ATP5MC2

Summary

ATP5MC2 (ATP synthase membrane subunit c locus 2, HGNC:842) is a protein-coding gene on chromosome 12q13.13, encoding ATP synthase F(0) complex subunit C2, mitochondrial (Q06055). Mitochondrial membrane ATP synthase (F(1)F(0) ATP synthase or Complex V) produces ATP from ADP in the presence of a proton gradient across the membrane which is generated by electron transport complexes of the respiratory chain.

This gene encodes a subunit of mitochondrial ATP synthase. Mitochondrial ATP synthase catalyzes ATP synthesis, utilizing an electrochemical gradient of protons across the inner membrane during oxidative phosphorylation. ATP synthase is composed of two linked multi-subunit complexes: the soluble catalytic core, F1, and the membrane-spanning component, Fo, comprising the proton channel. The catalytic portion of mitochondrial ATP synthase consists of 5 different subunits (alpha, beta, gamma, delta, and epsilon) assembled with a stoichiometry of 3 alpha, 3 beta, and single representatives of the gamma, delta, and epsilon subunits. The proton channel likely has nine subunits (a, b, c, d, e, f, g, F6 and 8). There are three separate genes which encode subunit c of the proton channel and they specify precursors with different import sequences but identical mature proteins. The protein encoded by this gene is one of three precursors of subunit c. This gene has multiple pseudogenes.

Source: NCBI Gene 517 — RefSeq curated summary.

At a glance

• GWAS associations: 8
• Clinical variants (ClinVar): 33 total
• MANE Select transcript: NM_005176

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:842
Approved symbol	ATP5MC2
Name	ATP synthase membrane subunit c locus 2
Location	12q13.13
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000135390
Ensembl biotype	protein_coding
OMIM	603193
Entrez	517

Gene structure

Transcript identifiers

Ensembl transcripts: 33 — 30 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000338662, ENST00000394349, ENST00000495596, ENST00000549164, ENST00000549748, ENST00000550241, ENST00000552120, ENST00000552242, ENST00000673498, ENST00000894451, ENST00000894452, ENST00000894453, ENST00000894454, ENST00000894455, ENST00000894456, ENST00000894457, ENST00000894458, ENST00000894459, ENST00000936908, ENST00000936909, ENST00000936910, ENST00000936911, ENST00000936912, ENST00000936913, ENST00000936914, ENST00000936915, ENST00000936916, ENST00000936917, ENST00000947896, ENST00000947897, ENST00000947898, ENST00000947899, ENST00000947900

RefSeq mRNA: 9 — MANE Select: NM_005176 NM_001002031, NM_001330269, NM_001369753, NM_001369754, NM_001369755, NM_001369756, NM_001369757, NM_001369758, NM_005176

CCDS: CCDS31812, CCDS81694

Canonical transcript exons

ENST00000394349 — 5 exons

Exon	Start	End
ENSE00001518174	53676053	53676083
ENSE00001823591	53665170	53665428
ENSE00003468834	53669871	53669948
ENSE00003614399	53669148	53669341
ENSE00003632403	53672576	53672645

Expression profiles

Bgee: expression breadth ubiquitous, 285 present calls, max score 99.65.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 178.5420 / max 747.4011, expressed in 1827 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
131260	173.0525	1827
131259	2.5444	1039
131262	1.0428	418
131265	0.7650	349
131258	0.4643	210
131267	0.2241	87
131264	0.1535	72
131261	0.1173	64
131263	0.1028	54
131266	0.0552	25

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	99.65	gold quality
hindlimb stylopod muscle	UBERON:0004252	99.60	gold quality
gastrocnemius	UBERON:0001388	99.59	gold quality
islet of Langerhans	UBERON:0000006	99.54	gold quality
right uterine tube	UBERON:0001302	99.53	gold quality
muscle layer of sigmoid colon	UBERON:0035805	99.53	gold quality
muscle of leg	UBERON:0001383	99.52	gold quality
adenohypophysis	UBERON:0002196	99.52	gold quality
body of stomach	UBERON:0001161	99.51	gold quality
granulocyte	CL:0000094	99.50	gold quality
embryo	UBERON:0000922	99.50	gold quality
right adrenal gland	UBERON:0001233	99.49	gold quality
left adrenal gland cortex	UBERON:0035825	99.49	gold quality
pituitary gland	UBERON:0000007	99.48	gold quality
body of pancreas	UBERON:0001150	99.48	gold quality
left adrenal gland	UBERON:0001234	99.48	gold quality
heart left ventricle	UBERON:0002084	99.48	gold quality
ganglionic eminence	UBERON:0004023	99.48	gold quality
right adrenal gland cortex	UBERON:0035827	99.48	gold quality
rectum	UBERON:0001052	99.47	gold quality
cardiac ventricle	UBERON:0002082	99.47	gold quality
mucosa of transverse colon	UBERON:0004991	99.47	gold quality
right atrium auricular region	UBERON:0006631	99.47	gold quality
metanephros cortex	UBERON:0010533	99.47	gold quality
transverse colon	UBERON:0001157	99.45	gold quality
adrenal cortex	UBERON:0001235	99.44	gold quality
left ovary	UBERON:0002119	99.44	gold quality
body of tongue	UBERON:0011876	99.44	gold quality
skin of abdomen	UBERON:0001416	99.43	gold quality
skin of leg	UBERON:0001511	99.43	gold quality

Single-cell (SCXA)

Detected in 10 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-MTAB-10042	yes	1890.13
E-MTAB-6819	yes	612.62
E-HCAD-4	yes	191.96
E-CURD-122	yes	15.15
E-HCAD-1	yes	12.01
E-GEOD-135922	yes	8.60
E-MTAB-8205	no	1489.11
E-GEOD-125970	no	1008.14
E-MTAB-6701	no	10.39
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

34 targeting ATP5MC2, 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-6825-5P	99.96	69.81	3431
HSA-MIR-146A-5P	99.96	68.93	988
HSA-MIR-146B-5P	99.96	69.13	977
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-7153-5P	99.94	68.89	1006
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-374C-5P	99.80	72.06	2910
HSA-MIR-655-3P	99.80	72.19	2909
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-30B-3P	99.70	65.76	2325
HSA-MIR-3689A-3P	99.70	65.73	2306
HSA-MIR-3689B-3P	99.70	65.71	2311
HSA-MIR-3689C	99.70	65.71	2311
HSA-MIR-6779-5P	99.70	65.76	2363
HSA-MIR-3175	99.65	66.30	2031
HSA-MIR-6134	99.63	65.68	1537
HSA-MIR-7106-5P	99.53	67.47	3574
HSA-MIR-125A-5P	99.36	70.59	1640
HSA-MIR-125B-5P	99.36	70.36	1662
HSA-MIR-6852-5P	99.17	66.69	2073
HSA-MIR-6799-5P	99.14	65.72	2093
HSA-MIR-661	99.09	65.94	2062
HSA-MIR-2355-5P	98.83	65.51	1589
HSA-MIR-6715B-3P	98.80	68.07	1204
HSA-MIR-16-1-3P	98.70	69.23	1538
HSA-MIR-6751-3P	98.44	66.35	835

Literature-anchored findings (GeneRIF, showing 1)

• ATP5G1, ATP5G2, and ATP5G3 of the ATP synthase are not involved in forming the permeability transition pore. (PMID:28289229)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
mus_musculus	Atp5mc2	ENSMUSG00000062683
rattus_norvegicus	Atp5mc2	ENSRNOG00000015320
rattus_norvegicus	AABR07007730.1	ENSRNOG00000018045
rattus_norvegicus	Atp5mc2l1	ENSRNOG00000032518
rattus_norvegicus		ENSRNOG00000062268
caenorhabditis_elegans		WBGENE00022336

Paralogs (2): ATP5MC3 (ENSG00000154518), ATP5MC1 (ENSG00000159199)

Protein

Protein identifiers

ATP synthase F(0) complex subunit C2, mitochondrial — Q06055 (reviewed: Q06055)

Alternative names: ATP synthase lipid-binding protein, ATP synthase membrane subunit c locus 2, ATP synthase proteolipid P2, ATP synthase proton-transporting mitochondrial F(0) complex subunit C2, ATPase protein 9, ATPase subunit c

All UniProt accessions (2): Q06055, F8W041

UniProt curated annotations — full annotation on UniProt →

Function. Mitochondrial membrane ATP synthase (F(1)F(0) ATP synthase or Complex V) produces ATP from ADP in the presence of a proton gradient across the membrane which is generated by electron transport complexes of the respiratory chain. F-type ATPases consist of two structural domains, F(1) - containing the extramembraneous catalytic core and F(0) - containing the membrane proton channel, linked together by a central stalk and a peripheral stalk. During catalysis, ATP synthesis in the catalytic domain of F(1) is coupled via a rotary mechanism of the central stalk subunits to proton translocation. Part of the complex F(0) domain. A homomeric c-ring of probably 10 subunits is part of the complex rotary element.

Subunit / interactions. F-type ATPases have 2 components, CF(1) - the catalytic core - and CF(0) - the membrane proton channel. CF(1) has five subunits: alpha(3), beta(3), gamma(1), delta(1), epsilon(1). CF(0) has three main subunits: a, b and c. Interacts with DNAJC30; interaction is direct.

Subcellular location. Mitochondrion membrane.

Post-translational modifications. Trimethylated by ATPSCKMT at Lys-109. Methylation is required for proper incorporation of the C subunit into the ATP synthase complex and mitochondrial respiration.

Miscellaneous. There are three genes which encode the mitochondrial ATP synthase proteolipid and they specify precursors with different import sequences but identical mature proteins. Is the major protein stored in the storage bodies of animals or humans affected with ceroid lipofuscinosis (Batten disease).

Similarity. Belongs to the ATPase C chain family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q06055-1	1	yes
Q06055-2	2
Q06055-3	3

RefSeq proteins (9): NP_001002031, NP_001317198, NP_001356682, NP_001356683, NP_001356684, NP_001356685, NP_001356686, NP_001356687, NP_005167* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000454	ATP_synth_F0_csu	Family
IPR002379	ATPase_proteolipid_c-like_dom	Domain
IPR020537	ATP_synth_F0_csu_DDCD_BS	Binding_site
IPR035921	F/V-ATP_Csub_sf	Homologous_superfamily
IPR038662	ATP_synth_F0_csu_sf	Homologous_superfamily

Pfam: PF00137

UniProt features (12 total): sequence conflict 2, transmembrane region 2, splice variant 2, sequence variant 2, transit peptide 1, chain 1, site 1, modified residue 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q06055-F1	71.83	0.50

Functional residue map

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

Catalytic / active sites (1): 124 (reversibly protonated during proton transport)

Post-translational modifications (1): 109

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-163210	Formation of ATP by chemiosmotic coupling
R-HSA-8949613	Cristae formation
R-HSA-1428517	Aerobic respiration and respiratory electron transport
R-HSA-1430728	Metabolism
R-HSA-1592230	Mitochondrial biogenesis
R-HSA-1852241	Organelle biogenesis and maintenance

MSigDB gene sets: 266 (showing top): E2F_Q4_01, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, HSIAO_HOUSEKEEPING_GENES, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, TGACCTY_ERR1_Q2, GOBP_NUCLEOSIDE_PHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, YY1_Q6, REACTOME_FORMATION_OF_ATP_BY_CHEMIOSMOTIC_COUPLING, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, IRF7_01, FREAC3_01, GOBP_ATP_BIOSYNTHETIC_PROCESS

GO Biological Process (3): proton motive force-driven ATP synthesis (GO:0015986), monoatomic ion transport (GO:0006811), proton transmembrane transport (GO:1902600)

GO Molecular Function (3): lipid binding (GO:0008289), proton transmembrane transporter activity (GO:0015078), protein binding (GO:0005515)

GO Cellular Component (6): mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), proton-transporting two-sector ATPase complex, proton-transporting domain (GO:0033177), proton-transporting ATP synthase complex (GO:0045259), membrane (GO:0016020), mitochondrial membrane (GO:0031966)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Aerobic respiration and respiratory electron transport	1
Mitochondrial biogenesis	1
Metabolism	1
Organelle biogenesis and maintenance	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
binding	2
proton-transporting two-sector ATPase complex	2
ATP biosynthetic process	1
transport	1
monoatomic cation transmembrane transport	1
monoatomic cation transmembrane transporter activity	1
proton transmembrane transport	1
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
membrane protein complex	1
cation channel complex	1
respiratory chain complex	1
catalytic complex	1
cellular anatomical structure	1
mitochondrion	1
mitochondrial envelope	1
organelle membrane	1

Protein interactions and networks

STRING

2300 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ATP5MC2	UQCRFS1	P47985	918
ATP5MC2	CLCN3	P51790	772
ATP5MC2	ATP5F1E	P56381	611
ATP5MC2	MAPT	P10636	601
ATP5MC2	ATP5F1C	P36542	585
ATP5MC2	ATP5F1D	P30049	583
ATP5MC2	ATP5PD	O75947	580
ATP5MC2	PPT1	P50897	572
ATP5MC2	ATP5PO	P48047	559
ATP5MC2	ATP5MG	O75964	556
ATP5MC2	ATP5F1A	P25705	549
ATP5MC2	ATP5MF	P56134	538
ATP5MC2	CTSD	P07339	531
ATP5MC2	ATP5ME	P56385	522
ATP5MC2	ATP5PB	P24539	513

IntAct

10 interactions, top by confidence:

A	B	Type	Score
	AGPS	psi-mi:“MI:0915”(physical association)	0.400
	TK2	psi-mi:“MI:0915”(physical association)	0.400
ATP5MC2	CYSLTR2	psi-mi:“MI:0915”(physical association)	0.370
DNAJC30	ATP5MC2	psi-mi:“MI:0915”(physical association)	0.370
TDP2	ATP5MC2	psi-mi:“MI:0915”(physical association)	0.370
ATP13A2	ATP5MC2	psi-mi:“MI:0915”(physical association)	0.370
	ATP5MC2	psi-mi:“MI:0915”(physical association)	0.370
MT-ATP6	ATP5MC2	psi-mi:“MI:0914”(association)	0.350
OR5H1	RBFOX3	psi-mi:“MI:0914”(association)	0.350

BioGRID (6): ATP5G2 (Affinity Capture-MS), ATP5G2 (Two-hybrid), ATP5G2 (Affinity Capture-MS), ATP5G2 (Two-hybrid), TDP2 (Two-hybrid), ATP5G2 (Two-hybrid)

ESM2 similar proteins: A1XQS5, A6H666, A8XDX2, B0VYY5, B3DHU2, G5EDB8, O14046, P00842, P05496, P07926, P10175, P11432, P16000, P16221, P17605, P23968, P32876, P48201, P48772, P56383, P56384, Q01931, Q03672, Q06055, Q06056, Q06645, Q06646, Q0V9J0, Q0VCH8, Q2LCR3, Q2TA24, Q37315, Q3ZC75, Q53CG1, Q59550, Q5RAP9, Q5RFL2, Q5SWH9, Q71S46, Q7JX57

Diamond homologs: A1SHI6, A1XQS5, A3PN84, A4WNY7, A5CDC6, A6H4Q2, A8EX89, A8GLV9, A8GUJ2, A8XDX2, A9HDM8, A9RAH4, A9WGS9, B3CQT8, B8G6H1, B9LBM5, C0HK59, C3PM50, C4K0P2, O05331, O08310, P00840, P00842, P05496, P07926, P0C518, P0C519, P13547, P14571, P15014, P16000, P17254, P17605, P21537, P21905, P26855, P32876, P48201, P48880, P48881

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	22
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

594 predictions. Top by Δscore:

Variant	Effect	Δscore
12:53669875:T:C	donor_gain	1.0000
12:53676047:CCTTA:C	donor_loss	1.0000
12:53676048:CTTAC:C	donor_loss	1.0000
12:53676049:TTAC:T	donor_loss	1.0000
12:53676050:TA:T	donor_loss	1.0000
12:53676052:C:CA	donor_loss	1.0000
12:53669143:CTTA:C	donor_loss	0.9900
12:53669145:T:TA	donor_loss	0.9900
12:53669146:AC:A	donor_loss	0.9900
12:53669147:C:CG	donor_loss	0.9900
12:53669872:T:TA	donor_gain	0.9900
12:53669953:C:CT	acceptor_gain	0.9900
12:53669954:A:T	acceptor_gain	0.9900
12:53669963:A:C	acceptor_gain	0.9900
12:53672646:C:CC	acceptor_gain	0.9900
12:53676052:CCTG:C	donor_gain	0.9900
12:53665428:CCTGG:C	acceptor_gain	0.9800
12:53665429:CTGGT:C	acceptor_loss	0.9800
12:53665430:T:C	acceptor_loss	0.9800
12:53669142:T:C	donor_gain	0.9800
12:53669292:C:CC	acceptor_gain	0.9800
12:53669948:CCTA:C	acceptor_loss	0.9800
12:53669949:C:T	acceptor_loss	0.9800
12:53669950:T:C	acceptor_loss	0.9800
12:53669958:A:AC	acceptor_gain	0.9800
12:53676051:A:AC	donor_gain	0.9800
12:53676052:C:CC	donor_gain	0.9800
12:53665429:C:CC	acceptor_gain	0.9700
12:53669867:GTA:G	donor_loss	0.9700
12:53669868:TACC:T	donor_loss	0.9700

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000033756 (12:53679753 A>G), RS1000135264 (12:53673767 G>C), RS1000402026 (12:53673608 G>A), RS1000514610 (12:53668670 T>C), RS1000818770 (12:53666136 C>G), RS1000912360 (12:53666360 G>A), RS1001038839 (12:53678458 G>T), RS1001071670 (12:53674747 C>T), RS1001260698 (12:53681039 T>G), RS1001540095 (12:53672646 C>G,T), RS1001542629 (12:53669013 C>T), RS1001649186 (12:53675244 A>T), RS1001971638 (12:53679959 A>G), RS1002702031 (12:53665790 G>A), RS1002795690 (12:53666049 T>C)

Disease associations

OMIM: gene MIM:603193 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST000611_9	Height	9.000000e-07
GCST002702_65	Height	7.000000e-18
GCST005956_70	Waist-to-hip ratio adjusted for BMI	4.000000e-13
GCST005958_9	Waist-to-hip ratio adjusted for BMI (age >50)	1.000000e-08
GCST005962_20	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	7.000000e-13
GCST008839_548	Height	5.000000e-22
GCST009391_80	Metabolite levels	2.000000e-06
GCST90000025_969	Appendicular lean mass	5.000000e-13

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0004980	appendicular lean mass

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: transporter — F-type ATPase

CTD chemical–gene interactions

21 total (human), top 21 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, increases methylation	3
sodium arsenite	decreases expression, increases abundance	2
triphenyl phosphate	affects expression	1
arsenite	affects binding, increases reaction	1
CGP 52608	affects binding, increases reaction	1
ICG 001	increases expression	1
MT19c compound	decreases expression	1
Acetaminophen	affects cotreatment, decreases expression	1
Air Pollutants	affects methylation, increases abundance	1
Arsenic	increases abundance, decreases expression	1
Benzo(a)pyrene	increases methylation, decreases methylation	1
Doxorubicin	increases expression	1
Ketoconazole	increases expression	1
Lead	affects expression	1
Lipopolysaccharides	affects cotreatment, decreases expression	1
Tretinoin	decreases expression	1
Aflatoxin B1	increases methylation	1
Sodium Selenite	increases expression	1
Okadaic Acid	decreases expression	1
Copper Sulfate	decreases expression	1
Particulate Matter	increases abundance, affects methylation	1

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2SF	Abcam HEK293T ATP5MC2 KO	Transformed cell line	Female

Clinical trials (associated diseases)

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