DMAC2L

Summary

DMAC2L (distal membrane arm assembly component 2 like, HGNC:18799) is a protein-coding gene on chromosome 14q21.3, encoding ATP synthase subunit s, mitochondrial (Q99766). Involved in regulation of mitochondrial membrane ATP synthase.

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. This gene encodes the subunit s, also known as factor B, of the proton channel. This subunit is necessary for the energy transduction activity of the ATP synthase complexes. Alternatively spliced transcript variants encoding different isoforms have been identified.

Source: NCBI Gene 27109 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 60 total — 1 pathogenic
• MANE Select transcript: NM_001382507

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18799
Approved symbol	DMAC2L
Name	distal membrane arm assembly component 2 like
Location	14q21.3
Locus type	gene with protein product
Status	Approved
Aliases	HSU79253, ATPW
Ensembl gene	ENSG00000125375
Ensembl biotype	protein_coding
OMIM	618579
Entrez	27109

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 16 protein_coding, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000245448, ENST00000311459, ENST00000358473, ENST00000426751, ENST00000553774, ENST00000554204, ENST00000554438, ENST00000554951, ENST00000555939, ENST00000556962, ENST00000557421, ENST00000672419, ENST00000672910, ENST00000904299, ENST00000904300, ENST00000904301, ENST00000929463, ENST00000929464, ENST00000929465

RefSeq mRNA: 7 — MANE Select: NM_001382507 NM_001003803, NM_001003805, NM_001370605, NM_001382507, NM_001382509, NM_001382510, NM_015684

CCDS: CCDS32075, CCDS32076, CCDS45102

Canonical transcript exons

ENST00000557421 — 6 exons

Exon	Start	End
ENSE00002465857	50325609	50327957
ENSE00002469347	50312324	50312389
ENSE00002496144	50314591	50314626
ENSE00003502536	50323945	50324116
ENSE00003603634	50322511	50322719
ENSE00003814712	50321483	50321594

Expression profiles

Bgee: expression breadth ubiquitous, 294 present calls, max score 95.31.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.6762 / max 75.1101, expressed in 1748 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
139489	5.8255	1683
139490	1.8359	1037
139488	0.0148	5

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sperm	CL:0000019	95.31	gold quality
right uterine tube	UBERON:0001302	94.19	gold quality
male germ cell	CL:0000015	93.58	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	93.24	gold quality
biceps brachii	UBERON:0001507	93.18	gold quality
endothelial cell	CL:0000115	92.58	gold quality
triceps brachii	UBERON:0001509	92.56	gold quality
gluteal muscle	UBERON:0002000	91.28	gold quality
oocyte	CL:0000023	91.25	gold quality
diaphragm	UBERON:0001103	90.93	gold quality
adult organism	UBERON:0007023	90.90	gold quality
heart right ventricle	UBERON:0002080	89.88	gold quality
upper leg skin	UBERON:0004262	89.88	gold quality
right testis	UBERON:0004534	89.71	gold quality
penis	UBERON:0000989	89.70	gold quality
left testis	UBERON:0004533	89.67	gold quality
muscle of leg	UBERON:0001383	89.61	gold quality
gastrocnemius	UBERON:0001388	89.58	gold quality
muscle organ	UBERON:0001630	89.40	gold quality
vastus lateralis	UBERON:0001379	89.18	gold quality
endometrium epithelium	UBERON:0004811	88.98	gold quality
oral cavity	UBERON:0000167	88.83	gold quality
testis	UBERON:0000473	88.66	gold quality
monocyte	CL:0000576	88.62	gold quality
skeletal muscle tissue	UBERON:0001134	88.62	gold quality
mononuclear cell	CL:0000842	88.54	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	88.44	gold quality
quadriceps femoris	UBERON:0001377	88.37	gold quality
leukocyte	CL:0000738	88.08	gold quality
skin of hip	UBERON:0001554	87.78	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.60

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MYC

miRNA regulators (miRDB)

13 targeting DMAC2L, 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-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-6768-5P	99.92	67.36	1942
HSA-MIR-1290	99.59	69.90	2079
HSA-MIR-4721	99.26	66.05	818
HSA-MIR-3922-5P	98.77	66.53	1059
HSA-MIR-921	97.09	66.45	562
HSA-MIR-4662A-3P	97.02	67.77	941
HSA-MIR-514A-3P	96.43	67.77	1048
HSA-MIR-514B-3P	96.43	67.77	1048
HSA-MIR-10525-3P	96.32	68.04	699
HSA-MIR-1291	96.28	65.89	1224
HSA-MIR-6775-3P	95.76	65.91	982

Literature-anchored findings (GeneRIF, showing 1)

• The study is the first to show that ATP5S is one of the target genes of miR-34a. (PMID:26385595)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	dmac2l	ENSDARG00000012072
mus_musculus	Dmac2l	ENSMUSG00000054894
rattus_norvegicus	Dmac2l	ENSRNOG00000004893
drosophila_melanogaster	CG10731	FBGN0034081
caenorhabditis_elegans		WBGENE00015460
caenorhabditis_elegans		WBGENE00050937

Protein

Protein identifiers

ATP synthase subunit s, mitochondrial — Q99766 (reviewed: Q99766)

Alternative names: ATP synthase-coupling factor B, Distal membrane arm assembly complex 2-like protein, Mitochondrial ATP synthase regulatory component factor B

All UniProt accessions (5): Q99766, A0A5F9ZGZ2, A0A5K1VW82, A0A8I5KUF2, G3V467

UniProt curated annotations — full annotation on UniProt →

Function. Involved in regulation of mitochondrial membrane ATP synthase. Necessary for H(+) conduction of ATP synthase. Facilitates energy-driven catalysis of ATP synthesis by blocking a proton leak through an alternative proton exit pathway.

Subunit / interactions. Homotetramer. Associates with ATP synthase.

Subcellular location. Mitochondrion. Mitochondrion inner membrane.

Similarity. Belongs to the ATP synthase subunit s family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q99766-1	1	yes
Q99766-2	2
Q99766-3	3

RefSeq proteins (7): NP_001003803, NP_001003805, NP_001357534, NP_001369436, NP_001369438, NP_001369439, NP_056499 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR032675	LRR_dom_sf	Homologous_superfamily

UniProt features (14 total): splice variant 4, repeat 4, binding site 2, transit peptide 1, chain 1, sequence variant 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q99766-F1	91.27	0.85

Functional residue map

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

Ligand- & substrate-binding residues (2): 59; 93

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: 147 (showing top): GRUETZMANN_PANCREATIC_CANCER_DN, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_NUCLEOSIDE_PHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, REACTOME_FORMATION_OF_ATP_BY_CHEMIOSMOTIC_COUPLING, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_MONOATOMIC_CATION_TRANSPORT, PUJANA_CHEK2_PCC_NETWORK, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, BROWNE_HCMV_INFECTION_48HR_DN, GOBP_ATP_BIOSYNTHETIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_BIOSYNTHETIC_PROCESS, GOBP_NUCLEOSIDE_TRIPHOSPHATE_METABOLIC_PROCESS, GOBP_NUCLEOSIDE_TRIPHOSPHATE_BIOSYNTHETIC_PROCESS, BROWNE_HCMV_INFECTION_14HR_DN

GO Biological Process (3): ATP biosynthetic process (GO:0006754), proton transmembrane transport (GO:1902600), monoatomic ion transport (GO:0006811)

GO Molecular Function (3): proton transmembrane transporter activity (GO:0015078), metal ion binding (GO:0046872), protein binding (GO:0005515)

GO Cellular Component (5): cytoplasm (GO:0005737), mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), proton-transporting ATP synthase complex (GO:0045259), membrane (GO:0016020)

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
cellular anatomical structure	2
purine ribonucleotide biosynthetic process	1
purine ribonucleoside triphosphate biosynthetic process	1
ATP metabolic process	1
monoatomic cation transmembrane transport	1
transport	1
monoatomic cation transmembrane transporter activity	1
proton transmembrane transport	1
cation binding	1
binding	1
intracellular anatomical structure	1
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
proton-transporting two-sector ATPase complex	1
cation channel complex	1
respiratory chain complex	1
catalytic complex	1

Protein interactions and networks

STRING

1024 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DMAC2L	ATP5PD	O75947	681
DMAC2L	ATP5PB	P24539	635
DMAC2L	ATP5MC3	P48201	617
DMAC2L	ATP5PO	P48047	587
DMAC2L	ATP5MC1	P05496	524
DMAC2L	ATP5F1C	P36542	509
DMAC2L	ATP5PF	P18859	498
DMAC2L	COX7A2	P14406	491
DMAC2L	ATP5ME	P56385	482
DMAC2L	ATP5F1B	P06576	462
DMAC2L	ATP5MF	P56134	444
DMAC2L	ATP6V1G1	O75348	444
DMAC2L	NDUFAF3	Q9BU61	421
DMAC2L	MRPL34	Q9BQ48	414
DMAC2L	ATP5MG	O75964	413

IntAct

25 interactions, top by confidence:

A	B	Type	Score
ATP5PB	ATP5PD	psi-mi:“MI:0915”(physical association)	0.760
SPINK2	STRN	psi-mi:“MI:0914”(association)	0.530
MFSD4A	HIP1R	psi-mi:“MI:0914”(association)	0.530
THOC2		psi-mi:“MI:0914”(association)	0.350
LLGL2	RBBP6	psi-mi:“MI:0914”(association)	0.350
Tnks	SDC2	psi-mi:“MI:0914”(association)	0.350
ING3	TRRAP	psi-mi:“MI:0914”(association)	0.350
MYO5C	CLIC1	psi-mi:“MI:0914”(association)	0.350
Sesn2	CASTOR2	psi-mi:“MI:0914”(association)	0.350
RNASEH2B	SAP18	psi-mi:“MI:0914”(association)	0.350
KIF2A	EIF3F	psi-mi:“MI:0914”(association)	0.350
KLC3	KLC1	psi-mi:“MI:0914”(association)	0.350
MYH13	C1orf226	psi-mi:“MI:0914”(association)	0.350
PPIA		psi-mi:“MI:0914”(association)	0.350
TRMT2A	ANKHD1	psi-mi:“MI:0914”(association)	0.350
CCL4	PEX14	psi-mi:“MI:0914”(association)	0.350
TRMT2A	ANKRD28	psi-mi:“MI:0914”(association)	0.350
SLC25A16	TOMM70	psi-mi:“MI:0914”(association)	0.350
FECH	POTEF	psi-mi:“MI:0914”(association)	0.350
		psi-mi:“MI:0914”(association)	0.350

BioGRID (28): ATP5S (Affinity Capture-MS), ATP5S (Affinity Capture-MS), ATP5S (Affinity Capture-MS), ATP5S (Affinity Capture-MS), ATP5S (Affinity Capture-MS), ATP5S (Affinity Capture-MS), ATP5S (Affinity Capture-MS), ATP5S (Affinity Capture-MS), ATP5S (Affinity Capture-MS), ATP5S (Affinity Capture-MS), ATP5S (Affinity Capture-MS), ATP5S (Affinity Capture-MS), ATP5S (Affinity Capture-MS), ATP5S (Affinity Capture-MS), ATP5S (Affinity Capture-MS)

ESM2 similar proteins: A1Z6J5, A2BGU9, A2RTX5, A6H639, A8HMZ4, H2KYZ5, O42895, O45228, O60678, O70467, O74421, O74999, O94710, P00480, P22027, P27680, P51556, P84010, Q0P4D1, Q2KHV5, Q4QQT5, Q4R5S4, Q4R7L8, Q4V339, Q5BKM6, Q5R9E6, Q5RAG3, Q5XI79, Q5XIM4, Q6GQ37, Q6J756, Q758X6, Q7L592, Q7Z7L7, Q80ZJ6, Q8BPC6, Q8IUF1, Q8SYD0, Q8VEH6, Q922H1

Diamond homologs: P22027, Q4R5S4, Q5R9E6, Q5XIM4, Q99766, Q9CRA7, Q9NW81

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	36
Likely benign	17
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
1342871	NM_024884.3(L2HGDH):c.1A>G (p.Met1Val)	Pathogenic

SpliceAI

1683 predictions. Top by Δscore:

Variant	Effect	Δscore
14:50321595:G:GG	donor_gain	1.0000
14:50322502:T:A	acceptor_gain	1.0000
14:50322506:A:AG	acceptor_gain	1.0000
14:50322506:AACAG:A	acceptor_gain	1.0000
14:50322507:A:G	acceptor_gain	1.0000
14:50322507:ACAG:A	acceptor_gain	1.0000
14:50322509:A:AG	acceptor_gain	1.0000
14:50322509:AG:A	acceptor_gain	1.0000
14:50322509:AGG:A	acceptor_gain	1.0000
14:50322509:AGGGT:A	acceptor_gain	1.0000
14:50322510:G:A	acceptor_gain	1.0000
14:50322510:G:GG	acceptor_gain	1.0000
14:50322510:GGG:G	acceptor_gain	1.0000
14:50322510:GGGT:G	acceptor_gain	1.0000
14:50322510:GGGTG:G	acceptor_gain	1.0000
14:50325717:G:GT	donor_gain	1.0000
14:50325720:G:GG	donor_gain	1.0000
14:50330182:C:CC	acceptor_gain	1.0000
14:50332312:T:TA	donor_gain	1.0000
14:50312939:G:GT	donor_gain	0.9900
14:50312953:C:G	donor_gain	0.9900
14:50312973:A:AG	donor_gain	0.9900
14:50312973:A:G	donor_gain	0.9900
14:50312977:G:GG	donor_gain	0.9900
14:50322507:ACAGG:A	acceptor_gain	0.9900
14:50322508:C:G	acceptor_gain	0.9900
14:50322716:ATGG:A	donor_loss	0.9900
14:50322717:TGGG:T	donor_loss	0.9900
14:50322718:GG:G	donor_gain	0.9900
14:50322719:GG:G	donor_gain	0.9900

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000138062 (14:50318055 C>T), RS1000287528 (14:50312541 G>A,C), RS1000289769 (14:50321729 C>G,T), RS1000565441 (14:50310162 T>C), RS1000644332 (14:50322084 A>G), RS1000668178 (14:50316109 G>T), RS1000804876 (14:50315873 G>T), RS1000985660 (14:50323843 A>G), RS1001051286 (14:50310534 A>C), RS1001143201 (14:50316879 CTTT>C,CTTTT), RS1001238438 (14:50311957 T>TG), RS1001460112 (14:50318544 A>G), RS1001491760 (14:50312926 G>A), RS1001806809 (14:50318826 A>G), RS1001887748 (14:50324453 C>T)

Disease associations

OMIM: gene MIM:618579 | disease phenotypes: MIM:236792

GenCC curated gene-disease

Mondo (1): L-2-hydroxyglutaric aciduria (MONDO:0009370)

Orphanet (1): L-2-hydroxyglutaric aciduria (Orphanet:79314)

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST002312_10	Periodontal disease-related phenotype (Socransky)	8.000000e-06

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

36 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression	4
entinostat	decreases expression, affects cotreatment	2
Acetaminophen	increases expression	2
Estradiol	increases expression, affects cotreatment, decreases expression	2
Smoke	decreases expression	2
GSK-J4	decreases expression	1
dicrotophos	decreases expression	1
urushiol	increases expression	1
methylmercuric chloride	decreases expression	1
glycidyl methacrylate	decreases expression	1
trichostatin A	decreases expression	1
sulforaphane	decreases expression	1
sodium arsenite	increases abundance, affects cotreatment, decreases expression	1
cobaltous chloride	decreases expression	1
manganese chloride	decreases expression, increases abundance, affects cotreatment	1
beta-methylcholine	affects expression	1
K 7174	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
dorsomorphin	affects cotreatment, decreases expression	1
NSC 689534	affects binding, decreases expression	1
Irinotecan	decreases expression	1
Sunitinib	increases expression	1
Vorinostat	decreases expression	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1
Copper	affects binding, decreases expression	1
Coumestrol	decreases expression	1
Doxorubicin	decreases expression	1
Formaldehyde	decreases expression	1
Isoniazid	increases expression	1
Manganese	affects cotreatment, decreases expression, increases abundance	1

Clinical trials (associated diseases)

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