NFU1

Summary

NFU1 (NFU1 iron-sulfur cluster scaffold, HGNC:16287) is a protein-coding gene on chromosome 2p13.3, encoding NFU1 iron-sulfur cluster scaffold homolog, mitochondrial (Q9UMS0). Iron-sulfur cluster scaffold protein which can assemble [4Fe-4S] clusters and deliver them to target proteins. It is a selective cancer dependency (DepMap: 11.3% of cell lines).

This gene encodes a protein that is localized to mitochondria and plays a critical role in iron-sulfur cluster biogenesis. The encoded protein assembles and transfers 4Fe-4S clusters to target apoproteins including succinate dehydrogenase and lipoic acid synthase. Mutations in this gene are a cause of multiple mitochondrial dysfunctions syndrome-1, and pseudogenes of this gene are located on the short arms of chromosomes 1 and 3. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene.

Source: NCBI Gene 27247 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Definitive, ClinGen) — +1 more curated relationship
• Clinical variants (ClinVar): 191 total — 10 pathogenic, 6 likely-pathogenic
• Phenotypes (HPO): 76
• Cancer dependency (DepMap): dependent in 11.3% of screened cell lines
• MANE Select transcript: NM_001002755

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16287
Approved symbol	NFU1
Name	NFU1 iron-sulfur cluster scaffold
Location	2p13.3
Locus type	gene with protein product
Status	Approved
Aliases	CGI-33, NifU, NIFUC
Ensembl gene	ENSG00000169599
Ensembl biotype	protein_coding
OMIM	608100
Entrez	27247

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 6 nonsense_mediated_decay, 5 protein_coding

ENST00000303698, ENST00000410022, ENST00000419370, ENST00000438184, ENST00000450796, ENST00000462320, ENST00000471185, ENST00000474230, ENST00000484177, ENST00000875857, ENST00000923206

RefSeq mRNA: 4 — MANE Select: NM_001002755 NM_001002755, NM_001002756, NM_001374284, NM_015700

CCDS: CCDS33217, CCDS42694, CCDS46315

Canonical transcript exons

ENST00000410022 — 8 exons

Exon	Start	End
ENSE00001164604	69400364	69400538
ENSE00001589213	69396126	69396290
ENSE00001660348	69437361	69437435
ENSE00003552130	69415185	69415299
ENSE00003574368	69423582	69423717
ENSE00003592068	69419538	69419604
ENSE00004283234	69431902	69432005
ENSE00004283235	69406022	69406082

Expression profiles

Bgee: expression breadth ubiquitous, 291 present calls, max score 98.19.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 66.3140 / max 438.3402, expressed in 1823 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
28908	60.0071	1823
28909	5.8457	1704
28910	0.2376	84
28911	0.2204	78
202227	0.0032	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
heart right ventricle	UBERON:0002080	98.19	gold quality
biceps brachii	UBERON:0001507	98.05	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	97.87	gold quality
hindlimb stylopod muscle	UBERON:0004252	97.26	gold quality
gluteal muscle	UBERON:0002000	97.04	gold quality
vastus lateralis	UBERON:0001379	97.01	gold quality
gastrocnemius	UBERON:0001388	96.90	gold quality
cardiac ventricle	UBERON:0002082	96.90	gold quality
heart left ventricle	UBERON:0002084	96.90	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	96.90	gold quality
muscle of leg	UBERON:0001383	96.89	gold quality
muscle organ	UBERON:0001630	96.88	gold quality
quadriceps femoris	UBERON:0001377	96.76	gold quality
skeletal muscle tissue	UBERON:0001134	96.62	gold quality
triceps brachii	UBERON:0001509	96.19	gold quality
adipose tissue	UBERON:0001013	95.97	gold quality
tibial artery	UBERON:0007610	95.92	gold quality
popliteal artery	UBERON:0002250	95.90	gold quality
apex of heart	UBERON:0002098	95.78	gold quality
connective tissue	UBERON:0002384	95.73	gold quality
calcaneal tendon	UBERON:0003701	95.64	gold quality
subcutaneous adipose tissue	UBERON:0002190	95.63	gold quality
left coronary artery	UBERON:0001626	95.59	gold quality
heart	UBERON:0000948	95.57	gold quality
left ventricle myocardium	UBERON:0006566	95.51	gold quality
aorta	UBERON:0000947	95.49	gold quality
adipose tissue of abdominal region	UBERON:0007808	95.47	gold quality
deltoid	UBERON:0001476	95.46	gold quality
peritoneum	UBERON:0002358	95.34	gold quality
omental fat pad	UBERON:0010414	95.34	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.94
E-CURD-112	no	2.55

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

14 targeting NFU1, 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-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-146A-3P	99.13	68.99	1881
HSA-MIR-382-3P	98.83	67.10	1074
HSA-MIR-3921	97.81	67.45	1431
HSA-MIR-4633-5P	96.17	66.36	501

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 11.3% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 25)

• Analyses of genomic DNA, transcripts, and translation products indicate that alternative splicing of a common pre-mRNA results in synthesis of two Nfu isoforms with distinct subcellular localizations. (PMID:12886008)
• Laforin interacts with HIRIP5. (PMID:12915448)
• NFU binds to NifS and reduces the persulfide bond on activated NifS (following formation of the persulfide bond by abstraction of S from the Cys amino acid), yielding inorganic sulfide on a time frame that is compatible with Fe-S cluster assembly. (PMID:19146390)
• NFU is a functionally competent reducing agent for cysteinyl persulfide bond cleavage, releasing inorganic sulfide for incorporation into the iron-sulfur-bound [2Fe-2S] cluster, a reactivity that may be facilitated by flexibility of the C-terminal domain. (PMID:19722697)
• Mutations in iron-sulfur cluster scaffold genes NFU1 and BOLA3 cause a fatal deficiency of multiple respiratory chain and 2-oxoacid dehydrogenase enzymes [case report] (PMID:21944046)
• A fatal mitochondrial disease is associated with defective NFU1 function in the maturation of a subset of mitochondrial Fe-S proteins (PMID:22077971)
• This study provides new insights into the molecular bases of NFU1 disease. (PMID:23179554)
• A new NFU1 mutation is reported in a patient presenting with a milder phenotype characterized by a later onset, a slowly progressive spastic paraparesis with relapsing-remitting episodes, mild cognitive impairment and a long survival. (PMID:25758857)
• a leaky splicing regulation due to a splice site mutation (c.545+5G>A) that produces small amounts of wild type NFU1 mRNA that might result in enough protein to partially lipoylate and restore the activity of lipoic acid-dependent enzymes and the assembly and activity of complex I. (PMID:26688339)
• NFU1 gene mutations may cause severe mitochondrial respiratory chain defects, mitochondrial encephalomyopathies and death, early in life (Review) (PMID:27381105)
• a direct role for human Nfu in the process of [2Fe-2S] cluster trafficking and delivery (PMID:27538573)
• Study used NMR spectroscopy and small-angle X-ray scattering data to determine the 3D structure of human mitochondrial NFU1 in its apo- and iron-sulfur cluster-containing holo-form. Apo- NFU1 is monomeric, whereas holo-NFU1 consists of a trimer of three [4Fe-4S] cluster-linked dimers. (PMID:27818104)
• Analysis of protein stability and oligomeric state demonstrates that the Gly208Cys mutant increases the propensity to dimerize and perturbs the secondary structure composition. These changes appear to underlie the severely decreased ability of mutant NFU1 to accept an Fe/S cluster from physiologically relevant sources. (PMID:28161430)
• Novel NFU1 variants were identified in Chinese patients with multiple mitochondrial dysfunctions syndrome. (PMID:28470589)
• report the results of an investigation on the effect of these substitutions on both cluster coordination and NFU1 structure and function (PMID:28906593)
• Gly189Arg substitution on NFU1 is associated with multiple mitochondrial dysfunctions syndrome 1. (PMID:28906594)
• data support a hypothesis in which Nfu can serve as an alternative carrier protein for chaperone-mediated cluster release and delivery in Fe-S cluster biogenesis and trafficking (PMID:29211945)
• A pathway for assembling 4Fe-4S clusters in mitochondrial iron-sulfur protein biogenesis. (PMID:31724821)
• Multiple mitochondrial dysfunctions syndrome 1: An unusual cause of developmental pulmonary hypertension. (PMID:31970900)
• Assembly of the [4Fe-4S] cluster of NFU1 requires the coordinated donation of two [2Fe-2S] clusters from the scaffold proteins, ISCU2 and ISCA1. (PMID:32776106)
• ISCA1 Orchestrates ISCA2 and NFU1 in the Maturation of Human Mitochondrial [4Fe-4S] Proteins. (PMID:33711344)
• Phenotypic continuum of NFU1-related disorders. (PMID:36256512)
• Patient-specific variants of NFU1/NFU-1 disrupt cholinergic signaling in a model of multiple mitochondrial dysfunctions syndrome 1. (PMID:36645076)
• Structural Plasticity of NFU1 Upon Interaction with Binding Partners: Insights into the Mitochondrial [4Fe-4S] Cluster Pathway. (PMID:37211204)
• BOLA3 and NFU1 link mitoribosome iron-sulfur cluster assembly to multiple mitochondrial dysfunctions syndrome. (PMID:37823603)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
mus_musculus	Nfu1	ENSMUSG00000029993
rattus_norvegicus	Nfu1	ENSRNOG00000018410
drosophila_melanogaster	CG32857	FBGN0052857
drosophila_melanogaster	CG33502	FBGN0053502
drosophila_melanogaster	CG32500	FBGN0285970
caenorhabditis_elegans		WBGENE00003064

Protein

Protein identifiers

NFU1 iron-sulfur cluster scaffold homolog, mitochondrial — Q9UMS0 (reviewed: Q9UMS0)

Alternative names: HIRA-interacting protein 5

All UniProt accessions (6): C9J8Q1, Q9UMS0, F8W9P7, F8WAV1, F8WET4, H7C537

UniProt curated annotations — full annotation on UniProt →

Function. Iron-sulfur cluster scaffold protein which can assemble [4Fe-4S] clusters and deliver them to target proteins.

Subunit / interactions. Monomer and homohexamer; the apo-NFU1 is a monomer, while the holo-NFU1 is a hexamer composed of a trimer of dimer that is probably linked by some 4Fe-4S cluster. Interacts with HIRA and EPM2A/laforin. Interacts with BOLA3. Interacts with HSPA9.

Subcellular location. Mitochondrion. Cytoplasm. Cytosol.

Tissue specificity. Ubiquitous. Expression in adult lung is weak compared to fetal lung.

Disease relevance. Multiple mitochondrial dysfunctions syndrome 1 (MMDS1) [MIM:605711] A severe disorder of systemic energy metabolism, resulting in weakness, respiratory failure, lack of neurologic development, lactic acidosis, hyperglycinemia and early death. Some patients show failure to thrive, pulmonary hypertension, hypotonia and irritability. Biochemical features include severe combined deficiency of the 2-oxoacid dehydrogenases, defective lipoic acid synthesis and reduction in activity of mitochondrial respiratory chain complexes. The disease is caused by variants affecting the gene represented in this entry. Spastic paraplegia 93, autosomal recessive (SPG93) [MIM:620938] A form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or the weakness and stiffness may spread to other parts of the body. Some SPG93 patients have neurodevelopmental delay with severe hypotonia. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the NifU family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9UMS0-1	1	yes
Q9UMS0-2	2
Q9UMS0-3	3

RefSeq proteins (4): NP_001002755, NP_001002756, NP_001361213, NP_056515 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001075	NIF_FeS_clus_asmbl_NifU_C	Domain
IPR014824	Nfu/NifU_N	Domain
IPR034904	FSCA_dom_sf	Homologous_superfamily
IPR036498	Nfu/NifU_N_sf	Homologous_superfamily

Pfam: PF01106, PF08712

UniProt features (40 total): sequence variant 15, strand 9, helix 5, mutagenesis site 2, binding site 2, splice variant 2, transit peptide 1, chain 1, region of interest 1, sequence conflict 1, turn 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
2LTM	SOLUTION NMR
2M5O	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UMS0-F1	79.07	0.61

Functional residue map

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

Ligand- & substrate-binding residues (2): 210; 213

Mutagenesis-validated functional residues (2):

Position	Phenotype
189	alters protein structure. increases likelihood of existing as monomer. decreases ability to receive a fe/s clusters from

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9857492	Protein lipoylation

MSigDB gene sets: 245 (showing top): STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, GOBP_PROTEIN_MATURATION, ZHANG_BREAST_CANCER_PROGENITORS_UP, RIGGINS_TAMOXIFEN_RESISTANCE_DN, GATGKMRGCG_UNKNOWN, NUYTTEN_EZH2_TARGETS_DN, GOCC_MITOCHONDRIAL_MATRIX, BLALOCK_ALZHEIMERS_DISEASE_DN, BOCHKIS_FOXA2_TARGETS, STEIN_ESRRA_TARGETS_UP, GOMF_METAL_CLUSTER_BINDING, GOMF_IRON_ION_BINDING, GOMF_2_IRON_2_SULFUR_CLUSTER_BINDING, GOMF_4_IRON_4_SULFUR_CLUSTER_BINDING

GO Biological Process (2): iron-sulfur cluster assembly (GO:0016226), protein maturation (GO:0051604)

GO Molecular Function (6): iron ion binding (GO:0005506), 2 iron, 2 sulfur cluster binding (GO:0051537), 4 iron, 4 sulfur cluster binding (GO:0051539), protein binding (GO:0005515), metal ion binding (GO:0046872), iron-sulfur cluster binding (GO:0051536)

GO Cellular Component (6): nucleus (GO:0005634), nucleoplasm (GO:0005654), mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), cytosol (GO:0005829), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Post-translational protein modification	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
iron-sulfur cluster binding	2
intracellular membrane-bounded organelle	2
cytoplasm	2
metallo-sulfur cluster assembly	1
gene expression	1
protein metabolic process	1
transition metal ion binding	1
binding	1
cation binding	1
metal cluster binding	1
nuclear lumen	1
mitochondrion	1
intracellular organelle lumen	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1690 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NFU1	ISCU	Q9H1K1	917
NFU1	BOLA3	Q53S33	908
NFU1	IBA57	Q5T440	896
NFU1	ISCA2	Q86U28	892
NFU1	EPM2A	O95278	886
NFU1	ISCA1	Q9BUE6	877
NFU1	LIAS	O43766	873
NFU1	GLRX5	Q86SX6	842
NFU1	FXN	Q16595	834
NFU1	HSCB	Q8IWL3	826
NFU1	NFS1	Q9Y697	816
NFU1	FDX2	Q6P4F2	815
NFU1	LYRM4	Q9HD34	811
NFU1	BOLA1	Q9Y3E2	797
NFU1	NUBPL	Q8TB37	788

IntAct

80 interactions, top by confidence:

A	B	Type	Score
TFIP11	NFU1	psi-mi:“MI:0915”(physical association)	0.720
NFU1	TRIM23	psi-mi:“MI:0915”(physical association)	0.560
CALCOCO2	NFU1	psi-mi:“MI:0915”(physical association)	0.560
AGTRAP	NFU1	psi-mi:“MI:0915”(physical association)	0.560
TRIM23	NFU1	psi-mi:“MI:0915”(physical association)	0.560
NFU1	AGTRAP	psi-mi:“MI:0915”(physical association)	0.560
NFU1	CALCOCO2	psi-mi:“MI:0915”(physical association)	0.560
NFU1	APOC4	psi-mi:“MI:0915”(physical association)	0.560
NFU1	CIDEB	psi-mi:“MI:0915”(physical association)	0.560
NFU1	ZSCAN5A	psi-mi:“MI:0915”(physical association)	0.560
CMTM5	NFU1	psi-mi:“MI:0915”(physical association)	0.560
COIL	NFU1	psi-mi:“MI:0915”(physical association)	0.560
SDCBP2	NFU1	psi-mi:“MI:0915”(physical association)	0.560
MORN3	NFU1	psi-mi:“MI:0915”(physical association)	0.560
APOC4	NFU1	psi-mi:“MI:0915”(physical association)	0.560
APOC1	NFU1	psi-mi:“MI:0915”(physical association)	0.560
ZNF688	NFU1	psi-mi:“MI:0915”(physical association)	0.560
MDK	NFU1	psi-mi:“MI:0915”(physical association)	0.560
ZSCAN5A	NFU1	psi-mi:“MI:0915”(physical association)	0.560
CIDEB	NFU1	psi-mi:“MI:0915”(physical association)	0.560
RHBDD2	NFU1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (62): NFU1 (Two-hybrid), NFU1 (Two-hybrid), NFU1 (Two-hybrid), AGTRAP (Two-hybrid), NFU1 (Two-hybrid), NFU1 (Affinity Capture-MS), HIRA (Two-hybrid), NFU1 (Affinity Capture-MS), NFU1 (Affinity Capture-MS), NFU1 (Two-hybrid), NFU1 (Reconstituted Complex), NFU1 (Affinity Capture-Western), NFU1 (Co-fractionation), NFU1 (Co-fractionation), REXO2 (Co-fractionation)

ESM2 similar proteins: A0A2Z5WA18, B3MRT7, B3NYF7, B4H303, B4IMF6, B4JWR9, B4M375, B4NE93, B4PZ52, B4R3T1, B5DKJ8, B5YM03, B7FRE8, C5DL56, C5DQ08, G8BAW7, O18216, P19097, P22572, P24529, P32795, P32860, P34454, P38431, P48596, P54150, P54151, P54813, P60315, Q0DHL4, Q1DUF5, Q55CS9, Q626C1, Q6FJ31, Q6FMB3, Q6VBQ8, Q754U8, Q765N2, Q7YRD0, Q84WU8

Diamond homologs: A1AGT8, A4VLM9, A4WFK2, A4XUA5, A5W5N3, A6TF37, A6V6X0, A7ZSU3, A8A5M2, B0KKI2, B1IP51, B1J6F5, B1LHL4, B1X760, B2U3M4, B3MRT7, B3NYF7, B4H303, B4IMF6, B4JWR9, B4M375, B4NE93, B4PZ52, B4R3T1, B5DKJ8, B5XTS2, B5YTW5, B6I2X8, B7L4U4, B7LSB7, B7M1X0, B7MDP0, B7N147, B7NE19, B7NMH9, B7UKB9, B7VB28, C1DLW0, C3K9S0, C4ZVW3

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 51 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.

GO biological processes:

GO term	Partners	Fold	FDR
iron-sulfur cluster assembly	5	66.9×	2e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	10
Likely pathogenic	6
Uncertain significance	65
Likely benign	60
Benign	31

Top pathogenic / likely-pathogenic (16)

Variant ID	HGVS	Classification
30700	NM_001002755.4(NFU1):c.622G>T (p.Gly208Cys)	Pathogenic
3338679	NFU1, 1-BP DEL, 146C	Pathogenic
3338680	NM_001002755.4(NFU1):c.721G>C (p.Val241Leu)	Pathogenic
3338683	NM_001002755.4(NFU1):c.362T>C (p.Val121Ala)	Pathogenic
3338684	NM_001002755.4(NFU1):c.295C>G (p.Leu99Val)	Pathogenic
3338685	NM_001002755.4(NFU1):c.263T>C (p.Phe88Ser)	Pathogenic
3338690	NFU1, 55.6-KB DEL, EX4-8DEL	Pathogenic
3716398	NM_001002755.4(NFU1):c.264del (p.Thr90fs)	Pathogenic
3730503	NM_001002755.4(NFU1):c.507del (p.Val170fs)	Pathogenic
488563	NM_001002755.4(NFU1):c.545+5G>A	Pathogenic
1285476	NM_001002755.4(NFU1):c.565G>A (p.Gly189Arg)	Likely pathogenic
1285477	NM_001002755.4(NFU1):c.545G>T (p.Arg182Leu)	Likely pathogenic
214869	NM_001002755.4(NFU1):c.303-2A>T	Likely pathogenic
4537853	NM_001002755.4(NFU1):c.239_240del (p.Val80fs)	Likely pathogenic
647954	NC_000002.11:g.(?69627476)(69627690_?)dup	Likely pathogenic
804384	NM_001002755.4(NFU1):c.485-1G>C	Likely pathogenic

SpliceAI

1359 predictions. Top by Δscore:

Variant	Effect	Δscore
2:69400358:GCATA:G	donor_loss	1.0000
2:69400359:CATA:C	donor_loss	1.0000
2:69400360:ATAC:A	donor_loss	1.0000
2:69400361:TA:T	donor_loss	1.0000
2:69400363:CC:C	donor_loss	1.0000
2:69400376:TTC:T	donor_gain	1.0000
2:69400377:TCT:T	donor_gain	1.0000
2:69400383:T:TA	donor_gain	1.0000
2:69415181:TTAC:T	donor_loss	1.0000
2:69415182:TA:T	donor_loss	1.0000
2:69415183:A:AT	donor_loss	1.0000
2:69415184:CCT:C	donor_loss	1.0000
2:69415184:CCTG:C	donor_gain	1.0000
2:69415296:TTTC:T	acceptor_gain	1.0000
2:69415298:TCC:T	acceptor_loss	1.0000
2:69415300:C:CG	acceptor_loss	1.0000
2:69415301:T:A	acceptor_loss	1.0000
2:69419601:CTGC:C	acceptor_gain	1.0000
2:69419602:TGC:T	acceptor_gain	1.0000
2:69419603:GC:G	acceptor_gain	1.0000
2:69419603:GCCT:G	acceptor_loss	1.0000
2:69419604:CC:C	acceptor_gain	1.0000
2:69419605:C:CA	acceptor_loss	1.0000
2:69419605:C:CC	acceptor_gain	1.0000
2:69419606:T:C	acceptor_loss	1.0000
2:69423584:AG:A	donor_gain	1.0000
2:69423585:G:C	donor_gain	1.0000
2:69423714:CTCA:C	acceptor_gain	1.0000
2:69423716:CA:C	acceptor_gain	1.0000
2:69423718:C:CC	acceptor_gain	1.0000

AlphaMissense

1667 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:69400401:A:G	L228P	1.000
2:69400425:A:G	L220P	1.000
2:69400447:A:G	C213R	1.000
2:69400455:C:T	C210Y	1.000
2:69400473:A:G	L204P	1.000
2:69400518:C:T	G189E	1.000
2:69406025:A:T	I181K	1.000
2:69423663:A:G	F74S	1.000
2:69400394:A:C	F230L	0.999
2:69400394:A:T	F230L	0.999
2:69400396:A:G	F230L	0.999
2:69400413:A:C	I224S	0.999
2:69400413:A:T	I224N	0.999
2:69400416:C:T	G223E	0.999
2:69400446:C:T	C213Y	0.999
2:69400454:A:C	C210W	0.999
2:69400456:A:G	C210R	0.999
2:69400462:C:G	G208R	0.999
2:69400479:A:T	V202E	0.999
2:69400493:A:C	F197L	0.999
2:69400493:A:T	F197L	0.999
2:69400495:A:G	F197L	0.999
2:69400518:C:A	G189V	0.999
2:69400519:C:G	G189R	0.999
2:69400519:C:T	G189R	0.999
2:69400521:T:A	D188V	0.999
2:69400521:T:G	D188A	0.999
2:69400527:T:G	Q186P	0.999
2:69400530:A:T	V185E	0.999
2:69406022:C:G	R182P	0.999

dbSNP variants (sampled 300 via entrez): RS1000023770 (2:69404195 G>A,T), RS1000054777 (2:69403949 C>T), RS1000150002 (2:69433342 C>T), RS1000174764 (2:69436916 C>T), RS1000194671 (2:69395758 CT>C,CTT), RS1000196529 (2:69438155 T>A,C), RS1000229306 (2:69428389 C>T), RS1000240631 (2:69428146 G>A), RS1000312901 (2:69438412 C>G,T), RS1000346685 (2:69419458 A>T), RS1000390316 (2:69434583 A>C), RS1000403808 (2:69433041 T>G), RS1000423914 (2:69402852 G>C), RS1000582047 (2:69421458 C>A), RS1000617173 (2:69429767 G>A)

Disease associations

OMIM: gene MIM:608100 | disease phenotypes: MIM:605711, MIM:620938

GenCC curated gene-disease

Disease	Classification	Inheritance
multiple mitochondrial dysfunctions syndrome 1	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
mitochondrial disease	Definitive	AR

Mondo (2): multiple mitochondrial dysfunctions syndrome 1 (MONDO:0011582), spastic paraplegia 93, autosomal recessive (MONDO:0975796)

Orphanet (1): Multiple mitochondrial dysfunctions syndrome type 1 (Orphanet:401869)

HPO phenotypes

76 total (30 of 76 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000486	Strabismus
HP:0000508	Ptosis
HP:0000544	External ophthalmoplegia
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0001252	Hypotonia
HP:0001254	Lethargy
HP:0001258	Spastic paraplegia
HP:0001263	Global developmental delay
HP:0001276	Hypertonia
HP:0001285	Spastic tetraparesis
HP:0001288	Gait disturbance
HP:0001298	Encephalopathy
HP:0001324	Muscle weakness
HP:0001336	Myoclonus
HP:0001348	Brisk reflexes
HP:0001508	Failure to thrive
HP:0001522	Death in infancy
HP:0001762	Talipes equinovarus
HP:0001941	Acidosis
HP:0001945	Fever
HP:0002061	Lower limb spasticity
HP:0002066	Gait ataxia
HP:0002071	Abnormality of extrapyramidal motor function
HP:0002079	Hypoplasia of the corpus callosum
HP:0002092	Pulmonary arterial hypertension
HP:0002093	Respiratory insufficiency
HP:0002133	Status epilepticus
HP:0002151	Increased circulating lactate concentration

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, increases expression	2
Air Pollutants	affects expression, increases abundance, decreases expression	2
Valproic Acid	affects expression, increases expression	2
aristolochic acid I	increases expression	1
bisphenol F	increases expression	1
dicrotophos	decreases expression	1
methylmercuric chloride	decreases expression	1
tetrahydropalmatine	decreases expression	1
beta-lapachone	decreases expression	1
arsenite	affects binding, increases reaction	1
perfluorooctanoic acid	decreases expression	1
manganese chloride	increases abundance, increases expression	1
corosolic acid	decreases expression	1
bisphenol B	increases expression	1
abrine	decreases expression	1
bisphenol AF	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Benzo(a)pyrene	affects methylation	1
Cisplatin	increases expression	1
Doxorubicin	increases expression	1
Hydrogen Peroxide	affects expression	1
Ivermectin	decreases expression	1
Lead	increases expression	1
Manganese	increases abundance, increases expression	1
Ozone	affects expression, increases abundance	1
Phthalic Acids	affects methylation	1
Plant Extracts	affects cotreatment, increases expression	1
Urethane	decreases expression	1
Cyclosporine	increases expression	1
Gold Compounds	decreases expression	1

Clinical trials (associated diseases)

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