NDUFAF5

Summary

NDUFAF5 (NADH:ubiquinone oxidoreductase complex assembly factor 5, HGNC:15899) is a protein-coding gene on chromosome 20p12.1, encoding Arginine-hydroxylase NDUFAF5, mitochondrial (Q5TEU4). Arginine hydroxylase that mediates hydroxylation of ‘Arg-111’ of NDUFS7 and is involved in the assembly of mitochondrial NADH:ubiquinone oxidoreductase complex (complex I, MT-ND1) at early stages.

The NADH-ubiquinone oxidoreductase complex (complex I) of the mitochondrial respiratory chain catalyzes the transfer of electrons from NADH to ubiquinone, and consists of at least 43 subunits. The complex is located in the inner mitochondrial membrane. This gene encodes a mitochondrial protein that is associated with the matrix face of the mitochondrial inner membrane and is required for complex I assembly. A mutation in this gene results in mitochondrial complex I deficiency. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 79133 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Leigh syndrome (Definitive, ClinGen) — +5 more curated relationships
• Clinical variants (ClinVar): 478 total — 23 pathogenic, 52 likely-pathogenic
• Phenotypes (HPO): 52
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_024120

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15899
Approved symbol	NDUFAF5
Name	NADH:ubiquinone oxidoreductase complex assembly factor 5
Location	20p12.1
Locus type	gene with protein product
Status	Approved
Aliases	dJ842G6.1
Ensembl gene	ENSG00000101247
Ensembl biotype	protein_coding
OMIM	612360
Entrez	79133

Gene structure

Transcript identifiers

Ensembl transcripts: 20 — 13 protein_coding_CDS_not_defined, 6 protein_coding, 1 nonsense_mediated_decay

ENST00000378081, ENST00000378106, ENST00000463598, ENST00000464269, ENST00000469177, ENST00000475968, ENST00000476124, ENST00000476200, ENST00000476536, ENST00000477732, ENST00000479682, ENST00000479716, ENST00000481249, ENST00000485738, ENST00000486772, ENST00000487478, ENST00000874782, ENST00000874783, ENST00000934787, ENST00000949288

RefSeq mRNA: 5 — MANE Select: NM_024120 NM_001039375, NM_001352403, NM_001352406, NM_001352407, NM_024120

CCDS: CCDS13118, CCDS33441

Canonical transcript exons

ENST00000378106 — 11 exons

Exon	Start	End
ENSE00001918799	13785028	13785290
ENSE00003464753	13816875	13816957
ENSE00003485729	13816463	13816546
ENSE00003488853	13801486	13801683
ENSE00003591029	13794838	13794941
ENSE00003615327	13808842	13808902
ENSE00003621253	13793180	13793227
ENSE00003634546	13787312	13787352
ENSE00003656081	13817118	13821580
ENSE00003665472	13798461	13798500
ENSE00003684436	13788589	13788652

Expression profiles

Bgee: expression breadth ubiquitous, 261 present calls, max score 94.99.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 13.2964 / max 114.9794, expressed in 1808 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
183609	13.2830	1808
209000	0.0134	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	94.99	gold quality
right atrium auricular region	UBERON:0006631	94.57	gold quality
hindlimb stylopod muscle	UBERON:0004252	93.76	gold quality
heart left ventricle	UBERON:0002084	93.06	gold quality
cardiac ventricle	UBERON:0002082	92.98	gold quality
gastrocnemius	UBERON:0001388	92.88	gold quality
heart right ventricle	UBERON:0002080	92.86	gold quality
muscle of leg	UBERON:0001383	92.78	gold quality
cortical plate	UBERON:0005343	92.63	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	92.53	gold quality
skin of leg	UBERON:0001511	92.20	gold quality
biceps brachii	UBERON:0001507	92.05	gold quality
skin of abdomen	UBERON:0001416	91.96	gold quality
left testis	UBERON:0004533	91.93	gold quality
heart	UBERON:0000948	91.92	gold quality
adrenal tissue	UBERON:0018303	91.85	gold quality
calcaneal tendon	UBERON:0003701	91.78	gold quality
right testis	UBERON:0004534	91.67	gold quality
cardiac atrium	UBERON:0002081	91.66	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	91.39	gold quality
tibial nerve	UBERON:0001323	91.33	gold quality
muscle layer of sigmoid colon	UBERON:0035805	91.19	gold quality
rectum	UBERON:0001052	90.82	gold quality
cerebellar cortex	UBERON:0002129	90.82	gold quality
cerebellar hemisphere	UBERON:0002245	90.79	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	90.72	gold quality
prefrontal cortex	UBERON:0000451	90.49	gold quality
right hemisphere of cerebellum	UBERON:0014890	90.46	gold quality
ectocervix	UBERON:0012249	90.17	gold quality
lower esophagus muscularis layer	UBERON:0035833	90.12	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.16

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

69 targeting NDUFAF5, 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-513A-5P	100.00	69.77	2465
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-374B-5P	99.90	69.98	2734
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-605-3P	99.88	69.22	1833
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-4694-3P	99.79	69.53	2640
HSA-MIR-577	99.78	69.13	2479
HSA-MIR-4502	99.65	66.99	1021
HSA-MIR-4804-3P	99.65	67.78	866
HSA-MIR-651-5P	99.64	68.49	1104
HSA-MIR-4499	99.62	67.29	1470
HSA-MIR-3975	99.62	65.97	697
HSA-MIR-1249-5P	99.61	66.55	2049
HSA-MIR-6797-5P	99.61	66.55	2084

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 9)

• C20orf7 is crucial in the assembly of complex I and mutations in C20orf7 cause mitochondrial disease (PMID:18940309)
• A new cause of Leigh syndrome can be a defect in early complex I assembly due to C20orf7 mutations. (PMID:19542079)
• analysis of the combined OXPHOS complex I and IV defect, due to mutated complex I assembly factor C20ORF7 (PMID:21607760)
• However, similar to another family member, RdmB, it catalyzes the introduction of a hydroxyl group, in the case of NDUFAF5, into Arg-73 in the NDUFS7 subunit of human complex I (PMID:27226634)
• Our report adds significant new information to the mutational spectrum of NDUFAF5, further delineating the phenotypic heterogeneity of this mitochondrial defect. (PMID:30473481)
• Nuclear DNA Mutation Causing a Phenotypic Leber Hereditary Optic Neuropathy Plus. (PMID:32918965)
• Mitochondrial Factor C20orf7 Facilitates the EMT-Mediated Cancer Cell Migration and the Proliferation of Colon Cancer In Vitro and In Vivo. (PMID:36421786)
• Unique prenatal manifestations of biallelic NDUFAF5 variants: expansion of phenotype. (PMID:37718619)
• Phenotypic Heterogeneity in Patients with Mutations in the Mitochondrial Complex I Assembly Gene NDUFAF5. (PMID:37752895)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ndufaf5	ENSDARG00000061629
mus_musculus	Ndufaf5	ENSMUSG00000027384
rattus_norvegicus	Ndufaf5	ENSRNOG00000004784
drosophila_melanogaster	CG8067	FBGN0033891
caenorhabditis_elegans		WBGENE00010721

Protein

Protein identifiers

Arginine-hydroxylase NDUFAF5, mitochondrial — Q5TEU4 (reviewed: Q5TEU4)

Alternative names: NADH dehydrogenase [ubiquinone] 1 alpha subcomplex assembly factor 5, Putative methyltransferase NDUFAF5

All UniProt accessions (2): Q5TEU4, B3KR61

UniProt curated annotations — full annotation on UniProt →

Function. Arginine hydroxylase that mediates hydroxylation of ‘Arg-111’ of NDUFS7 and is involved in the assembly of mitochondrial NADH:ubiquinone oxidoreductase complex (complex I, MT-ND1) at early stages. May also have methyltransferase activity.

Subunit / interactions. Interacts with NDUFAF8, leading to stabilize NDUFAF5. Interacts with NDUFS7. Interacts with PYURF (via TRM112 domain); the interaction is direct and stabilizes NDUFAF5 protein.

Subcellular location. Mitochondrion inner membrane.

Disease relevance. Mitochondrial complex I deficiency, nuclear type 16 (MC1DN16) [MIM:618238] 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. MC1DN16 transmission pattern is consistent with autosomal recessive inheritance. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the methyltransferase superfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q5TEU4-1	1	yes
Q5TEU4-2	2

RefSeq proteins (5): NP_001034464, NP_001339332, NP_001339335, NP_001339336, NP_077025* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR013216	Methyltransf_11	Domain
IPR029063	SAM-dependent_MTases_sf	Homologous_superfamily
IPR050602	Malonyl-ACP_OMT	Family

Pfam: PF08241

UniProt features (7 total): sequence variant 4, transit peptide 1, chain 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5TEU4-F1	85.43	0.75

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: 225 (showing top): GOBP_MITOCHONDRIAL_RESPIRATORY_CHAIN_COMPLEX_ASSEMBLY, WEI_MYCN_TARGETS_WITH_E_BOX, GOCC_MITOCHONDRIAL_ENVELOPE, GGCKCATGS_UNKNOWN, ATGCTGG_MIR338, TTGGAGA_MIR5155P_MIR519E, DODD_NASOPHARYNGEAL_CARCINOMA_UP, GOBP_METHYLATION, GOCC_LUMENAL_SIDE_OF_MEMBRANE, GOCC_ORGANELLE_INNER_MEMBRANE, GOCC_SIDE_OF_MEMBRANE, GOMF_S_ADENOSYLMETHIONINE_DEPENDENT_METHYLTRANSFERASE_ACTIVITY, GOMF_TRANSFERASE_ACTIVITY_TRANSFERRING_ONE_CARBON_GROUPS, MODULE_49, GOMF_MONOOXYGENASE_ACTIVITY

GO Biological Process (2): methylation (GO:0032259), mitochondrial respiratory chain complex I assembly (GO:0032981)

GO Molecular Function (6): monooxygenase activity (GO:0004497), S-adenosylmethionine-dependent methyltransferase activity (GO:0008757), protein binding (GO:0005515), methyltransferase activity (GO:0008168), oxidoreductase activity (GO:0016491), transferase activity (GO:0016740)

GO Cellular Component (4): mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), matrix side of mitochondrial inner membrane (GO:0099617), 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
catalytic activity	2
metabolic process	1
NADH dehydrogenase complex assembly	1
mitochondrial respiratory chain complex assembly	1
oxidoreductase activity	1
methyltransferase activity	1
binding	1
transferase activity, transferring one-carbon groups	1
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
mitochondrial inner membrane	1
lumenal side of membrane	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1682 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NDUFAF5	NDUFAF6	Q330K2	929
NDUFAF5	NDUFS3	O75489	891
NDUFAF5	NDUFAF2	Q8N183	889
NDUFAF5	NDUFAF4	Q9P032	885
NDUFAF5	FOXRED1	Q96CU9	878
NDUFAF5	NDUFAF8	A1L188	859
NDUFAF5	NDUFS7	O75251	857
NDUFAF5	NDUFS8	O00217	853
NDUFAF5	NDUFS2	O75306	852
NDUFAF5	NUBPL	Q8TB37	819
NDUFAF5	NDUFS4	O43181	814
NDUFAF5	NDUFAF3	Q9BU61	804
NDUFAF5	CRLS1	Q9UJA2	802
NDUFAF5	NDUFAF1	Q9Y375	795
NDUFAF5	NDUFS1	P28331	762

IntAct

82 interactions, top by confidence:

A	B	Type	Score
NDUFAF8	NDUFAF5	psi-mi:“MI:0915”(physical association)	0.750
NDUFAF8	NDUFAF5	psi-mi:“MI:0914”(association)	0.750
NDUFAF5	NDUFAF8	psi-mi:“MI:0914”(association)	0.750
NDUFS3	NDUFS8	psi-mi:“MI:0914”(association)	0.730
GRPEL2	DBT	psi-mi:“MI:0914”(association)	0.710
NDUFS7	NDUFS8	psi-mi:“MI:0914”(association)	0.640
KLHL22	TMEM223	psi-mi:“MI:0914”(association)	0.640
NDUFAF4	NDUFS8	psi-mi:“MI:0914”(association)	0.640
KLHL22	METTL15	psi-mi:“MI:0914”(association)	0.640
TRMT61B	MTIF2	psi-mi:“MI:0914”(association)	0.610
NPPA	A2ML1	psi-mi:“MI:0914”(association)	0.530
NDUFAF5	XRCC2	psi-mi:“MI:0914”(association)	0.530
MRPL38	DUSP14	psi-mi:“MI:0914”(association)	0.530
COX5B	COX7A2L	psi-mi:“MI:0914”(association)	0.530
AVP	ATE1	psi-mi:“MI:0914”(association)	0.530
DTX3	ITSN1	psi-mi:“MI:0914”(association)	0.530
MRPL23	BCKDHA	psi-mi:“MI:0914”(association)	0.530
NDUFS7	NDUFV2	psi-mi:“MI:0914”(association)	0.530

BioGRID (136): NDUFAF5 (Affinity Capture-MS), NDUFAF5 (Affinity Capture-MS), NDUFAF5 (Affinity Capture-MS), NME2P1 (Affinity Capture-MS), PPM1E (Affinity Capture-MS), XRCC2 (Affinity Capture-MS), RAD51D (Affinity Capture-MS), HBA2 (Affinity Capture-MS), HBB (Affinity Capture-MS), NDUFAF5 (Affinity Capture-MS), NDUFAF5 (Affinity Capture-MS), NDUFAF5 (Affinity Capture-MS), NDUFAF5 (Affinity Capture-MS), NDUFAF5 (Affinity Capture-MS), NDUFAF5 (Affinity Capture-Western)

ESM2 similar proteins: A2APY7, A3KP37, A7YW45, B2GV71, M1BYJ7, O08691, O08701, O14744, O46504, O80543, P20373, P41819, P49900, P78540, P78697, Q1JPL4, Q2LZ79, Q337B8, Q3KRD0, Q4G064, Q4R5M3, Q4V7R3, Q58DL1, Q5R698, Q5RBS1, Q5TEU4, Q66KM2, Q66L51, Q6AY46, Q6BSY5, Q6C7H6, Q6FKY3, Q6NUA1, Q6NYF0, Q6PI48, Q6YXZ7, Q75C90, Q7SYK1, Q7T0W5, Q80XC2

Diamond homologs: A0A8D5M692, A0L3L9, A2APY7, A3DBD7, A3KP37, A4SGV9, A6UYW3, B2GV71, B3PI89, O80543, P45249, Q2HEW5, Q2KXN6, Q5RBS1, Q5TEU4, Q5ZT34, Q609U9, Q6D3C1, Q9RX93, A0A8X8M4W6, A0KAF5, A0PLV5, A0PQ29, A1K8U5, A1KG35, A1SAJ8, A1SE26, A1W9K6, A1WVM4, A4G5P1, A4WAG4, A5TZT8, A5VRJ7, A6V4P3, A6W0X8, A6WZN1, A9M6C1, A9WRT1, B0CHP1, B1JYJ6

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 77 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	11	31.4×	8e-12
Respiratory electron transport	12	19.7×	8e-11
Aerobic respiration and respiratory electron transport	11	16.8×	3e-09
Mitochondrial protein degradation	7	13.8×	4e-05
Mitochondrial translation initiation	5	10.9×	3e-03
Mitochondrial ribosome-associated quality control	5	10.6×	3e-03

GO biological processes:

GO term	Partners	Fold	FDR
mitochondrial respiratory chain complex I assembly	7	40.5×	2e-07
mitochondrial electron transport, NADH to ubiquinone	7	35.4×	2e-07
proton motive force-driven mitochondrial ATP synthesis	7	26.0×	1e-06
aerobic respiration	7	24.4×	2e-06
mitochondrial translation	5	12.2×	5e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	23
Likely pathogenic	52
Uncertain significance	91
Likely benign	228
Benign	28

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1957246	NM_024120.5(NDUFAF5):c.733C>T (p.Gln245Ter)	Pathogenic
1965673	NM_024120.5(NDUFAF5):c.476T>G (p.Leu159Ter)	Pathogenic
1966453	NM_024120.5(NDUFAF5):c.751dup (p.Met251fs)	Pathogenic
2015745	NM_024120.5(NDUFAF5):c.603_627del (p.Gln202fs)	Pathogenic
2094481	NM_024120.5(NDUFAF5):c.773T>A (p.Leu258Ter)	Pathogenic
2123793	NM_024120.5(NDUFAF5):c.217dup (p.Glu73fs)	Pathogenic
2189888	NM_024120.5(NDUFAF5):c.363dup (p.Glu122fs)	Pathogenic
2202530	NM_024120.5(NDUFAF5):c.806del (p.Asn269fs)	Pathogenic
2426805	NC_000020.10:g.(?13775474)(13775597_?)del	Pathogenic
2426806	NC_000020.10:g.(?13782122)(13782529_?)del	Pathogenic
2426807	NC_000020.10:g.(?13765662)(13775597_?)del	Pathogenic
2579156	NM_024120.5(NDUFAF5):c.223-2A>T	Pathogenic
2728796	NM_024120.5(NDUFAF5):c.823_840del (p.His275_Leu280del)	Pathogenic
2808216	NM_024120.5(NDUFAF5):c.710dup (p.Thr238fs)	Pathogenic
2824264	NM_024120.5(NDUFAF5):c.220G>T (p.Glu74Ter)	Pathogenic
2839416	NM_024120.5(NDUFAF5):c.387del (p.Glu130fs)	Pathogenic
2917871	NM_024120.5(NDUFAF5):c.582_583del (p.Leu194_Tyr195insTer)	Pathogenic
2982531	NM_024120.5(NDUFAF5):c.274del (p.Ala93fs)	Pathogenic
3248348	NC_000020.10:g.(?13765715)(13782349_?)del	Pathogenic
3642547	NM_024120.5(NDUFAF5):c.368dup (p.Asn123fs)	Pathogenic
3644486	NM_024120.5(NDUFAF5):c.533T>G (p.Leu178Ter)	Pathogenic
3645296	NM_024120.5(NDUFAF5):c.334_335del (p.Ile112fs)	Pathogenic
571	NM_024120.5(NDUFAF5):c.477A>C (p.Leu159Phe)	Pathogenic
1677179	NM_024120.5(NDUFAF5):c.519+2T>G	Likely pathogenic
1802978	NM_024120.5(NDUFAF5):c.752T>G (p.Met251Arg)	Likely pathogenic
1804830	NM_024120.5(NDUFAF5):c.519+2T>C	Likely pathogenic
1942040	NM_024120.5(NDUFAF5):c.375+1G>A	Likely pathogenic
1973722	NM_024120.5(NDUFAF5):c.479+1G>C	Likely pathogenic
1976579	NM_024120.5(NDUFAF5):c.328-2A>G	Likely pathogenic
2039861	NM_024120.5(NDUFAF5):c.263+1G>C	Likely pathogenic

SpliceAI

2129 predictions. Top by Δscore:

Variant	Effect	Δscore
20:13785285:G:GT	donor_gain	1.0000
20:13785287:GGAG:G	donor_gain	1.0000
20:13785288:GAGG:G	donor_gain	1.0000
20:13785289:AGGTG:A	donor_loss	1.0000
20:13785290:GGTG:G	donor_loss	1.0000
20:13785291:G:C	donor_loss	1.0000
20:13785292:T:G	donor_loss	1.0000
20:13788587:A:AG	acceptor_gain	1.0000
20:13788588:G:GG	acceptor_gain	1.0000
20:13794837:GAA:G	acceptor_gain	1.0000
20:13794837:GAAA:G	acceptor_gain	1.0000
20:13794837:GAAAA:G	acceptor_gain	1.0000
20:13798459:A:AG	acceptor_gain	1.0000
20:13798460:G:GG	acceptor_gain	1.0000
20:13798708:A:G	donor_gain	1.0000
20:13801482:ACAG:A	acceptor_loss	1.0000
20:13801484:A:AG	acceptor_gain	1.0000
20:13801484:A:G	acceptor_loss	1.0000
20:13801485:G:GC	acceptor_loss	1.0000
20:13801485:G:GG	acceptor_gain	1.0000
20:13801485:GATTC:G	acceptor_gain	1.0000
20:13801591:G:GT	donor_gain	1.0000
20:13801591:G:T	donor_gain	1.0000
20:13801657:A:T	donor_gain	1.0000
20:13801680:TGTGG:T	donor_loss	1.0000
20:13801681:GTG:G	donor_gain	1.0000
20:13801682:TGGTA:T	donor_loss	1.0000
20:13801684:G:GA	donor_loss	1.0000
20:13801685:T:A	donor_loss	1.0000
20:13808836:A:AG	acceptor_gain	1.0000

AlphaMissense

2244 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:13794931:A:C	S157R	0.998
20:13794933:C:A	S157R	0.998
20:13794933:C:G	S157R	0.998
20:13787334:G:C	R82P	0.997
20:13816908:C:A	A299D	0.997
20:13816935:G:A	G308E	0.997
20:13816528:G:C	A282P	0.996
20:13785224:A:C	K52N	0.995
20:13785224:A:T	K52N	0.995
20:13816937:T:A	W309R	0.995
20:13816937:T:C	W309R	0.995
20:13794923:T:C	L154P	0.994
20:13801556:T:C	L197P	0.994
20:13816939:G:C	W309C	0.994
20:13816939:G:T	W309C	0.994
20:13785207:T:C	F47L	0.993
20:13785209:C:A	F47L	0.993
20:13785209:C:G	F47L	0.993
20:13794934:A:C	S158R	0.993
20:13794936:T:A	S158R	0.993
20:13794936:T:G	S158R	0.993
20:13801559:G:C	R198P	0.993
20:13801649:T:C	L228P	0.993
20:13801667:T:C	F234S	0.993
20:13801523:G:A	G186D	0.992
20:13801556:T:A	L197H	0.992
20:13808866:T:G	Y248D	0.992
20:13816529:C:A	A282D	0.992
20:13801535:G:A	G190E	0.991
20:13801576:G:C	A204P	0.991

dbSNP variants (sampled 300 via entrez): RS1000152959 (20:13796334 G>A), RS1000257608 (20:13798028 T>C), RS1000262443 (20:13790088 G>T), RS1000413366 (20:13820093 C>T), RS1000549413 (20:13821039 G>A), RS1000808005 (20:13785735 G>A,C,T), RS1000952608 (20:13816209 C>T), RS1000988814 (20:13815028 T>C), RS1000997843 (20:13787688 C>T), RS1001061586 (20:13807903 C>A,T), RS1001150174 (20:13821499 A>T), RS1001156632 (20:13785518 A>G), RS1001166129 (20:13814905 G>C), RS1001320184 (20:13796661 A>G), RS1001409336 (20:13807759 C>T)

Disease associations

OMIM: gene MIM:612360 | disease phenotypes: MIM:256000, MIM:618238, MIM:252010

GenCC curated gene-disease

Disease	Classification	Inheritance
mitochondrial complex I deficiency, nuclear type 16	Strong	Autosomal recessive
mitochondrial complex I deficiency, nuclear type 3	Strong	Autosomal recessive
Leigh syndrome with leukodystrophy	Supportive	Autosomal recessive
mitochondrial complex I deficiency	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
Leigh syndrome	Definitive	AR
mitochondrial disease	Definitive	AR

Mondo (7): mitochondrial complex I deficiency (MONDO:0100133), Leigh syndrome (MONDO:0009723), mitochondrial complex I deficiency, nuclear type 16 (MONDO:0032621), mitochondrial complex I deficiency, nuclear type 1 (MONDO:0100224), Leber plus disease (MONDO:0020478), (MONDO:0016815), mitochondrial complex I deficiency, nuclear type 3 (MONDO:0032608)

Orphanet (3): Isolated complex I deficiency (Orphanet:2609), Leigh syndrome (Orphanet:506), Leber plus disease (Orphanet:99718)

HPO phenotypes

52 total (30 of 52 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000114	Proximal tubulopathy
HP:0000252	Microcephaly
HP:0000407	Sensorineural hearing impairment
HP:0000486	Strabismus
HP:0000508	Ptosis
HP:0000543	Optic disc pallor
HP:0000618	Blindness
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000817	Reduced eye contact
HP:0000819	Diabetes mellitus
HP:0000846	Adrenal insufficiency
HP:0001138	Optic neuropathy
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001254	Lethargy
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001266	Choreoathetosis
HP:0001274	Agenesis of corpus callosum
HP:0001290	Generalized hypotonia
HP:0001298	Encephalopathy
HP:0001324	Muscle weakness
HP:0001332	Dystonia
HP:0001508	Failure to thrive
HP:0001511	Intrauterine growth retardation
HP:0001639	Hypertrophic cardiomyopathy

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

18 total (human), top 18 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases abundance, increases expression	3
Leflunomide	increases expression	2
Acetaminophen	affects cotreatment, decreases expression	2
Arsenic	affects methylation, increases abundance, increases expression	2
Cadmium Chloride	decreases expression	2
GSK-J4	increases expression	1
dicrotophos	decreases expression	1
beta-lapachone	increases expression	1
arsenite	increases methylation	1
zinc chloride	decreases expression	1
perfluorooctanoic acid	increases expression	1
nickel sulfate	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
K 7174	decreases expression	1
abrine	increases expression	1
Lipopolysaccharides	affects cotreatment, decreases expression	1
Methyl Methanesulfonate	increases expression	1
Zinc	decreases expression	1

Cellosaurus cell lines

2 cell lines: 1 induced pluripotent stem cell, 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D6NY	IBMS-iPSC-089	Induced pluripotent stem cell	Female
CVCL_E2DA	HAP1 NDUFAF5 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05162768	PHASE3	COMPLETED	Study to Evaluate Efficacy and Safety of Elamipretide in Subjects With Primary Mitochondrial Disease From Nuclear DNA Mutations (nPMD)
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)
NCT02544217	PHASE1	COMPLETED	A Dose-escalating Clinical Trial With KH176
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
NCT05277363	Not specified	WITHDRAWN	A Study of the Natural Course of SURF1 Deficiency
NCT05554835	Not specified	RECRUITING	Global Registry and Natural History Study for Mitochondrial Disorders
NCT06967831	Not specified	RECRUITING	Drug Repurposing for Mitochondrial Disorders Using iPSCs Derived Neural Cells