NDUFV2

Summary

NDUFV2 (NADH:ubiquinone oxidoreductase core subunit V2, HGNC:7717) is a protein-coding gene on chromosome 18p11.22, encoding NADH dehydrogenase [ubiquinone] flavoprotein 2, mitochondrial (P19404). Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which catalyzes electron transfer from NADH through the respiratory chain, using ubiquinone as an electron acceptor. It is a selective cancer dependency (DepMap: 24.4% of cell lines).

The NADH-ubiquinone oxidoreductase complex (complex I) of the mitochondrial respiratory chain catalyzes the transfer of electrons from NADH to ubiquinone, and consists of at least 43 subunits. The complex is located in the inner mitochondrial membrane. This gene encodes the 24 kDa subunit of complex I, and is involved in electron transfer. Mutations in this gene are implicated in Parkinson’s disease, bipolar disorder, schizophrenia, and have been found in one case of early onset hypertrophic cardiomyopathy and encephalopathy. A non-transcribed pseudogene of this locus is found on chromosome 19.

Source: NCBI Gene 4729 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Definitive, ClinGen) — +4 more curated relationships
• GWAS associations: 6
• Clinical variants (ClinVar): 150 total — 9 pathogenic, 6 likely-pathogenic
• Phenotypes (HPO): 47
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 24.4% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_021074

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7717
Approved symbol	NDUFV2
Name	NADH:ubiquinone oxidoreductase core subunit V2
Location	18p11.22
Locus type	gene with protein product
Status	Approved
Aliases	CI-24k
Ensembl gene	ENSG00000178127
Ensembl biotype	protein_coding
OMIM	600532
Entrez	4729

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 17 protein_coding, 4 protein_coding_CDS_not_defined, 1 retained_intron, 1 nonsense_mediated_decay

ENST00000318388, ENST00000400033, ENST00000465096, ENST00000474350, ENST00000474740, ENST00000483511, ENST00000497577, ENST00000577703, ENST00000583375, ENST00000860023, ENST00000860024, ENST00000860025, ENST00000860026, ENST00000860027, ENST00000860028, ENST00000860029, ENST00000860030, ENST00000860031, ENST00000860032, ENST00000916515, ENST00000916516, ENST00000916517, ENST00000956588

RefSeq mRNA: 1 — MANE Select: NM_021074 NM_021074

CCDS: CCDS11842

Canonical transcript exons

ENST00000318388 — 8 exons

Exon	Start	End
ENSE00001278013	9102699	9102797
ENSE00003462251	9119326	9119388
ENSE00003466165	9124874	9124983
ENSE00003532654	9126831	9126907
ENSE00003677402	9119474	9119590
ENSE00003685323	9122513	9122681
ENSE00003686559	9117838	9117903
ENSE00003849461	9134186	9134341

Expression profiles

Bgee: expression breadth ubiquitous, 137 present calls, max score 99.26.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 108.3900 / max 501.1244, expressed in 1827 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
169328	105.7698	1827
169327	2.0882	1317
169332	0.2843	96
169331	0.1949	68
169329	0.0527	15

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	99.26	gold quality
gastrocnemius	UBERON:0001388	99.21	gold quality
hindlimb stylopod muscle	UBERON:0004252	99.20	gold quality
muscle of leg	UBERON:0001383	99.16	gold quality
right lobe of liver	UBERON:0001114	99.01	gold quality
heart left ventricle	UBERON:0002084	98.91	gold quality
right atrium auricular region	UBERON:0006631	98.91	gold quality
right adrenal gland	UBERON:0001233	98.81	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	98.74	gold quality
adrenal tissue	UBERON:0018303	98.72	gold quality
heart	UBERON:0000948	98.71	gold quality
right adrenal gland cortex	UBERON:0035827	98.71	gold quality
left adrenal gland	UBERON:0001234	98.66	gold quality
adrenal gland	UBERON:0002369	98.60	gold quality
left adrenal gland cortex	UBERON:0035825	98.60	gold quality
lower esophagus	UBERON:0013473	98.48	gold quality
lower esophagus muscularis layer	UBERON:0035833	98.48	gold quality
liver	UBERON:0002107	98.42	gold quality
mucosa of transverse colon	UBERON:0004991	98.38	gold quality
esophagus	UBERON:0001043	98.34	gold quality
islet of Langerhans	UBERON:0000006	98.33	gold quality
rectum	UBERON:0001052	98.33	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	98.30	gold quality
muscle layer of sigmoid colon	UBERON:0035805	98.28	gold quality
body of pancreas	UBERON:0001150	98.27	gold quality
body of stomach	UBERON:0001161	98.26	gold quality
esophagus mucosa	UBERON:0002469	98.26	gold quality
tonsil	UBERON:0002372	98.19	gold quality
fundus of stomach	UBERON:0001160	98.18	gold quality
metanephros cortex	UBERON:0010533	98.18	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-6379	no	1077.95
E-MTAB-7303	no	704.98
E-HCAD-8	no	45.45
E-CURD-120	no	29.39
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): SP1

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 24.4% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 23)

• mutation causes early onset hypertrophic cardiomyopathy and encephalopathy (PMID:12754703)
• Polymorphisms of this gene may be one of the genetic risk factors for bipolar disorder. (PMID:12815743)
• Polymorphisms in the promoter region of NDUFV2 are a genetic risk factor for bipolar disorder. The association of the haplotypes -602G> A and -3542G> A polymorphisms with bipolar disorder was seen both in Japanese case-control samples and NIMH trios. (PMID:15450783)
• NDUFV2 individual genotypes were not associated with schizophrenia, but the haplotype consisting of the two single nucleotide polymorphisms were significantly associated with schizophrenia. (PMID:16508936)
• Sp1 was abnormally expressed in schizophrenia and its mRNA alteration pattern paralleled that of NDUFV1 and NDUFV2 in schizophrenic patients. (PMID:17786189)
• genetic variants of NDUFV2 may increase risk for bipolar disorder. (PMID:18199248)
• This protein has been found differentially expressed in the temporal lobe from patients with schizophrenia. (PMID:19034380)
• This study found that the expressions of NDUFV2 were up-regulated in those from patients with Japanese bipolar II disorder and the mRNA levels of this gene were down-regulated in Caucasian schizophrenia. (PMID:19135101)
• Using shotgun mass spectrometry, we found this protein differentially expressed in the dorsolateral prefrontal cortex from patients with schizophrenia. (PMID:19165527)
• Data show that the haplotype consisting of rs6506640 (-342G > A) and rs906807 (86C > T) on the mitochondrial gene NDUFV2 is found to be associated with bipolar disorder. (PMID:19194776)
• The results show mitochondrial haplotypes associated with polymorphism of this gene are associated with elite middle and sprint power endurance in Japanese athletes (PMID:20551160)
• Our findings suggest further studies addressing the role of NDUFV2 variation in Parkinson’s disease may be warranted. (PMID:20971673)
• Three single nucleotide polymorphisms in the NDUFV2 gene, were studies in bipolar disorder pateints and controls. (PMID:20978456)
• There is no statistical significance between NDUFV2 gene promoter variants and susceptibility to schizophrenia in Han Chinese. (PMID:21190551)
• The mitochondrial targeting sequence of NDUFV2 is located at the N-terminus of the precursor protein. Impairment of mitochondrial localization of NDUFV2 as a mechanistic basis for early-onset hypertrophic cardiomyopathy and encephalopathy was established. (PMID:21548921)
• We have identified NDUFV2 mutations in two families with Complex I deficiency, including a novel mutation. (PMID:26008862)
• haplotype T-C consisting of rs12457810 and rs12964485 in the 5’-upstream region of NDUFV2 may be a protective factor for the development of MDD in Han Chinese (PMID:26544616)
• NDUFV2 pseudogene (NDUFV2P1) contributes to mitochondrial complex I deficits in schizophrenia. (PMID:30531937)
• Whole genome and exome sequencing identify NDUFV2 mutations as a new cause of progressive cavitating leukoencephalopathy. (PMID:33811136)
• Identifying Mitochondrial-Related Genes NDUFA10 and NDUFV2 as Prognostic Markers for Prostate Cancer through Biclustering. (PMID:34124242)
• Genome sequencing and RNA-seq analyses of mitochondrial complex I deficiency revealed Alu insertion-mediated deletion in NDUFV2. (PMID:34405929)
• Sex-specific genetic regulation of adipose mitochondria and metabolic syndrome by Ndufv2. (PMID:34697471)
• Association between single-nucleotide polymorphism rs145497186 related to NDUFV2 and lumbar disc degeneration: a pilot case-control study. (PMID:36309697)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ndufv2	ENSDARG00000013044
mus_musculus	Ndufv2	ENSMUSG00000024099
rattus_norvegicus	Ndufv2	ENSRNOG00000042503
drosophila_melanogaster	ND-24	FBGN0030853
caenorhabditis_elegans		WBGENE00009992

Protein

Protein identifiers

NADH dehydrogenase [ubiquinone] flavoprotein 2, mitochondrial — P19404 (reviewed: P19404)

Alternative names: NADH-ubiquinone oxidoreductase 24 kDa subunit

All UniProt accessions (4): E7EPT4, P19404, J3KRB4, J3QS34

UniProt curated annotations — full annotation on UniProt →

Function. Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which catalyzes electron transfer from NADH through the respiratory chain, using ubiquinone as an electron acceptor. Parts of the peripheral arm of the enzyme, where the electrons from NADH are accepted by flavin mononucleotide (FMN) and then passed along a chain of iron-sulfur clusters by electron tunnelling to the final acceptor ubiquinone. Contains one iron-sulfur cluster.

Subunit / interactions. Core subunit of respiratory chain NADH dehydrogenase (Complex I) which is composed of 45 different subunits. This is a component of the flavoprotein-sulfur (FP) fragment of the enzyme.

Subcellular location. Mitochondrion inner membrane.

Disease relevance. Mitochondrial complex I deficiency, nuclear type 7 (MC1DN7) [MIM:618229] A form of mitochondrial complex I deficiency, the most common biochemical signature of mitochondrial disorders, a group of highly heterogeneous conditions characterized by defective oxidative phosphorylation, which collectively affects 1 in 5-10000 live births. Clinical disorders have variable severity, ranging from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, non-specific encephalopathy, cardiomyopathy, myopathy, liver disease, Leigh syndrome, Leber hereditary optic neuropathy, and some forms of Parkinson disease. MC1DN7 transmission pattern is consistent with autosomal recessive inheritance. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Binds 1 [2Fe-2S] cluster.

Similarity. Belongs to the complex I 24 kDa subunit family.

RefSeq proteins (1): NP_066552* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002023	NuoE-like	Family
IPR036249	Thioredoxin-like_sf	Homologous_superfamily
IPR041921	NuoE_N	Homologous_superfamily
IPR042128	NuoE_dom	Domain

Pfam: PF01257

Catalyzed reactions (Rhea), 1 shown:

• a ubiquinone + NADH + 5 H(+)(in) = a ubiquinol + NAD(+) + 4 H(+)(out) (RHEA:29091)

UniProt features (23 total): helix 8, binding site 4, strand 3, turn 2, modified residue 2, transit peptide 1, chain 1, region of interest 1, sequence variant 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
9I4I	ELECTRON MICROSCOPY	2.63
9TI4	ELECTRON MICROSCOPY	2.66
5XTB	ELECTRON MICROSCOPY	3.4
9CWT	ELECTRON MICROSCOPY	3.44
5XTD	ELECTRON MICROSCOPY	3.7
5XTH	ELECTRON MICROSCOPY	3.9
5XTI	ELECTRON MICROSCOPY	17.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P19404-F1	87.04	0.84

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 (4): 135; 140; 176; 180

Post-translational modifications (2): 61, 193

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-611105	Respiratory electron transport
R-HSA-6799198	Complex I biogenesis
R-HSA-1428517	Aerobic respiration and respiratory electron transport
R-HSA-1430728	Metabolism

MSigDB gene sets: 341 (showing top): MODULE_93, GOBP_MUSCLE_TISSUE_DEVELOPMENT, MODULE_151, MODULE_77, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, MORF_HDAC1, MORF_UBE2N, HSIAO_HOUSEKEEPING_GENES, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_NUCLEOSIDE_PHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_MONOATOMIC_CATION_TRANSPORT, PUJANA_CHEK2_PCC_NETWORK, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS

GO Biological Process (6): mitochondrial electron transport, NADH to ubiquinone (GO:0006120), nervous system development (GO:0007399), aerobic respiration (GO:0009060), proton motive force-driven mitochondrial ATP synthesis (GO:0042776), cardiac muscle tissue development (GO:0048738), proton transmembrane transport (GO:1902600)

GO Molecular Function (8): NADH dehydrogenase (ubiquinone) activity (GO:0008137), electron transfer activity (GO:0009055), oxidoreductase activity (GO:0016491), metal ion binding (GO:0046872), 2 iron, 2 sulfur cluster binding (GO:0051537), NADH dehydrogenase activity (GO:0003954), protein binding (GO:0005515), iron-sulfur cluster binding (GO:0051536)

GO Cellular Component (4): mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), respiratory chain complex I (GO:0045271), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Aerobic respiration and respiratory electron transport	1
Respiratory electron transport	1
Metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
aerobic electron transport chain	1
mitochondrial ATP synthesis coupled electron transport	1
system development	1
cellular respiration	1
mitochondrion	1
oxidative phosphorylation	1
proton motive force-driven ATP synthesis	1
heart development	1
striated muscle tissue development	1
monoatomic cation transmembrane transport	1
NADH dehydrogenase activity	1
electron transfer activity	1
proton transmembrane transporter activity	1
oxidoreduction-driven active transmembrane transporter activity	1
oxidoreductase activity, acting on NAD(P)H, quinone or similar compound as acceptor	1
active monoatomic ion transmembrane transporter activity	1
molecular_function	1
catalytic activity	1
cation binding	1
iron-sulfur cluster binding	1
oxidoreductase activity, acting on NAD(P)H	1
binding	1
metal cluster binding	1
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
NADH dehydrogenase complex	1
respiratory chain complex	1
transmembrane transporter complex	1
cellular anatomical structure	1

Protein interactions and networks

STRING

3233 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NDUFV2	NDUFS1	P28331	999
NDUFV2	NDUFV1	P49821	999
NDUFV2	NDUFS3	O75489	994
NDUFV2	NDUFS2	O75306	993
NDUFV2	NDUFS8	O00217	992
NDUFV2	NDUFS7	O75251	991
NDUFV2	NDUFA2	O43678	985
NDUFV2	NDUFS6	O75380	985
NDUFV2	NDUFS4	O43181	975
NDUFV2	NDUFV3	P56181	974
NDUFV2	NDUFA6	P56556	953
NDUFV2	NDUFA9	Q16795	949
NDUFV2	NDUFB5	O43674	887
NDUFV2	NDUFB6	O95139	866
NDUFV2	NDUFB9	Q9Y6M9	863

IntAct

375 interactions, top by confidence:

A	B	Type	Score
NDUFS3	NDUFS2	psi-mi:“MI:0914”(association)	0.850
NDUFS2	NDUFS3	psi-mi:“MI:0914”(association)	0.850
NDUFV2	CCNC	psi-mi:“MI:0915”(physical association)	0.780
CCNC	NDUFV2	psi-mi:“MI:0915”(physical association)	0.780
NDUFA9	NDUFS2	psi-mi:“MI:0915”(physical association)	0.740
NDUFS3	NDUFS8	psi-mi:“MI:0914”(association)	0.730
NDUFV2	NDUFS2	psi-mi:“MI:0914”(association)	0.730
NDUFS6	NDUFS8	psi-mi:“MI:0914”(association)	0.640
HSCB	NDUFV2	psi-mi:“MI:0915”(physical association)	0.560
NDUFV2	FAM114A2	psi-mi:“MI:0915”(physical association)	0.560
NDUFV2	GOLM1	psi-mi:“MI:0915”(physical association)	0.560
AP2B1	NDUFV2	psi-mi:“MI:0915”(physical association)	0.560
CALM1	NDUFV2	psi-mi:“MI:0915”(physical association)	0.560
CTNNB1	NDUFV2	psi-mi:“MI:0915”(physical association)	0.560
FANCG	NDUFV2	psi-mi:“MI:0915”(physical association)	0.560
FYN	NDUFV2	psi-mi:“MI:0915”(physical association)	0.560
HNRNPK	NDUFV2	psi-mi:“MI:0915”(physical association)	0.560
KRT33B	NDUFV2	psi-mi:“MI:0915”(physical association)	0.560
NAP1L3	NDUFV2	psi-mi:“MI:0915”(physical association)	0.560
NVL	NDUFV2	psi-mi:“MI:0915”(physical association)	0.560
OCLN	NDUFV2	psi-mi:“MI:0915”(physical association)	0.560
OTX1	NDUFV2	psi-mi:“MI:0915”(physical association)	0.560
PDZK1	NDUFV2	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (310): NDUFV2 (Affinity Capture-MS), NDUFV2 (Affinity Capture-MS), NDUFV2 (Affinity Capture-MS), COX2 (Co-fractionation), ND1 (Co-fractionation), NDUFA6 (Co-fractionation), NDUFS2 (Co-fractionation), NDUFV2 (Co-fractionation), NDUFV2 (Co-fractionation), NDUFV2 (Co-fractionation), NDUFV2 (Co-fractionation), NDUFV2 (Co-fractionation), TPI1 (Co-fractionation), NDUFV2 (Proximity Label-MS), NDUFV2 (Affinity Capture-MS)

ESM2 similar proteins: A7SDA8, A8XKG6, O04226, O17732, O22769, O22854, O23813, O65361, O82802, P04394, P05314, P11498, P19234, P19404, P22944, P25374, P29914, P38500, P40915, P40939, P49448, P52873, P54888, P70076, Q05920, Q0MQI7, Q0MQI8, Q0MQI9, Q12611, Q18164, Q20719, Q29554, Q29RK2, Q39161, Q42997, Q43644, Q54F10, Q55FT1, Q64428, Q64HZ8

Diamond homologs: O13691, O22769, P04394, P19404, Q0MQI7, Q0MQI8, Q0MQI9, Q20719, Q54F10, Q9D6J6, O52681, O66842, P19234, P29914, P40915, P56909, P56910, P57255, P65574, P9WIV4, P9WIV5, Q1RJJ1, Q46505, Q4UM09, Q56221, Q68X20, Q8K9Y4, Q92ID9, Q9I0J8, Q9ZDH5, P07324, P0A1Y8, P0A1Y9, P0AFD1, P0AFD2, P0AFD3, P22317, Q89AU3, O52682

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
SP1	“up-regulates quantity by expression”	NDUFV2	“transcriptional regulation”
SRC	“up-regulates activity”	NDUFV2	phosphorylation
NDUFV2	“form complex”	“NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 136 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
Complex I biogenesis	14	26.9×	4e-14
Respiratory electron transport	14	15.5×	7e-11
Aerobic respiration and respiratory electron transport	13	13.4×	2e-09

GO biological processes:

GO term	Partners	Fold	FDR
mitochondrial electron transport, NADH to ubiquinone	11	33.1×	6e-12
proton motive force-driven mitochondrial ATP synthesis	13	28.8×	5e-13
aerobic respiration	13	27.1×	6e-13
mitochondrial respiratory chain complex I assembly	7	24.2×	3e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	9
Likely pathogenic	6
Uncertain significance	64
Likely benign	32
Benign	11

Top pathogenic / likely-pathogenic (15)

Variant ID	HGVS	Classification
1457142	NM_021074.5(NDUFV2):c.237_246del (p.Leu80fs)	Pathogenic
1901338	NM_021074.5(NDUFV2):c.394dup (p.Ile132fs)	Pathogenic
1983996	NM_021074.5(NDUFV2):c.230_236del (p.Ala77fs)	Pathogenic
1993808	NM_021074.5(NDUFV2):c.505_506del (p.Phe169fs)	Pathogenic
2398092	NM_021074.5(NDUFV2):c.491_492insGT (p.Pro165fs)	Pathogenic
279920	NM_021074.5(NDUFV2):c.120+5_120+8del	Pathogenic
2822108	NM_021074.5(NDUFV2):c.206dup (p.Asn69fs)	Pathogenic
4689201	NM_021074.5(NDUFV2):c.206del (p.Asn69fs)	Pathogenic
4811719	NM_021074.5(NDUFV2):c.492_502del (p.Pro165fs)	Pathogenic
1704593	NC_000018.9:g.(9124982_9126828)_(9126906_9134183)del	Likely pathogenic
2054766	NM_021074.5(NDUFV2):c.300+2T>A	Likely pathogenic
214866	NM_021074.5(NDUFV2):c.569A>G (p.Asp190Gly)	Likely pathogenic
3256772	NM_021074.5(NDUFV2):c.346G>C (p.Ala116Pro)	Likely pathogenic
3780012	NM_021074.5(NDUFV2):c.587del (p.Asp195_Leu196insTer)	Likely pathogenic
445415	NM_021074.5(NDUFV2):c.434_435del (p.Asn144_Ser145insTer)	Likely pathogenic

SpliceAI

1031 predictions. Top by Δscore:

Variant	Effect	Δscore
18:9102796:GG:G	donor_gain	1.0000
18:9102797:GG:G	donor_gain	1.0000
18:9119324:A:AG	acceptor_gain	1.0000
18:9119325:G:GG	acceptor_gain	1.0000
18:9119325:GCACA:G	acceptor_gain	1.0000
18:9119472:A:AG	acceptor_gain	1.0000
18:9119472:AGAG:A	acceptor_gain	1.0000
18:9119473:G:GG	acceptor_gain	1.0000
18:9119473:G:GT	acceptor_loss	1.0000
18:9119473:GA:G	acceptor_gain	1.0000
18:9119473:GAGG:G	acceptor_gain	1.0000
18:9119586:ACAAG:A	donor_loss	1.0000
18:9119587:CAAGG:C	donor_loss	1.0000
18:9119588:AAG:A	donor_loss	1.0000
18:9119592:T:A	donor_loss	1.0000
18:9122677:GCTTG:G	donor_gain	1.0000
18:9122678:C:G	donor_gain	1.0000
18:9126825:TTCCA:T	acceptor_loss	1.0000
18:9126826:TCCA:T	acceptor_loss	1.0000
18:9126827:CCA:C	acceptor_loss	1.0000
18:9126829:A:AG	acceptor_gain	1.0000
18:9126829:AGGAG:A	acceptor_gain	1.0000
18:9126830:G:GG	acceptor_gain	1.0000
18:9126830:G:T	acceptor_loss	1.0000
18:9126830:GGA:G	acceptor_gain	1.0000
18:9126830:GGAGG:G	acceptor_gain	1.0000
18:9126903:CCAAG:C	donor_loss	1.0000
18:9126904:CAAGG:C	donor_loss	1.0000
18:9126905:AAGG:A	donor_loss	1.0000
18:9126906:AGG:A	donor_loss	1.0000

AlphaMissense

1628 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
18:9122564:T:C	F118L	1.000
18:9122566:T:A	F118L	1.000
18:9122566:T:G	F118L	1.000
18:9124930:T:C	C176R	1.000
18:9122615:T:C	C135R	0.999
18:9122616:G:A	C135Y	0.999
18:9122616:G:T	C135F	0.999
18:9122617:C:G	C135W	0.999
18:9122630:T:C	C140R	0.999
18:9122631:G:A	C140Y	0.999
18:9122632:C:G	C140W	0.999
18:9124931:G:A	C176Y	0.999
18:9124932:T:G	C176W	0.999
18:9124937:G:A	G178E	0.999
18:9124942:T:C	C180R	0.999
18:9124943:G:A	C180Y	0.999
18:9124944:T:G	C180W	0.999
18:9119538:T:C	L83P	0.998
18:9119547:C:A	A86D	0.998
18:9119568:T:G	L93W	0.998
18:9122615:T:A	C135S	0.998
18:9122616:G:C	C135S	0.998
18:9122630:T:A	C140S	0.998
18:9122631:G:C	C140S	0.998
18:9122631:G:T	C140F	0.998
18:9124930:T:A	C176S	0.998
18:9124931:G:C	C176S	0.998
18:9124936:G:A	G178R	0.998
18:9124936:G:C	G178R	0.998
18:9124936:G:T	G178W	0.998

dbSNP variants (sampled 300 via entrez): RS1000079601 (18:9120147 C>T), RS1000197358 (18:9103376 A>G), RS1000206267 (18:9110856 T>C), RS1000329540 (18:9100967 T>C), RS1000427352 (18:9110530 A>C,T), RS1000523561 (18:9118552 T>A), RS1000568152 (18:9112179 C>T), RS1000593908 (18:9105473 A>G), RS1000786515 (18:9130359 C>T), RS1000982079 (18:9112026 T>TG), RS1001137145 (18:9130615 A>C), RS1001275748 (18:9127010 G>A), RS1001314215 (18:9100913 A>G), RS1001428356 (18:9101180 G>A,T), RS1001523130 (18:9124700 A>G)

Disease associations

OMIM: gene MIM:600532 | disease phenotypes: MIM:618229, MIM:252010, MIM:556500

GenCC curated gene-disease

Disease	Classification	Inheritance
mitochondrial complex I deficiency, nuclear type 7	Strong	Autosomal recessive
Leigh syndrome with leukodystrophy	Supportive	Autosomal recessive
mitochondrial complex I deficiency	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
mitochondrial disease	Definitive	AR
Leigh syndrome	Limited	AR

Mondo (5): mitochondrial complex I deficiency, nuclear type 7 (MONDO:0032612), mitochondrial complex I deficiency, nuclear type 1 (MONDO:0100224), Parkinson disease, mitochondrial (MONDO:0010796), (MONDO:0016815), mitochondrial complex I deficiency (MONDO:0100133)

Orphanet (0):

HPO phenotypes

47 total (30 of 47 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000114	Proximal tubulopathy
HP:0000252	Microcephaly
HP:0000407	Sensorineural hearing impairment
HP:0000486	Strabismus
HP:0000508	Ptosis
HP:0000543	Optic disc pallor
HP:0000618	Blindness
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000817	Reduced eye contact
HP:0000819	Diabetes mellitus
HP:0001138	Optic neuropathy
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001254	Lethargy
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001290	Generalized hypotonia
HP:0001298	Encephalopathy
HP:0001324	Muscle weakness
HP:0001508	Failure to thrive
HP:0001511	Intrauterine growth retardation
HP:0001522	Death in infancy
HP:0001639	Hypertrophic cardiomyopathy
HP:0001943	Hypoglycemia
HP:0002013	Vomiting
HP:0002093	Respiratory insufficiency
HP:0002240	Hepatomegaly
HP:0002352	Leukoencephalopathy

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST002949_21	Epilepsy and lamotrigine-induced maculopapular eruptions	6.000000e-07
GCST003073_17	Cerebral amyloid deposition (PET imaging)	4.000000e-06
GCST003073_9	Cerebral amyloid deposition (PET imaging)	3.000000e-07
GCST003485_12	Response to fenofibrate (HDL cholesterol levels)	7.000000e-07
GCST008161_99	Waist circumference adjusted for body mass index	4.000000e-07
GCST90002401_560	Platelet distribution width	6.000000e-09

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:1001253	maculopapular eruption
EFO:0007707	cerebral amyloid deposition measurement
EFO:0007805	HDL cholesterol change measurement
EFO:0007789	BMI-adjusted waist circumference
EFO:0007984	platelet component distribution width

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
C537475	Mitochondrial complex I deficiency (supp.)
C564015	Parkinson Disease, Mitochondrial (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2363065 (PROTEIN COMPLEX), CHEMBL6066946 (SINGLE PROTEIN)

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

ChEMBL bioactivities

10 potent at pChembl≥5 of 20 total, top 10 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.24	Kd	570.6	nM	CHEMBL3752910
6.24	ED50	570.6	nM	CHEMBL3752910
6.06	IC50	870	nM	R-(+)-MARMIN-6’-UNDECANOATE
6.04	IC50	920	nM	R-(+)-MARMIN-6’-LINOLEATE
5.63	IC50	2350	nM	R-(+)-MARMIN-6’-LINOLEATE
5.51	IC50	3080	nM	R-(+)-MARMIN-6’-OCTANOATE
5.43	IC50	3670	nM	R-(+)-MARMIN-6’-UNDECANOATE
5.43	IC50	3710	nM	R-(+)-MARMIN-6’-OCTANOATE
5.31	IC50	4900	nM	(+)-9’-ISOVALEROXYLARICIRESINOL
5.04	IC50	9100	nM	(+)-9’-ISOVALEROXYLARICIRESINOL

PubChem BioAssay actives

9 with measured affinity, of 30 total; 5 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149896: Binding affinity to human NDUFV2 incubated for 45 mins by Kinobead based pull down assay	kd	0.5706	uM
[(E,3R)-2-hydroxy-2,6-dimethyl-8-(2-oxochromen-7-yl)oxyoct-6-en-3-yl] undecanoate	739270: Inhibition of mitochondrial ETC complex 1 in human T47D cells assessed as inhibition of 1% O2-induced HIF1 activation incubated for 30 mins prior to 1% O2-challenge measured after 16 hrs by luciferase reporter assay	ic50	0.8700	uM
[(E,3R)-2-hydroxy-2,6-dimethyl-8-(2-oxochromen-7-yl)oxyoct-6-en-3-yl] (9Z,12Z)-octadeca-9,12-dienoate	739270: Inhibition of mitochondrial ETC complex 1 in human T47D cells assessed as inhibition of 1% O2-induced HIF1 activation incubated for 30 mins prior to 1% O2-challenge measured after 16 hrs by luciferase reporter assay	ic50	0.9200	uM
[(E,3R)-2-hydroxy-2,6-dimethyl-8-(2-oxochromen-7-yl)oxyoct-6-en-3-yl] octanoate	739270: Inhibition of mitochondrial ETC complex 1 in human T47D cells assessed as inhibition of 1% O2-induced HIF1 activation incubated for 30 mins prior to 1% O2-challenge measured after 16 hrs by luciferase reporter assay	ic50	3.0800	uM
[(2S,3R,4R)-2-(4-hydroxy-3-methoxyphenyl)-4-[(4-hydroxy-3-methoxyphenyl)methyl]oxolan-3-yl]methyl 3-methylbutanoate	739269: Inhibition of mitochondrial ETC complex 1 in human T47D cells assessed as inhibition of 1,10-phenanthroline-induced HIF1 activation incubated for 30 mins prior to 1,10-phenanthroline-challenge measured after 16 hrs by luciferase reporter assay	ic50	4.9000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, decreases methylation, increases expression	3
Acetaminophen	affects cotreatment, decreases expression	2
Cadmium	decreases expression, increases abundance, increases expression	2
Valproic Acid	decreases methylation, increases expression	2
Aflatoxin B1	decreases methylation, increases methylation	2
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
GSK-J4	increases expression	1
sotorasib	affects cotreatment, decreases expression	1
dicrotophos	decreases expression	1
O,O-diethyl O-3,5,6-trichloro-2-pyridyl phosphate	affects response to substance, affects expression	1
beta-lapachone	increases expression	1
arsenite	affects binding, increases reaction	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
aflatoxin B2	increases methylation	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
azoxystrobin	increases expression	1
K 7174	decreases expression	1
bisphenol S	affects expression	1
picoxystrobin	increases expression	1
trametinib	decreases expression, affects cotreatment	1
NVP-BKM120	affects cotreatment, decreases expression	1
bisphenol AF	increases expression	1
Resveratrol	increases expression	1
Sunitinib	decreases expression	1
Glyphosate	increases expression	1
Benzo(a)pyrene	affects methylation	1
Doxorubicin	increases expression	1
Isoniazid	decreases expression	1
Ivermectin	decreases expression	1

ChEMBL screening assays

5 unique, capped per target: 5 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2353025	Binding	Inhibition of mitochondrial ETC complex 1 in human T47D cells assessed as inhibition of 1% O2-induced HIF1 activation at 30 uM incubated for 30 mins prior to 1% O2-challenge measured after 16 hrs by luciferase reporter assay	Semisynthetic studies identify mitochondria poisons from botanical dietary supplements–geranyloxycoumarins from Aegle marmelos. — Bioorg Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05162768	PHASE3	COMPLETED	Study to Evaluate Efficacy and Safety of Elamipretide in Subjects With Primary Mitochondrial Disease From Nuclear DNA Mutations (nPMD)
NCT04300608	Not specified	UNKNOWN	Measures of Mitochondria Dysfunction in PD