NDUFAF6

Summary

NDUFAF6 (NADH:ubiquinone oxidoreductase complex assembly factor 6, HGNC:28625) is a protein-coding gene on chromosome 8q22.1, encoding NADH dehydrogenase (ubiquinone) complex I, assembly factor 6 (Q330K2). Involved in the assembly of mitochondrial NADH:ubiquinone oxidoreductase complex (complex I) at early stages.

This gene encodes a protein that localizes to mitochondria and contains a predicted phytoene synthase domain. The encoded protein plays an important role in the assembly of complex I (NADH-ubiquinone oxidoreductase) of the mitochondrial respiratory chain through regulation of subunit ND1 biogenesis. Mutations in this gene are associated with complex I enzymatic deficiency.

Source: NCBI Gene 137682 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Definitive, ClinGen) — +5 more curated relationships
• GWAS associations: 28
• Clinical variants (ClinVar): 278 total — 12 pathogenic, 12 likely-pathogenic
• Phenotypes (HPO): 63
• MANE Select transcript: NM_152416

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28625
Approved symbol	NDUFAF6
Name	NADH:ubiquinone oxidoreductase complex assembly factor 6
Location	8q22.1
Locus type	gene with protein product
Status	Approved
Aliases	lncREST, MGC40214
Ensembl gene	ENSG00000156170
Ensembl biotype	protein_coding
OMIM	612392
Entrez	137682

Gene structure

Transcript identifiers

Ensembl transcripts: 35 — 17 protein_coding_CDS_not_defined, 10 nonsense_mediated_decay, 8 protein_coding

ENST00000396111, ENST00000396113, ENST00000396124, ENST00000454358, ENST00000517976, ENST00000518258, ENST00000518608, ENST00000519034, ENST00000519136, ENST00000519804, ENST00000520632, ENST00000520757, ENST00000521063, ENST00000521587, ENST00000521840, ENST00000522683, ENST00000523184, ENST00000523337, ENST00000523378, ENST00000523905, ENST00000697354, ENST00000697355, ENST00000697356, ENST00000697357, ENST00000697358, ENST00000697359, ENST00000697360, ENST00000697361, ENST00000697362, ENST00000697363, ENST00000697364, ENST00000697365, ENST00000697366, ENST00000875013, ENST00000940120

RefSeq mRNA: 20 — MANE Select: NM_152416 NM_001330582, NM_001354514, NM_001354515, NM_001354516, NM_001354517, NM_001354518, NM_001354519, NM_001354521, NM_001354522, NM_001354524, NM_001354525, NM_001354527, NM_001354528, NM_001354529, NM_001354530, NM_001354531, NM_001354532, NM_001354533, NM_001354534, NM_152416

CCDS: CCDS6266, CCDS83307

Canonical transcript exons

ENST00000396124 — 9 exons

Exon	Start	End
ENSE00003498045	95035454	95035576
ENSE00003674674	95031995	95032094
ENSE00003970392	95024989	95025205
ENSE00003970397	95057809	95058710
ENSE00003970404	95046994	95047127
ENSE00003970407	95052174	95052230
ENSE00003970412	95048457	95048558
ENSE00003970420	95041570	95041626
ENSE00003970427	95045545	95045647

Expression profiles

Bgee: expression breadth ubiquitous, 242 present calls, max score 94.75.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 24.3679 / max 352.9309, expressed in 1816 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
89810	13.1199	1795
89811	6.1118	1685
89804	2.5609	805
89809	1.1789	686
89805	0.6256	268
89803	0.3473	162
89812	0.2997	122
89806	0.1237	39

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right uterine tube	UBERON:0001302	94.75	gold quality
tibialis anterior	UBERON:0001385	94.48	gold quality
deltoid	UBERON:0001476	92.86	gold quality
vastus lateralis	UBERON:0001379	92.34	gold quality
gastrocnemius	UBERON:0001388	91.62	gold quality
muscle of leg	UBERON:0001383	91.60	gold quality
hindlimb stylopod muscle	UBERON:0004252	91.47	gold quality
quadriceps femoris	UBERON:0001377	91.42	gold quality
body of pancreas	UBERON:0001150	90.91	gold quality
biceps brachii	UBERON:0001507	90.33	gold quality
skeletal muscle tissue	UBERON:0001134	90.26	gold quality
rectum	UBERON:0001052	90.02	gold quality
right lobe of liver	UBERON:0001114	89.85	gold quality
right lobe of thyroid gland	UBERON:0001119	89.49	gold quality
left lobe of thyroid gland	UBERON:0001120	89.40	gold quality
muscle tissue	UBERON:0002385	89.39	gold quality
heart left ventricle	UBERON:0002084	89.35	gold quality
ileal mucosa	UBERON:0000331	89.12	gold quality
cardiac ventricle	UBERON:0002082	89.00	gold quality
left ventricle myocardium	UBERON:0006566	88.96	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	88.90	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	88.81	gold quality
thyroid gland	UBERON:0002046	88.77	gold quality
apex of heart	UBERON:0002098	88.57	gold quality
mucosa of transverse colon	UBERON:0004991	88.56	gold quality
cerebellar hemisphere	UBERON:0002245	88.36	gold quality
cerebellar cortex	UBERON:0002129	88.15	gold quality
ganglionic eminence	UBERON:0004023	88.14	gold quality
small intestine Peyer’s patch	UBERON:0003454	88.04	gold quality
tibial nerve	UBERON:0001323	87.79	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.59

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F1

miRNA regulators (miRDB)

34 targeting NDUFAF6, 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-340-5P	100.00	72.50	4437
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-433-3P	99.98	69.37	1203
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-548E-3P	99.82	70.59	3514
HSA-MIR-132-3P	99.73	70.56	1424
HSA-MIR-212-3P	99.73	70.65	1424
HSA-MIR-7152-5P	99.60	69.33	2094
HSA-MIR-4728-3P	99.47	68.94	981
HSA-MIR-5009-3P	99.45	69.43	1341
HSA-MIR-149-5P	99.25	67.16	1315
HSA-MIR-670-3P	99.03	68.88	2404
HSA-MIR-4801	98.96	69.42	2096
HSA-MIR-3938	98.72	66.07	834
HSA-MIR-508-3P	98.66	69.62	887
HSA-MIR-1261	98.62	68.10	896
HSA-MIR-4731-3P	98.56	68.60	1860
HSA-MIR-758-3P	98.42	68.60	1122
HSA-MIR-2681-3P	98.18	65.28	577
HSA-MIR-3129-3P	97.85	67.63	1246
HSA-MIR-5583-5P	97.85	67.61	1243
HSA-MIR-4797-3P	97.48	67.14	989
HSA-MIR-610	96.84	67.98	905
HSA-MIR-490-5P	96.75	65.81	661
HSA-MIR-7973	96.48	65.54	502

Literature-anchored findings (GeneRIF, showing 8)

• C8orf38 is a crucial factor required for the translation and/or integration of ND1 into an early-stage assembly intermediate (PMID:22019594)
• In a forward genetic screen to identify genes that cause neurodegeneration, we identified sicily, the Drosophila melanogaster homologue of human C8ORF38, the loss of which causes Leigh syndrome. (PMID:23509070)
• Affected kidney and lung showed specific loss of the mitochondria-located NDUFAF6 isoform and ultrastructural characteristics of mitochondrial dysfunction. Accordingly, affected tissues had defects in mitochondrial respiration and complex I biogenesis that were corrected with NDUFAF6 cDNA transfection. Our results demonstrate that the Acadian variant of Fanconi Syndrome results from mitochondrial respiratory chain complex (PMID:27466185)
• This paper confirms NDUFAF6 as a genuine morbid gene and proposes the coupling of exome sequencing with mRNA analysis as a method useful for enhancing the exome sequencing detection rate when the simple application of classical inheritance models fails. (PMID:27623250)
• NDUFAF6 encodes a complex I assembly factor and mutations result in complex I deficiency, Leigh syndrome or Acadian variant Fanconi syndrome. Human NDUFAF6 is a mitochondria-targeted 333-amino acid protein belonging to the family of squalene and phytoene synthases. (PMID:28476317)
• NDUFAF6-related Leigh syndrome is a relevant cause of childhood onset dystonia and isolated bilateral striatal necrosis [review] (PMID:30642748)
• Genetic Effects of NDUFAF6 rs6982393 and APOE on Alzheimer’s Disease in Chinese Rural Elderly: A Cross-Sectional Population-Based Study. (PMID:35237031)
• Systematic analysis of NDUFAF6 in complex I assembly and mitochondrial disease. (PMID:38720117)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ndufaf6	ENSDARG00000053652
mus_musculus	Ndufaf6	ENSMUSG00000050323
rattus_norvegicus	Ndufaf6	ENSRNOG00000040040
drosophila_melanogaster	sicily	FBGN0030352
caenorhabditis_elegans		WBGENE00007145

Paralogs (1): MMGT1 (ENSG00000169446)

Protein

Protein identifiers

NADH dehydrogenase (ubiquinone) complex I, assembly factor 6 — Q330K2 (reviewed: Q330K2)

Alternative names: Putative phytoene synthase

All UniProt accessions (12): Q330K2, A0A075B6P0, A0A8V8TLC1, E5RFN5, E5RGD6, E5RHX9, H0YB05, H0YB46, H0YBQ9, H0YBT9, H0YC61, H7C250

UniProt curated annotations — full annotation on UniProt →

Function. Involved in the assembly of mitochondrial NADH:ubiquinone oxidoreductase complex (complex I) at early stages. May play a role in the biogenesis of complex I subunit MT-ND1.

Subcellular location. Mitochondrion inner membrane Cytoplasm. Nucleus.

Tissue specificity. Widely expressed. A lower expression is observed in lung and kidney compared to heart, muscle and liver. In the kidney, expression is high in the basal zone of the proximal tubular cells.

Disease relevance. Mitochondrial complex I deficiency, nuclear type 17 (MC1DN17) [MIM:618239] 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. MC1DN17 transmission pattern is consistent with autosomal recessive inheritance. The disease is caused by variants affecting the gene represented in this entry. Fanconi renotubular syndrome 5 (FRTS5) [MIM:618913] A form of Fanconi renotubular syndrome, a disease due to a generalized dysfunction of the proximal kidney tubule resulting in decreased solute and water reabsorption. Patients have polydipsia and polyuria with phosphaturia, glycosuria and aminoaciduria. They may develop hypophosphatemic rickets or osteomalacia, acidosis and a tendency toward dehydration. Some eventually develop renal insufficiency. FRTS5 is an autosomal recessive mitochondrial disorder characterized by proximal renotubular dysfunction from birth, followed by progressive kidney disease and pulmonary fibrosis. The disease is caused by variants affecting the gene represented in this entry. A homozygous disease-causing variant located in intron 2 leads to aberrant splicing and altered isoform synthesis. Kidney and lung tissues from affected individuals show specific loss of mitochondrial isoform 1. Patient cells show defects in mitochondrial complex I assembly and altered mitochondrial respiration.

Similarity. Belongs to the NDUFAF6 family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q330K2-1	1	yes
Q330K2-2	2
Q330K2-3	3

RefSeq proteins (20): NP_001317511, NP_001341443, NP_001341444, NP_001341445, NP_001341446, NP_001341447, NP_001341448, NP_001341450, NP_001341451, NP_001341453, NP_001341454, NP_001341456, NP_001341457, NP_001341458, NP_001341459, NP_001341460, NP_001341461, NP_001341462, NP_001341463, NP_689629* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002060	Squ/phyt_synthse	Family
IPR008949	Isoprenoid_synthase_dom_sf	Homologous_superfamily

Pfam: PF00494

UniProt features (12 total): sequence variant 7, splice variant 3, transit peptide 1, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q330K2-F1	87.70	0.83

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

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

MSigDB gene sets: 212 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_DN, GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_DN, GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_DN, GOBP_MITOCHONDRIAL_RESPIRATORY_CHAIN_COMPLEX_ASSEMBLY, WEI_MYCN_TARGETS_WITH_E_BOX, GOCC_MITOCHONDRIAL_ENVELOPE, NIKOLSKY_BREAST_CANCER_8Q12_Q22_AMPLICON, chr8q22, DODD_NASOPHARYNGEAL_CARCINOMA_UP, GOCC_ORGANELLE_INNER_MEMBRANE, GOCC_ORGANELLE_ENVELOPE, BRUINS_UVC_RESPONSE_LATE, GOBP_NADH_DEHYDROGENASE_COMPLEX_ASSEMBLY, REACTOME_COMPLEX_I_BIOGENESIS, GSE14415_ACT_VS_CTRL_NATURAL_TREG_UP

GO Biological Process (2): mitochondrial respiratory chain complex I assembly (GO:0032981), biosynthetic process (GO:0009058)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (5): nucleus (GO:0005634), cytoplasm (GO:0005737), mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-3 pathways:

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

GO top-level categories

Rollup of top GO terms by namespace:

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

Protein interactions and networks

STRING

1975 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NDUFAF6	NDUFAF5	Q5TEU4	929
NDUFAF6	NDUFAF1	Q9Y375	913
NDUFAF6	FOXRED1	Q96CU9	864
NDUFAF6	NDUFAF4	Q9P032	857
NDUFAF6	NDUFAF2	Q8N183	831
NDUFAF6	NDUFAF3	Q9BU61	820
NDUFAF6	NDUFS3	O75489	789
NDUFAF6	SURF1	Q15526	756
NDUFAF6	COX15	Q7KZN9	730
NDUFAF6	NDUFS7	O75251	728
NDUFAF6	NDUFS4	O43181	722
NDUFAF6	NUBPL	Q8TB37	708
NDUFAF6	BCS1L	Q9Y276	701
NDUFAF6	NDUFS1	P28331	700
NDUFAF6	TMEM126B	Q8IUX1	697

IntAct

6 interactions, top by confidence:

A	B	Type	Score
GALNT6	NDUFS4	psi-mi:“MI:0914”(association)	0.530
FSTL1	HLA-DPB1	psi-mi:“MI:0914”(association)	0.350
FSTL1	A2ML1	psi-mi:“MI:0914”(association)	0.350
INSR	UBXN8	psi-mi:“MI:0914”(association)	0.350
INSR	RIMOC1	psi-mi:“MI:0914”(association)	0.350

BioGRID (9): NDUFAF6 (Affinity Capture-MS), NDUFAF6 (Two-hybrid), NDUFAF6 (Two-hybrid), NDUFAF6 (Positive Genetic), NDUFAF6 (Affinity Capture-MS), NDUFAF6 (Affinity Capture-MS), NDUFAF6 (Affinity Capture-MS), NDUFAF6 (Affinity Capture-MS), NDUFAF6 (Affinity Capture-RNA)

ESM2 similar proteins: A0JNU3, A1L1F1, A2AIL4, A4IHH4, A4QP75, B3MGZ0, B4GGT6, F6ZFR0, O00746, O08776, O55137, O55171, O88202, O88267, P36776, P49753, P87355, Q28CM7, Q32LB9, Q330K2, Q3B8B2, Q3T056, Q4R816, Q4VK78, Q566Y1, Q58DL1, Q59HJ6, Q5EBA1, Q5RJV0, Q6DFN1, Q80YD1, Q810S1, Q86U10, Q8BWN8, Q8CGK3, Q8HY87, Q8NC60, Q924S5, Q96BQ1, Q99KK9

Diamond homologs: A2AIL4, A7YVD7, D3ZN43, Q330K2, Q54E48, Q9VYS5

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	12
Likely pathogenic	12
Uncertain significance	109
Likely benign	64
Benign	39

Top pathogenic / likely-pathogenic (24)

Variant ID	HGVS	Classification
1064539	NM_152416.4(NDUFAF6):c.420+2_420+3insTA	Pathogenic
2133218	NM_152416.4(NDUFAF6):c.440_441insTT (p.Leu147_Thr148insTer)	Pathogenic
2427377	NC_000008.10:g.(?96057753)(96064478_?)del	Pathogenic
2989000	NM_152416.4(NDUFAF6):c.485_492dup (p.Asp165fs)	Pathogenic
372255	NM_152416.4(NDUFAF6):c.805C>G (p.His269Asp)	Pathogenic
372256	NM_152416.4(NDUFAF6):c.226T>C (p.Ser76Pro)	Pathogenic
372258	NM_152416.4(NDUFAF6):c.206A>T (p.Asp69Val)	Pathogenic
372259	NM_152416.4(NDUFAF6):c.820A>G (p.Arg274Gly)	Pathogenic
503873	NM_152416.4(NDUFAF6):c.559_563del (p.Tyr187fs)	Pathogenic
521473	NM_152416.4(NDUFAF6):c.485dup (p.Asn162fs)	Pathogenic
547	NM_152416.4(NDUFAF6):c.296A>G (p.Gln99Arg)	Pathogenic
929496	NM_152416.4(NDUFAF6):c.555_559del (p.Tyr187fs)	Pathogenic
1029199	NM_152416.4(NDUFAF6):c.420+1_420+2dup	Likely pathogenic
214213	NM_152416.4(NDUFAF6):c.307_308del (p.Val104fs)	Likely pathogenic
3767217	NM_152416.4(NDUFAF6):c.536A>G (p.Glu179Gly)	Likely pathogenic
3775662	NM_152416.4(NDUFAF6):c.198-2A>C	Likely pathogenic
422361	NM_152416.4(NDUFAF6):c.600del (p.Asp201fs)	Likely pathogenic
430873	NM_152416.4(NDUFAF6):c.328G>T (p.Gly110Ter)	Likely pathogenic
4541385	NM_152416.4(NDUFAF6):c.648C>A (p.Cys216Ter)	Likely pathogenic
4759937	NM_152416.4(NDUFAF6):c.581-1G>A	Likely pathogenic
4813841	NM_152416.4(NDUFAF6):c.322del (p.Thr108fs)	Likely pathogenic
523019	NM_152416.4(NDUFAF6):c.719G>T (p.Gly240Val)	Likely pathogenic
523560	NM_152416.4(NDUFAF6):c.841C>G (p.Pro281Ala)	Likely pathogenic
870771	NC_000008.11:g.95045545del	Likely pathogenic

SpliceAI

3023 predictions. Top by Δscore:

Variant	Effect	Δscore
8:94930494:A:AC	donor_gain	1.0000
8:94930495:C:CC	donor_gain	1.0000
8:94930495:CG:C	donor_gain	1.0000
8:94930727:CT:C	acceptor_gain	1.0000
8:94939855:CGTA:C	donor_loss	1.0000
8:94939856:GTACC:G	donor_loss	1.0000
8:94939857:TA:T	donor_loss	1.0000
8:94940825:CTTAC:C	donor_loss	1.0000
8:94940827:TACC:T	donor_loss	1.0000
8:94940828:AC:A	donor_loss	1.0000
8:94940829:C:G	donor_loss	1.0000
8:94941087:TGTAC:T	acceptor_gain	1.0000
8:95032107:A:G	donor_gain	1.0000
8:95035449:TATA:T	acceptor_loss	1.0000
8:95035451:TAGGT:T	acceptor_loss	1.0000
8:95035452:A:AG	acceptor_gain	1.0000
8:95035452:A:C	acceptor_loss	1.0000
8:95035453:G:GG	acceptor_gain	1.0000
8:95035573:G:GT	donor_gain	1.0000
8:95035574:A:T	donor_gain	1.0000
8:95035574:AAGG:A	donor_loss	1.0000
8:95035575:AGGT:A	donor_loss	1.0000
8:95035576:GGTAA:G	donor_loss	1.0000
8:95035577:G:A	donor_loss	1.0000
8:95035578:T:A	donor_loss	1.0000
8:95041625:GA:G	donor_gain	1.0000
8:95041627:G:GG	donor_gain	1.0000
8:95041646:GTCT:G	donor_gain	1.0000
8:95041647:TCTT:T	donor_gain	1.0000
8:95045540:TGTAG:T	acceptor_loss	1.0000

AlphaMissense

2164 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:95047041:G:C	A210P	0.993
8:95035569:T:C	L138P	0.992
8:95035502:T:C	F116L	0.991
8:95035504:T:A	F116L	0.991
8:95035504:T:G	F116L	0.991
8:95035505:T:A	W117R	0.991
8:95035505:T:C	W117R	0.991
8:95045614:A:C	S183R	0.991
8:95045616:C:A	S183R	0.991
8:95045616:C:G	S183R	0.991
8:95047047:G:C	G212R	0.991
8:95048551:T:C	L270P	0.991
8:95047024:C:A	A204E	0.990
8:95047036:G:A	G208E	0.990
8:95047068:G:C	A219P	0.990
8:95052174:G:C	A273P	0.990
8:95041626:A:C	R159S	0.989
8:95041626:A:T	R159S	0.989
8:95047023:G:C	A204P	0.988
8:95052175:C:A	A273D	0.988
8:95057851:T:C	F306L	0.987
8:95057853:T:A	F306L	0.987
8:95057853:T:G	F306L	0.987
8:95047048:G:A	G212D	0.986
8:95057828:T:C	L298P	0.986
8:95047035:G:A	G208R	0.985
8:95047035:G:C	G208R	0.985
8:95032071:G:C	A92P	0.984
8:95047108:C:G	P232R	0.984
8:95048529:G:C	A263P	0.984

dbSNP variants (sampled 300 via entrez): RS1000005275 (8:95107052 C>A,T), RS1000010687 (8:95019115 G>C), RS1000038833 (8:94971543 G>A), RS1000079298 (8:95011583 C>A), RS1000083256 (8:95079588 T>C), RS1000103467 (8:94904594 T>C), RS1000110320 (8:95074901 A>G), RS1000114659 (8:95111469 GA>G), RS1000127895 (8:94928716 G>A,C), RS1000132096 (8:94989130 T>C), RS1000134157 (8:94979522 A>C), RS1000169236 (8:94975878 A>C), RS1000180584 (8:94929068 T>C,G), RS1000187199 (8:94979246 G>A,T), RS1000193226 (8:95070115 A>G)

Disease associations

OMIM: gene MIM:612392 | disease phenotypes: MIM:618239, MIM:618913, MIM:256000, MIM:252010

GenCC curated gene-disease

Disease	Classification	Inheritance
mitochondrial complex I deficiency, nuclear type 17	Strong	Autosomal recessive
Leigh syndrome with leukodystrophy	Supportive	Autosomal recessive
primary Fanconi syndrome	Supportive	Autosomal dominant
Fanconi renotubular syndrome 5	Limited	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	Definitive	AR

Mondo (8): mitochondrial complex I deficiency, nuclear type 17 (MONDO:0032622), Fanconi renotubular syndrome 5 (MONDO:0030056), mitochondrial complex I deficiency (MONDO:0100133), mitochondrial disease (MONDO:0044970), Leigh syndrome (MONDO:0009723), mitochondrial complex I deficiency, nuclear type 1 (MONDO:0100224), (MONDO:0016815), primary Fanconi syndrome (MONDO:0007600)

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

HPO phenotypes

63 total (30 of 63 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000093	Proteinuria
HP:0000117	Renal phosphate wasting
HP:0000822	Hypertension
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001288	Gait disturbance
HP:0001324	Muscle weakness
HP:0001332	Dystonia
HP:0001510	Growth delay
HP:0001763	Pes planus
HP:0001824	Weight loss
HP:0001943	Hypoglycemia
HP:0001944	Dehydration
HP:0002049	Proximal renal tubular acidosis
HP:0002063	Rigidity
HP:0002097	Emphysema
HP:0002148	Hypophosphatemia
HP:0002150	Hypercalciuria
HP:0002151	Increased circulating lactate concentration
HP:0002206	Pulmonary fibrosis
HP:0002376	Developmental regression
HP:0002650	Scoliosis
HP:0002653	Bone pain
HP:0002659	Increased susceptibility to fractures
HP:0002705	High, narrow palate
HP:0002749	Osteomalacia

GWAS associations

28 associations (top):

Study	Trait	p-value
GCST001817_10	Metabolite levels (HVA-5-HIAA Factor score)	6.000000e-06
GCST001824_10	Metabolite levels (HVA)	6.000000e-06
GCST002245_25	Alzheimer’s disease (late onset)	8.000000e-08
GCST002792_5	Vincristine-induced peripheral neuropathy in acute lymphoblastic leukemia	4.000000e-08
GCST004615_56	Hemoglobin concentration	6.000000e-09
GCST005440_14	Alcohol dependence symptom count	8.000000e-06
GCST005580_68	Intraocular pressure	6.000000e-12
GCST005580_80	Intraocular pressure	2.000000e-11
GCST005667_39	Central corneal thickness	3.000000e-10
GCST005983_33	Serum uric acid levels	8.000000e-10
GCST006629_65	Pulse pressure	2.000000e-08
GCST006976_125	Macular thickness	2.000000e-10
GCST007269_99	Pulse pressure	1.000000e-08
GCST007511_4	Alzheimer’s disease (late onset)	9.000000e-08
GCST007725_33	Serum uric acid levels	7.000000e-12
GCST009021_19	Alzheimer’s disease	2.000000e-08
GCST009864_5	Fasting plasma glucose	1.000000e-06
GCST010083_359	Hemoglobin levels	1.000000e-12
GCST010241_251	Apolipoprotein A1 levels	4.000000e-08
GCST010242_59	HDL cholesterol levels	4.000000e-09
GCST011365_137	Myocardial infarction	4.000000e-06
GCST90000654_44	Central corneal thickness	1.000000e-14
GCST90002383_500	Hematocrit	5.000000e-29
GCST90002384_248	Hemoglobin	3.000000e-29
GCST90002401_512	Platelet distribution width	1.000000e-19
GCST90002403_634	Red blood cell count	3.000000e-13
GCST90013405_103	Liver enzyme levels (alanine transaminase)	3.000000e-11
GCST90013442_10	Keratoconus	3.000000e-10

EFO canonical traits (14, from GWAS)

EFO ID	Trait name
EFO:0005131	HVA measurement
EFO:0005132	5-HIAA measurement
EFO:0004509	hemoglobin measurement
EFO:0007835	alcohol dependence measurement
EFO:0004695	intraocular pressure measurement
EFO:0005213	central corneal thickness
EFO:0004761	uric acid measurement
EFO:0005763	pulse pressure measurement
EFO:1001870	late-onset Alzheimers disease
EFO:0004614	apolipoprotein A 1 measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004348	hematocrit
EFO:0007984	platelet component distribution width
EFO:0004305	erythrocyte count

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

16 total (human), top 16 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Acetaminophen	affects cotreatment, decreases expression	3
Valproic Acid	decreases expression, affects cotreatment, increases expression	3
bisphenol A	decreases expression	2
dicrotophos	decreases expression	1
mono-(2-ethylhexyl)phthalate	increases expression	1
sodium arsenite	decreases expression	1
ICG 001	increases expression	1
(+)-JQ1 compound	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	decreases expression	1
Atrazine	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Gallic Acid	decreases expression	1
Hydralazine	affects cotreatment, increases expression	1
Lipopolysaccharides	decreases expression, affects cotreatment	1
Tretinoin	decreases expression	1
Copper Sulfate	decreases expression	1

Cellosaurus cell lines

2 cell lines: 1 transformed cell line, 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D9L2	Ubigene HEK293 NDUFAF6 KO	Transformed cell line	Female
CVCL_XQ87	HAP1 NDUFAF6 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

113 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
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
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)
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)?
NCT02544217	PHASE1	COMPLETED	A Dose-escalating Clinical Trial With KH176
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
NCT06065852	Not specified	RECRUITING	National Registry of Rare Kidney Diseases
NCT04378075	PHASE2/PHASE3	TERMINATED	A Study to Evaluate Efficacy and Safety of Vatiquinone for Treating Mitochondrial Disease in Participants With Refractory Epilepsy
NCT01642056	PHASE1/PHASE2	COMPLETED	EPI-743 for Metabolism or Mitochondrial Disorders
NCT03384420	PHASE1/PHASE2	COMPLETED	A Study to Evaluate the Safety and Therapeutic Effects of Transplantation of MNV-BM-BLD in Pediatric Patients With Pearson Syndrome
NCT06051448	PHASE1/PHASE2	COMPLETED	Promoting Resilience in Stress Management (PRISM) and Clinical-focused Narrative (CFN) Pilot in Adults With Primary Mitochondrial Disease (PMD).