TMEM70

Summary

TMEM70 (transmembrane protein 70, HGNC:26050) is a protein-coding gene on chromosome 8q21.11, encoding Transmembrane protein 70, mitochondrial (Q9BUB7). Scaffold protein that participates in the c-ring assembly of mitochondrial ATP synthase (F(1)F(0) ATP synthase or complex V) by facilitating the membrane insertion and oligomer formation of the subunit c/ATP5MC1 through its interaction.

This gene likely encodes a mitochondrial membrane protein. The encoded protein may play a role in biogenesis of mitochondrial ATP synthase. Mutations in this gene have been associated with neonatal mitochondrial encephalocardiomyopathy due to ATP synthase deficiency. Alternatively spliced transcript variants have been described.

Source: NCBI Gene 54968 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 2
• Clinical variants (ClinVar): 380 total — 19 pathogenic, 13 likely-pathogenic
• Phenotypes (HPO): 61
• Druggable target: yes
• MANE Select transcript: NM_017866

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26050
Approved symbol	TMEM70
Name	transmembrane protein 70
Location	8q21.11
Locus type	gene with protein product
Status	Approved
Aliases	MC5DN2, FLJ20533
Ensembl gene	ENSG00000175606
Ensembl biotype	protein_coding
OMIM	612418
Entrez	54968

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 2 protein_coding, 2 retained_intron, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000312184, ENST00000416961, ENST00000517439, ENST00000517614, ENST00000519551, ENST00000520167, ENST00000523794

RefSeq mRNA: 2 — MANE Select: NM_017866 NM_001040613, NM_017866

CCDS: CCDS47876, CCDS6215

Canonical transcript exons

ENST00000312184 — 3 exons

Exon	Start	End
ENSE00001366010	73976195	73976491
ENSE00002130124	73981155	73982783
ENSE00003477572	73978756	73978861

Expression profiles

Bgee: expression breadth ubiquitous, 290 present calls, max score 98.22.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 37.1763 / max 469.1954, expressed in 1819 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
89390	36.4262	1819
205225	0.7501	477

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
vastus lateralis	UBERON:0001379	98.22	gold quality
deltoid	UBERON:0001476	98.14	gold quality
gluteal muscle	UBERON:0002000	98.14	gold quality
quadriceps femoris	UBERON:0001377	98.12	gold quality
biceps brachii	UBERON:0001507	98.03	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	97.90	gold quality
diaphragm	UBERON:0001103	97.76	gold quality
heart right ventricle	UBERON:0002080	97.75	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	97.54	gold quality
skeletal muscle tissue	UBERON:0001134	97.23	gold quality
triceps brachii	UBERON:0001509	97.13	gold quality
body of tongue	UBERON:0011876	97.11	gold quality
vena cava	UBERON:0004087	96.98	gold quality
tibialis anterior	UBERON:0001385	96.80	gold quality
adult organism	UBERON:0007023	96.79	gold quality
muscle organ	UBERON:0001630	96.74	gold quality
gastrocnemius	UBERON:0001388	96.56	gold quality
hindlimb stylopod muscle	UBERON:0004252	96.50	gold quality
sperm	CL:0000019	96.41	gold quality
muscle of leg	UBERON:0001383	96.37	gold quality
left ventricle myocardium	UBERON:0006566	96.36	gold quality
muscle tissue	UBERON:0002385	96.31	gold quality
pons	UBERON:0000988	96.19	gold quality
mucosa of sigmoid colon	UBERON:0004993	96.03	gold quality
lateral nuclear group of thalamus	UBERON:0002736	95.99	gold quality
male germ cell	CL:0000015	95.97	gold quality
orbitofrontal cortex	UBERON:0004167	95.82	gold quality
mucosa of urinary bladder	UBERON:0001259	95.69	gold quality
myocardium	UBERON:0002349	95.56	gold quality
tongue	UBERON:0001723	95.54	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-GEOD-75367	no	1958.99
E-GEOD-124858	no	99.47
E-MTAB-10137	no	7.82
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

34 targeting TMEM70, 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-4795-3P	100.00	74.62	4024
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-4715-3P	99.98	66.03	670
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-1299	99.77	71.24	2389
HSA-MIR-2116-3P	99.74	64.32	889
HSA-MIR-4677-5P	99.70	70.09	1940
HSA-MIR-875-3P	99.63	69.47	2548
HSA-MIR-567	99.63	68.57	1219
HSA-MIR-3685	99.62	68.83	1621
HSA-MIR-578	99.46	68.36	1787
HSA-MIR-3191-5P	99.24	66.52	1722
HSA-MIR-9898	99.00	67.89	500
HSA-MIR-1288-5P	98.85	67.01	734
HSA-MIR-518C-5P	98.53	69.20	1640
HSA-MIR-224-5P	98.33	70.12	1256
HSA-MIR-4704-3P	98.28	69.33	1300
HSA-MIR-7113-5P	97.88	67.33	1735
HSA-MIR-424-3P	97.20	65.86	385

Literature-anchored findings (GeneRIF, showing 20)

• TMEM70 is involved in mitochondrial ATP synthase biogenesis in higher eukaryotes. (PMID:18953340)
• Gene mapping and complementation studies have identified mutations in TMEM70 gene encoding a 30kD mitochondrial protein of unknown function as the cause of hypertrophic cardiomyopathy and encephalopathy. (PMID:19103153)
• ATP synthase deficiency with mutation in TMEM70 should be considered in the diagnosis and management of ill neonates with early onset of muscular hypotonia, HCMP and hypospadias in boys accompanied by lactic acidosis, hyperammonaemia and 3-MGC-uria. (PMID:20335238)
• Complex V TMEM70 deficiency results in mitochondrial nucleoid disorganization. (PMID:20920610)
• No TMEM70 protein could be found in cells and isolated mitochondria from patients with ATP synthase deficiency due to TMEM70 c.317-single nucleotide polymorphism mutation. (PMID:20937241)
• The study identifies TMEM70 gene defect as a pan-ethnic disorder and further redefines it as the most common cause of nuclear-origin ATP synthase deficiency. (PMID:21147908)
• TMEM70 mutations are involved in the pathogenesis of 3-methylglutaconic acid (3-MGA) acydoses in populations of different ethnic origin and become a useful genetic marker for this disease. (PMID:21815885)
• The authors report a fragmented mitochondrial network and swollen and irregularly shaped mitochondria with partial to complete loss of the cristae in fibroblasts of a patient with a novel TMEM70 gene deletion. (PMID:21945727)
• Fibroblasts from 10 patients with TMEM70 317-2A>G homozygous mutation showed a significant 82-89% decrease of ATP synthase and 50-162% increase of respiratory chain complex IV and 22-53% increase of complex III. (PMID:22433607)
• this study suggests that mutant TMEM70 associates in high molecular weight complexes (470-550 kDa) when expressed in Hela cells and exerts a direct action in ATP synthase biogenesis and assembly, mediating the incorporation of F1 moieties. (PMID:22986587)
• Pulmonary hypertension has rarely been reported in mitochondrial disorders and, so far, it has been described in association with TMEM70 deficiency only in one patient (PMID:24485043)
• These data indicate that the biological function of TMEM70 in the ATP synthase biogenesis may be mediated through interaction with other protein(s). (PMID:24576557)
• TMEM70 deficiency is a panethnic, multisystemic disease with variable outcome depending mainly on adequate management of hyperammonaemic crises in the neonatal period and early childhood. (PMID:25326274)
• Chinese family with dual LQT1 and HCM phenotypes associated with tetrad heterozygous mutations in KCNQ1, MYH7, MYLK2, and TMEM70 mutations. (PMID:25825456)
• In summary, TMEM70 mutations can cause distinct ultrastructural mitochondrial degeneration and almost complete deficiency of ATP synthase but are still amenable to treatment. (PMID:26550569)
• cause of hyperammonemia in TMEM70 deficiency was previously assumed to be related to carbamoyl phosphate synthase 1 deficiency, but our finding of hypercitrullinemia rules out this possibility. We thus propose a different etiology for the hyperammonemia seen in these patients (PMID:30950220)
• Delayed appearance of 3-methylglutaconic aciduria in neonates with early onset metabolic cardiomyopathies: A potential pitfall for the diagnosis. (PMID:31729175)
• TMEM70 functions in the assembly of complexes I and V. (PMID:32275929)
• TMEM70 forms oligomeric scaffolds within mitochondrial cristae promoting in situ assembly of mammalian ATP synthase proton channel. (PMID:33359711)
• TMEM70 and TMEM242 help to assemble the rotor ring of human ATP synthase and interact with assembly factors for complex I. (PMID:33753518)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	tmem70	ENSDARG00000078773
mus_musculus	Tmem70	ENSMUSG00000025940
rattus_norvegicus	Tmem70	ENSRNOG00000006608
drosophila_melanogaster	CG7506	FBGN0035805
caenorhabditis_elegans		WBGENE00009330

Protein

Protein identifiers

Transmembrane protein 70, mitochondrial — Q9BUB7 (reviewed: Q9BUB7)

All UniProt accessions (2): Q9BUB7, D4PHA6

UniProt curated annotations — full annotation on UniProt →

Function. Scaffold protein that participates in the c-ring assembly of mitochondrial ATP synthase (F(1)F(0) ATP synthase or complex V) by facilitating the membrane insertion and oligomer formation of the subunit c/ATP5MC1 through its interaction. Therefore, participates in the early stage of mitochondrial ATP synthase biogenesis and also protects subunit c/ATP5MC1 against intramitochondrial proteolysis. In addition, binds the mitochondrial proton-transporting ATP synthase complexes I and may play a role in the stability of its membrane-bound subassemblies.

Subunit / interactions. Homooligomer. Interacts (homooligomer form) with ATP5MC1; this interaction facilitates the oligomer formation of subunit c/ATP5MC1 (c-ring) and the c-ring membrane insertion and also protects ATP5MC1 against intramitochondrial proteolysis. Interacts with the core subunits TMEM126B, NDUFAF1, ECSIT and ACAD9 of the MCIA complex. Interacts with ATP5MC3, TMEM242 and TIMMDC1.

Subcellular location. Mitochondrion inner membrane.

Tissue specificity. Lower expressed in the heart than in the liver (at protein level).

Disease relevance. Mitochondrial complex V deficiency, nuclear type 2 (MC5DN2) [MIM:614052] A mitochondrial disorder with heterogeneous clinical manifestations including dysmorphic features, psychomotor retardation, hypotonia, growth retardation, cardiomyopathy, enlarged liver, hypoplastic kidneys and elevated lactate levels in urine, plasma and cerebrospinal fluid. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the TMEM70 family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9BUB7-1	1	yes
Q9BUB7-2	2
Q9BUB7-3	3

RefSeq proteins (2): NP_001035703, NP_060336* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR009724	TMEM70	Family
IPR045325	TMEM70/TMEM186/TMEM223	Family

Pfam: PF06979

UniProt features (15 total): sequence variant 5, topological domain 3, splice variant 3, transmembrane region 2, transit peptide 1, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BUB7-F1	73.16	0.30

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 329 (showing top): GSE45365_NK_CELL_VS_BCELL_DN, AGGAAGC_MIR5163P, GOBP_MITOCHONDRIAL_RESPIRATORY_CHAIN_COMPLEX_ASSEMBLY, WEI_MYCN_TARGETS_WITH_E_BOX, ONKEN_UVEAL_MELANOMA_UP, GOCC_MITOCHONDRIAL_ENVELOPE, NIKOLSKY_BREAST_CANCER_8Q12_Q22_AMPLICON, DODD_NASOPHARYNGEAL_CARCINOMA_UP, GOBP_PROTEIN_HOMOOLIGOMERIZATION, GGTGAAG_MIR412, RASHI_RESPONSE_TO_IONIZING_RADIATION_6, BOQUEST_STEM_CELL_DN, RICKMAN_TUMOR_DIFFERENTIATED_MODERATELY_VS_POORLY_DN, GOCC_ORGANELLE_INNER_MEMBRANE, chr8q21

GO Biological Process (4): mitochondrial respiratory chain complex I assembly (GO:0032981), mitochondrial proton-transporting ATP synthase complex assembly (GO:0033615), protein complex oligomerization (GO:0051259), protein homooligomerization (GO:0051260)

GO Molecular Function (3): protein-macromolecule adaptor activity (GO:0030674), mitochondrial proton-transporting ATP synthase complex binding (GO:0140260), protein binding (GO:0005515)

GO Cellular Component (6): nucleoplasm (GO:0005654), mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), mitochondrial crista (GO:0030061), mitochondrial membrane (GO:0031966), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
mitochondrial respiratory chain complex assembly	2
mitochondrion	2
NADH dehydrogenase complex assembly	1
proton-transporting ATP synthase complex assembly	1
protein-containing complex assembly	1
protein complex oligomerization	1
protein binding	1
molecular adaptor activity	1
protein-containing complex binding	1
binding	1
nuclear lumen	1
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
mitochondrial inner membrane	1
mitochondrial envelope	1
organelle membrane	1

Protein interactions and networks

STRING

1218 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TMEM70	ATPAF2	Q8N5M1	957
TMEM70	OPALIN	Q96PE5	952
TMEM70	FOXRED1	Q96CU9	890
TMEM70	MT-ATP8	P03928	875
TMEM70	DMAC2	Q9NW81	796
TMEM70	MT-ATP6	P00846	789
TMEM70	ATPAF1	Q5TC12	769
TMEM70	TMEM242	Q9NWH2	699
TMEM70	TMEM186	Q96B77	690
TMEM70	ATP5F1E	P56381	656
TMEM70	TIMMDC1	Q9NPL8	625
TMEM70	NDUFAF1	Q9Y375	622
TMEM70	NDUFB10	O96000	608
TMEM70	NDUFAF3	Q9BU61	598
TMEM70	TMEM38A	Q9H6F2	593

IntAct

72 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
HSPD1	NUDT19	psi-mi:“MI:0914”(association)	0.710
LPAR3	TMEM70	psi-mi:“MI:0915”(physical association)	0.560
RAB2A	TMEM70	psi-mi:“MI:0915”(physical association)	0.560
TMEM70	LPAR3	psi-mi:“MI:0915”(physical association)	0.560
NDUFS5	NDUFS8	psi-mi:“MI:0914”(association)	0.530
UQCRFS1	NDUFAB1	psi-mi:“MI:0914”(association)	0.530
IMPDH1	BCAT2	psi-mi:“MI:0914”(association)	0.530
TMEM70	BDKRB2	psi-mi:“MI:0915”(physical association)	0.370
PCNA	TMEM70	psi-mi:“MI:0915”(physical association)	0.370
TMEM70	E6	psi-mi:“MI:0915”(physical association)	0.370
TMEM70	E7	psi-mi:“MI:0915”(physical association)	0.370
ECSIT	NDUFS2	psi-mi:“MI:0914”(association)	0.350
NMES1	NDUFS8	psi-mi:“MI:0914”(association)	0.350
COQ9	NDUFS8	psi-mi:“MI:0914”(association)	0.350
NDUFA4	NDUFS8	psi-mi:“MI:0914”(association)	0.350
NDUFA4	COX7A2L	psi-mi:“MI:0914”(association)	0.350
	TMEM223	psi-mi:“MI:0914”(association)	0.350
RTN1	TMEM120B	psi-mi:“MI:0914”(association)	0.350
TNFSF18	TMEM120B	psi-mi:“MI:0914”(association)	0.350
TMEM70	FDXR	psi-mi:“MI:0914”(association)	0.350
FFAR1	SLC12A8	psi-mi:“MI:0914”(association)	0.350
RTN3	ESYT2	psi-mi:“MI:0914”(association)	0.350
TSPAN15	TMEM223	psi-mi:“MI:0914”(association)	0.350
TNFSF18	FAM171A2	psi-mi:“MI:0914”(association)	0.350

BioGRID (258): TMEM70 (Two-hybrid), TMEM70 (Affinity Capture-MS), TMEM70 (Affinity Capture-MS), TMEM70 (Affinity Capture-MS), TMEM70 (Affinity Capture-MS), TMEM70 (Affinity Capture-MS), TMEM70 (Affinity Capture-MS), TMEM70 (Affinity Capture-MS), TMEM70 (Affinity Capture-MS), TMEM70 (Affinity Capture-MS), ACSS1 (Affinity Capture-MS), CHDH (Affinity Capture-MS), TMEM70 (Affinity Capture-MS), MIPEP (Affinity Capture-MS), TMEM70 (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: A6H773, Q5ZLJ4, Q921N7, Q95SS8, Q9BUB7

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 95 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.

GO biological processes:

GO term	Partners	Fold	FDR
mitochondrial electron transport, NADH to ubiquinone	5	20.6×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	19
Likely pathogenic	13
Uncertain significance	170
Likely benign	121
Benign	27

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1074442	NM_017866.6(TMEM70):c.100dup (p.Ala34fs)	Pathogenic
1458977	NM_017866.6(TMEM70):c.368del (p.Pro123fs)	Pathogenic
1459750	NM_017866.6(TMEM70):c.197del (p.Pro66fs)	Pathogenic
1506132	NM_017866.6(TMEM70):c.304C>T (p.Arg102Ter)	Pathogenic
203989	NM_017866.6(TMEM70):c.117_118dup (p.Ser40fs)	Pathogenic
2085324	NM_017866.6(TMEM70):c.492del (p.Gly165fs)	Pathogenic
2683619	NM_017866.6(TMEM70):c.141del (p.Pro48fs)	Pathogenic
2743770	NM_017866.6(TMEM70):c.177dup (p.Ala60fs)	Pathogenic
2914675	NM_017866.6(TMEM70):c.505C>T (p.Arg169Ter)	Pathogenic
2917119	NM_017866.6(TMEM70):c.224G>A (p.Trp75Ter)	Pathogenic
30957	NM_017866.6(TMEM70):c.336T>A (p.Tyr112Ter)	Pathogenic
30958	NM_017866.6(TMEM70):c.238C>T (p.Arg80Ter)	Pathogenic
3696897	NM_017866.6(TMEM70):c.434del (p.Tyr145fs)	Pathogenic
4688749	NM_017866.6(TMEM70):c.446del (p.Gly149fs)	Pathogenic
4707290	NM_017866.6(TMEM70):c.48_49del (p.Cys17fs)	Pathogenic
4717817	NM_017866.6(TMEM70):c.316+1G>C	Pathogenic
4725979	NM_017866.6(TMEM70):c.441del (p.Met148fs)	Pathogenic
4736011	NM_017866.6(TMEM70):c.130_142del (p.Gly44fs)	Pathogenic
488624	NM_017866.6(TMEM70):c.378dup (p.Thr127fs)	Pathogenic
1176561	NM_017866.6(TMEM70):c.701A>C (p.His234Pro)	Likely pathogenic
203987	NM_017866.6(TMEM70):c.578C>T (p.Thr193Ile)	Likely pathogenic
2153484	NM_017866.6(TMEM70):c.211-6_220del	Likely pathogenic
2189749	NM_017866.6(TMEM70):c.211-2A>G	Likely pathogenic
2426365	NC_000008.10:g.(?74890971)(74891116_?)del	Likely pathogenic
3595870	NM_017866.6(TMEM70):c.54_73del (p.Arg19fs)	Likely pathogenic
3595872	NM_017866.6(TMEM70):c.382C>T (p.Gln128Ter)	Likely pathogenic
3595873	NM_017866.6(TMEM70):c.464_465insT (p.Val157fs)	Likely pathogenic
3595874	NM_017866.6(TMEM70):c.582_583del (p.Phe195fs)	Likely pathogenic
3595875	NM_017866.6(TMEM70):c.620del (p.His207fs)	Likely pathogenic
3707871	NM_017866.6(TMEM70):c.210+1G>A	Likely pathogenic

SpliceAI

452 predictions. Top by Δscore:

Variant	Effect	Δscore
8:73976489:CAG:C	donor_loss	1.0000
8:73976490:AG:A	donor_loss	1.0000
8:73976491:GGT:G	donor_loss	1.0000
8:73976492:GTAGG:G	donor_loss	1.0000
8:73976493:T:G	donor_loss	1.0000
8:73978862:G:GG	donor_gain	1.0000
8:73981151:TTAG:T	acceptor_loss	1.0000
8:73981152:TAGG:T	acceptor_loss	1.0000
8:73981153:AGGTG:A	acceptor_loss	1.0000
8:73981154:GGT:G	acceptor_gain	1.0000
8:73976696:A:T	donor_gain	0.9900
8:73978751:A:AG	acceptor_gain	0.9900
8:73978752:ATAG:A	acceptor_loss	0.9900
8:73978754:A:AG	acceptor_gain	0.9900
8:73978754:AG:A	acceptor_loss	0.9900
8:73978755:G:A	acceptor_loss	0.9900
8:73978755:G:GG	acceptor_gain	0.9900
8:73978857:GTTTG:G	donor_gain	0.9900
8:73978862:G:GA	donor_loss	0.9900
8:73978863:T:TC	donor_loss	0.9900
8:73978864:AA:A	donor_loss	0.9900
8:73981153:A:AG	acceptor_gain	0.9900
8:73981154:G:GG	acceptor_gain	0.9900
8:73981154:GGTGT:G	acceptor_gain	0.9900
8:73981149:A:AG	acceptor_gain	0.9800
8:73981150:T:G	acceptor_gain	0.9800
8:73976492:G:GG	donor_gain	0.9700
8:73981153:AG:A	acceptor_gain	0.9700
8:73981153:AGGT:A	acceptor_gain	0.9700
8:73981154:GG:G	acceptor_gain	0.9700

AlphaMissense

1678 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:73981181:A:C	S115R	0.999
8:73981183:T:A	S115R	0.999
8:73981183:T:G	S115R	0.999
8:73981421:T:C	F195L	0.998
8:73981422:T:C	F195S	0.998
8:73981423:T:A	F195L	0.998
8:73981423:T:G	F195L	0.998
8:73981344:G:C	R169P	0.997
8:73981347:T:C	L170S	0.996
8:73981422:T:G	F195C	0.996
8:73981338:T:A	V167D	0.995
8:73981373:T:G	Y179D	0.995
8:73981515:T:C	F226S	0.995
8:73981286:A:C	S150R	0.994
8:73981288:C:A	S150R	0.994
8:73981288:C:G	S150R	0.994
8:73981514:T:C	F226L	0.994
8:73981515:T:G	F226C	0.994
8:73981516:T:A	F226L	0.994
8:73981516:T:G	F226L	0.994
8:73981379:G:C	A181P	0.993
8:73981500:T:A	V221D	0.992
8:73981542:T:C	L235P	0.992
8:73981380:C:A	A181D	0.991
8:73981373:T:C	Y179H	0.990
8:73981473:T:C	F212S	0.990
8:73981479:C:A	A214D	0.990
8:73981494:T:C	L219P	0.990
8:73981305:C:G	P156R	0.989
8:73981421:T:G	F195V	0.989

dbSNP variants (sampled 300 via entrez): RS1000113948 (8:73977376 C>T), RS1000297655 (8:73977759 C>G,T), RS1001296527 (8:73977052 A>C), RS1001577448 (8:73976738 T>A), RS1001863039 (8:73980478 T>G), RS1002226075 (8:73981827 A>T), RS1002400512 (8:73980263 A>G), RS1002701427 (8:73975656 T>C), RS1003240817 (8:73980357 C>T), RS1003694183 (8:73977521 A>C,G), RS1003833100 (8:73977268 G>A), RS1004032178 (8:73978206 C>T), RS1004158608 (8:73974636 G>A,C), RS1005034665 (8:73976709 T>C), RS1005089258 (8:73976635 A>C,G)

Disease associations

OMIM: gene MIM:612418 | disease phenotypes: MIM:614052, MIM:604273

GenCC curated gene-disease

Disease	Classification	Inheritance
mitochondrial complex V (ATP synthase) deficiency, nuclear type 2	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
mitochondrial disease	Definitive	AR

Mondo (4): mitochondrial complex V (ATP synthase) deficiency, nuclear type 2 (MONDO:0013546), autosomal recessive disease (MONDO:0006025), mitochondrial proton-transporting ATP synthase complex deficiency (MONDO:0014471), neurodevelopmental disorder (MONDO:0700092)

Orphanet (2): TMEM70-related mitochondrial encephalo-cardio-myopathy (Orphanet:1194), Isolated ATP synthase deficiency (Orphanet:254913)

HPO phenotypes

61 total (30 of 61 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000023	Inguinal hernia
HP:0000028	Cryptorchidism
HP:0000047	Hypospadias
HP:0000077	Abnormality of the kidney
HP:0000154	Wide mouth
HP:0000252	Microcephaly
HP:0000278	Retrognathia
HP:0000308	Microretrognathia
HP:0000322	Short philtrum
HP:0000343	Long philtrum
HP:0000369	Low-set ears
HP:0000431	Wide nasal bridge
HP:0000463	Anteverted nares
HP:0000518	Cataract
HP:0000822	Hypertension
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001271	Polyneuropathy
HP:0001290	Generalized hypotonia
HP:0001298	Encephalopathy
HP:0001337	Tremor
HP:0001371	Flexion contracture
HP:0001508	Failure to thrive
HP:0001510	Growth delay
HP:0001511	Intrauterine growth retardation
HP:0001518	Small for gestational age
HP:0001522	Death in infancy

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST009391_1314	Metabolite levels	3.000000e-06
GCST010204_138	Low density lipoprotein cholesterol levels	4.000000e-11

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0010519	pantothenic acid measurement
EFO:0004611	low density lipoprotein cholesterol measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625
C567528	Encephalocardiomyopathy, Mitochondrial, Neonatal, Due To Atp Synthase Deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067193 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

26 total (human), top 26 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression	2
Particulate Matter	decreases expression, increases abundance	2
aristolochic acid I	increases expression	1
dicrotophos	decreases expression	1
methylmercuric chloride	decreases expression	1
arsenite	affects binding, increases reaction	1
sodium arsenite	decreases expression	1
nivalenol	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Arsenic Trioxide	increases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Dichlorodiphenyl Dichloroethylene	increases expression	1
Doxorubicin	increases expression	1
Hydrogen Peroxide	affects expression	1
Ivermectin	decreases expression	1
Lead	affects expression	1
Methyl Methanesulfonate	decreases expression	1
Plant Extracts	affects cotreatment, increases expression	1
Smoke	decreases expression	1
Tretinoin	decreases expression	1
Thapsigargin	decreases expression	1
Okadaic Acid	increases expression	1
Copper Sulfate	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652659	Binding	Binding affinity to human TMEM70 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_TT04	HAP1 TMEM70 (-) 1	Cancer cell line	Male
CVCL_TT05	HAP1 TMEM70 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT03013777	Not specified	COMPLETED	A Trial of Cognitive Behavioral Therapy in Familial Dysautonomia
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism
NCT03229928	Not specified	COMPLETED	Clinical Testing of a Real-Time Behavior Measurement Tool: Measuring Outcomes for CHAnge