TIMM50

Summary

TIMM50 (translocase of inner mitochondrial membrane 50, HGNC:23656) is a protein-coding gene on chromosome 19q13.2, encoding Mitochondrial import inner membrane translocase subunit TIM50 (Q3ZCQ8). Essential component of the TIM23 complex, a complex that mediates the translocation of transit peptide-containing proteins across the mitochondrial inner membrane. It is a selective cancer dependency (DepMap: 31.9% of cell lines).

This gene encodes a subunit of the TIM23 inner mitochondrial membrane translocase complex. The encoded protein functions as the receptor subunit that recognizes the mitochondrial targeting signal, or presequence, on protein cargo that is destined for the mitochondrial inner membrane and matrix. This protein may also play a role in maintaining the membrane permeability barrier, and knockdown of this gene in human cells results in the release of cytochrome c and apoptosis.

Source: NCBI Gene 92609 — RefSeq curated summary.

At a glance

• Gene–disease (curated): 3-methylglutaconic aciduria type 9 (Definitive, ClinGen)
• Clinical variants (ClinVar): 487 total — 4 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 44
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 31.9% of screened cell lines
• MANE Select transcript: NM_001001563

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23656
Approved symbol	TIMM50
Name	translocase of inner mitochondrial membrane 50
Location	19q13.2
Locus type	gene with protein product
Status	Approved
Aliases	TIM50L, TIM50
Ensembl gene	ENSG00000105197
Ensembl biotype	protein_coding
OMIM	607381
Entrez	92609

Gene structure

Transcript identifiers

Ensembl transcripts: 22 — 10 protein_coding, 6 retained_intron, 5 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000544017, ENST00000594583, ENST00000595286, ENST00000595527, ENST00000595961, ENST00000596239, ENST00000597552, ENST00000597666, ENST00000597782, ENST00000598125, ENST00000599733, ENST00000599794, ENST00000600878, ENST00000601252, ENST00000601358, ENST00000601403, ENST00000602028, ENST00000602265, ENST00000607714, ENST00000922947, ENST00000922948, ENST00000966009

RefSeq mRNA: 2 — MANE Select: NM_001001563 NM_001001563, NM_001329559

CCDS: CCDS33023

Canonical transcript exons

ENST00000607714 — 11 exons

Exon	Start	End
ENSE00003470851	39485544	39485602
ENSE00003484762	39481883	39482033
ENSE00003537184	39488539	39488645
ENSE00003584630	39485688	39485807
ENSE00003669952	39483135	39483156
ENSE00003689868	39486187	39486291
ENSE00003697128	39489719	39493779
ENSE00003697318	39480838	39480961
ENSE00003717156	39482885	39482916
ENSE00003784859	39488061	39488217
ENSE00003791191	39486397	39486495

Expression profiles

Bgee: expression breadth ubiquitous, 259 present calls, max score 98.57.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 68.4164 / max 391.6529, expressed in 1823 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
175779	64.5265	1823
175780	3.8899	1537

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left testis	UBERON:0004533	98.57	gold quality
right testis	UBERON:0004534	98.56	gold quality
apex of heart	UBERON:0002098	98.24	gold quality
hindlimb stylopod muscle	UBERON:0004252	97.22	gold quality
right atrium auricular region	UBERON:0006631	96.75	gold quality
gastrocnemius	UBERON:0001388	96.50	gold quality
right lobe of thyroid gland	UBERON:0001119	96.39	gold quality
heart left ventricle	UBERON:0002084	96.19	gold quality
left lobe of thyroid gland	UBERON:0001120	96.12	gold quality
mucosa of transverse colon	UBERON:0004991	95.96	gold quality
ganglionic eminence	UBERON:0004023	95.92	gold quality
testis	UBERON:0000473	95.91	gold quality
lower esophagus muscularis layer	UBERON:0035833	95.90	gold quality
stromal cell of endometrium	CL:0002255	95.89	gold quality
lower esophagus	UBERON:0013473	95.89	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	95.85	gold quality
cardiac ventricle	UBERON:0002082	95.84	gold quality
right frontal lobe	UBERON:0002810	95.73	gold quality
metanephros cortex	UBERON:0010533	95.73	gold quality
muscle of leg	UBERON:0001383	95.72	gold quality
right adrenal gland	UBERON:0001233	95.69	gold quality
left adrenal gland	UBERON:0001234	95.68	gold quality
left adrenal gland cortex	UBERON:0035825	95.68	gold quality
anterior cingulate cortex	UBERON:0009835	95.60	gold quality
left coronary artery	UBERON:0001626	95.55	gold quality
muscle layer of sigmoid colon	UBERON:0035805	95.55	gold quality
prefrontal cortex	UBERON:0000451	95.49	gold quality
body of stomach	UBERON:0001161	95.48	gold quality
cingulate cortex	UBERON:0003027	95.47	gold quality
body of uterus	UBERON:0009853	95.46	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-7249	yes	11.20
E-ANND-3	yes	8.41
E-MTAB-7606	no	527.56
E-GEOD-93593	no	7.47

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CREB1, ETS1, TP53

miRNA regulators (miRDB)

90 targeting TIMM50, 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-3613-3P	100.00	76.36	7965
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-4524A-3P	99.72	66.85	2406
HSA-MIR-30B-3P	99.70	65.76	2325
HSA-MIR-3689A-3P	99.70	65.73	2306
HSA-MIR-3689B-3P	99.70	65.71	2311
HSA-MIR-3689C	99.70	65.71	2311
HSA-MIR-6779-5P	99.70	65.76	2363
HSA-MIR-1283	99.69	72.42	3009
HSA-MIR-1303	99.65	69.77	1662
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-3136-3P	99.57	66.59	781

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 31.9% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 16)

• Tim50 is important for both mitochondrial function and early neuronal development (PMID:15044455)
• Tim50a, a nuclear isoform of the mitochondrial Tim50, interacts with coilin, snRNPs, and SMN (PMID:16008839)
• TIM50, was upregulated in a non-small cell lung carcinoma cell line (H1299) that expressed the p53 mutants R175H and R273H compared to cells lacking p53. (PMID:21621504)
• The far-UV CD spectra of Tim50(IMS) in native and denatured states revealed that the protein has a significantly folded secondary structure consisted of alpha-helixes and beta-sheets. (PMID:21742040)
• Tim50 regulates 3betaHSD2 expression and activity, representing a new role for translocases in steroidogenesis. (PMID:21930695)
• the interaction of divalent metal ions with the intermembrane space domain of Tim50 (Tim50(IMS)) and the interaction of presequence peptides with Tim50(IMS) in presence of Ca(2+) ion was investigated. (PMID:23098911)
• TIM50 has a role in regulating cell proliferation and apoptosis through decreasing mitochondrial membrane potential in breast cancer cell (PMID:26289846)
• Missense mutations in TIMM50 are likely manifesting by severe intellectual disability and epilepsy accompanied by 3-methylglutaconic aciduria and variable mitochondrial complex V deficiency. (PMID:27573165)
• Expression of TIM50 was downregulated in hypertrophic hearts. (PMID:28432072)
• These results indicate that mutations in TIMM50 cause multiple mitochondrial bioenergetic dysfunction and that functional TIMM50 is essential for cell survival in OxPhos-dependent conditions. (PMID:30190335)
• Amino acid changes that suppress the association of Tim50 with Cytochrome P450 side-chain cleavage enzyme ablate metabolic activity. (PMID:30348838)
• High TIMM50 expression is associated with non-small cell lung cancer progression. (PMID:30604908)
• TIMM50 deficiency causes a severe mitochondrial dysfunction by targeting key aspects of mitochondrial physiology, such as the maintenance of proper mitochondrial morphology, OXPHOS assembly, and mitochondrial respiratory capacity. (PMID:31058414)
• Complete resolution of epileptic spasms with vigabatrin in a patient with 3-methylglutaconic aciduria caused by TIMM50 gene mutation. (PMID:32369862)
• MiR-7 mediates mitochondrial impairment to trigger apoptosis and necroptosis in Rhabdomyosarcoma. (PMID:32810522)
• Novel variants underlying autosomal recessive neurodevelopmental disorders with intellectual disability in Iranian consanguineous families. (PMID:35019165)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	timm50	ENSDARG00000031098
mus_musculus	Timm50	ENSMUSG00000003438
rattus_norvegicus	Timm50	ENSRNOG00000037638
drosophila_melanogaster	ttm3	FBGN0032971
drosophila_melanogaster	ttm2	FBGN0035124
drosophila_melanogaster	ttm50	FBGN0250874
caenorhabditis_elegans		WBGENE00011897

Paralogs (5): CTDSPL2 (ENSG00000137770), CTDSP1 (ENSG00000144579), CTDSPL (ENSG00000144677), CTDSP2 (ENSG00000175215), CTDNEP1 (ENSG00000175826)

Protein

Protein identifiers

Mitochondrial import inner membrane translocase subunit TIM50 — Q3ZCQ8 (reviewed: Q3ZCQ8)

All UniProt accessions (11): Q3ZCQ8, M0QXC3, M0R003, M0R047, M0R0C3, M0R1Y4, M0R2D2, M0R2F8, M0R2Q2, M0R2Z3, M0R303

UniProt curated annotations — full annotation on UniProt →

Function. Essential component of the TIM23 complex, a complex that mediates the translocation of transit peptide-containing proteins across the mitochondrial inner membrane. Has some phosphatase activity in vitro; however such activity may not be relevant in vivo. May participate in the release of snRNPs and SMN from the Cajal body.

Subunit / interactions. Component of the TIM23 complex at least composed of TIMM23, TIMM17 (TIMM17A or TIMM17B) and TIMM50; within this complex, directly interacts with TIMM23. The complex interacts with the TIMM44 component of the PAM complex and with DNAJC15. Interacts with COIL and snRNPs.

Subcellular location. Mitochondrion inner membrane Nucleus speckle.

Tissue specificity. Widely expressed. Expressed at higher level in brain, kidney and liver (at protein level).

Disease relevance. 3-methylglutaconic aciduria 9 (MGCA9) [MIM:617698] An autosomal recessive disease characterized by early-onset seizures, severely delayed psychomotor development and intellectual disability. Patients have hypotonia or spasticity, and laboratory investigations show increased serum lactate and 3-methylglutaconic aciduria. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The FCP1 homology domain does not contain the canonical D-x-D-x-[TV] active site, suggesting that it probably does not display phosphatase activity in vivo.

Similarity. Belongs to the TIM50 family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q3ZCQ8-1	1	yes
Q3ZCQ8-2	2, Tim50a
Q3ZCQ8-3	3

RefSeq proteins (2): NP_001001563, NP_001316488 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004274	FCP1_dom	Domain
IPR023214	HAD_sf	Homologous_superfamily
IPR036412	HAD-like_sf	Homologous_superfamily
IPR050365	TIM50	Family

Pfam: PF03031

UniProt features (20 total): sequence variant 7, splice variant 3, topological domain 2, modified residue 2, transit peptide 1, chain 1, transmembrane region 1, domain 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q3ZCQ8-F1	80.62	0.48

Functional residue map

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

Post-translational modifications (2): 45, 341

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-1268020	Mitochondrial protein import

MSigDB gene sets: 247 (showing top): HORIUCHI_WTAP_TARGETS_DN, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ORGANELLE, WEI_MYCN_TARGETS_WITH_E_BOX, GOBP_APOPTOTIC_SIGNALING_PATHWAY, GOBP_RELEASE_OF_CYTOCHROME_C_FROM_MITOCHONDRIA, GOCC_MITOCHONDRIAL_ENVELOPE, AACTTT_UNKNOWN, TCCAGAT_MIR5165P, KUUSELO_PANCREATIC_CANCER_19Q13_AMPLIFICATION, GOBP_PROTEIN_LOCALIZATION_TO_ORGANELLE, GOBP_DEPHOSPHORYLATION, GOBP_PROTEIN_DEPHOSPHORYLATION, GOBP_PROTEIN_TRANSMEMBRANE_TRANSPORT, GOBP_MEMBRANE_ORGANIZATION

GO Biological Process (6): release of cytochrome c from mitochondria (GO:0001836), protein dephosphorylation (GO:0006470), intracellular protein transport (GO:0006886), mitochondrial membrane organization (GO:0007006), protein import into mitochondrial matrix (GO:0030150), protein transport (GO:0015031)

GO Molecular Function (8): RNA binding (GO:0003723), phosphoprotein phosphatase activity (GO:0004721), protein serine/threonine phosphatase activity (GO:0004722), protein tyrosine phosphatase activity (GO:0004725), interleukin-2 receptor binding (GO:0005134), ribonucleoprotein complex binding (GO:0043021), cysteine-type endopeptidase activator activity (GO:0140608), protein binding (GO:0005515)

GO Cellular Component (9): nucleoplasm (GO:0005654), mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), TIM23 mitochondrial import inner membrane translocase complex (GO:0005744), endoplasmic reticulum (GO:0005783), Golgi apparatus (GO:0005794), nuclear speck (GO:0016607), nucleus (GO:0005634), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Protein localization	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular membrane-bounded organelle	4
cytoplasm	3
intracellular protein localization	2
phosphoprotein phosphatase activity	2
cellular anatomical structure	2
endomembrane system	2
apoptotic mitochondrial changes	1
apoptotic signaling pathway	1
dephosphorylation	1
protein modification process	1
protein transport	1
intracellular transport	1
mitochondrion	1
mitochondrion organization	1
membrane organization	1
protein transmembrane import into intracellular organelle	1
protein localization to mitochondrion	1
import into the mitochondrion	1
mitochondrial protein import pathway	1
transport	1
establishment of protein localization	1
nucleic acid binding	1
phosphatase activity	1
catalytic activity, acting on a protein	1
cytokine receptor binding	1
growth factor receptor binding	1
protein-containing complex binding	1
cysteine-type endopeptidase activity	1
endopeptidase activator activity	1
binding	1
nuclear lumen	1
organelle inner membrane	1
mitochondrial membrane	1
inner mitochondrial membrane protein complex	1
nuclear ribonucleoprotein granule	1

Protein interactions and networks

STRING

2092 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TIMM50	TIMM17A	Q99595	999
TIMM50	TIMM21	Q9BVV7	987
TIMM50	TIMM23	O14925	979
TIMM50	TIMM17B	O60830	956
TIMM50	TIMM44	O43615	941
TIMM50	DNAJC19	Q96DA6	934
TIMM50	TOMM22	Q9NS69	911
TIMM50	PAM16	Q9Y3D7	880
TIMM50	TIMM22	Q9Y584	814
TIMM50	TIMM13	P62206	802
TIMM50	TOMM40	O96008	794
TIMM50	TOMM70	O94826	792
TIMM50	TIMM8A	O60220	783
TIMM50	TIMM10	P62072	759
TIMM50	TOMM20	Q15388	742

IntAct

215 interactions, top by confidence:

A	B	Type	Score
MAP3K14	CHUK	psi-mi:“MI:0914”(association)	0.950
RAF1	TIMM50	psi-mi:“MI:0915”(physical association)	0.740
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
TIMM17B	TIMM23	psi-mi:“MI:0914”(association)	0.670
RAF1	CALU	psi-mi:“MI:0914”(association)	0.640
MAPK7	PFDN6	psi-mi:“MI:0914”(association)	0.640
ARAF	TIMM50	psi-mi:“MI:0915”(physical association)	0.550
ILK	HAX1	psi-mi:“MI:0914”(association)	0.530
IRAK1	SEC16A	psi-mi:“MI:0914”(association)	0.530
TUBB3	POTEF	psi-mi:“MI:0914”(association)	0.530
PRKCZ	IPO5	psi-mi:“MI:0914”(association)	0.530
ZNF195	BAG2	psi-mi:“MI:0914”(association)	0.530
TRIM28	ZNF316	psi-mi:“MI:0914”(association)	0.530
TIMM50	ZNF724	psi-mi:“MI:0914”(association)	0.530
ZG16B	ITIH2	psi-mi:“MI:0914”(association)	0.530
SALL1	TIMM50	psi-mi:“MI:0914”(association)	0.530
ILK	ILVBL	psi-mi:“MI:0914”(association)	0.530

BioGRID (334): TIMM50 (Affinity Capture-MS), TIMM50 (Affinity Capture-MS), TIMM50 (Affinity Capture-MS), TIMM50 (Affinity Capture-MS), TIMM50 (Affinity Capture-MS), TIMM50 (Affinity Capture-MS), TIMM50 (Affinity Capture-MS), TIMM50 (Affinity Capture-MS), TIMM50 (Affinity Capture-MS), TIMM50 (Affinity Capture-MS), TIMM50 (Affinity Capture-MS), TIMM50 (Affinity Capture-MS), TIMM50 (Affinity Capture-MS), TIMM50 (Affinity Capture-Western), TIMM50 (Affinity Capture-MS)

ESM2 similar proteins: A2VE14, A2VE52, A7MB28, A9X1D0, B0VX69, B1MTJ4, B2KI88, B5FW36, B7ZUF3, C1FXW2, D3Z7P3, E2RBS6, G3V6U9, O43502, O54804, O73884, O94925, O95544, P0DKC3, P0DKC4, P13264, P35790, P58058, Q01134, Q08DW9, Q3SZB3, Q3ZCQ8, Q4R4U1, Q4R766, Q5RA95, Q5RAJ8, Q5RKN4, Q5U1X1, Q5ZIN0, Q5ZML9, Q6AXQ0, Q6AYR2, Q6AYT7, Q7Z6V5, Q86TU7

Diamond homologs: A4QNX6, M9PFN0, O13636, O14595, O15194, O59718, O95476, P0CN66, P0CN67, P38757, P58465, P58466, Q02776, Q05D32, Q07800, Q07949, Q08BB5, Q09695, Q1RMV9, Q20432, Q28HW9, Q29I63, Q3B7T6, Q3KQB6, Q3TP92, Q3ZCQ8, Q4I099, Q4PEW9, Q4WI16, Q54GB2, Q59W44, Q5B4P0, Q5F3Z7, Q5RAJ8, Q5S7T7, Q5U395, Q5U3T3, Q5XIK8, Q61C05, Q66KM5

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
TIMM50	“form complex”	“TIM23 complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 212 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
RIP-mediated NFkB activation via ZBP1	9	41.1×	1e-10
TRAF6 mediated NF-kB activation	8	24.9×	2e-07
TICAM1, RIP1-mediated IKK complex recruitment	5	20.4×	2e-04
TAK1-dependent IKK and NF-kappa-B activation	9	18.4×	2e-07
IKK complex recruitment mediated by RIP1	5	16.9×	3e-04
TNFR1-induced NF-kappa-B signaling pathway	7	16.0×	2e-05
Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells	5	12.1×	8e-04
Activation of NF-kappaB in B cells	9	12.1×	8e-06

GO biological processes:

GO term	Partners	Fold	FDR
non-canonical NF-kappaB signal transduction	8	37.2×	2e-08
canonical NF-kappaB signal transduction	10	20.2×	3e-08
tumor necrosis factor-mediated signaling pathway	9	16.4×	1e-06
obsolete positive regulation of NF-kappaB transcription factor activity	11	12.5×	6e-07
negative regulation of cytokine production involved in inflammatory response	5	11.6×	7e-03
cellular response to hydrogen peroxide	8	10.3×	2e-04
MAPK cascade	9	7.6×	6e-04
negative regulation of canonical NF-kappaB signal transduction	7	6.7×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	2
Uncertain significance	215
Likely benign	219
Benign	24

Top pathogenic / likely-pathogenic (6)

Variant ID	HGVS	Classification
208697	NM_001001563.5(TIMM50):c.805G>A (p.Gly269Ser)	Pathogenic
488622	NM_001001563.5(TIMM50):c.664G>A (p.Ala222Thr)	Pathogenic
559479	NM_001001563.5(TIMM50):c.260G>C (p.Gly87Ala)	Pathogenic
559480	NM_001001563.5(TIMM50):c.26C>A (p.Ser9Ter)	Pathogenic
1723218	NM_001001563.5(TIMM50):c.328C>T (p.Gln110Ter)	Likely pathogenic
440792	NM_001001563.5(TIMM50):c.446C>T (p.Thr149Met)	Likely pathogenic

SpliceAI

1530 predictions. Top by Δscore:

Variant	Effect	Δscore
19:39483126:A:AG	acceptor_gain	1.0000
19:39483127:C:G	acceptor_gain	1.0000
19:39483131:CCAGA:C	acceptor_loss	1.0000
19:39483132:CAGAT:C	acceptor_loss	1.0000
19:39483133:A:AG	acceptor_gain	1.0000
19:39483134:G:GA	acceptor_gain	1.0000
19:39483134:GA:G	acceptor_gain	1.0000
19:39485684:ACAG:A	acceptor_loss	1.0000
19:39485685:CAGA:C	acceptor_loss	1.0000
19:39485686:A:AG	acceptor_gain	1.0000
19:39485686:A:T	acceptor_loss	1.0000
19:39485687:G:GC	acceptor_loss	1.0000
19:39485687:G:GG	acceptor_gain	1.0000
19:39485801:GTG:G	donor_gain	1.0000
19:39486185:A:AG	acceptor_gain	1.0000
19:39486185:AGCT:A	acceptor_gain	1.0000
19:39486186:G:GG	acceptor_gain	1.0000
19:39486186:GCT:G	acceptor_gain	1.0000
19:39486186:GCTG:G	acceptor_gain	1.0000
19:39486389:A:AG	acceptor_gain	1.0000
19:39486390:C:G	acceptor_gain	1.0000
19:39486395:A:AG	acceptor_gain	1.0000
19:39486395:A:C	acceptor_loss	1.0000
19:39486395:AGACT:A	acceptor_gain	1.0000
19:39486396:G:GT	acceptor_gain	1.0000
19:39486396:GA:G	acceptor_gain	1.0000
19:39486396:GAC:G	acceptor_gain	1.0000
19:39486396:GACT:G	acceptor_gain	1.0000
19:39486396:GACTG:G	acceptor_gain	1.0000
19:39486471:A:G	donor_gain	1.0000

AlphaMissense

2271 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:39485802:T:A	W163R	1.000
19:39485802:T:C	W163R	1.000
19:39485804:G:C	W163C	1.000
19:39485804:G:T	W163C	1.000
19:39486199:T:A	W169R	1.000
19:39486199:T:C	W169R	1.000
19:39486495:G:C	K232N	1.000
19:39486495:G:T	K232N	1.000
19:39485719:T:A	L135H	0.999
19:39485764:T:A	L150H	0.999
19:39485767:T:A	V151D	0.999
19:39486197:G:A	G168D	0.999
19:39486201:G:C	W169C	0.999
19:39486201:G:T	W169C	0.999
19:39486205:T:C	F171L	0.999
19:39486207:T:A	F171L	0.999
19:39486207:T:G	F171L	0.999
19:39486214:C:A	R174S	0.999
19:39486260:A:T	E189V	0.999
19:39486266:T:A	V191D	0.999
19:39486275:C:A	T194K	0.999
19:39486454:T:C	F219L	0.999
19:39486456:C:A	F219L	0.999
19:39486456:C:G	F219L	0.999
19:39486463:G:C	A222P	0.999
19:39488163:T:A	W267R	0.999
19:39488163:T:C	W267R	0.999
19:39488165:G:C	W267C	0.999
19:39488165:G:T	W267C	0.999
19:39488200:T:C	L279P	0.999

dbSNP variants (sampled 300 via entrez): RS1000103677 (19:39489189 G>C), RS1000227549 (19:39488723 A>C,G), RS1000287213 (19:39493888 G>T), RS1000402347 (19:39482758 T>G), RS1000803942 (19:39493704 C>G), RS1000946826 (19:39489765 A>C,G), RS1001108896 (19:39490544 A>G), RS1001109074 (19:39483617 C>G,T), RS1001324427 (19:39490759 C>A,T), RS1001558733 (19:39483542 C>A), RS1001627579 (19:39479687 C>T), RS1001747910 (19:39479498 G>A,T), RS1001802478 (19:39494201 C>G,T), RS1002374972 (19:39479556 C>T), RS1002941715 (19:39491919 A>G)

Disease associations

OMIM: gene MIM:607381 | disease phenotypes: MIM:617698

GenCC curated gene-disease

Disease	Classification	Inheritance
3-methylglutaconic aciduria type 9	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
3-methylglutaconic aciduria type 9	Definitive	AR

Mondo (2): 3-methylglutaconic aciduria type 9 (MONDO:0044724), mitochondrial disease (MONDO:0044970)

Orphanet (2): 3-methylglutaconic aciduria type 9 (Orphanet:505216), Mitochondrial disease (Orphanet:68380)

HPO phenotypes

44 total (30 of 44 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000020	Urinary incontinence
HP:0000218	High palate
HP:0000470	Short neck
HP:0000486	Strabismus
HP:0000527	Long eyelashes
HP:0000648	Optic atrophy
HP:0000718	Aggressive behavior
HP:0000750	Delayed speech and language development
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001266	Choreoathetosis
HP:0001276	Hypertonia
HP:0001284	Areflexia
HP:0001290	Generalized hypotonia
HP:0001298	Encephalopathy
HP:0001324	Muscle weakness
HP:0001344	Absent speech
HP:0001347	Hyperreflexia
HP:0001508	Failure to thrive
HP:0001533	Slender build
HP:0002007	Frontal bossing
HP:0002059	Cerebral atrophy
HP:0002133	Status epilepticus
HP:0002151	Increased circulating lactate concentration
HP:0002167	Abnormal speech pattern
HP:0002169	Clonus
HP:0002194	Delayed gross motor development

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295842 (SINGLE PROTEIN)

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

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.73	Kd	1850	nM	CHEMBL5653589
5.73	ED50	1850	nM	CHEMBL5653589
5.45	Kd	3588	nM	CHEMBL3752910
5.45	ED50	3588	nM	CHEMBL3752910

PubChem BioAssay actives

2 with measured affinity, of 5 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149590: Binding affinity to human TIMM50 incubated for 45 mins by Kinobead based pull down assay	kd	1.8496	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149590: Binding affinity to human TIMM50 incubated for 45 mins by Kinobead based pull down assay	kd	3.5879	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression	2
alpha-pinene	affects cotreatment, decreases expression, increases abundance	1
perfluorooctanoic acid	increases expression	1
methacrylaldehyde	decreases expression, increases abundance, affects cotreatment	1
microcystin RR	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
4-phenylbutyric acid	decreases expression	1
perfluorooctane sulfonic acid	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
bisphenol S	increases expression	1
LDN 193189	affects cotreatment, decreases expression	1
bisphenol AF	increases expression	1
Acrolein	affects cotreatment, decreases expression, increases abundance	1
Air Pollutants	affects cotreatment, decreases expression, increases abundance	1
Arsenic	increases methylation	1
Benzo(a)pyrene	affects methylation	1
Cadmium	decreases expression	1
Dichlorodiphenyl Dichloroethylene	increases expression	1
Doxorubicin	decreases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Gallic Acid	increases expression	1
Hydralazine	increases expression, affects cotreatment	1
Ivermectin	decreases expression	1
Ozone	affects cotreatment, decreases expression, increases abundance	1
Pesticides	decreases methylation	1
Silicon Dioxide	increases expression	1
Smoke	decreases expression	1
T-2 Toxin	increases expression	1
Testosterone	increases expression	1
Thiram	decreases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4119028	Binding	Binding affinity to TIMM50 in human NCI-H358 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — Bioorg Med Chem

Clinical trials (associated diseases)

103 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
NCT00432744	PHASE3	COMPLETED	Phase III Trial of Coenzyme Q10 in Mitochondrial Disease
NCT05162768	PHASE3	COMPLETED	Study to Evaluate Efficacy and Safety of Elamipretide in Subjects With Primary Mitochondrial Disease From Nuclear DNA Mutations (nPMD)
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
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
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).
NCT01252979	EARLY_PHASE1	COMPLETED	Ketones & Mitochondrial Heteroplasmy
NCT00786539	Not specified	COMPLETED	Mitochondria Inborn Errors of Metabolism and ANT Defects in Mitochondria Diseases
NCT00829270	Not specified	COMPLETED	Economic and Medical Evaluation of the Whole Mitochondrial DNA Screening by Surveyor and Mitochips Techniques
NCT00831948	Not specified	UNKNOWN	Identification of Large-Scale Mutations of POLG Gene by QMPSF in Patients With Mitochondrial DNA Instability.
NCT01001585	Not specified	TERMINATED	Anesthetic Effects in Mitochondrial Disease
NCT01148550	Not specified	SUSPENDED	Longitudinal Study of Mitochondrial Hepatopathies