mitochondrial complex V (ATP synthase) deficiency, nuclear type 2

Summary

mitochondrial complex V (ATP synthase) deficiency, nuclear type 2 (MONDO:0013546) is a disease caused by TMEM70 (GenCC Definitive), with 3 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: TMEM70 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 345
• Phenotypes (HPO): 30

Clinical features

Signs & symptoms

Clinical features (HPO)

30 HPO clinical features (Orphanet curated; top 30 by frequency):

HPO ID	Term	Frequency
HP:0000252	Microcephaly	Very frequent (80-99%)
HP:0000322	Short philtrum	Very frequent (80-99%)
HP:0000369	Low-set ears	Very frequent (80-99%)
HP:0001252	Hypotonia	Very frequent (80-99%)
HP:0001562	Oligohydramnios	Very frequent (80-99%)
HP:0001987	Hyperammonemia	Very frequent (80-99%)
HP:0002342	Intellectual disability, moderate	Very frequent (80-99%)
HP:0002383	Infectious encephalitis	Very frequent (80-99%)
HP:0003535	3-Methylglutaconic aciduria	Very frequent (80-99%)
HP:0011343	Moderate global developmental delay	Very frequent (80-99%)
HP:0000028	Cryptorchidism	Frequent (30-79%)
HP:0000047	Hypospadias	Frequent (30-79%)
HP:0000154	Wide mouth	Frequent (30-79%)
HP:0000278	Retrognathia	Frequent (30-79%)
HP:0001371	Flexion contracture	Frequent (30-79%)
HP:0001510	Growth delay	Frequent (30-79%)
HP:0001511	Intrauterine growth retardation	Frequent (30-79%)
HP:0001522	Death in infancy	Frequent (30-79%)
HP:0001635	Congestive heart failure	Frequent (30-79%)
HP:0001639	Hypertrophic cardiomyopathy	Frequent (30-79%)
HP:0001641	Abnormal pulmonary valve morphology	Frequent (30-79%)
HP:0001646	Abnormal aortic valve morphology	Frequent (30-79%)
HP:0002120	Cerebral cortical atrophy	Frequent (30-79%)
HP:0002240	Hepatomegaly	Frequent (30-79%)
HP:0002878	Respiratory failure	Frequent (30-79%)
HP:0007370	Aplasia/Hypoplasia of the corpus callosum	Frequent (30-79%)
HP:0100490	Camptodactyly of finger	Frequent (30-79%)
HP:0000077	Abnormality of the kidney	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0011675	Arrhythmia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	mitochondrial complex V (ATP synthase) deficiency, nuclear type 2
Mondo ID	MONDO:0013546
MeSH	C567528
OMIM	614052
Orphanet	1194
DOID	DOID:0060331
SNOMED CT	718212006
UMLS	C3279699
MedGen	481329
GARD	0016561
Is cancer (heuristic)	no

Also known as: 3-MGCA type IV (3-MGCA-4) (formerly) · MC5DN2 · mitochondrial complex V (ATP synthase) deficiency, nuclear type 2 · mitochondrial encephalo-cardio-myopathy due to F1Fo ATPase deficiency · mitochondrial encephalo-cardio-myopathy due to isolated ATP synthase deficiency · mitochondrial encephalo-cardio-myopathy due to isolated mitochondrial respiratory chain complex V deficiency · TMEM70 defect

Data availability: 345 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › developmental anomaly of metabolic origin › inborn mitochondrial metabolism disorder › mitochondrial oxidative phosphorylation disorder › mitochondrial respiratory chain complex deficiency › mitochondrial complex V (ATP synthase) deficiency, nuclear type 2

Related subtypes (8): mitochondrial complex V (ATP synthase) deficiency, nuclear type 1, mitochondrial complex V (ATP synthase) deficiency, nuclear type 3, mitochondrial complex V (ATP synthase) deficiency, nuclear type 4B, mitochondrial complex III deficiency, mitochondrial complex V (ATP synthase) deficiency, nuclear type 5, mitochondrial complex IV deficiency, nuclear-type, mitochondrial complex I deficiency, SDHC-related Mitochondrial Disease

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

345 retrieved; paginated sample, class counts are floors:

151 uncertain significance, 118 likely benign, 20 pathogenic, 20 benign, 16 conflicting classifications of pathogenicity, 11 likely pathogenic, 7 pathogenic/likely pathogenic, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
583679	NC_000008.11:g.(?73976262)(73981641_?)del	LOC130000614	Pathogenic	criteria provided, single submitter
1456580	NC_000008.10:g.(?74890971)(74903809_?)del	LY96	Pathogenic	criteria provided, single submitter
1074442	NM_017866.6(TMEM70):c.100dup (p.Ala34fs)	TMEM70	Pathogenic	criteria provided, single submitter
1458977	NM_017866.6(TMEM70):c.368del (p.Pro123fs)	TMEM70	Pathogenic	criteria provided, single submitter
1459750	NM_017866.6(TMEM70):c.197del (p.Pro66fs)	TMEM70	Pathogenic	criteria provided, single submitter
1506132	NM_017866.6(TMEM70):c.304C>T (p.Arg102Ter)	TMEM70	Pathogenic	criteria provided, single submitter
1524311	NM_017866.6(TMEM70):c.359del (p.Thr120fs)	TMEM70	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1900244	NM_017866.6(TMEM70):c.497_498del (p.Tyr166fs)	TMEM70	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
203989	NM_017866.6(TMEM70):c.117_118dup (p.Ser40fs)	TMEM70	Pathogenic	criteria provided, multiple submitters, no conflicts
2085324	NM_017866.6(TMEM70):c.492del (p.Gly165fs)	TMEM70	Pathogenic	criteria provided, single submitter
2138392	NM_017866.6(TMEM70):c.30_31dup (p.Ala11fs)	TMEM70	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2743770	NM_017866.6(TMEM70):c.177dup (p.Ala60fs)	TMEM70	Pathogenic	criteria provided, single submitter
2914675	NM_017866.6(TMEM70):c.505C>T (p.Arg169Ter)	TMEM70	Pathogenic	criteria provided, single submitter
2917119	NM_017866.6(TMEM70):c.224G>A (p.Trp75Ter)	TMEM70	Pathogenic	criteria provided, single submitter
30957	NM_017866.6(TMEM70):c.336T>A (p.Tyr112Ter)	TMEM70	Pathogenic	no assertion criteria provided
30958	NM_017866.6(TMEM70):c.238C>T (p.Arg80Ter)	TMEM70	Pathogenic	criteria provided, multiple submitters, no conflicts
3696897	NM_017866.6(TMEM70):c.434del (p.Tyr145fs)	TMEM70	Pathogenic	criteria provided, single submitter
419199	NM_017866.6(TMEM70):c.578_579del (p.Thr193fs)	TMEM70	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4688749	NM_017866.6(TMEM70):c.446del (p.Gly149fs)	TMEM70	Pathogenic	criteria provided, single submitter
4707290	NM_017866.6(TMEM70):c.48_49del (p.Cys17fs)	TMEM70	Pathogenic	criteria provided, single submitter
4717817	NM_017866.6(TMEM70):c.316+1G>C	TMEM70	Pathogenic	criteria provided, single submitter
4725979	NM_017866.6(TMEM70):c.441del (p.Met148fs)	TMEM70	Pathogenic	criteria provided, single submitter
4736011	NM_017866.6(TMEM70):c.130_142del (p.Gly44fs)	TMEM70	Pathogenic	criteria provided, single submitter
488624	NM_017866.6(TMEM70):c.378dup (p.Thr127fs)	TMEM70	Pathogenic	criteria provided, single submitter
540	NM_017866.6(TMEM70):c.317-2A>G	TMEM70	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
807712	NM_017866.6(TMEM70):c.105dup (p.Val36fs)	TMEM70	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
817459	NM_017866.6(TMEM70):c.500del (p.Val167fs)	TMEM70	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2153484	NM_017866.6(TMEM70):c.211-6_220del	TMEM70	Likely pathogenic	criteria provided, single submitter
2189749	NM_017866.6(TMEM70):c.211-2A>G	TMEM70	Likely pathogenic	criteria provided, single submitter
2426365	NC_000008.10:g.(?74890971)(74891116_?)del	TMEM70	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
TMEM70	Definitive	Autosomal recessive	mitochondrial complex V (ATP synthase) deficiency, nuclear type 2	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TMEM70	Orphanet:1194	TMEM70-related mitochondrial encephalo-cardio-myopathy

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TMEM70	HGNC:26050	ENSG00000175606	Q9BUB7	Transmembrane protein 70, mitochondrial	gencc,clinvar
JPH1	HGNC:14201	ENSG00000104369	Q9HDC5	Junctophilin-1	clinvar
LY96	HGNC:17156	ENSG00000154589	Q9Y6Y9	Lymphocyte antigen 96	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TMEM70	Transmembrane protein 70, mitochondrial	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.
JPH1	Junctophilin-1	Junctophilins contribute to the formation of junctional membrane complexes (JMCs) which link the plasma membrane with the endoplasmic or sarcoplasmic reticulum in excitable cells.
LY96	Lymphocyte antigen 96	Binds bacterial lipopolysaccharide (LPS).

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TMEM70	Other/Unknown	no		TMEM70, TMEM70/TMEM186/TMEM223
JPH1	Other/Unknown	no		MORN, Junctophilin
LY96	Other/Unknown	no		ML_dom, Ig_E-set, LY96

Expression context

Cohort genes with no expression data: 0.

3 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
vastus lateralis	2
deltoid	1
gluteal muscle	1
quadriceps femoris	1
tibialis anterior	1
leukocyte	1
monocyte	1
mononuclear cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TMEM70	290	ubiquitous	marker	vastus lateralis, deltoid, gluteal muscle
JPH1	213	broad	marker	quadriceps femoris, vastus lateralis, tibialis anterior
LY96	252	ubiquitous	marker	monocyte, mononuclear cell, leukocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LY96	2,007
JPH1	1,646
TMEM70	1,548

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
LY96	Q9Y6Y9	9
JPH1	Q9HDC5	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TMEM70	Q9BUB7	73.16

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 43. Enrichment computed across 3 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Caspase activation via extrinsic apoptotic signalling pathway	1	1427.5×	0.006	LY96
TRIF-mediated programmed cell death	1	1268.9×	0.006	LY96
Diseases of Immune System	1	878.5×	0.006	LY96
Diseases associated with the TLR signaling cascade	1	878.5×	0.006	LY96
Caspase activation via Death Receptors in the presence of ligand	1	761.3×	0.006	LY96
IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation	1	761.3×	0.006	LY96
Regulation of TBK1, IKKε (IKBKE)-mediated activation of IRF3, IRF7	1	761.3×	0.006	LY96
TRAF6-mediated induction of TAK1 complex within TLR4 complex	1	713.8×	0.006	LY96
MyD88 deficiency (TLR2/4)	1	601.0×	0.006	LY96
Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE)	1	601.0×	0.006	LY96
IRAK4 deficiency (TLR2/4)	1	571.0×	0.006	LY96
Regulation of TLR by endogenous ligand	1	496.5×	0.006	LY96
IKK complex recruitment mediated by RIP1	1	496.5×	0.006	LY96
Respiratory syncytial virus (RSV) attachment and entry	1	496.5×	0.006	LY96
Antigen processing-Cross presentation	1	317.2×	0.009	LY96
Heme signaling	1	215.5×	0.009	LY96
Respiratory Syncytial Virus Infection Pathway	1	196.9×	0.009	LY96
TRIF (TICAM1)-mediated TLR4 signaling	1	190.3×	0.009	LY96
TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation	1	190.3×	0.009	LY96
MyD88 dependent cascade initiated on endosome	1	190.3×	0.009	LY96
MyD88-independent TLR4 cascade	1	184.2×	0.009	LY96
Toll Like Receptor 7/8 (TLR7/8) Cascade	1	184.2×	0.009	LY96
Toll Like Receptor 9 (TLR9) Cascade	1	175.7×	0.009	LY96
Toll Like Receptor TLR6:TLR2 Cascade	1	175.7×	0.009	LY96
Toll Like Receptor 2 (TLR2) Cascade	1	173.0×	0.009	LY96
Apoptosis	1	167.9×	0.009	LY96
Toll Like Receptor TLR1:TLR2 Cascade	1	167.9×	0.009	LY96
RSV-host interactions	1	156.4×	0.010	LY96
MyD88:MAL(TIRAP) cascade initiated on plasma membrane	1	152.3×	0.010	LY96
Programmed Cell Death	1	146.4×	0.010	LY96

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
detection of lipopolysaccharide	1	1123.5×	0.009	LY96
mitochondrial proton-transporting ATP synthase complex assembly	1	702.2×	0.009	TMEM70
positive regulation of lipopolysaccharide-mediated signaling pathway	1	510.7×	0.009	LY96
regulation of cardiac muscle contraction by calcium ion signaling	1	432.1×	0.009	JPH1
calcium ion transport into cytosol	1	401.2×	0.009	JPH1
regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum	1	224.7×	0.012	JPH1
protein complex oligomerization	1	224.7×	0.012	TMEM70
toll-like receptor signaling pathway	1	200.6×	0.012	LY96
toll-like receptor 4 signaling pathway	1	175.5×	0.012	LY96
mitochondrial respiratory chain complex I assembly	1	137.0×	0.014	TMEM70
cellular defense response	1	106.0×	0.016	LY96
muscle organ development	1	55.6×	0.028	JPH1
positive regulation of tumor necrosis factor production	1	51.1×	0.028	LY96
response to lipopolysaccharide	1	41.6×	0.031	LY96
protein homooligomerization	1	40.7×	0.031	TMEM70
cellular response to lipopolysaccharide	1	32.7×	0.036	LY96
cell surface receptor signaling pathway	1	21.4×	0.052	LY96
inflammatory response	1	12.6×	0.082	LY96
innate immune response	1	11.2×	0.087	LY96

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 3

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TMEM70	0	0
JPH1	0	0
LY96	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
LY96	87	Binding:86, ADMET:1
TMEM70	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	TMEM70, JPH1, LY96

Undrugged target profiles

3 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
TMEM70	1	—
JPH1	0	—
LY96	87	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.