NDUFA10

Summary

NDUFA10 (NADH:ubiquinone oxidoreductase subunit A10, HGNC:7684) is a protein-coding gene on chromosome 2q37.3, encoding NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 10, mitochondrial (O95299). Accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), that is believed not to be involved in catalysis. It is a selective cancer dependency (DepMap: 23.0% of cell lines).

The protein encoded by this gene is a component of 42 kDa complex I, the first enzyme complex in the electron transport chain of mitochondria. This protein has NADH dehydrogenase activity and oxidoreductase activity. It transfers electrons from NADH to the respiratory chain. A mutation in this gene was found in an individual with Leigh syndrome.

Source: NCBI Gene 4705 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial complex I deficiency, nuclear type 22 (Strong, GenCC) — +3 more curated relationships
• GWAS associations: 4
• Clinical variants (ClinVar): 394 total — 3 pathogenic, 5 likely-pathogenic
• Phenotypes (HPO): 14
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 23.0% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_004544

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7684
Approved symbol	NDUFA10
Name	NADH:ubiquinone oxidoreductase subunit A10
Location	2q37.3
Locus type	gene with protein product
Status	Approved
Aliases	CI-42k
Ensembl gene	ENSG00000130414
Ensembl biotype	protein_coding
OMIM	603835
Entrez	4705

Gene structure

Transcript identifiers

Ensembl transcripts: 61 — 35 protein_coding, 15 nonsense_mediated_decay, 10 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000252711, ENST00000307300, ENST00000404554, ENST00000407129, ENST00000414580, ENST00000419408, ENST00000443626, ENST00000444548, ENST00000448880, ENST00000471378, ENST00000476216, ENST00000485344, ENST00000497536, ENST00000620965, ENST00000676491, ENST00000676782, ENST00000676784, ENST00000676929, ENST00000677057, ENST00000677114, ENST00000677155, ENST00000677263, ENST00000677294, ENST00000677324, ENST00000677368, ENST00000677395, ENST00000677407, ENST00000677490, ENST00000677567, ENST00000677692, ENST00000677764, ENST00000677979, ENST00000678158, ENST00000678188, ENST00000678289, ENST00000678455, ENST00000678468, ENST00000678562, ENST00000678737, ENST00000678832, ENST00000678898, ENST00000678914, ENST00000679158, ENST00000679183, ENST00000679308, ENST00000679332, ENST00000902963, ENST00000902964, ENST00000902965, ENST00000902966, ENST00000902967, ENST00000902968, ENST00000902969, ENST00000902970, ENST00000902971, ENST00000928964, ENST00000928965, ENST00000928966, ENST00000961863, ENST00000961864, ENST00000961865

RefSeq mRNA: 4 — MANE Select: NM_004544 NM_001322019, NM_001322020, NM_001410987, NM_004544

CCDS: CCDS2531, CCDS92982, CCDS92983, CCDS92984

Canonical transcript exons

ENST00000252711 — 10 exons

Exon	Start	End
ENSE00000787391	240011617	240011696
ENSE00000895766	240014739	240014860
ENSE00001349878	240025227	240025342
ENSE00001873510	239957372	239961186
ENSE00003499314	240005210	240005295
ENSE00003532784	240022172	240022340
ENSE00003535386	239990074	239990182
ENSE00003574331	240007316	240007370
ENSE00003605999	240021197	240021412
ENSE00003606348	240018553	240018639

Expression profiles

Bgee: expression breadth ubiquitous, 291 present calls, max score 98.71.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 87.5423 / max 386.6482, expressed in 1828 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
34817	85.5042	1828
34818	2.0381	1289

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	98.71	gold quality
heart left ventricle	UBERON:0002084	98.36	gold quality
cardiac ventricle	UBERON:0002082	98.33	gold quality
right atrium auricular region	UBERON:0006631	98.29	gold quality
mucosa of transverse colon	UBERON:0004991	98.11	gold quality
heart right ventricle	UBERON:0002080	97.96	gold quality
right adrenal gland	UBERON:0001233	97.89	gold quality
left adrenal gland	UBERON:0001234	97.85	gold quality
left adrenal gland cortex	UBERON:0035825	97.77	gold quality
right adrenal gland cortex	UBERON:0035827	97.75	gold quality
transverse colon	UBERON:0001157	97.54	gold quality
rectum	UBERON:0001052	97.51	gold quality
gastrocnemius	UBERON:0001388	97.46	gold quality
hindlimb stylopod muscle	UBERON:0004252	97.44	gold quality
heart	UBERON:0000948	97.41	gold quality
adrenal cortex	UBERON:0001235	97.34	gold quality
adrenal gland	UBERON:0002369	97.34	gold quality
right hemisphere of cerebellum	UBERON:0014890	97.33	gold quality
skin of abdomen	UBERON:0001416	97.30	gold quality
skin of leg	UBERON:0001511	97.26	gold quality
muscle of leg	UBERON:0001383	97.24	gold quality
cerebellar hemisphere	UBERON:0002245	97.23	gold quality
right frontal lobe	UBERON:0002810	97.22	gold quality
body of stomach	UBERON:0001161	97.16	gold quality
diaphragm	UBERON:0001103	97.12	gold quality
triceps brachii	UBERON:0001509	97.08	gold quality
cerebellar cortex	UBERON:0002129	97.08	gold quality
mucosa of sigmoid colon	UBERON:0004993	96.99	gold quality
colonic mucosa	UBERON:0000317	96.97	gold quality
biceps brachii	UBERON:0001507	96.87	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-GEOD-100618	no	1183.60
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

110 targeting NDUFA10, 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-4533	100.00	69.48	2758
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-433-3P	99.98	69.37	1203
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-23B-5P	99.98	66.07	587
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-23A-5P	99.94	65.39	468
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-10395-5P	99.86	67.35	676
HSA-MIR-383-3P	99.85	65.84	1359
HSA-MIR-1321	99.84	65.30	1811

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 23.0% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 4)

• NDUFA10 was found to be differentially methylated and expressed in human squamous cell carcinomas. (PMID:22461910)
• Identifying Mitochondrial-Related Genes NDUFA10 and NDUFV2 as Prognostic Markers for Prostate Cancer through Biclustering. (PMID:34124242)
• Most mitochondrial dGTP is tightly bound to respiratory complex I through the NDUFA10 subunit. (PMID:35739187)
• An Exploration of the Coherent Effects between METTL3 and NDUFA10 on Alzheimer’s Disease. (PMID:37373264)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	ndufa10	ENSDARG00000013333
mus_musculus	Ndufa10	ENSMUSG00000026260
rattus_norvegicus	Ndufa10	ENSRNOG00000016470
rattus_norvegicus	Ndufa10l1	ENSRNOG00000062245
drosophila_melanogaster	ND-42	FBGN0019957
caenorhabditis_elegans		WBGENE00019401

Paralogs (3): DGUOK (ENSG00000114956), DCK (ENSG00000156136), TK2 (ENSG00000166548)

Protein

Protein identifiers

NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 10, mitochondrial — O95299 (reviewed: O95299)

Alternative names: Complex I-42kD, NADH-ubiquinone oxidoreductase 42 kDa subunit

All UniProt accessions (28): O95299, A0A087WXC5, A0A7I2V2F6, A0A7I2V2I6, A0A7I2V2J5, A0A7I2V2N6, A0A7I2V2Q2, A0A7I2V2W9, A0A7I2V2X3, A0A7I2V327, A0A7I2V3D4, A0A7I2V3H5, A0A7I2V419, A0A7I2V438, A0A7I2V458, A0A7I2V4N8, A0A7I2V594, A0A7I2V5B2, A0A7I2V5L0, A0A7I2V5U7, A0A7I2YQU0, C9J6X0, E7ESZ7, F8WEH0, H7C1Y7, H7C2W5, H7C2X4, Q8N1B9

UniProt curated annotations — full annotation on UniProt →

Function. Accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), that is believed not to be involved in catalysis. Complex I functions in the transfer of electrons from NADH to the respiratory chain. The immediate electron acceptor for the enzyme is believed to be ubiquinone.

Subunit / interactions. Complex I is composed of 45 different subunits. This a component of the hydrophobic protein fraction.

Subcellular location. Mitochondrion matrix.

Post-translational modifications. Phosphorylation at Ser-250 by PINK1 is required for the binding and/or reduction of the complex I substrate ubiquinone.

Disease relevance. Mitochondrial complex I deficiency, nuclear type 22 (MC1DN22) [MIM:618243] 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. MC1DN22 transmission pattern is consistent with autosomal recessive inheritance. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Binds 1 FAD per subunit.

Similarity. Belongs to the complex I NDUFA10 subunit family.

Isoforms (2)

UniProt ID	Names	Canonical?
O95299-1	1	yes
O95299-2	2

RefSeq proteins (4): NP_001308948, NP_001308949, NP_001397916, NP_004535* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR015828	NDUFA10	Family
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR031314	DNK_dom	Domain
IPR050566	Deoxyribonucleoside_kinase	Family

Pfam: PF01712

UniProt features (10 total): splice variant 3, sequence variant 3, modified residue 2, transit peptide 1, chain 1

Structure

Experimental structures (PDB)

6 structures.

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

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O95299-F1	84.79	0.54

Functional residue map

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

Post-translational modifications (2): 250, 285

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: 215 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_DN, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_NUCLEOSIDE_PHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, CREB_Q4, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY, GOBP_ATP_BIOSYNTHETIC_PROCESS, GOBP_OXIDATIVE_PHOSPHORYLATION, GOBP_CARBOHYDRATE_DERIVATIVE_BIOSYNTHETIC_PROCESS, GOBP_NUCLEOSIDE_TRIPHOSPHATE_METABOLIC_PROCESS, GOBP_NUCLEOSIDE_TRIPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_ELECTRON_TRANSPORT_CHAIN

GO Biological Process (4): mitochondrial electron transport, NADH to ubiquinone (GO:0006120), aerobic respiration (GO:0009060), proton motive force-driven mitochondrial ATP synthesis (GO:0042776), proton transmembrane transport (GO:1902600)

GO Molecular Function (1): NADH dehydrogenase (ubiquinone) activity (GO:0008137)

GO Cellular Component (5): cytoplasm (GO:0005737), mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), mitochondrial matrix (GO:0005759), respiratory chain complex I (GO:0045271)

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
mitochondrion	2
aerobic electron transport chain	1
mitochondrial ATP synthesis coupled electron transport	1
cellular respiration	1
oxidative phosphorylation	1
proton motive force-driven ATP synthesis	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
intracellular anatomical structure	1
cellular anatomical structure	1
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
intracellular organelle lumen	1
NADH dehydrogenase complex	1
respiratory chain complex	1
transmembrane transporter complex	1

Protein interactions and networks

STRING

2006 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NDUFA10	NDUFB10	O96000	981
NDUFA10	NDUFA7	O95182	958
NDUFA10	NDUFA5	Q16718	954
NDUFA10	NDUFB4	O95168	949
NDUFA10	NDUFA2	O43678	947
NDUFA10	NDUFB2	O95178	918
NDUFA10	NDUFS2	O75306	905
NDUFA10	NDUFA9	Q16795	887
NDUFA10	NDUFS1	P28331	881
NDUFA10	NDUFV1	P49821	828
NDUFA10	NDUFS3	O75489	820
NDUFA10	NDUFB9	Q9Y6M9	818
NDUFA10	NDUFA1	O15239	806
NDUFA10	NDUFS8	O00217	805
NDUFA10	NDUFA6	P56556	789

IntAct

119 interactions, top by confidence:

A	B	Type	Score
NDUFS3	NDUFS8	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
PLK1	EVI5	psi-mi:“MI:0914”(association)	0.660
NDUFS6	NDUFS8	psi-mi:“MI:0914”(association)	0.640
NDUFA9	NDUFS4	psi-mi:“MI:0914”(association)	0.640
NDUFA9	NDUFS8	psi-mi:“MI:0914”(association)	0.530
NDUFV2	NDUFS8	psi-mi:“MI:0914”(association)	0.530
NDUFC2	NDUFS4	psi-mi:“MI:0914”(association)	0.530
DNAJC30	NDUFS8	psi-mi:“MI:0914”(association)	0.530
NDUFA1	NDUFA7	psi-mi:“MI:0914”(association)	0.530
NDUFA7	NDUFA1	psi-mi:“MI:0914”(association)	0.530
NDUFA9	NDUFA1	psi-mi:“MI:0914”(association)	0.530
RAB8A	EXOC5	psi-mi:“MI:0914”(association)	0.510
DDX21	MED19	psi-mi:“MI:2364”(proximity)	0.480
NDUFA10	NDUFA5	psi-mi:“MI:0915”(physical association)	0.400
SAT2	NDUFA10	psi-mi:“MI:0915”(physical association)	0.400
ASB2	NDUFA10	psi-mi:“MI:0915”(physical association)	0.400
NDUFA10	rep	psi-mi:“MI:0915”(physical association)	0.400
NDUFA2	NDUFS8	psi-mi:“MI:0915”(physical association)	0.400
NDUFA10	PCNA	psi-mi:“MI:0915”(physical association)	0.370
NDUFA10	rep	psi-mi:“MI:0915”(physical association)	0.370
NDUFA11	NDUFS8	psi-mi:“MI:0914”(association)	0.350
Rab5c		psi-mi:“MI:0914”(association)	0.350

BioGRID (243): NDUFA10 (Affinity Capture-MS), MTIF2 (Affinity Capture-MS), ACAD10 (Affinity Capture-MS), CLUH (Affinity Capture-MS), KDM1B (Affinity Capture-MS), DECR1 (Affinity Capture-MS), RNF123 (Affinity Capture-MS), PLXDC2 (Affinity Capture-MS), SIRT3 (Affinity Capture-MS), CLPP (Affinity Capture-MS), NDUFAF5 (Affinity Capture-MS), SPATA20 (Affinity Capture-MS), RSPRY1 (Affinity Capture-MS), NDUFAF7 (Affinity Capture-MS), DHRS4 (Affinity Capture-MS)

ESM2 similar proteins: A0A0G2K344, A2VE39, A4IHT9, D2HRF1, O02697, O23617, O80738, O95299, P0C1Q3, P0CB89, P0CB90, P32871, P35574, P42336, P42337, P42338, P48736, Q0MQB6, Q0MQB7, Q0WUI9, Q295E6, Q2TBU5, Q3UHB1, Q502J0, Q561S0, Q5EBA1, Q5R981, Q5U2Z5, Q6GN91, Q6GQ76, Q7L5N7, Q803R5, Q80YD1, Q86UY8, Q8BTI9, Q8BYI6, Q8C5P5, Q8IYB8, Q8N1G2, Q923J1

Diamond homologs: O95299, P0CB89, P0CB90, P34942, P91929, Q0MQB6, Q0MQB7, Q54UT2, Q561S0, Q99LC3, P0C1F9, P0C1G0, Q54YL2, Q74HC2, Q74HC3, Q9J579

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
NDUFA10	“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 118 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	20	39.9×	5e-25
Respiratory electron transport	21	24.1×	1e-21
Aerobic respiration and respiratory electron transport	19	20.3×	5e-18

GO biological processes:

GO term	Partners	Fold	FDR
mitochondrial electron transport, NADH to ubiquinone	18	64.5×	5e-26
proton motive force-driven mitochondrial ATP synthesis	19	50.0×	2e-25
aerobic respiration	19	47.1×	6e-25
mitochondrial respiratory chain complex I assembly	7	28.8×	8e-07

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	5
Uncertain significance	193
Likely benign	81
Benign	57

Top pathogenic / likely-pathogenic (8)

Variant ID	HGVS	Classification
30393	NM_004544.4(NDUFA10):c.425A>G (p.Gln142Arg)	Pathogenic
372194	NM_004544.4(NDUFA10):c.881T>C (p.Leu294Pro)	Pathogenic
372195	NM_004544.4(NDUFA10):c.384_385insAAT (p.Ser128_Tyr129insAsn)	Pathogenic
1327627	NM_004544.4(NDUFA10):c.296G>A (p.Gly99Glu)	Likely pathogenic
2577650	NM_004544.4(NDUFA10):c.415C>T (p.Arg139Cys)	Likely pathogenic
30392	NM_004544.4(NDUFA10):c.1A>G (p.Met1Val)	Likely pathogenic
3767163	NM_004544.4(NDUFA10):c.890T>C (p.Leu297Pro)	Likely pathogenic
452968	NM_004544.4(NDUFA10):c.548-2A>G	Likely pathogenic

SpliceAI

2511 predictions. Top by Δscore:

Variant	Effect	Δscore
2:239990073:CCT:C	donor_gain	1.0000
2:239990073:CCTCT:C	donor_gain	1.0000
2:239990181:CC:C	acceptor_gain	1.0000
2:239990182:CC:C	acceptor_gain	1.0000
2:240005202:GCAC:G	donor_loss	1.0000
2:240005203:CACTT:C	donor_loss	1.0000
2:240005204:ACTT:A	donor_loss	1.0000
2:240005205:CTTA:C	donor_loss	1.0000
2:240005206:TTAC:T	donor_loss	1.0000
2:240005207:TAC:T	donor_loss	1.0000
2:240005208:A:AC	donor_gain	1.0000
2:240005208:ACAG:A	donor_loss	1.0000
2:240005209:C:CC	donor_gain	1.0000
2:240005209:CA:C	donor_gain	1.0000
2:240005209:CAGT:C	donor_gain	1.0000
2:240005209:CAGTA:C	donor_gain	1.0000
2:240005292:CCAC:C	acceptor_gain	1.0000
2:240005293:CACC:C	acceptor_gain	1.0000
2:240005295:CCTAA:C	acceptor_loss	1.0000
2:240005296:CTAAG:C	acceptor_loss	1.0000
2:240005297:T:G	acceptor_loss	1.0000
2:240007310:TCTTA:T	donor_loss	1.0000
2:240007311:CTTA:C	donor_loss	1.0000
2:240007312:TTA:T	donor_loss	1.0000
2:240007314:A:AT	donor_loss	1.0000
2:240007366:TTTCA:T	acceptor_gain	1.0000
2:240007367:TTCA:T	acceptor_gain	1.0000
2:240007368:TCA:T	acceptor_gain	1.0000
2:240007369:CA:C	acceptor_gain	1.0000
2:240007369:CAC:C	acceptor_gain	1.0000

AlphaMissense

2333 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:240018605:A:C	S165R	0.996
2:240018605:A:T	S165R	0.996
2:240018607:T:G	S165R	0.996
2:240021241:C:G	R139P	0.994
2:240021306:A:C	F117L	0.993
2:240021306:A:T	F117L	0.993
2:240021308:A:G	F117L	0.993
2:240018603:T:A	D166V	0.991
2:240018618:C:G	R161P	0.990
2:240018593:G:C	F169L	0.989
2:240018593:G:T	F169L	0.989
2:240018595:A:G	F169L	0.989
2:240018604:C:G	D166H	0.989
2:240011665:A:G	L234P	0.988
2:240021221:C:G	A146P	0.988
2:240021273:A:C	S128R	0.988
2:240021273:A:T	S128R	0.988
2:240021275:T:G	S128R	0.988
2:240021307:A:G	F117S	0.988
2:240021242:G:T	R139S	0.987
2:240021268:C:G	R130P	0.987
2:240018603:T:G	D166A	0.986
2:240021238:A:G	L140P	0.986
2:240021265:A:G	L131P	0.986
2:240022231:A:T	V62E	0.985
2:240005253:A:G	W283R	0.984
2:240005253:A:T	W283R	0.984
2:240018606:C:A	S165I	0.984
2:240021220:G:T	A146D	0.983
2:240018627:A:T	V158E	0.981

dbSNP variants (sampled 300 via entrez): RS1000031801 (2:239933287 G>T), RS1000058797 (2:239993626 T>C), RS1000104643 (2:239997706 A>G), RS1000104658 (2:239933491 G>A), RS1000127056 (2:239960615 A>G,T), RS1000137736 (2:239950707 A>C), RS1000169279 (2:239918110 A>G), RS1000186886 (2:239991654 G>A), RS1000194251 (2:239892604 C>G,T), RS1000195983 (2:239961626 T>C), RS1000305169 (2:239933729 A>G,T), RS1000323834 (2:239991952 A>G), RS1000356419 (2:239928613 C>T), RS1000357302 (2:239922247 T>A), RS1000363691 (2:240022980 A>T)

Disease associations

OMIM: gene MIM:603835 | disease phenotypes: MIM:256000, MIM:618243, MIM:252010, MIM:181500

GenCC curated gene-disease

Disease	Classification	Inheritance
mitochondrial complex I deficiency, nuclear type 22	Strong	Autosomal recessive
Leigh syndrome with leukodystrophy	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
mitochondrial disease	Moderate	AR
Leigh syndrome	Limited	AR

Mondo (5): Leigh syndrome (MONDO:0009723), mitochondrial complex I deficiency, nuclear type 22 (MONDO:0032626), mitochondrial complex I deficiency, nuclear type 1 (MONDO:0100224), schizophrenia (MONDO:0005090), (MONDO:0016815)

Orphanet (2): Leigh syndrome (Orphanet:506), NON RARE IN EUROPE: Schizophrenia (Orphanet:3140)

HPO phenotypes

14 total (15 of 14 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001511	Intrauterine growth retardation
HP:0001639	Hypertrophic cardiomyopathy
HP:0002093	Respiratory insufficiency
HP:0002421	Poor head control
HP:0002490	Increased CSF lactate
HP:0003128	Lactic acidosis
HP:0003593	Infantile onset
HP:0003623	Neonatal onset
HP:0011923	Decreased activity of mitochondrial complex I
HP:0025116	Fetal distress
HP:0032653	Elevated lactate:pyruvate ratio
HP:0100753	Schizophrenia

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST002105_1	Odorant perception (isobutyraldehyde)	6.000000e-10
GCST007692_13	Chronic obstructive pulmonary disease	3.000000e-06
GCST008477_11	Emphysema annual change measurement in smokers (adjusted lung density)	4.000000e-06
GCST009391_1554	Metabolite levels	4.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0007626	emphysema imaging measurement
EFO:0009776	ornithine measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D007888	Leigh Disease	C10.228.140.163.100.412; C16.320.565.189.412; C16.320.565.202.810.444; C18.452.132.100.412; C18.452.648.189.412; C18.452.648.202.810.444; C18.452.660.520

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2089 (SINGLE PROTEIN), CHEMBL2363065 (PROTEIN COMPLEX)

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
7.95	Kd	11.18	nM	CHEMBL5653589
7.95	ED50	11.18	nM	CHEMBL5653589
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-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148838: Binding affinity to human NDUFA10 incubated for 45 mins by Kinobead based pull down assay	kd	0.0112	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

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects cotreatment, decreases methylation, decreases expression, increases expression	3
Fluorouracil	affects response to substance, increases expression	3
bisphenol F	affects cotreatment, decreases methylation, increases expression	2
sodium arsenite	decreases expression, increases abundance, affects cotreatment	2
Acetaminophen	decreases expression	2
Doxorubicin	affects expression, increases expression	2
Rotenone	decreases expression, increases expression	2
Tretinoin	affects cotreatment, decreases expression	2
nobiletin	decreases reaction, increases expression	1
sodium arsenate	decreases reaction, increases expression	1
beta-lapachone	increases expression	1
arsenite	affects binding, increases reaction	1
afimoxifene	decreases response to substance	1
perfluorooctanoic acid	decreases expression	1
ochratoxin A	increases expression	1
benzo(e)pyrene	increases methylation	1
di-n-butylphosphoric acid	affects expression	1
clothianidin	increases expression	1
bisphenol B	increases expression	1
bisphenol S	affects expression	1
bisphenol AF	increases expression	1
Arsenic Trioxide	increases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Arsenic	decreases expression, increases abundance	1
Benzo(a)pyrene	decreases methylation	1
Cocaine	affects expression	1
Diethylstilbestrol	decreases expression	1
Ivermectin	decreases expression	1
Methapyrilene	increases methylation	1
Methotrexate	increases 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
CHEMBL5651880	Binding	Binding affinity to human NDUFA10 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

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00000374	PHASE4	COMPLETED	Treatment for First-Episode Schizophrenia
NCT00001656	PHASE4	COMPLETED	Comparison of Clozapine vs Olanzapine in Childhood-Onset Psychotic Disorders
NCT00007774	PHASE4	COMPLETED	To Determine if Olanzapine is More Cost Effective Than Haloperidol for the Treatment of Schizophrenia
NCT00014001	PHASE4	COMPLETED	CATIE- Schizophrenia Trial
NCT00018668	PHASE4	COMPLETED	Antipsychotic Response in Schizophrenia
NCT00034801	PHASE4	COMPLETED	Olanzapine Versus Active Comparator in the Treatment of Depression in Patients With Schizophrenia
NCT00034905	PHASE4	COMPLETED	A Comparison of Seroquel vs. Risperidone in Schizophrenia
NCT00036088	PHASE4	COMPLETED	Olanzapine Versus An Active Comparator in the Treatment of Schizophrenia
NCT00044187	PHASE4	COMPLETED	The Assessment of a Weight-Gain Agent for the Treatment of Olanzapine-Associated Anti-Obesity Agent in Patients With Schizophrenia, Schizophreniform Disorder, Schizoaffective Disorder, and Bipolar I Disorder
NCT00044655	PHASE4	COMPLETED	Switching Medication to Treat Schizophrenia
NCT00048828	PHASE4	COMPLETED	Treating Drug-Resistant Childhood Schizophrenia
NCT00053703	PHASE4	COMPLETED	Treatment of Early Onset Schizophrenia Spectrum Disorders (TEOSS)
NCT00056498	PHASE4	COMPLETED	Risperidone Treatment in Schizophrenia Patients Who Are Currently Taking Clozapine
NCT00061802	PHASE4	COMPLETED	Efficacy and Safety of Two Atypical Antipsychotics vs. Placebo in Patients With an Acute Exacerbation of Either Schizophrenia or Schizoaffective Disorder
NCT00080327	PHASE4	COMPLETED	Study of Three Doses of Aripiprazole in Patients With Acute Schizophrenia
NCT00088049	PHASE4	COMPLETED	Study of Olanzapine vs. Aripiprazole in the Treatment of Schizophrenia
NCT00090012	PHASE4	COMPLETED	Comparison of Continuing Olanzapine to Switching to Quetiapine in Overweight or Obese Patients With Schizophrenia and Schizoaffective Disorder
NCT00100776	PHASE4	COMPLETED	Efficacy of High Dose Olanzapine for the Treatment of Schizophrenia and Schizoaffective Disorder
NCT00103571	PHASE4	COMPLETED	Olanzapine Versus Aripiprazole in the Treatment of Acutely Ill Patients With Schizophrenia
NCT00108368	PHASE4	COMPLETED	The Effects of Risperidone and Olanzapine on Thinking
NCT00114595	PHASE4	COMPLETED	Ethyl-Eicosapentaenoic Acid and Tardive Dyskinesia
NCT00130923	PHASE4	COMPLETED	Risperidone Long-acting Versus Oral Risperidone in Patients With Schizophrenia and Alcohol Use Disorder
NCT00137020	PHASE4	COMPLETED	Clinical Effect Of Cross Titration Of Antipsychotics With Ziprasidone In Schizophrenia Or Schizoaffective Disorder
NCT00140166	PHASE4	COMPLETED	Treatment of Acute Schizophrenia With Vitamin Therapy
NCT00145847	PHASE4	COMPLETED	Naltrexone Treatment of Alcohol Abuse in Schizophrenia
NCT00148564	PHASE4	COMPLETED	Energy Homeostasis Under Treatment With Atypical Antipsychotics
NCT00156715	PHASE4	COMPLETED	Efficacy of Quetiapine in the Treatment of Patients With Schizophrenia and a Comorbid Substance Use Disorder
NCT00158223	PHASE4	COMPLETED	Effectiveness of Pimozide in Augmenting the Effects of Clozapine in the Treatment of Schizophrenia
NCT00159081	PHASE4	COMPLETED	One Year Drug Treatment in First-Episode Schizophrenia
NCT00159120	PHASE4	COMPLETED	Maintenance Treatment vs. Stepwise Drug Discontinuation in First-Episode Schizophrenia
NCT00159133	PHASE4	COMPLETED	Prodrome-Based Early Intervention With Antipsychotics vs. Benzodiazepines in First-Episode Schizophrenia
NCT00159757	PHASE4	TERMINATED	12 Week Open, Non-Comparative Switch Study Of Oral Ziprazidone In Previously Treated Schizophrenic Patients
NCT00167817	PHASE4	COMPLETED	Effect of Switch to Aripiprazole on Health and Smoking Parameters in Patients With Schizophrenia: A Pilot Study
NCT00169026	PHASE4	TERMINATED	Alcoholism and Schizophrenia: Effects of Clozapine
NCT00169039	PHASE4	TERMINATED	Clozapine Versus Chlorpromazine for Treatment-Unresponsive Schizophrenia
NCT00169065	PHASE4	COMPLETED	Effectiveness of Clozapine Versus Olanzapine for Treatment-resistant Schizophrenia
NCT00169091	PHASE4	TERMINATED	Clozapine Versus Haloperidol for Treating the First Episode of Schizophrenia
NCT00176423	PHASE4	COMPLETED	Efficacy Study of Galantamine for Cognitive Impairments in Schizophrenia
NCT00176436	PHASE4	COMPLETED	Atomoxetine for Treatment of Weight Gain in Olanzapine or Clozapine Patients
NCT00177008	PHASE4	COMPLETED	Aripiprazole for the Treatment of Schizophrenia With Co-Morbid Social Anxiety