NUBPL

Summary

NUBPL (NUBP iron-sulfur cluster assembly factor, mitochondrial, HGNC:20278) is a protein-coding gene on chromosome 14q12, encoding Iron-sulfur cluster transfer protein NUBPL (Q8TB37). Iron-sulfur cluster transfer protein involved in the assembly of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I).

This gene encodes a member of the Mrp/NBP35 ATP-binding proteins family. The encoded protein is required for the assembly of the respiratory chain NADH dehydrogenase (complex I), an oligomeric enzymatic complex located in the inner mitochondrial membrane. Mutations in this gene cause mitochondrial complex I deficiency. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 80224 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 3
• Clinical variants (ClinVar): 311 total — 12 pathogenic, 9 likely-pathogenic
• Phenotypes (HPO): 51
• MANE Select transcript: NM_025152

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20278
Approved symbol	NUBPL
Name	NUBP iron-sulfur cluster assembly factor, mitochondrial
Location	14q12
Locus type	gene with protein product
Status	Approved
Aliases	FLJ12660, IND1, huInd1
Ensembl gene	ENSG00000151413
Ensembl biotype	protein_coding
OMIM	613621
Entrez	80224

Gene structure

Transcript identifiers

Ensembl transcripts: 22 — 13 protein_coding, 5 protein_coding_CDS_not_defined, 3 nonsense_mediated_decay, 1 retained_intron

ENST00000281081, ENST00000418681, ENST00000547839, ENST00000548937, ENST00000549838, ENST00000550005, ENST00000550355, ENST00000550649, ENST00000551015, ENST00000551314, ENST00000552489, ENST00000552814, ENST00000552888, ENST00000858672, ENST00000858673, ENST00000858674, ENST00000858675, ENST00000858676, ENST00000858677, ENST00000937194, ENST00000955293, ENST00000955294

RefSeq mRNA: 3 — MANE Select: NM_025152 NM_001201573, NM_001201574, NM_025152

CCDS: CCDS41940

Canonical transcript exons

ENST00000281081 — 11 exons

Exon	Start	End
ENSE00002401919	31859118	31861224
ENSE00002402272	31561404	31561547
ENSE00003462040	31673484	31673574
ENSE00003516630	31846471	31846591
ENSE00003555119	31565014	31565048
ENSE00003606721	31599289	31599379
ENSE00003616570	31562068	31562215
ENSE00003629548	31826629	31826714
ENSE00003644494	31787780	31787873
ENSE00003680305	31673355	31673394
ENSE00003691386	31850119	31850201

Expression profiles

Bgee: expression breadth ubiquitous, 267 present calls, max score 89.86.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 10.3708 / max 84.8505, expressed in 1766 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
139105	10.2449	1763
139104	0.1259	21

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	89.86	gold quality
adrenal tissue	UBERON:0018303	86.14	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	85.38	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.45	gold quality
bronchial epithelial cell	CL:0002328	82.73	gold quality
sural nerve	UBERON:0015488	82.71	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	82.61	gold quality
heart left ventricle	UBERON:0002084	82.19	gold quality
right atrium auricular region	UBERON:0006631	82.19	gold quality
lower lobe of lung	UBERON:0008949	82.19	gold quality
cardiac ventricle	UBERON:0002082	82.00	gold quality
hindlimb stylopod muscle	UBERON:0004252	81.76	gold quality
heart	UBERON:0000948	81.57	gold quality
ventricular zone	UBERON:0003053	81.56	gold quality
muscle of leg	UBERON:0001383	81.47	gold quality
biceps brachii	UBERON:0001507	81.19	gold quality
cardiac atrium	UBERON:0002081	81.18	gold quality
right adrenal gland cortex	UBERON:0035827	80.92	gold quality
gastrocnemius	UBERON:0001388	80.80	gold quality
tendon	UBERON:0000043	80.69	gold quality
right adrenal gland	UBERON:0001233	80.52	gold quality
rectum	UBERON:0001052	80.35	gold quality
colonic epithelium	UBERON:0000397	80.07	gold quality
epithelium of bronchus	UBERON:0002031	79.97	gold quality
skeletal muscle organ	UBERON:0014892	79.93	gold quality
muscle organ	UBERON:0001630	79.92	gold quality
bronchus	UBERON:0002185	79.55	gold quality
adrenal gland	UBERON:0002369	79.51	gold quality
left adrenal gland	UBERON:0001234	79.50	gold quality
left adrenal gland cortex	UBERON:0035825	79.25	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.73
E-CURD-10	no	112.23

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

78 targeting NUBPL, 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-3163	100.00	77.23	8605
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-362-3P	99.91	66.38	1267
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-374B-5P	99.90	69.98	2734
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-369-3P	99.85	70.52	2264
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-5010-3P	99.83	70.60	2357
HSA-MIR-4694-3P	99.79	69.53	2640
HSA-MIR-4679	99.76	69.19	1229
HSA-MIR-12130	99.75	65.47	452
HSA-MIR-4719	99.73	72.10	3329
HSA-MIR-12129	99.72	67.45	1311
HSA-MIR-4677-5P	99.70	70.09	1940
HSA-MIR-466	99.67	70.85	2863
HSA-MIR-3177-5P	99.65	70.38	1174
HSA-MIR-3679-3P	99.64	69.88	1599
HSA-MIR-549A-3P	99.54	68.17	825

Literature-anchored findings (GeneRIF, showing 10)

• These data identify huInd1 as a new assembly factor for human respiratory complex I with a possible role in the delivery of one or more Fe/S clusters to complex I subunits.[Ind1] (PMID:19752196)
• Mutations in NUBPL is associated with complex I deficiency. (PMID:20818383)
• Our data show that NUBPL mutations are associated with a unique, consistent, and recognizable MRI pattern. (PMID:23553477)
• huInd1 binds to the untranslated region of the TEM-1 mRNA at 3’ site and thereby reducing the possibility of its endonucleolytic cleavage, resulting in over-expression of TEM-1. (PMID:25240856)
• Inhibition of ERK suppressed the NUBPL-induced changes in EMT and cell motility. (PMID:28346728)
• 5 missense variants in NUBPL gene were compared. The resulting NUBPL/Ind1 protein variants were tested in Yarrowia lipolytica for protein stability and complex I levels, oxidoreductase activity and assembly intermediates. 4 missense mutations are pathogenic, and mutants are sensitive to low temperature. (PMID:29982452)
• Mitochondrial complex I NUBPL mutations cause combined dystonia with bilateral striatal necrosis and cerebellar atrophy. (PMID:30897263)
• Novel compound heterozygous pathogenic variants in nucleotide-binding protein like protein (NUBPL) cause leukoencephalopathy with multi-systemic involvement. (PMID:31787496)
• NUBPL mitochondrial disease: new patients and review of the genetic and clinical spectrum. (PMID:32518176)
• Expanding the Spectrum of NUBPL-Related Leukodystrophy. (PMID:36868263)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	nubpl	ENSDARG00000054821
mus_musculus	Nubpl	ENSMUSG00000035142
rattus_norvegicus	Nubpl	ENSRNOG00000027444
drosophila_melanogaster	Nubpl	FBGN0032986

Paralogs (2): NUBP2 (ENSG00000095906), NUBP1 (ENSG00000103274)

Protein

Protein identifiers

Iron-sulfur cluster transfer protein NUBPL — Q8TB37 (reviewed: Q8TB37)

Alternative names: IND1 homolog, Nucleotide-binding protein-like, huInd1

All UniProt accessions (7): Q8TB37, F8VP02, F8VZR8, F8W061, F8W0A2, H0YHR7, X5D2R5

UniProt curated annotations — full annotation on UniProt →

Function. Iron-sulfur cluster transfer protein involved in the assembly of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I). May deliver one or more Fe-S clusters to complex I subunits.

Subcellular location. Mitochondrion.

Tissue specificity. Highest expression in liver and kidney. expressed at significant levels in small intestine and brain (at protein level).

Disease relevance. Mitochondrial complex I deficiency, nuclear type 21 (MC1DN21) [MIM:618242] 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. MC1DN21 transmission pattern is consistent with autosomal recessive inheritance. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Binds 1 [4Fe-4S] cluster.

Miscellaneous. May be due to exon skipping.

Similarity. Belongs to the Mrp/NBP35 ATP-binding proteins family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8TB37-1	1	yes
Q8TB37-2	2

RefSeq proteins (2): NP_001188502, NP_079428* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000808	Mrp-like_CS	Conserved_site
IPR019591	Mrp/NBP35_ATP-bd	Family
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR033756	YlxH/NBP35	Family
IPR044304	NUBPL-like	Family

Pfam: PF10609

UniProt features (11 total): sequence variant 4, mutagenesis site 2, splice variant 2, transit peptide 1, chain 1, binding site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8TB37-F1	85.40	0.70

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 (1): 75–82

Mutagenesis-validated functional residues (2):

Position	Phenotype
247	defect in complex i assembly; when associated with a-244.
244	defect in complex i assembly; when associated with a-247.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-6799198	Complex I biogenesis

MSigDB gene sets: 233 (showing top): ATF_B, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GOBP_MITOCHONDRIAL_RESPIRATORY_CHAIN_COMPLEX_ASSEMBLY, CREBP1_Q2, chr14q12, CREB_Q4, OCT1_07, CREB_Q2_01, CREB_Q3, ATF_01, CHIANG_LIVER_CANCER_SUBCLASS_CTNNB1_UP, CREBP1CJUN_01, CREB_01, GOCC_MITOCHONDRIAL_MATRIX, CGTSACG_PAX3_B

GO Biological Process (3): mitochondrion organization (GO:0007005), iron-sulfur cluster assembly (GO:0016226), mitochondrial respiratory chain complex I assembly (GO:0032981)

GO Molecular Function (7): ATP binding (GO:0005524), metal ion binding (GO:0046872), 4 iron, 4 sulfur cluster binding (GO:0051539), ATP-dependent FeS chaperone activity (GO:0140663), nucleotide binding (GO:0000166), protein binding (GO:0005515), iron-sulfur cluster binding (GO:0051536)

GO Cellular Component (3): mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), plasma membrane (GO:0005886)

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
organelle organization	1
metallo-sulfur cluster assembly	1
NADH dehydrogenase complex assembly	1
mitochondrial respiratory chain complex assembly	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
cation binding	1
iron-sulfur cluster binding	1
metallochaperone activity	1
ATP-dependent activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
metal cluster binding	1
cytoplasm	1
intracellular membrane-bounded organelle	1
mitochondrion	1
intracellular organelle lumen	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

1564 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NUBPL	FOXRED1	Q96CU9	851
NUBPL	NDUFAF4	Q9P032	851
NUBPL	NDUFAF5	Q5TEU4	819
NUBPL	NDUFS2	O75306	813
NUBPL	ISCA1	Q9BUE6	807
NUBPL	NDUFAF3	Q9BU61	793
NUBPL	NDUFS8	O00217	789
NUBPL	NFU1	Q9UMS0	788
NUBPL	IBA57	Q5T440	786
NUBPL	NDUFS3	O75489	779
NUBPL	NDUFAF2	Q8N183	773
NUBPL	ISCA2	Q86U28	758
NUBPL	NDUFV1	P49821	747
NUBPL	NDUFAF1	Q9Y375	745
NUBPL	NDUFV2	P19404	738

IntAct

54 interactions, top by confidence:

A	B	Type	Score
DNAJB11	HSPA5	psi-mi:“MI:0914”(association)	0.830
NUBPL	NUBP2	psi-mi:“MI:0915”(physical association)	0.600
KDM8	NUBPL	psi-mi:“MI:0915”(physical association)	0.560
TMEM9	ESYT2	psi-mi:“MI:0914”(association)	0.530
LAMP3	METTL15	psi-mi:“MI:0914”(association)	0.530
UQCRFS1	NDUFAB1	psi-mi:“MI:0914”(association)	0.530
SPCS3	ENTPD6	psi-mi:“MI:0914”(association)	0.530
NUBPL	MTUS2	psi-mi:“MI:0915”(physical association)	0.370
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350
PPP1CA	ACO2	psi-mi:“MI:0914”(association)	0.350
BCL2L14		psi-mi:“MI:0914”(association)	0.350
TNFRSF10A	NAP1L4	psi-mi:“MI:0914”(association)	0.350
ATAD3A	TMEM223	psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
	BTAF1	psi-mi:“MI:0914”(association)	0.350
CUL4A	DDX39A	psi-mi:“MI:0914”(association)	0.350
CUL4B	GGTLC3	psi-mi:“MI:0914”(association)	0.350
ITM2B	ILVBL	psi-mi:“MI:0914”(association)	0.350
rs27_rs27l_human	HBD	psi-mi:“MI:0914”(association)	0.350
GPR45	VWA8	psi-mi:“MI:0914”(association)	0.350
GZMH	DENND11	psi-mi:“MI:0914”(association)	0.350
GML	POTEF	psi-mi:“MI:0914”(association)	0.350
NAAA	HAX1	psi-mi:“MI:0914”(association)	0.350
ALPI	RTCA	psi-mi:“MI:0914”(association)	0.350
SDF2L1	MANBA	psi-mi:“MI:0914”(association)	0.350
ADAM7	RIOK3	psi-mi:“MI:0914”(association)	0.350
SNX21	ACOT8	psi-mi:“MI:0914”(association)	0.350
VSIG4	TNFRSF10B	psi-mi:“MI:0914”(association)	0.350

BioGRID (78): NUBPL (Affinity Capture-MS), NUBPL (Affinity Capture-MS), NUBPL (Affinity Capture-MS), NUBPL (Affinity Capture-MS), NUBPL (Proximity Label-MS), NUBPL (Affinity Capture-MS), NUBPL (Affinity Capture-MS), NUBPL (Affinity Capture-MS), NUBPL (Affinity Capture-MS), NUBPL (Affinity Capture-MS), NUBPL (Two-hybrid), KDM8 (Two-hybrid), NUBPL (Affinity Capture-MS), NUBPL (Affinity Capture-MS), NUBPL (Affinity Capture-MS)

ESM2 similar proteins: A0JME6, A6QLY4, B5X0W9, F6HDM2, G4YEI5, O49472, P08030, P09556, P13995, P35914, P47956, P47957, P54886, P54889, P85094, Q01637, Q08C33, Q0P5C2, Q32KX0, Q32LQ3, Q3T099, Q43153, Q4R826, Q54NZ6, Q54NZ8, Q5M8W9, Q5PQ71, Q5R4M8, Q5R9E1, Q5RC03, Q5U3Z3, Q5ZKA5, Q68FS1, Q6DF67, Q6I7R3, Q6NY77, Q8HXZ6, Q8K009, Q8LG77, Q8TB37

Diamond homologs: A1C7T4, A4QNM5, A7RUD5, A7SE07, A8PW87, A8WWQ7, A9V7A1, B0X4N8, B0XDJ0, B3M9R3, B3NIP2, B3RPX4, B4H7P4, B4IAD1, B4IUH5, B4IYG8, B4KY56, B4LGB4, B4N4D9, B4PES4, B4QJ46, B6K1G6, O24999, O49472, O58667, O66946, O94442, P0AF08, P0AF09, P0CO88, P0CO89, P40558, P45135, P50863, P53381, P53382, P53383, P53384, P65442, P72190

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	12
Likely pathogenic	9
Uncertain significance	146
Likely benign	54
Benign	52

Top pathogenic / likely-pathogenic (21)

Variant ID	HGVS	Classification
1388237	NM_025152.3(NUBPL):c.423T>A (p.Cys141Ter)	Pathogenic
214884	NM_025152.3(NUBPL):c.201_202insG (p.Gln68fs)	Pathogenic
2682369	NC_000014.8:g.(32142781_32256985)_(32257080_32295834)del	Pathogenic
2816858	NM_025152.3(NUBPL):c.163C>T (p.Arg55Ter)	Pathogenic
3645600	NM_025152.3(NUBPL):c.579dup (p.Ser194fs)	Pathogenic
4766165	NM_025152.3(NUBPL):c.709C>T (p.Gln237Ter)	Pathogenic
50214	NM_025152.3(NUBPL):c.667_668insCCTTGTGCTG (p.Glu223delinsAlaLeuCysTer)	Pathogenic
50217	NM_025152.3(NUBPL):c.579A>C (p.Leu193Phe)	Pathogenic
635348	NM_025152.3(NUBPL):c.726C>G (p.Phe242Leu)	Pathogenic
685158	GRCh37/hg19 14q12(chr14:32117154-32214183)x1	Pathogenic
817927	NM_025152.3(NUBPL):c.774dup (p.Ala259fs)	Pathogenic
915894	NM_025152.3(NUBPL):c.351G>A (p.Met117Ile)	Pathogenic
2627223	NM_025152.3(NUBPL):c.423-1G>A	Likely pathogenic
2955173	NM_025152.3(NUBPL):c.423-1G>T	Likely pathogenic
3669990	NM_025152.3(NUBPL):c.608-1G>C	Likely pathogenic
3764546	NM_025152.3(NUBPL):c.448del (p.Glu150fs)	Likely pathogenic
3899261	GRCh37/hg19 14q12(chr14:32317254-32323465)x1	Likely pathogenic
3906930	NM_025152.3(NUBPL):c.261del (p.Ala89fs)	Likely pathogenic
432144	NM_025152.3(NUBPL):c.526C>T (p.Gln176Ter)	Likely pathogenic
4845507	NM_025152.3(NUBPL):c.622_623del (p.Ser208fs)	Likely pathogenic
985663	NM_025152.3(NUBPL):c.257-2A>G	Likely pathogenic

SpliceAI

4187 predictions. Top by Δscore:

Variant	Effect	Δscore
14:31562211:AGCAG:A	donor_loss	1.0000
14:31562212:GCAG:G	donor_gain	1.0000
14:31562212:GCAGG:G	donor_loss	1.0000
14:31562213:CAG:C	donor_loss	1.0000
14:31562214:AGGTA:A	donor_loss	1.0000
14:31562215:GG:G	donor_loss	1.0000
14:31562216:G:A	donor_loss	1.0000
14:31562217:T:A	donor_loss	1.0000
14:31563447:GCTTC:G	donor_gain	1.0000
14:31563453:G:GG	donor_gain	1.0000
14:31565012:A:AG	acceptor_gain	1.0000
14:31565013:G:GA	acceptor_gain	1.0000
14:31565013:GT:G	acceptor_gain	1.0000
14:31599287:A:AG	acceptor_gain	1.0000
14:31599288:G:GA	acceptor_gain	1.0000
14:31599375:ACAGA:A	donor_gain	1.0000
14:31599376:CAGA:C	donor_gain	1.0000
14:31599377:AGA:A	donor_gain	1.0000
14:31599378:GA:G	donor_gain	1.0000
14:31599378:GAG:G	donor_gain	1.0000
14:31599378:GAGTA:G	donor_loss	1.0000
14:31599380:GTA:G	donor_loss	1.0000
14:31599380:GTAA:G	donor_gain	1.0000
14:31599381:T:G	donor_loss	1.0000
14:31599383:A:AG	donor_gain	1.0000
14:31599384:G:GG	donor_gain	1.0000
14:31673482:A:AG	acceptor_gain	1.0000
14:31673483:G:GG	acceptor_gain	1.0000
14:31673483:GTAT:G	acceptor_gain	1.0000
14:31727552:T:G	donor_gain	1.0000

AlphaMissense

2051 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:31562204:C:T	S82F	0.997
14:31673489:C:T	S143F	0.997
14:31787786:T:A	W174R	0.996
14:31787786:T:C	W174R	0.996
14:31562201:A:T	K81I	0.995
14:31562212:G:C	A85P	0.995
14:31599308:T:C	L104P	0.995
14:31787788:G:C	W174C	0.995
14:31787788:G:T	W174C	0.995
14:31787808:T:A	V181D	0.995
14:31826641:T:A	V207D	0.995
14:31562204:C:A	S82Y	0.994
14:31562198:G:A	G80E	0.993
14:31846491:C:A	N238K	0.993
14:31846491:C:G	N238K	0.993
14:31846537:T:C	F254L	0.993
14:31846539:T:A	F254L	0.993
14:31846539:T:G	F254L	0.993
14:31599302:G:A	G102D	0.992
14:31673489:C:A	S143Y	0.992
14:31673531:G:T	R157I	0.992
14:31562203:T:C	S82P	0.991
14:31565020:T:C	L88P	0.991
14:31599310:G:C	D105H	0.991
14:31673488:T:C	S143P	0.991
14:31673527:T:A	W156R	0.991
14:31673527:T:C	W156R	0.991
14:31673531:G:C	R157T	0.991
14:31673532:A:C	R157S	0.991
14:31673532:A:T	R157S	0.991

dbSNP variants (sampled 300 via entrez): RS1000003744 (14:31729369 G>A,T), RS1000005595 (14:31657176 A>G), RS1000006258 (14:31663620 C>G,T), RS1000019841 (14:31567797 G>A), RS1000029869 (14:31684379 T>C), RS1000045706 (14:31692300 T>C,G), RS1000050637 (14:31741536 C>A,T), RS1000055277 (14:31581707 T>C), RS1000059029 (14:31823384 A>T), RS1000063023 (14:31785221 ATATT>A), RS1000064428 (14:31699308 A>G,T), RS1000080882 (14:31777689 C>A), RS1000089355 (14:31618582 T>A,C,G), RS1000122562 (14:31630080 A>G), RS1000124366 (14:31633851 G>T)

Disease associations

OMIM: gene MIM:613621 | disease phenotypes: MIM:618242, MIM:252010

GenCC curated gene-disease

Disease	Classification	Inheritance
mitochondrial complex I deficiency, nuclear type 21	Definitive	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 (5): mitochondrial complex I deficiency, nuclear type 21 (MONDO:0032625), mitochondrial complex I deficiency, nuclear type 1 (MONDO:0100224), mitochondrial complex I deficiency (MONDO:0100133), intellectual disability (MONDO:0001071), mitochondrial oxidative phosphorylation disorder (MONDO:0016387)

Orphanet (3): Isolated complex I deficiency (Orphanet:2609), Mitochondrial oxidative phosphorylation disorder (Orphanet:223713), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

51 total (30 of 51 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:0000817	Reduced eye contact
HP:0000819	Diabetes mellitus
HP:0001138	Optic neuropathy
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001254	Lethargy
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001288	Gait disturbance
HP:0001298	Encephalopathy
HP:0001317	Abnormal cerebellum morphology
HP:0001324	Muscle weakness
HP:0001347	Hyperreflexia
HP:0001508	Failure to thrive
HP:0001510	Growth delay
HP:0001511	Intrauterine growth retardation
HP:0001639	Hypertrophic cardiomyopathy
HP:0001943	Hypoglycemia
HP:0002013	Vomiting
HP:0002093	Respiratory insufficiency

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST000201_3	Response to iloperidone treatment (QT prolongation)	2.000000e-06
GCST000265_2	Brain lesion load	6.000000e-06
GCST008522_62	Bitter alcoholic beverage consumption	9.000000e-07

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0010092	bitter alcoholic beverage consumption measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
C537475	Mitochondrial complex I deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs7142881	Toxicity	3	iloperidone	Acquired Long QT Syndrome (aLQTS)

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs7142881	NUBPL	3	0.00	1	iloperidone

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression, affects methylation	7
bisphenol S	affects expression, decreases methylation	2
Air Pollutants	affects cotreatment, increases abundance, increases oxidation, decreases expression	2
Valproic Acid	increases expression	2
Cyclosporine	decreases expression	2
Cadmium Chloride	increases abundance, increases expression	2
aristolochic acid I	decreases expression	1
dicrotophos	decreases expression	1
methylmercuric chloride	decreases expression	1
methyleugenol	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
sodium arsenite	decreases expression	1
cobaltous chloride	decreases expression	1
butyraldehyde	decreases expression	1
perfluorooctanoic acid	increases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
ICG 001	increases expression	1
abrine	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
Resveratrol	affects cotreatment, increases expression	1
Fulvestrant	increases methylation	1
Acetaminophen	decreases expression	1
Acrolein	affects cotreatment, increases oxidation, increases abundance	1
Arsenic	affects methylation	1
Cadmium	increases abundance, increases expression	1
Cisplatin	decreases expression	1
Dimethyl Sulfoxide	increases expression	1
Gallic Acid	increases expression	1
Hydrogen Peroxide	affects expression	1

Cellosaurus cell lines

3 cell lines: 3 finite cell line

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

Cellosaurus	Name	Category	Sex
CVCL_BX19	GM24529	Finite cell line	Female
CVCL_F0YX	GM29343	Finite cell line	Female
CVCL_F0YY	GM29344	Finite cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT05162768	PHASE3	COMPLETED	Study to Evaluate Efficacy and Safety of Elamipretide in Subjects With Primary Mitochondrial Disease From Nuclear DNA Mutations (nPMD)
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study
NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD
NCT02591446	Not specified	COMPLETED	Transcranial Magnetic Stimulation Studies in Autism Spectrum Disorders
NCT02714868	Not specified	COMPLETED	Evaluation of Project TEAM (Teens Making Environmental and Activity Modifications)
NCT02721394	Not specified	UNKNOWN	FCT With Young Children With ID in the UK: A Feasibility Project V.1
NCT02746614	Not specified	COMPLETED	Psychomotor Therapy Effects in Adaptive Behavior and Motor Proficiency in Intellectual Disability