associated protein involved in the first steps of cytochrome c oxidase complex (complex IV) biogenesis. Stimulates the translation of MT-CO1 mRNA and is a constituent of early MT-CO1 assembly intermediates.

Subunit / interactions. Associates with the mitochondrial ribosome.

Subcellular location. Mitochondrion inner membrane.

Similarity. Belongs to the TMEM223 family.

RefSeq proteins (1): NP_001073970* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR026100	Tmem223	Family
IPR045325	TMEM70/TMEM186/TMEM223	Family

Pfam: PF06979

UniProt features (9 total): topological domain 3, transmembrane region 2, sequence variant 2, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-A0PJW6-F1	73.52	0.11

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9864848	Complex IV assembly

MSigDB gene sets: 117 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_DN, GOBP_RESPIRATORY_CHAIN_COMPLEX_IV_ASSEMBLY, GOBP_MITOCHONDRIAL_RESPIRATORY_CHAIN_COMPLEX_ASSEMBLY, GOBP_CYTOCHROME_COMPLEX_ASSEMBLY, GOCC_MITOCHONDRIAL_ENVELOPE, GOCC_ORGANELLE_INNER_MEMBRANE, GOMF_RIBONUCLEOPROTEIN_COMPLEX_BINDING, GOMF_RIBOSOME_BINDING, GOCC_ORGANELLE_ENVELOPE, BRUINS_UVC_RESPONSE_EARLY_LATE, KATSANOU_ELAVL1_TARGETS_UP, BONOME_OVARIAN_CANCER_SURVIVAL_SUBOPTIMAL_DEBULKING, GOMF_PROTEIN_CONTAINING_COMPLEX_BINDING, ATF6_TARGET_GENES, CHAF1B_TARGET_GENES

GO Biological Process (1): mitochondrial respiratory chain complex IV assembly (GO:0033617)

GO Molecular Function (1): mitochondrial ribosome binding (GO:0097177)

GO Cellular Component (3): mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Respiratory electron transport	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
mitochondrion	1
respiratory chain complex IV assembly	1
mitochondrial respiratory chain complex assembly	1
ribosome binding	1
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
cellular anatomical structure	1

Protein interactions and networks

STRING

494 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TMEM223	TMEM53	Q6P2H8	591
TMEM223	UQCC5	Q8WVI0	577
TMEM223	TMEM101	Q96IK0	562
TMEM223	TMEM147	Q9BVK8	540
TMEM223	TMEM238	C9JI98	525
TMEM223	TMEM154	Q6P9G4	486
TMEM223	PIGS	Q96S52	484
TMEM223	PDZK1IP1	Q13113	457
TMEM223	TMEM38A	Q9H6F2	434
TMEM223	UQCC6	Q69YU5	418
TMEM223	OXA1L	Q15070	391
TMEM223	GATAD1	Q8WUU5	383
TMEM223	TMEM183A	Q8IXX5	370
TMEM223	TMEM151A	Q8N4L1	370
TMEM223	COMMD10	Q9Y6G5	366

IntAct

86 interactions, top by confidence:

A	B	Type	Score
KLHL22	TMEM223	psi-mi:“MI:0914”(association)	0.640
TRDN	TMEM223	psi-mi:“MI:0914”(association)	0.640
MME	TMEM223	psi-mi:“MI:0914”(association)	0.530
KCNA5	TMEM223	psi-mi:“MI:0914”(association)	0.530
SLC7A1	TMEM223	psi-mi:“MI:0914”(association)	0.530
SLC39A5	TMEM223	psi-mi:“MI:0914”(association)	0.530
TOR1AIP2	TMEM223	psi-mi:“MI:0914”(association)	0.530
LPAR1	TMEM223	psi-mi:“MI:0914”(association)	0.530
IPPK	TMEM223	psi-mi:“MI:0914”(association)	0.530
PCDHAC2	TMEM223	psi-mi:“MI:0914”(association)	0.530
TMEM223	TMEM259	psi-mi:“MI:0915”(physical association)	0.400
UPK1A	TMEM223	psi-mi:“MI:0914”(association)	0.350
CHRNA3	TMEM223	psi-mi:“MI:0914”(association)	0.350
ADGRE5	TMEM223	psi-mi:“MI:0914”(association)	0.350
PDCD1	TMEM223	psi-mi:“MI:0914”(association)	0.350
LRRTM1	TMEM223	psi-mi:“MI:0914”(association)	0.350
HTR3C	TMEM223	psi-mi:“MI:0914”(association)	0.350

BioGRID (87): TMEM223 (Affinity Capture-MS), TMEM223 (Affinity Capture-MS), TMEM223 (Affinity Capture-MS), TMEM223 (Affinity Capture-MS), TMEM223 (Affinity Capture-MS), TMEM223 (Affinity Capture-MS), MTHFR (Affinity Capture-MS), TMEM223 (Affinity Capture-MS), TMEM223 (Affinity Capture-MS), CTH (Affinity Capture-MS), TMEM223 (Affinity Capture-MS), C3orf52 (Affinity Capture-MS), TMEM223 (Affinity Capture-MS), TMEM223 (Affinity Capture-MS), HLA-C (Affinity Capture-MS)

ESM2 similar proteins: A0PJW6, A5PJW2, B3DI94, B5DFG1, O00411, O95382, P49753, Q059A4, Q0V9C9, Q3SX05, Q4KLZ1, Q4KM93, Q4R5Q4, Q4VAE3, Q53S58, Q5EA71, Q5T1A1, Q5XIC2, Q643R3, Q66LN0, Q6DC58, Q6NVG1, Q76MJ5, Q7YS91, Q80YU0, Q863F8, Q8BPE4, Q8BWM0, Q8N159, Q8NFF5, Q8VCA6, Q8VD26, Q921N7, Q96AN5, Q96KR6, Q99MQ3, Q9BQ95, Q9BUB7, Q9BYK8, Q9CQE2

Diamond homologs: A0PJW6, A5PJW2, Q6DC58, Q9CQE2

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
Cardiac conduction	5	12.4×	5e-03
Neuronal System	9	9.1×	9e-05
Muscle contraction	5	8.8×	1e-02

GO biological processes:

GO term	Partners	Fold	FDR
regulation of membrane potential	5	19.9×	2e-03
monoatomic ion transmembrane transport	5	17.9×	2e-03
response to endoplasmic reticulum stress	5	14.4×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	44
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2731 predictions. Top by Δscore:

Variant	Effect	Δscore
11:62775769:A:AG	acceptor_gain	1.0000
11:62775770:G:GC	acceptor_gain	1.0000
11:62775770:GCTCC:G	acceptor_gain	1.0000
11:62775898:G:GT	donor_gain	1.0000
11:62775926:CGCAG:C	donor_loss	1.0000
11:62775927:GCAG:G	donor_gain	1.0000
11:62775928:C:T	donor_gain	1.0000
11:62775928:CAGGT:C	donor_loss	1.0000
11:62775932:T:A	donor_loss	1.0000
11:62776378:TCCCA:T	acceptor_loss	1.0000
11:62776379:CCCA:C	acceptor_loss	1.0000
11:62776380:CCAGA:C	acceptor_loss	1.0000
11:62776381:CAGAA:C	acceptor_loss	1.0000
11:62776382:A:AG	acceptor_gain	1.0000
11:62776382:A:AT	acceptor_loss	1.0000
11:62776383:G:GT	acceptor_gain	1.0000
11:62776383:GA:G	acceptor_gain	1.0000
11:62776383:GAA:G	acceptor_gain	1.0000
11:62776383:GAAT:G	acceptor_gain	1.0000
11:62776383:GAATA:G	acceptor_gain	1.0000
11:62776469:AGGTG:A	donor_loss	1.0000
11:62776471:G:GG	donor_gain	1.0000
11:62776472:T:G	donor_loss	1.0000
11:62778105:G:GT	donor_gain	1.0000
11:62778119:GCT:G	donor_gain	1.0000
11:62782823:AAG:A	donor_loss	1.0000
11:62782824:AG:A	donor_loss	1.0000
11:62782825:GGT:G	donor_loss	1.0000
11:62782826:G:T	donor_loss	1.0000
11:62782827:T:G	donor_loss	1.0000

AlphaMissense

1265 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:62790656:A:C	F192L	0.988
11:62790656:A:T	F192L	0.988
11:62790658:A:G	F192L	0.988
11:62790657:A:C	F192C	0.984
11:62791884:A:C	F37L	0.981
11:62791884:A:T	F37L	0.981
11:62791886:A:G	F37L	0.981
11:62790698:G:C	F178L	0.980
11:62790698:G:T	F178L	0.980
11:62790700:A:G	F178L	0.980
11:62790699:A:G	F178S	0.975
11:62790654:T:A	D193V	0.969
11:62790657:A:G	F192S	0.967
11:62791820:A:G	W59R	0.966
11:62791820:A:T	W59R	0.966
11:62790675:A:G	F186S	0.964
11:62790693:A:G	L180S	0.964
11:62790764:G:C	C156W	0.964
11:62790722:T:A	K170N	0.959
11:62790722:T:G	K170N	0.959
11:62791860:G:C	F45L	0.959
11:62791860:G:T	F45L	0.959
11:62791862:A:G	F45L	0.959
11:62790658:A:T	F192I	0.956
11:62791885:A:C	F37C	0.956
11:62790655:C:G	D193H	0.955
11:62790765:C:T	C156Y	0.954
11:62791841:A:G	C52R	0.954
11:62790633:C:G	R200P	0.952
11:62790766:A:G	C156R	0.951

dbSNP variants (sampled 300 via entrez): RS1000009827 (11:62780240 C>T), RS1000011074 (11:62780484 C>A,G,T), RS1000067794 (11:62786746 T>C,G), RS1000081793 (11:62786984 T>C), RS1000374223 (11:62791454 T>G), RS1000506168 (11:62775232 A>G), RS1000571143 (11:62777086 G>A), RS1000579824 (11:62784424 C>T), RS1000632081 (11:62784190 A>G,T), RS1000921235 (11:62777438 A>G), RS1001085217 (11:62787648 G>A,C,T), RS1001205308 (11:62771775 G>A), RS1001272030 (11:62787085 C>T), RS1001360268 (11:62778545 T>G), RS1001400844 (11:62781567 G>A,C)

Disease associations

OMIM: gene MIM:620434 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST005956_2	Waist-to-hip ratio adjusted for BMI	1.000000e-08
GCST005962_51	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	1.000000e-07

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

22 total (human), top 22 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
aristolochic acid I	decreases expression	1
sodium arsenite	decreases expression	1
cobaltous chloride	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
cylindrospermopsin	increases expression	1
abrine	decreases expression	1
jinfukang	increases expression	1
Acetaminophen	decreases expression	1
Dichlorodiphenyl Dichloroethylene	increases expression	1
Ethyl Methanesulfonate	decreases expression	1
Methyl Methanesulfonate	decreases expression	1
Smoke	decreases expression	1
Thiram	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Urethane	decreases expression	1
Vincristine	decreases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	1
Cyclosporine	decreases expression	1
Sodium Selenite	increases expression	1
Cadmium Chloride	decreases expression	1
Copper Sulfate	decreases expression	1
Particulate Matter	decreases expression	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_TS92	HAP1 TMEM223 (-) 1	Cancer cell line	Male
CVCL_TS93	HAP1 TMEM223 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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