FBXL4

Summary

FBXL4 (F-box and leucine rich repeat protein 4, HGNC:13601) is a protein-coding gene on chromosome 6q16.1-q16.2, encoding F-box/LRR-repeat protein 4 (Q9UKA2). Substrate-recognition component of the mitochondria-localized SCF-FBXL4 ubiquitin E3 ligase complex that plays a role in the restriction of mitophagy by controlling the degradation of BNIP3 and NIX mitophagy receptors.

This gene encodes a member of the F-box protein family, which are characterized by an approximately 40 amino acid motif, the F-box. F-box proteins constitute one subunit of modular E3 ubiquitin ligase complexes, called SCF complexes, which function in phosphorylation-dependent ubiquitination. The F-box domain mediates protein-protein interactions and binds directly to S-phase kinase-associated protein 1. In addition to an F-box domain, the encoded protein contains at least 9 tandem leucine-rich repeats. The ubiquitin ligase complex containing the encoded protein may function in cell-cycle control by regulating levels of lysine-specific demethylase 4A. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 26235 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 10
• Clinical variants (ClinVar): 649 total — 36 pathogenic, 39 likely-pathogenic
• Phenotypes (HPO): 119
• MANE Select transcript: NM_001278716

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13601
Approved symbol	FBXL4
Name	F-box and leucine rich repeat protein 4
Location	6q16.1-q16.2
Locus type	gene with protein product
Status	Approved
Aliases	FBL4, FBL5
Ensembl gene	ENSG00000112234
Ensembl biotype	protein_coding
OMIM	605654
Entrez	26235

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 23 protein_coding

ENST00000229971, ENST00000369244, ENST00000892539, ENST00000892540, ENST00000892541, ENST00000892542, ENST00000892543, ENST00000892544, ENST00000892546, ENST00000892548, ENST00000892550, ENST00000892552, ENST00000892554, ENST00000892556, ENST00000892558, ENST00000892560, ENST00000935939, ENST00000945097, ENST00000945098, ENST00000945099, ENST00000945100, ENST00000945101, ENST00000945102

RefSeq mRNA: 2 — MANE Select: NM_001278716 NM_001278716, NM_012160

CCDS: CCDS5041

Canonical transcript exons

ENST00000369244 — 10 exons

Exon	Start	End
ENSE00000760856	98875415	98875727
ENSE00000760857	98880553	98880624
ENSE00001124957	98926477	98927060
ENSE00001176012	98917374	98917719
ENSE00001176017	98927705	98927822
ENSE00001265086	98899268	98899481
ENSE00001265126	98905426	98905670
ENSE00001449304	98868535	98874441
ENSE00001449308	98934762	98934879
ENSE00001449309	98947806	98947946

Expression profiles

Bgee: expression breadth ubiquitous, 265 present calls, max score 88.43.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 17.8042 / max 108.5483, expressed in 1809 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
74785	16.4963	1807
74784	1.3079	796

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
adrenal tissue	UBERON:0018303	88.43	gold quality
corpus epididymis	UBERON:0004359	86.03	gold quality
calcaneal tendon	UBERON:0003701	84.59	gold quality
islet of Langerhans	UBERON:0000006	84.18	gold quality
caput epididymis	UBERON:0004358	82.49	gold quality
cauda epididymis	UBERON:0004360	81.77	gold quality
choroid plexus epithelium	UBERON:0003911	81.72	gold quality
stromal cell of endometrium	CL:0002255	81.25	gold quality
gastrocnemius	UBERON:0001388	81.08	gold quality
muscle of leg	UBERON:0001383	80.82	gold quality
right adrenal gland cortex	UBERON:0035827	80.47	gold quality
right adrenal gland	UBERON:0001233	80.30	gold quality
hindlimb stylopod muscle	UBERON:0004252	79.96	gold quality
pancreas	UBERON:0001264	79.76	gold quality
monocyte	CL:0000576	79.53	gold quality
adrenal gland	UBERON:0002369	79.31	gold quality
left adrenal gland	UBERON:0001234	79.29	gold quality
germinal epithelium of ovary	UBERON:0001304	79.26	gold quality
tibia	UBERON:0000979	79.20	gold quality
tendon	UBERON:0000043	79.16	gold quality
leukocyte	CL:0000738	79.06	gold quality
body of pancreas	UBERON:0001150	78.97	gold quality
mononuclear cell	CL:0000842	78.95	gold quality
descending thoracic aorta	UBERON:0002345	78.82	gold quality
left adrenal gland cortex	UBERON:0035825	78.58	gold quality
rectum	UBERON:0001052	78.56	gold quality
ventricular zone	UBERON:0003053	78.42	gold quality
gall bladder	UBERON:0002110	78.35	gold quality
tibial nerve	UBERON:0001323	78.24	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	78.18	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.21
E-ENAD-17	no	283.19

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

50 targeting FBXL4, 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-12121	99.99	66.64	255
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-6835-3P	99.93	70.49	2904
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-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-137-3P	99.87	74.74	2401
HSA-MIR-636	99.80	69.58	1500
HSA-MIR-548AG	99.77	69.25	1492
HSA-MIR-3680-3P	99.75	72.51	3095
HSA-MIR-2681-5P	99.75	67.64	1655
HSA-MIR-4422	99.72	72.07	2908
HSA-MIR-548AI	99.69	69.24	1494
HSA-MIR-548BA	99.69	69.14	1514
HSA-MIR-570-5P	99.69	69.24	1494

Literature-anchored findings (GeneRIF, showing 16)

• SKP1-Cul1-F-box and leucine-rich repeat protein 4 (SCF-FbxL4) ubiquitin ligase regulates lysine demethylase 4A (KDM4A)/Jumonji domain-containing 2A (JMJD2A) protein (PMID:21757720)
• Mutations in FBXL4 are disease causing and establish FBXL4 as a mitochondrial protein with a possible role in maintaining mtDNA integrity and stability. (PMID:23993193)
• These data strongly support a role for FBXL4 in controlling bioenergetic homeostasis and mtDNA maintenance. (PMID:23993194)
• A clinical pattern of early-onset encephalopathy, persistent lactic acidosis, profound muscular hypotonia and typical facial dysmorphism should prompt initiation of molecular genetic analysis of FBXL4. (PMID:25868664)
• On clinical indication of mitochondrial encephalomyopathy, sequencing of FBXL4 should be performed, even when the activity levels of the MRC enzymes are normal (PMID:27182039)
• Overall, FBXL4 defects account for at least 0.7% (6 out of 808) of subjects suspected to have a mitochondrial disorder, and as high as 14.3% (4 out of 28) in young children with congenital lactic acidosis and clinical features of mitochondrial disease. Including FBLX4 in the mitochondrial diseases panel should be particularly important for patients with congenital lactic acidosis (PMID:27743463)
• Study found a common genomic copy number loss at 6q16.1-16.2, containing the FBXL4 gene in prostate cancer bone metastases. Loss of FBXL4 was also detected in primary tumors and it was highly associated with prognostic factors including high Gleason score, PSA, as well as poor patient survival, suggesting that FBXL4 loss contributes to prostate cancer progression. (PMID:28698647)
• Biallelic pathogenic variants in FBXL4 are associated with an encephalopathic mtDNA maintenance defect syndrome that is a multisystem disease. (PMID:28940506)
• FBXL4 protein promotes mitochondrial fusion. The C584R FBXL4 variant cannot promote mitochondrial fusion. (PMID:31442532)
• FBXL4 deficiency increases mitochondrial removal by autophagy. (PMID:32525278)
• Novel homozygous mutation in the FBXL4 gene is associated with mitochondria DNA depletion syndrome-13. (PMID:32559514)
• FBXL4 ubiquitin ligase deficiency promotes mitophagy by elevating NIX levels. (PMID:37102372)
• FBXL4 suppresses mitophagy by restricting the accumulation of NIX and BNIP3 mitophagy receptors. (PMID:37161784)
• Excessive BNIP3- and BNIP3L-dependent mitophagy underlies the pathogenesis of FBXL4-mutated mitochondrial DNA depletion syndrome. (PMID:37876279)
• FBXL4: safeguarding against mitochondrial depletion through suppression of mitophagy. (PMID:38423516)
• PPTC7 antagonizes mitophagy by promoting BNIP3 and NIX degradation via SCF[FBXL4]. (PMID:38992176)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	fbxl4	ENSDARG00000026941
mus_musculus	Fbxl4	ENSMUSG00000040410
rattus_norvegicus	Fbxl4	ENSRNOG00000005641
drosophila_melanogaster	Fbxl4	FBGN0030555
drosophila_melanogaster	CG12402	FBGN0038202
caenorhabditis_elegans		WBGENE00017138

Paralogs (15): FBXL3 (ENSG00000005812), FBXL19 (ENSG00000099364), FBXL15 (ENSG00000107872), FBXL20 (ENSG00000108306), FBXL5 (ENSG00000118564), FBXL16 (ENSG00000127585), SKP2 (ENSG00000145604), FBXL17 (ENSG00000145743), FBXL2 (ENSG00000153558), FBXL18 (ENSG00000155034), FBXL13 (ENSG00000161040), FBXL14 (ENSG00000171823), FBXL6 (ENSG00000182325), FBXL7 (ENSG00000183580), FBXL22 (ENSG00000197361)

Protein

Protein identifiers

F-box/LRR-repeat protein 4 — Q9UKA2 (reviewed: Q9UKA2)

Alternative names: F-box and leucine-rich repeat protein 4, F-box protein FBL4/FBL5

All UniProt accessions (1): Q9UKA2

UniProt curated annotations — full annotation on UniProt →

Function. Substrate-recognition component of the mitochondria-localized SCF-FBXL4 ubiquitin E3 ligase complex that plays a role in the restriction of mitophagy by controlling the degradation of BNIP3 and NIX mitophagy receptors. Rescues also mitochondrial injury through reverting hyperactivation of DRP1-mediated mitochondrial fission.

Subunit / interactions. Part of a SCF (SKP1-CUL1-F-box) protein ligase complex. Interacts with VCP. Interacts with PPTC7; this interaction promotes destruction of BNIP3 and NIX and mitophagy suppression.

Subcellular location. Cytoplasm. Nucleus. Mitochondrion outer membrane.

Tissue specificity. Expressed in heart, kidney, liver, lung, pancreas, and placenta, but not in skeletal muscle.

Disease relevance. Mitochondrial DNA depletion syndrome 13 (MTDPS13) [MIM:615471] An autosomal recessive disorder characterized by early infantile onset of encephalopathy, hypotonia, lactic acidosis, and severe global developmental delay. Cells derived from patient tissues show defects in mitochondrial oxidative phosphorylation and decreased mtDNA content. The disease is caused by variants affecting the gene represented in this entry.

RefSeq proteins (2): NP_001265645, NP_036292 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001810	F-box_dom	Domain
IPR006553	Leu-rich_rpt_Cys-con_subtyp	Repeat
IPR032675	LRR_dom_sf	Homologous_superfamily
IPR036047	F-box-like_dom_sf	Homologous_superfamily
IPR057207	FBXL15_LRR	Domain

Pfam: PF12937, PF25372

UniProt features (26 total): repeat 9, sequence variant 7, sequence conflict 7, chain 1, domain 1, modified residue 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UKA2-F1	86.50	0.76

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 (1): 28

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-8951664	Neddylation
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation

MSigDB gene sets: 408 (showing top): MORF_ITGA2, GOBP_REGULATION_OF_AUTOPHAGY, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, MORF_RAD51L3, GOBP_MACROAUTOPHAGY, GOBP_NEGATIVE_REGULATION_OF_AUTOPHAGY, GOBP_REGULATION_OF_CATABOLIC_PROCESS, MORF_PRKCA, GOCC_MITOCHONDRIAL_ENVELOPE, GOBP_NEGATIVE_REGULATION_OF_MACROAUTOPHAGY, MORF_THPO, GOBP_SCF_DEPENDENT_PROTEASOMAL_UBIQUITIN_DEPENDENT_PROTEIN_CATABOLIC_PROCESS

GO Biological Process (5): autophagy of mitochondrion (GO:0000422), ubiquitin-dependent protein catabolic process (GO:0006511), SCF-dependent proteasomal ubiquitin-dependent protein catabolic process (GO:0031146), negative regulation of mitophagy (GO:1901525), mitophagy (GO:0000423)

GO Molecular Function (2): ubiquitin-like ligase-substrate adaptor activity (GO:1990756), protein binding (GO:0005515)

GO Cellular Component (10): ubiquitin ligase complex (GO:0000151), mitochondrion (GO:0005739), mitochondrial outer membrane (GO:0005741), mitochondrial intermembrane space (GO:0005758), cytosol (GO:0005829), nuclear speck (GO:0016607), SCF ubiquitin ligase complex (GO:0019005), nucleus (GO:0005634), cytoplasm (GO:0005737), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Post-translational protein modification	1
Class I MHC mediated antigen processing & presentation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
cytoplasm	2
intracellular membrane-bounded organelle	2
autophagy	1
protein ubiquitination	1
modification-dependent protein catabolic process	1
proteasome-mediated ubiquitin-dependent protein catabolic process	1
mitophagy	1
negative regulation of macroautophagy	1
regulation of mitophagy	1
negative regulation of autophagy of mitochondrion	1
autophagy of mitochondrion	1
macroautophagy	1
enzyme-substrate adaptor activity	1
binding	1
intracellular protein-containing complex	1
transferase complex	1
mitochondrial membrane	1
organelle outer membrane	1
mitochondrial envelope	1
organelle envelope lumen	1
nuclear ribonucleoprotein granule	1
cullin-RING ubiquitin ligase complex	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1408 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FBXL4	SKP1	P34991	800
FBXL4	CCNF	P41002	708
FBXL4	CUL1	Q13616	671
FBXL4	DGUOK	P78532	656
FBXL4	MGME1	Q9BQP7	635
FBXL4	BTRC	Q9Y297	603
FBXL4	TWNK	Q96RR1	585
FBXL4	SUCLA2	Q9P2R7	583
FBXL4	POLG	P54098	566
FBXL4	SUCLG1	P53597	564
FBXL4	RRM2B	Q7LG56	562
FBXL4	FAXC	Q5TGI0	552
FBXL4	ERLEC1	Q96DZ1	540
FBXL4	MPV17	P39210	540
FBXL4	POLG2	Q9UHN1	514

IntAct

26 interactions, top by confidence:

A	B	Type	Score
SKP1	MYCBP2	psi-mi:“MI:0914”(association)	0.640
TPP1	FBXL4	psi-mi:“MI:0915”(physical association)	0.560
DNM2	FBXL4	psi-mi:“MI:0915”(physical association)	0.560
ODAD3	CCDC22	psi-mi:“MI:0914”(association)	0.530
FBXL4	DUSP14	psi-mi:“MI:0914”(association)	0.530
Tpx2	NFKBIE	psi-mi:“MI:0914”(association)	0.350
Nedd1		psi-mi:“MI:0914”(association)	0.350
EXOSC2	WDR46	psi-mi:“MI:0914”(association)	0.350
Xpo1	IFT56	psi-mi:“MI:0914”(association)	0.350
BBS7	PER1	psi-mi:“MI:0914”(association)	0.350
CNPY2	COL2A1	psi-mi:“MI:0914”(association)	0.350
SKP1	BHLHE40	psi-mi:“MI:0914”(association)	0.350
ODAD2	OMA1	psi-mi:“MI:0914”(association)	0.350
SKP1	RNASET2	psi-mi:“MI:0914”(association)	0.350
CNPY2	GBA1	psi-mi:“MI:0914”(association)	0.350
SKP1	NDUFAB1	psi-mi:“MI:0914”(association)	0.350
SKP1	NDC80	psi-mi:“MI:0914”(association)	0.350
FBXL4	nrdD	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (186): FBXL4 (Affinity Capture-MS), FBXL4 (Affinity Capture-MS), FBXL4 (Affinity Capture-MS), FBXL4 (Affinity Capture-MS), FBXL4 (Affinity Capture-MS), ATG9B (Affinity Capture-MS), PLCD1 (Affinity Capture-MS), AIM1 (Affinity Capture-MS), HEPHL1 (Affinity Capture-MS), LYG2 (Affinity Capture-MS), DSG4 (Affinity Capture-MS), CRAT (Affinity Capture-MS), S100A3 (Affinity Capture-MS), VSIG8 (Affinity Capture-MS), PADI3 (Affinity Capture-MS)

ESM2 similar proteins: A0JM56, A0M8T3, A1X154, A4D7T3, A6NJI9, Q008S8, Q00PJ3, Q07DV3, Q07DX6, Q07DY6, Q07DZ7, Q07E17, Q07E30, Q07E43, Q09YH1, Q09YI3, Q09YJ5, Q09YK6, Q09YN0, Q0VD31, Q108U1, Q2IBB1, Q2IBB4, Q2IBE3, Q2IBF5, Q2IBG0, Q2QL84, Q2QLA4, Q2QLB5, Q2QLC6, Q2QLG0, Q2QLH1, Q32NR9, Q5PPX0, Q5ZLG9, Q6DCF6, Q6GQN5, Q6PJI9, Q6ZRR7, Q8BH70

Diamond homologs: Q0VD31, Q8BH70, Q9UKA2, Q9C5D2, Q9C626, Q9FE83, Q9S9X4, Q9SN10, Q9Z0Z3, A1A5X2, Q13309, Q32PG9, Q5BJ29, Q8S8F2, Q9UJT9

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	36
Likely pathogenic	39
Uncertain significance	359
Likely benign	88
Benign	18

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1370980	NM_001278716.2(FBXL4):c.527G>A (p.Trp176Ter)	Pathogenic
1453801	NC_000006.11:g.(?99347124)(99374864_?)del	Pathogenic
1454261	NM_001278716.2(FBXL4):c.45T>G (p.Tyr15Ter)	Pathogenic
1696828	NM_001278716.2(FBXL4):c.736dup (p.Ile246fs)	Pathogenic
2318750	NM_001278716.2(FBXL4):c.397C>T (p.Gln133Ter)	Pathogenic
265143	NM_001278716.2(FBXL4):c.1641_1642del (p.Cys547_Asp548delinsTer)	Pathogenic
2695330	NM_001278716.2(FBXL4):c.986G>A (p.Trp329Ter)	Pathogenic
280414	NM_001278716.2(FBXL4):c.618_621dup (p.Glu208fs)	Pathogenic
3363190	NM_001278716.2(FBXL4):c.517G>T (p.Glu173Ter)	Pathogenic
3594181	NM_001278716.2(FBXL4):c.141del (p.Asn48fs)	Pathogenic
3662601	NM_001278716.2(FBXL4):c.520_527del (p.Ile174fs)	Pathogenic
3662602	NM_001278716.2(FBXL4):c.516G>A (p.Trp172Ter)	Pathogenic
3690074	NM_001278716.2(FBXL4):c.272_273del (p.Phe91fs)	Pathogenic
437488	NM_001278716.2(FBXL4):c.106A>T (p.Arg36Ter)	Pathogenic
437489	NM_001278716.2(FBXL4):c.219T>A (p.Tyr73Ter)	Pathogenic
437491	NM_001278716.2(FBXL4):c.316C>T (p.Gln106Ter)	Pathogenic
437493	NM_001278716.2(FBXL4):c.1210C>T (p.Gln404Ter)	Pathogenic
437494	NM_001278716.2(FBXL4):c.1687C>T (p.Gln563Ter)	Pathogenic
437495	NM_001278716.2(FBXL4):c.273_277del (p.Phe91fs)	Pathogenic
437496	NM_001278716.2(FBXL4):c.326del (p.Ser109fs)	Pathogenic
437498	NM_001278716.2(FBXL4):c.1067del (p.Gly356fs)	Pathogenic
437499	NM_001278716.2(FBXL4):c.1648_1649del (p.Asp550fs)	Pathogenic
437500	NM_001278716.2(FBXL4):c.513-1G>A	Pathogenic
437502	NM_001278716.2(FBXL4):c.858+1G>T	Pathogenic
437503	NM_001278716.2(FBXL4):c.1317G>A (p.Glu439=)	Pathogenic
437505	NM_001278716.2(FBXL4):c.1389+3_1389+6del	Pathogenic
4718554	NM_001278716.2(FBXL4):c.1348_1360del (p.Cys450fs)	Pathogenic
4722807	NM_001278716.2(FBXL4):c.727del (p.Asp242_Met243insTer)	Pathogenic
4775712	NM_001278716.2(FBXL4):c.827_830dup (p.Asn277delinsLysTer)	Pathogenic
520628	NM_001278716.2(FBXL4):c.827del (p.Asn276fs)	Pathogenic

SpliceAI

2445 predictions. Top by Δscore:

Variant	Effect	Δscore
6:98904084:A:AC	donor_gain	1.0000
6:98904085:C:CC	donor_gain	1.0000
6:98905667:TAAG:T	acceptor_gain	1.0000
6:98905671:C:CC	acceptor_gain	1.0000
6:98947804:AC:A	donor_gain	1.0000
6:98947805:CC:C	donor_gain	1.0000
6:98880655:A:C	acceptor_gain	0.9900
6:98880666:A:C	acceptor_gain	0.9900
6:98880672:G:GC	acceptor_gain	0.9900
6:98904085:CTGA:C	donor_gain	0.9900
6:98904086:TGA:T	donor_gain	0.9900
6:98905669:AG:A	acceptor_gain	0.9900
6:98905671:C:CA	acceptor_loss	0.9900
6:98905672:T:C	acceptor_loss	0.9900
6:98927696:ATCAC:A	donor_loss	0.9900
6:98927697:TCACT:T	donor_loss	0.9900
6:98927698:CACTC:C	donor_loss	0.9900
6:98927699:ACTCA:A	donor_loss	0.9900
6:98927700:CTCAC:C	donor_loss	0.9900
6:98927701:TCA:T	donor_loss	0.9900
6:98927702:CAC:C	donor_loss	0.9900
6:98927703:AC:A	donor_gain	0.9900
6:98927703:ACC:A	donor_gain	0.9900
6:98927704:C:T	donor_loss	0.9900
6:98927704:CC:C	donor_gain	0.9900
6:98927704:CCC:C	donor_gain	0.9900
6:98932541:A:AC	donor_gain	0.9900
6:98932542:C:CC	donor_gain	0.9900
6:98947801:CGTA:C	donor_loss	0.9900
6:98947804:A:AC	donor_gain	0.9900

AlphaMissense

4087 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:98874359:A:C	C595W	1.000
6:98874360:C:T	C595Y	1.000
6:98874361:A:G	C595R	1.000
6:98874362:G:C	F594L	1.000
6:98874362:G:T	F594L	1.000
6:98874364:A:G	F594L	1.000
6:98874364:A:T	F594I	1.000
6:98874366:G:A	S593F	1.000
6:98874441:C:A	G568V	1.000
6:98874441:C:T	G568E	1.000
6:98875415:C:G	G568R	1.000
6:98875415:C:T	G568R	1.000
6:98875420:A:T	I566K	1.000
6:98875486:C:G	R544T	1.000
6:98875575:C:A	W514C	1.000
6:98875575:C:G	W514C	1.000
6:98875577:A:G	W514R	1.000
6:98875577:A:T	W514R	1.000
6:98875654:C:G	R488T	1.000
6:98917564:A:T	V223D	1.000
6:98917568:C:G	A222P	1.000
6:98917718:A:G	W172R	1.000
6:98917718:A:T	W172R	1.000
6:98926705:G:T	A95D	1.000
6:98926720:T:A	D90V	1.000
6:98926720:T:C	D90G	1.000
6:98926720:T:G	D90A	1.000
6:98926721:C:G	D90H	1.000
6:98926772:A:G	Y73H	1.000
6:98926792:C:T	G66E	1.000

dbSNP variants (sampled 300 via entrez): RS1000048906 (6:98933109 A>G), RS1000089726 (6:98925311 T>C), RS1000133624 (6:98903845 T>C), RS1000203915 (6:98936543 C>G,T), RS1000214502 (6:98918837 G>C), RS1000256398 (6:98921762 T>C), RS1000314296 (6:98928979 T>G), RS1000317168 (6:98921011 C>G), RS1000317747 (6:98887324 A>G), RS1000430293 (6:98928683 G>C), RS1000442541 (6:98913200 G>T), RS1000452177 (6:98870974 T>G), RS1000517589 (6:98886232 A>G), RS1000521924 (6:98891531 T>C), RS1000570527 (6:98878180 A>G,T)

Disease associations

OMIM: gene MIM:605654 | disease phenotypes: MIM:615471, MIM:256000, MIM:603041, MIM:301044

GenCC curated gene-disease

Disease	Classification	Inheritance
mitochondrial DNA depletion syndrome 13	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
mitochondrial disease	Definitive	AR
Leigh syndrome	Definitive	AR

Mondo (6): mitochondrial DNA depletion syndrome 13 (MONDO:0014198), Leigh syndrome (MONDO:0009723), mitochondrial disease (MONDO:0044970), mitochondrial DNA depletion syndrome (MONDO:0018158), developmental and epileptic encephalopathy, 85, with or without midline brain defects (MONDO:0026771), mitochondrial encephalomyopathy (MONDO:0004675)

Orphanet (5): Mitochondrial DNA depletion syndrome, encephalomyopathic form with variable craniofacial anomalies (Orphanet:369897), Leigh syndrome (Orphanet:506), Mitochondrial disease (Orphanet:68380), Moyamoya angiopathy (Orphanet:477768), Mitochondrial DNA depletion syndrome (Orphanet:35698)

HPO phenotypes

119 total (30 of 119 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000023	Inguinal hernia
HP:0000028	Cryptorchidism
HP:0000047	Hypospadias
HP:0000126	Hydronephrosis
HP:0000232	Everted lower lip vermilion
HP:0000238	Hydrocephalus
HP:0000252	Microcephaly
HP:0000275	Narrow face
HP:0000286	Epicanthus
HP:0000316	Hypertelorism
HP:0000319	Smooth philtrum
HP:0000331	Short chin
HP:0000336	Prominent supraorbital ridges
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000365	Hearing impairment
HP:0000369	Low-set ears
HP:0000411	Protruding ear
HP:0000431	Wide nasal bridge
HP:0000486	Strabismus
HP:0000494	Downslanted palpebral fissures
HP:0000508	Ptosis
HP:0000518	Cataract
HP:0000527	Long eyelashes
HP:0000574	Thick eyebrow
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000664	Synophrys
HP:0001250	Seizure

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST005839_10	Depression	3.000000e-08
GCST006041_46	Major depressive disorder	6.000000e-06
GCST006922_14	Regular attendance at a religious group	2.000000e-08
GCST006940_43	Neurociticism	1.000000e-10
GCST006944_3	Experiencing mood swings	4.000000e-08
GCST006948_43	Feeling nervous	3.000000e-08
GCST006948_44	Feeling nervous	2.000000e-10
GCST007576_139	Chronotype	1.000000e-09
GCST009391_162	Metabolite levels	6.000000e-06
GCST012490_564	Femur bone mineral density x serum urate levels interaction	1.000000e-11

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0009592	social interaction measurement
EFO:0007660	neuroticism measurement
EFO:0008475	mood instability measurement
EFO:0009597	feeling nervous measurement
EFO:0008328	chronotype measurement
EFO:0010487	glutamate measurement
EFO:0004531	urate measurement

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
D017237	Mitochondrial Encephalomyopathies	C05.651.460.620; C10.228.140.163.540; C10.668.491.500.500; C18.452.132.540; C18.452.660.560.620

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases abundance, decreases expression, affects cotreatment	4
perfluorooctane sulfonic acid	increases expression	2
Air Pollutants	increases abundance, affects cotreatment, decreases expression	2
Benzo(a)pyrene	affects methylation, increases methylation, increases mutagenesis	2
aristolochic acid I	decreases expression	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, decreases expression, increases abundance	1
pirinixic acid	affects binding, increases activity, increases expression	1
trichostatin A	increases expression	1
perfluorooctanoic acid	increases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
aflatoxin B2	decreases methylation, increases methylation	1
cupric oxide	decreases expression	1
methacrylaldehyde	affects cotreatment, decreases expression, increases abundance	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
K 7174	increases expression	1
perfluorohexanesulfonic acid	decreases expression	1
torcetrapib	increases expression	1
abrine	decreases expression	1
eprenetapopt	affects expression, affects reaction	1
Sunitinib	increases expression	1
Arsenic Trioxide	increases expression	1
Acrolein	increases abundance, affects cotreatment, decreases expression	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1
Demecolcine	decreases expression	1
Dimethyl Sulfoxide	increases expression	1
Ethyl Methanesulfonate	decreases expression	1
Formaldehyde	decreases expression	1

Cellosaurus cell lines

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

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

Cellosaurus	Name	Category	Sex
CVCL_E6FC	HeLa S3 FBXL4 KO clone #29	Cancer cell line	Female
CVCL_YT40	SHCDNi001-A	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

114 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
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)
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
NCT02544217	PHASE1	COMPLETED	A Dose-escalating Clinical Trial With KH176
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)?
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
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