FOXRED1

Summary

FOXRED1 (FAD dependent oxidoreductase domain containing 1, HGNC:26927) is a protein-coding gene on chromosome 11q24.2, encoding FAD-dependent oxidoreductase domain-containing protein 1 (Q96CU9). Required for the assembly of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I). It is a selective cancer dependency (DepMap: 14.4% of cell lines).

This gene encodes a protein that contains a FAD-dependent oxidoreductase domain. The encoded protein is localized to the mitochondria and may function as a chaperone protein required for the function of mitochondrial complex I. Mutations in this gene are associated with mitochondrial complex I deficiency. Alternatively spliced transcript variants have been observed for this gene.

Source: NCBI Gene 55572 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Definitive, ClinGen) — +5 more curated relationships
• Clinical variants (ClinVar): 543 total — 33 pathogenic, 25 likely-pathogenic
• Phenotypes (HPO): 57
• Cancer dependency (DepMap): dependent in 14.4% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_017547

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26927
Approved symbol	FOXRED1
Name	FAD dependent oxidoreductase domain containing 1
Location	11q24.2
Locus type	gene with protein product
Status	Approved
Aliases	H17
Ensembl gene	ENSG00000110074
Ensembl biotype	protein_coding
OMIM	613622
Entrez	55572

Gene structure

Transcript identifiers

Ensembl transcripts: 59 — 28 protein_coding, 17 retained_intron, 13 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000263578, ENST00000524751, ENST00000525083, ENST00000525770, ENST00000526366, ENST00000526525, ENST00000527004, ENST00000527875, ENST00000529802, ENST00000530642, ENST00000531257, ENST00000532101, ENST00000532125, ENST00000532590, ENST00000533395, ENST00000533839, ENST00000534011, ENST00000534315, ENST00000685484, ENST00000685601, ENST00000685765, ENST00000685844, ENST00000685857, ENST00000686242, ENST00000686888, ENST00000687699, ENST00000687786, ENST00000688100, ENST00000688588, ENST00000688927, ENST00000689283, ENST00000689477, ENST00000689765, ENST00000690512, ENST00000692039, ENST00000692336, ENST00000693133, ENST00000853291, ENST00000853292, ENST00000853293, ENST00000853294, ENST00000853295, ENST00000853296, ENST00000853297, ENST00000853298, ENST00000853299, ENST00000914550, ENST00000914551, ENST00000914552, ENST00000914553, ENST00000914554, ENST00000965171, ENST00000965172, ENST00000965173, ENST00000965174, ENST00000965175, ENST00000965176, ENST00000965177, ENST00000965178

RefSeq mRNA: 16 — MANE Select: NM_017547 NM_001425160, NM_001425161, NM_001425163, NM_001425164, NM_001425165, NM_001425166, NM_001425167, NM_001425168, NM_001425169, NM_001425170, NM_001425171, NM_001425172, NM_001425173, NM_001425174, NM_001425175, NM_017547

CCDS: CCDS8471

Canonical transcript exons

ENST00000263578 — 11 exons

Exon	Start	End
ENSE00001295679	126277435	126278126
ENSE00001686195	126271437	126271657
ENSE00002170067	126269154	126269291
ENSE00003461416	126277071	126277175
ENSE00003475777	126275794	126275870
ENSE00003500725	126276059	126276219
ENSE00003513436	126273336	126273454
ENSE00003542642	126275327	126275428
ENSE00003561078	126274927	126275021
ENSE00003663043	126272969	126273079
ENSE00003684113	126276394	126276523

Expression profiles

Bgee: expression breadth ubiquitous, 232 present calls, max score 94.86.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 11.8993 / max 145.9400, expressed in 1783 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
117492	11.6359	1777
117491	0.2634	113

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	94.86	gold quality
cerebellar hemisphere	UBERON:0002245	94.85	gold quality
cerebellar cortex	UBERON:0002129	94.77	gold quality
right frontal lobe	UBERON:0002810	94.03	gold quality
Brodmann (1909) area 9	UBERON:0013540	94.00	gold quality
right lobe of liver	UBERON:0001114	93.77	gold quality
cerebellum	UBERON:0002037	93.33	gold quality
anterior cingulate cortex	UBERON:0009835	92.89	gold quality
apex of heart	UBERON:0002098	92.50	gold quality
prefrontal cortex	UBERON:0000451	91.61	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	91.24	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	91.17	gold quality
hypothalamus	UBERON:0001898	91.15	gold quality
nucleus accumbens	UBERON:0001882	90.64	gold quality
putamen	UBERON:0001874	90.62	gold quality
caudate nucleus	UBERON:0001873	90.56	gold quality
right uterine tube	UBERON:0001302	90.54	gold quality
hindlimb stylopod muscle	UBERON:0004252	90.48	gold quality
amygdala	UBERON:0001876	90.37	gold quality
mucosa of transverse colon	UBERON:0004991	90.32	gold quality
adenohypophysis	UBERON:0002196	90.26	gold quality
heart left ventricle	UBERON:0002084	89.91	gold quality
neocortex	UBERON:0001950	89.80	gold quality
muscle of leg	UBERON:0001383	89.76	gold quality
gastrocnemius	UBERON:0001388	89.69	gold quality
right atrium auricular region	UBERON:0006631	89.65	gold quality
right adrenal gland	UBERON:0001233	89.58	gold quality
spinal cord	UBERON:0002240	89.56	gold quality
frontal cortex	UBERON:0001870	89.52	gold quality
left ovary	UBERON:0002119	89.43	gold quality

Single-cell (SCXA)

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

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

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

13 targeting FOXRED1, 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-3120-5P	100.00	65.56	965
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-4666A-5P	99.41	69.72	1887
HSA-MIR-661	99.09	65.94	2062
HSA-MIR-939-3P	98.97	65.07	2347
HSA-MIR-4700-5P	98.63	67.43	1915
HSA-MIR-8089	97.74	66.21	1698
HSA-MIR-4667-5P	97.61	66.67	1683
HSA-MIR-4288	97.11	67.23	1636
HSA-MIR-4653-3P	96.26	67.03	725
HSA-MIR-5191	95.22	64.69	354

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 14.4% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 5)

• Mutations in FOXRED1 are associated with complex I deficiency. (PMID:20818383)
• FOXRED1 is a crucial component in the productive assembly of respiratory chain complex I and that mutations in FOXRED1 leading to partial loss of function cause defects in complex I biogenesis. (PMID:25678554)
• A structural model of FOXRED1 reveals a large substrate-binding cavity and a putative oxygen-binding site. (PMID:25765152)
• Loss of FOXRED1, coupled with protein, choline and/or folate-deficient diets results in the depletion of glutathione, the dysregulation of nitric oxide metabolism and the peroxynitrite-mediated inactivation of complex I. (PMID:26235939)
• Results show that depletion of FOXRED1 in myoblasts results in decreased levels of fully assembled complexes I and II. FOXRED1 associates with the ND1-containing subcomplexes of ~370 kDa and ~620 kDa and that FOXRED1 activity is required for the formation of a 550-kDa subcomplex of complex I. (PMID:27215383)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	foxred1	ENSDARG00000099705
mus_musculus	Foxred1	ENSMUSG00000039048
rattus_norvegicus	Foxred1	ENSRNOG00000060379
drosophila_melanogaster	l(2)37Bb	FBGN0002021
drosophila_melanogaster	CG3270	FBGN0033093
caenorhabditis_elegans		WBGENE00010847

Paralogs (10): L2HGDH (ENSG00000087299), YPEL3 (ENSG00000090238), PDPR (ENSG00000090857), YPEL1 (ENSG00000100027), YPEL5 (ENSG00000119801), SARDH (ENSG00000123453), DMGDH (ENSG00000132837), AMT (ENSG00000145020), YPEL4 (ENSG00000166793), YPEL2 (ENSG00000175155)

Protein

Protein identifiers

FAD-dependent oxidoreductase domain-containing protein 1 — Q96CU9 (reviewed: Q96CU9)

All UniProt accessions (16): Q96CU9, A0A8I5KPI4, A0A8I5KQQ8, A0A8I5KRD2, A0A8I5KSK3, A0A8I5KTW5, A0A8I5KU12, A0A8I5KU90, A0A8I5KUS8, A0A8I5KXP7, A0A8I5KY79, A0A8I5KZ12, A0A8I5QL46, A0A8J9AK24, E9PNK9, E9PP78

UniProt curated annotations — full annotation on UniProt →

Function. Required for the assembly of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I). Involved in mid-late stages of complex I assembly.

Subunit / interactions. Associates with components of the mitochondrial respiratory chain complex I.

Subcellular location. Mitochondrion inner membrane.

Disease relevance. Mitochondrial complex I deficiency, nuclear type 19 (MC1DN19) [MIM:618241] 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. MC1DN19 transmission pattern is consistent with autosomal recessive inheritance. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (3)

UniProt ID	Names	Canonical?
Q96CU9-1	1	yes
Q96CU9-2	2
Q96CU9-3	3

RefSeq proteins (16): NP_001412089, NP_001412090, NP_001412092, NP_001412093, NP_001412094, NP_001412095, NP_001412096, NP_001412097, NP_001412098, NP_001412099, NP_001412100, NP_001412101, NP_001412102, NP_001412103, NP_001412104, NP_060017* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006076	FAD-dep_OxRdtase	Domain
IPR036188	FAD/NAD-bd_sf	Homologous_superfamily

Pfam: PF01266

UniProt features (17 total): mutagenesis site 6, sequence variant 6, splice variant 2, chain 1, transmembrane region 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96CU9-F1	90.12	0.82

Functional residue map

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

Mutagenesis-validated functional residues (6):

Position	Phenotype
327	no effect. able to restore complex i assembly when expressed in cells lacking foxred1.
349	no effect. able to restore complex i assembly when expressed in cells lacking foxred1.
359	not able to restore complex i assembly when expressed in cells lacking foxred1.
359	no effect. able to restore complex i assembly when expressed in cells lacking foxred1.
410	no effect. able to restore complex i assembly when expressed in cells lacking foxred1.
411	no effect. able to restore complex i assembly when expressed in cells lacking foxred1.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-6799198	Complex I biogenesis

MSigDB gene sets: 202 (showing top): GOBP_MITOCHONDRIAL_RESPIRATORY_CHAIN_COMPLEX_ASSEMBLY, E4F1_Q6, GOCC_MITOCHONDRIAL_ENVELOPE, ATF3_Q6, DOUGLAS_BMI1_TARGETS_DN, LASTOWSKA_NEUROBLASTOMA_COPY_NUMBER_DN, RYTTCCTG_ETS2_B, FISCHER_DREAM_TARGETS, NERF_Q2, MODULE_455, ATF_01, GOCC_ORGANELLE_INNER_MEMBRANE, SCGGAAGY_ELK1_02, ETS_Q4, chr11q24

GO Biological Process (1): mitochondrial respiratory chain complex I assembly (GO:0032981)

GO Molecular Function (1): oxidoreductase activity (GO:0016491)

GO Cellular Component (4): cytoplasm (GO:0005737), mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Respiratory electron transport	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
NADH dehydrogenase complex assembly	1
mitochondrial respiratory chain complex assembly	1
catalytic activity	1
intracellular anatomical structure	1
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1

Protein interactions and networks

STRING

1042 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FOXRED1	TMEM70	Q9BUB7	890
FOXRED1	NDUFAF5	Q5TEU4	878
FOXRED1	NDUFAF2	Q8N183	867
FOXRED1	NDUFAF6	Q330K2	864
FOXRED1	NDUFAF4	Q9P032	858
FOXRED1	NDUFAF1	Q9Y375	856
FOXRED1	NUBPL	Q8TB37	851
FOXRED1	DMAC2	Q9NW81	835
FOXRED1	NUBP1	P53384	829
FOXRED1	NDUFAF3	Q9BU61	819
FOXRED1	TMEM126B	Q8IUX1	817
FOXRED1	ACAD9	Q9H845	816
FOXRED1	NDUFS7	O75251	812
FOXRED1	NUBP2	Q9Y5Y2	797
FOXRED1	NDUFS4	O43181	784

IntAct

36 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
SNRPB	SART1	psi-mi:“MI:0914”(association)	0.640
NDUFS5	NDUFS8	psi-mi:“MI:0914”(association)	0.530
DDX21	MED19	psi-mi:“MI:2364”(proximity)	0.480
JUN	TPM3	psi-mi:“MI:0914”(association)	0.350
NS1		psi-mi:“MI:0914”(association)	0.350
COQ10B	ALDH1L1	psi-mi:“MI:0914”(association)	0.350
NDUFA4	NDUFS8	psi-mi:“MI:0914”(association)	0.350
CISD3	TIMM44	psi-mi:“MI:0914”(association)	0.350
MCCC2	ALDH1L1	psi-mi:“MI:0914”(association)	0.350
NDUFA4	COX7A2L	psi-mi:“MI:0914”(association)	0.350
	AP3B1	psi-mi:“MI:0914”(association)	0.350
S	COPE	psi-mi:“MI:0914”(association)	0.350
ITM2B	ILVBL	psi-mi:“MI:0914”(association)	0.350
S100A2	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
FOXRED1	CLPX	psi-mi:“MI:0914”(association)	0.350
AFG2A	ESYT2	psi-mi:“MI:0914”(association)	0.350
FECH	GTPBP10	psi-mi:“MI:0914”(association)	0.350
SFTPC	CYTH3	psi-mi:“MI:0914”(association)	0.350
ACAD9	ATP5PD	psi-mi:“MI:0914”(association)	0.350
ATF1	MYO1C	psi-mi:“MI:0914”(association)	0.350
CREB1	IGF2BP3	psi-mi:“MI:0914”(association)	0.350
CTNNA1	EFCAB5	psi-mi:“MI:0914”(association)	0.350
SOX2	MYO1C	psi-mi:“MI:0914”(association)	0.350
IMMP2L	MRPL45	psi-mi:“MI:2364”(proximity)	0.270
CFTR	UBA6	psi-mi:“MI:2364”(proximity)	0.270
GPKOW	ESYT2	psi-mi:“MI:2364”(proximity)	0.270
SF3B4	MED19	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (86): FOXRED1 (Affinity Capture-RNA), FOXRED1 (Affinity Capture-RNA), FOXRED1 (Affinity Capture-RNA), FOXRED1 (Affinity Capture-MS), FOXRED1 (Affinity Capture-MS), RTN4IP1 (Affinity Capture-MS), SUGCT (Affinity Capture-MS), COPRS (Affinity Capture-MS), HSPD1 (Affinity Capture-MS), CLPX (Affinity Capture-MS), MCCC1 (Affinity Capture-MS), MTIF2 (Affinity Capture-MS), NDUFAF7 (Affinity Capture-MS), HSPA8 (Affinity Capture-MS), NARS2 (Affinity Capture-MS)

ESM2 similar proteins: A0A0U2WCB2, A4IG53, A6NK44, A7GNY8, A8WFT6, B7HNI5, B9IY29, F4ZGF2, O00116, O49818, P0C5H0, P32232, P35520, P97275, Q04760, Q05B89, Q0V9K2, Q28CR0, Q3T0H0, Q42891, Q4G064, Q4KLB0, Q4R510, Q4R5F2, Q4V7D6, Q4V7R3, Q502D1, Q54L71, Q58H57, Q5EA45, Q66L51, Q6DCP1, Q6JQN1, Q6NTR1, Q6P7Q4, Q6PCI6, Q8C0I1, Q8H0V3, Q8L5Z4, Q8ZM36

Diamond homologs: A1A9V4, A4TLT6, A7FH13, A7ZKG4, A7ZZ17, A8AI19, A9MH03, A9N5Q2, A9R633, B1IV43, B1JHH1, B1LIV1, B1X9H2, B2K770, B2TTL2, B4T2Z2, B4TET2, B4TSS2, B5F947, B5FL04, B5QY05, B5RBE0, B5YVS9, B6I9D6, B7LFZ3, B7LT77, B7M934, B7MIK0, B7MTJ0, B7NAT4, B7NL75, B7UP73, C4ZRZ9, P23342, P40854, P40859, P40873, P40874, P58523, P58524

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	33
Likely pathogenic	25
Uncertain significance	144
Likely benign	265
Benign	14

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1946821	NM_017547.4(FOXRED1):c.1233C>G (p.Tyr411Ter)	Pathogenic
1970647	NM_017547.4(FOXRED1):c.733+1G>C	Pathogenic
2047717	NM_017547.4(FOXRED1):c.538C>T (p.Gln180Ter)	Pathogenic
2160051	NM_017547.4(FOXRED1):c.325_329del (p.Gly109fs)	Pathogenic
2228986	NM_017547.4(FOXRED1):c.530_534del (p.Val177fs)	Pathogenic
2722051	NM_017547.4(FOXRED1):c.685C>T (p.Arg229Ter)	Pathogenic
2750712	NM_017547.4(FOXRED1):c.483dup (p.Leu162fs)	Pathogenic
2757456	NM_017547.4(FOXRED1):c.86-1G>C	Pathogenic
2762776	NM_017547.4(FOXRED1):c.1145dup (p.Phe383fs)	Pathogenic
2768339	NM_017547.4(FOXRED1):c.332C>G (p.Ser111Ter)	Pathogenic
2781249	NM_017547.4(FOXRED1):c.184G>T (p.Glu62Ter)	Pathogenic
2806130	NM_017547.4(FOXRED1):c.277C>T (p.Arg93Ter)	Pathogenic
2828419	NM_017547.4(FOXRED1):c.392C>A (p.Ser131Ter)	Pathogenic
2830845	NM_017547.4(FOXRED1):c.1138del (p.His380fs)	Pathogenic
2839966	NM_017547.4(FOXRED1):c.343del (p.Ile115fs)	Pathogenic
2845014	NM_017547.4(FOXRED1):c.751C>T (p.Gln251Ter)	Pathogenic
2845647	NM_017547.4(FOXRED1):c.532C>T (p.Gln178Ter)	Pathogenic
2850062	NM_017547.4(FOXRED1):c.718C>T (p.Gln240Ter)	Pathogenic
2853773	NM_017547.4(FOXRED1):c.497del (p.Lys166fs)	Pathogenic
2866703	NM_017547.4(FOXRED1):c.803_804insTGAAAAAATAACATTCGCCTCTGCCCCTGCCCCAGCCCCAGCCCCCGCCCCAGCCCCAGCCGCTGCCACGGCCGCTGCCGCCTCACCCGCAGATGGCCAGCCCAAACGGNNNNNNNNNNAAAAAAAAAAAAAAAAAAAAGAAAAGGATCCATGA (p.Glu268delinsAspGluLysIleThrPheAlaSerAlaProAlaProAlaProAlaProAlaProAlaProAlaAlaAlaThrAlaAlaAlaAlaSerProAlaAspGlyGlnProLysArgXaaXaaXaaXaaLysLysLysLysLysLysGluLysAspProTer)	Pathogenic
2876685	NM_017547.4(FOXRED1):c.993C>A (p.Cys331Ter)	Pathogenic
2986010	NM_017547.4(FOXRED1):c.832G>T (p.Glu278Ter)	Pathogenic
2994310	NM_017547.4(FOXRED1):c.804del (p.Val269fs)	Pathogenic
2995310	NM_017547.4(FOXRED1):c.38del (p.Gly13fs)	Pathogenic
31048	NM_017547.4(FOXRED1):c.1054C>T (p.Arg352Trp)	Pathogenic
3244776	NC_000011.9:g.(?126139102)(126139206_?)del	Pathogenic
3623335	NM_017547.4(FOXRED1):c.90G>A (p.Trp30Ter)	Pathogenic
3665877	NM_017547.4(FOXRED1):c.162dup (p.Asp55fs)	Pathogenic
3726821	NM_017547.4(FOXRED1):c.862_871dup (p.Ala291fs)	Pathogenic
3902282	NM_017547.4(FOXRED1):c.1233_1234delinsGA (p.Tyr411_Asp412delinsTer)	Pathogenic

SpliceAI

1944 predictions. Top by Δscore:

Variant	Effect	Δscore
11:126273444:A:T	donor_gain	1.0000
11:126273452:GAG:G	donor_gain	1.0000
11:126273455:G:GG	donor_gain	1.0000
11:126273455:G:T	donor_loss	1.0000
11:126273456:T:A	donor_loss	1.0000
11:126275429:G:GG	donor_gain	1.0000
11:126275789:TGCA:T	acceptor_loss	1.0000
11:126275790:GCAG:G	acceptor_loss	1.0000
11:126275792:A:AG	acceptor_gain	1.0000
11:126275792:AG:A	acceptor_gain	1.0000
11:126275793:G:GA	acceptor_gain	1.0000
11:126275793:GG:G	acceptor_gain	1.0000
11:126275793:GGT:G	acceptor_gain	1.0000
11:126275793:GGTT:G	acceptor_gain	1.0000
11:126275793:GGTTT:G	acceptor_gain	1.0000
11:126275866:TCCAT:T	donor_gain	1.0000
11:126275867:CCAT:C	donor_gain	1.0000
11:126275867:CCATG:C	donor_loss	1.0000
11:126275868:CAT:C	donor_gain	1.0000
11:126275869:AT:A	donor_gain	1.0000
11:126275869:ATG:A	donor_loss	1.0000
11:126275871:G:GG	donor_gain	1.0000
11:126275872:T:A	donor_loss	1.0000
11:126276050:T:TA	acceptor_gain	1.0000
11:126276054:T:TA	acceptor_gain	1.0000
11:126276054:TGCA:T	acceptor_loss	1.0000
11:126276055:GCA:G	acceptor_loss	1.0000
11:126276056:CA:C	acceptor_loss	1.0000
11:126276057:A:AG	acceptor_gain	1.0000
11:126276058:G:GT	acceptor_gain	1.0000

AlphaMissense

3136 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:126271551:T:A	V67E	0.976
11:126276108:T:A	V287E	0.972
11:126277517:A:T	N430I	0.972
11:126271596:T:C	L82P	0.969
11:126276098:T:C	C284R	0.969
11:126271641:T:A	V97E	0.967
11:126276100:C:G	C284W	0.964
11:126277518:C:A	N430K	0.964
11:126277518:C:G	N430K	0.964
11:126276060:T:A	V271E	0.961
11:126277585:G:C	A453P	0.961
11:126271635:T:C	L95P	0.959
11:126271548:T:A	V66E	0.958
11:126271554:T:A	I68N	0.958
11:126271587:C:A	A79D	0.958
11:126275866:T:A	V269D	0.953
11:126276407:T:A	W329R	0.951
11:126276407:T:C	W329R	0.951
11:126277573:G:T	G449W	0.951
11:126274968:T:C	L193P	0.949
11:126271557:T:A	V69E	0.948
11:126271638:T:A	V96E	0.946
11:126277470:C:A	N414K	0.946
11:126277470:C:G	N414K	0.946
11:126274979:T:C	F197L	0.945
11:126274981:T:A	F197L	0.945
11:126274981:T:G	F197L	0.945
11:126273397:T:C	L160P	0.942
11:126277495:G:C	G423R	0.942
11:126276115:C:A	N289K	0.941

dbSNP variants (sampled 300 via entrez): RS1000064062 (11:126275666 CTG>C), RS1000086862 (11:126270664 A>T), RS1000137493 (11:126270277 A>G), RS1000331906 (11:126275983 C>T), RS1000764001 (11:126271718 G>A), RS1000901882 (11:126271449 A>G), RS1001293539 (11:126278408 G>A,T), RS1001397740 (11:126269764 A>G), RS1001461647 (11:126277320 T>C), RS1001589260 (11:126271860 G>A,T), RS1001771150 (11:126272905 T>C), RS1001912362 (11:126272599 C>T), RS1001977311 (11:126267680 A>G), RS1002767950 (11:126274373 G>A,C), RS1003140238 (11:126274927 G>A,T)

Disease associations

OMIM: gene MIM:613622 | disease phenotypes: MIM:618241, MIM:256000, MIM:252010

GenCC curated gene-disease

Disease	Classification	Inheritance
mitochondrial complex I deficiency, nuclear type 19	Definitive	Autosomal recessive
mitochondrial complex I deficiency, nuclear type 1	Strong	Autosomal recessive
Leigh syndrome	Moderate	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
Leigh syndrome	Moderate	AR
mitochondrial disease	Definitive	AR

Mondo (6): mitochondrial complex I deficiency, nuclear type 19 (MONDO:0032624), Leigh syndrome (MONDO:0009723), mitochondrial complex I deficiency, nuclear type 1 (MONDO:0100224), mitochondrial complex I deficiency (MONDO:0100133), mitochondrial disease (MONDO:0044970), (MONDO:0016815)

Orphanet (3): Leigh syndrome (Orphanet:506), Isolated complex I deficiency (Orphanet:2609), Mitochondrial disease (Orphanet:68380)

HPO phenotypes

57 total (30 of 57 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:0000737	Irritability
HP:0000817	Reduced eye contact
HP:0000819	Diabetes mellitus
HP:0001138	Optic neuropathy
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001254	Lethargy
HP:0001263	Global developmental delay
HP:0001272	Cerebellar atrophy
HP:0001288	Gait disturbance
HP:0001298	Encephalopathy
HP:0001324	Muscle weakness
HP:0001336	Myoclonus
HP:0001344	Absent speech
HP:0001508	Failure to thrive
HP:0001511	Intrauterine growth retardation
HP:0001639	Hypertrophic cardiomyopathy
HP:0001943	Hypoglycemia
HP:0002013	Vomiting

GWAS associations

0 associations (top):

MeSH disease descriptors (2)

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
C537475	Mitochondrial complex I deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	2
Valproic Acid	decreases methylation, affects expression	2
GSK-J4	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, increases methylation	1
beta-lapachone	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
perfluorooctanoic acid	decreases expression	1
CGP 52608	increases reaction, affects binding	1
K 7174	decreases expression	1
jinfukang	increases expression	1
NSC 689534	affects binding, decreases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Temozolomide	increases expression	1
Sunitinib	decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Acetaminophen	decreases expression	1
Arsenic	affects methylation	1
Atrazine	decreases expression	1
Carbamazepine	affects expression	1
Copper	affects binding, decreases expression	1
Doxorubicin	decreases expression	1
Ivermectin	decreases expression	1
Lead	decreases expression	1
Smoke	decreases expression	1
Tetrachlorodibenzodioxin	affects expression	1
Thiram	decreases expression	1
Cyclosporine	decreases expression	1
Aflatoxin B1	decreases methylation	1
Cadmium Chloride	decreases expression	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_SN91	HAP1 FOXRED1 (-) 1	Cancer cell line	Male
CVCL_SN92	HAP1 FOXRED1 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03351998	PHASE4	COMPLETED	Impact of Statin Therapy on Muscle Mitochondrial Function and Aerobic Capacity
NCT05162768	PHASE3	COMPLETED	Study to Evaluate Efficacy and Safety of Elamipretide in Subjects With Primary Mitochondrial Disease From Nuclear DNA Mutations (nPMD)
NCT00432744	PHASE3	COMPLETED	Phase III Trial of Coenzyme Q10 in Mitochondrial Disease
NCT06451757	PHASE3	RECRUITING	KHENERFIN Study: A Trial to Evaluate the Efficacy and Safety of Sonlicromanol in Primary Mitochondrial Diseases
NCT01721733	PHASE2	COMPLETED	Safety and Efficacy Study of EPI-743 in Children With Leigh Syndrome
NCT02352896	PHASE2	COMPLETED	Long-Term Safety and Efficacy Evaluation of EPI-743 in Children With Leigh Syndrome
NCT03747328	PHASE2	WITHDRAWN	ABI-009 (Nab-sirolimus) in Patients With Genetically-confirmed Leigh or Leigh-like Syndrome
NCT06843811	PHASE2	ENROLLING_BY_INVITATION	Sirolimus for Leigh Syndrome
NCT06990984	PHASE2	NOT_YET_RECRUITING	A Dose-ranging Study of TTI-0102 in Adults and Children With Leigh Syndrome Spectrum (LSS)
NCT02398201	PHASE2	COMPLETED	A Study of Bezafibrate in Mitochondrial Myopathy
NCT02473445	PHASE2	TERMINATED	A Long-term Extension of Study RP103-MITO-001 (NCT02023866) to Assess Cysteamine Bitartrate Delayed-release Capsules (RP103) in Children With Inherited Mitochondrial Disease
NCT02500628	PHASE2	COMPLETED	Heart Rate Variability in Response to Metformin Challenge
NCT02805790	PHASE2	COMPLETED	Safety, Tolerability, Efficacy of MTP-131 for Treatment of Mitochondrial Disease in Subjects From the MMPOWER Study
NCT02909400	PHASE2	COMPLETED	The KHENERGY Study
NCT02976038	PHASE2	TERMINATED	Open-Label Extension Trial to Characterize the Long-term Safety and Tolerability of Elamipretide in Subjects With Genetically Confirmed Primary Mitochondrial Myopathy (PMM)
NCT03177798	PHASE2	COMPLETED	Mitochondria and Chronic Kidney Disease
NCT03866954	PHASE2	WITHDRAWN	Trial of Erythrocyte Encapsulated Thymidine Phosphorylase In Mitochondrial Neurogastrointestinal Encephalomyopathy
NCT04165239	PHASE2	COMPLETED	The KHENERGYZE Study
NCT04604548	PHASE2	COMPLETED	The KHENEREXT Study
NCT04802707	PHASE2	RECRUITING	Deoxynucleosides Pyrimidines as Treatment for Mitochondrial Depletion Syndrome
NCT04846036	PHASE2	SUSPENDED	The KHENERGYC Study
NCT05650229	PHASE2	RECRUITING	Efficacy of KL1333 in Adult Patients With Primary Mitochondrial Disease
NCT05972954	PHASE2	COMPLETED	OMT-28 in Patients With Primary Mitochondrial Disease (PMD) (PMD-OPTION)
NCT06017869	PHASE2	RECRUITING	Evaluate the Safety and Therapeutic Effects of a Single Intravenous Infusion (IV) of Autologous CD34+ Cells Enriched With Allogenic Placenta-derived Mitochondria in Patients With a Diagnosis of Pearson Syndrome (PS)
NCT07514338	PHASE2	NOT_YET_RECRUITING	Open Label Extension to Assess Long Term Safety and Efficacy of KL1333 in Patients With Primary Mitochondrial Disease
NCT02544217	PHASE1	COMPLETED	A Dose-escalating Clinical Trial With KH176
NCT00060515	PHASE1	TERMINATED	RG2133 (2’,3’,5’-Tri-O-Acetyluridine) in Mitochondrial Disease
NCT02348125	PHASE1	UNKNOWN	Does Clinical Treatment of Mitochondrial Dysfunction Impact Autism Spectrum Disorder (ASD)?
NCT03888716	PHASE1	COMPLETED	A Phase Ia/Ib, SAD and MAD Study of of KL1333 in Healthy Subjects and Patients With Primary Mitochondrial Disease
NCT04086329	PHASE1	RECRUITING	Validation of Oxygen Nanosensor in Mitochondrial Myopathy
NCT04643249	PHASE1	COMPLETED	Drug-drug Interaction Study of KL1333 in Healthy Subjects
NCT05241262	PHASE1	RECRUITING	Study of N-acetylcysteine in the Treatment of Patients With the m.3243A>G Mutation and Low Brain Glutathione Levels
NCT05569122	PHASE1	RECRUITING	Applying pGz in Mitochondrial Disease
NCT06819683	PHASE1	RECRUITING	Validation of Nanosensor Oxygen Measurement
NCT07258667	PHASE1	NOT_YET_RECRUITING	Pilot Study of the Efficacy of Nicotinamide (Vitamin B3) in Leber’s Hereditary Optic Neuropathy
NCT04378075	PHASE2/PHASE3	TERMINATED	A Study to Evaluate Efficacy and Safety of Vatiquinone for Treating Mitochondrial Disease in Participants With Refractory Epilepsy
NCT01780168	Not specified	RECRUITING	The NIH MINI Study: Metabolism, Infection, and Immunity in Inborn Errors of Metabolism
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT01803906	Not specified	ENROLLING_BY_INVITATION	Tissue Sample Study for Mitochondrial Disorders
NCT03137355	Not specified	RECRUITING	The International Registry for Leigh Syndrome