MARCHF5

Summary

MARCHF5 (membrane associated ring-CH-type finger 5, HGNC:26025) is a protein-coding gene on chromosome 10q23.32-q23.33, encoding E3 ubiquitin-protein ligase MARCHF5 (Q9NX47). Mitochondrial E3 ubiquitin-protein ligase that plays a crucial role in the control of mitochondrial morphology by acting as a positive regulator of mitochondrial fission and as an important regulator of immune response. It is a selective cancer dependency (DepMap: 34.4% of cell lines).

MARCH5 is a ubiquitin ligase of the mitochondrial outer membrane that plays a role in the control of mitochondrial morphology by regulating mitofusin-2 (MFN2; MIM 608507) and DRP1 (DNM1L; MIM 603850) (Nakamura et al., 2006 [PubMed 16936636]).

Source: NCBI Gene 54708 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 26 total
• Cancer dependency (DepMap): dependent in 34.4% of screened cell lines
• MANE Select transcript: NM_017824

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26025
Approved symbol	MARCHF5
Name	membrane associated ring-CH-type finger 5
Location	10q23.32-q23.33
Locus type	gene with protein product
Status	Approved
Aliases	FLJ20445, MARCH-V, MITOL
Ensembl gene	ENSG00000198060
Ensembl biotype	protein_coding
OMIM	610637
Entrez	54708

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 3 protein_coding, 3 protein_coding_CDS_not_defined

ENST00000358935, ENST00000462465, ENST00000467521, ENST00000492319, ENST00000884892, ENST00000919474

RefSeq mRNA: 1 — MANE Select: NM_017824 NM_017824

CCDS: CCDS7420

Canonical transcript exons

ENST00000358935 — 6 exons

Exon	Start	End
ENSE00001124895	92349671	92349837
ENSE00001251726	92291167	92291529
ENSE00001354846	92351091	92353964
ENSE00003512702	92340673	92340803
ENSE00003603000	92349349	92349532
ENSE00003611851	92311135	92311337

Expression profiles

Bgee: expression breadth ubiquitous, 281 present calls, max score 96.07.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 41.2448 / max 183.6214, expressed in 1824 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
106232	34.8081	1823
106235	3.1045	1511
106234	1.5302	1095
106236	0.9542	582
106233	0.8479	610

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sperm	CL:0000019	96.07	gold quality
lower esophagus mucosa	UBERON:0035834	95.62	gold quality
secondary oocyte	CL:0000655	95.36	gold quality
esophagus squamous epithelium	UBERON:0006920	95.00	gold quality
ganglionic eminence	UBERON:0004023	94.70	gold quality
epithelium of esophagus	UBERON:0001976	94.47	gold quality
oocyte	CL:0000023	94.13	gold quality
cortical plate	UBERON:0005343	93.81	gold quality
esophagus mucosa	UBERON:0002469	93.74	gold quality
male germ cell	CL:0000015	93.51	gold quality
islet of Langerhans	UBERON:0000006	92.94	gold quality
cartilage tissue	UBERON:0002418	92.55	gold quality
right adrenal gland	UBERON:0001233	92.36	gold quality
right adrenal gland cortex	UBERON:0035827	92.35	gold quality
ventricular zone	UBERON:0003053	92.34	gold quality
embryo	UBERON:0000922	92.19	gold quality
minor salivary gland	UBERON:0001830	91.93	gold quality
amniotic fluid	UBERON:0000173	91.90	gold quality
left adrenal gland	UBERON:0001234	91.70	gold quality
left ovary	UBERON:0002119	91.57	gold quality
stromal cell of endometrium	CL:0002255	91.54	gold quality
left adrenal gland cortex	UBERON:0035825	91.27	gold quality
esophagus	UBERON:0001043	91.22	gold quality
gastrocnemius	UBERON:0001388	91.05	gold quality
mouth mucosa	UBERON:0003729	90.90	gold quality
left lobe of thyroid gland	UBERON:0001120	90.67	gold quality
adrenal gland	UBERON:0002369	90.60	gold quality
endocervix	UBERON:0000458	90.59	gold quality
body of pancreas	UBERON:0001150	90.59	gold quality
right lung	UBERON:0002167	90.49	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.80

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

179 targeting MARCHF5, 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-8485	100.00	77.57	4731
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3134	100.00	66.43	777
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
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-302E	99.96	70.74	2669
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-557	99.96	70.01	1640
HSA-LET-7C-3P	99.95	73.42	2862

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 34.4% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 33)

• A novel mitochondrial ubiquitin ligase, designated MITOL, which is localized in the mitochondrial outer membrane, plays a critical role in mitochondrial dynamics through the control of mitochondrial fission proteins. (PMID:16874301)
• MARCH-V has a crucial role in the control of mitochondrial morphology by regulating MFN2 and Drp1 activities. (PMID:16936636)
• MARCH5 is required for DRP1-dependent mitochondrial division. (PMID:17606867)
• Results indicate that MITOL plays a protective role against mitochondrial dysfunction caused by the mitochondrial accumulation of mSOD1 via the ubiquitin-proteasome pathway. (PMID:19741096)
• lack of MARCH5 results in mitochondrial elongation, which promotes cellular senescence by blocking Drp1 activity and/or promoting accumulation of Mfn1 at the mitochondria (PMID:20103533)
• study found that MITOL interacts with and ubiquitinates DeltaNAT-3Q71, a pathogenic ataxin-3 mutant, in mitochondria and attenuates its toxicity (PMID:20851218)
• MARCH5 is an authentic E3 ubiquitin ligase and catalyzes K63-linked polyubiquitination of TANK. MARCH5 modulates TLR7 signaling via releasing the inhibitory action of TANK toward TRAF6. (PMID:21625535)
• balance between LC1 activation by S-nitrosylation and down-regulation by MITOL is critical for neuronal cell survival (PMID:22308378)
• MITOL regulates ER tethering to mitochondria by activating Mfn2 via K192 ubiquitination. (PMID:23727017)
• A fine balance of Mfn1 levels is maintained by MARCH5-mediated quality control on acetylated Mfn1. (PMID:24722297)
• Our results indicate that HDAC6 is a critical regulator of MFN2 degradation by MARCH5, thus protecting mitochondrial connectivity from hypoxic stress. (PMID:26210454)
• MARCH5 binds MAVS only during viral stimulation when MAVS forms aggregates, and these interactions require the RING domain of MARCH5 and the CARD domain of MAVS. (PMID:26246171)
• Self-clearance mechanism of mitochondrial ligase MARCH5 contributes to mitochondria quality control.MARCH5 is regulated by auto-ubiquitination. (PMID:26476016)
• These findings and data showing MARCH5-dependent degradation of MiD49 upon stress support the possibility that MARCH5 regulation of MiD49 is a novel mechanism controlling mitochondrial fission and, consequently, the cellular response to stress. (PMID:26564796)
• the results of this study identified MARCH5 as a candidate oncogene in ovarian cancer and a potential target for ovarian cancer therapy. (PMID:27875077)
• MARCH5 directly interacts with FUNDC1 to mediate its ubiquitylation at lysine 119 for subsequent degradation. (PMID:28104734)
• Data demonstrate a lower abundance of MARCH5 protein in white adipose tissue from the obese group with subsequently impaired fasting blood glucose levels than in lean individuals with normal glucose tolerance, confirming that MARCH5 is reduced in the setting of obesity and metabolic dysregulation. (PMID:30512991)
• Study identified IRE1a as a novel substrate for MITOL. MITOL modifies the lysine (K) 481 of IRE1a by adding a K63-linked polyubiquitin chain, which in turn suppresses the activity and oligomerization of IRE1a. These data provide evidence that MITOL can directly regulate IRE1a through the mitochondria-associated ER membrane (MAM) and thus play an important role in determining cell fate under ER stress. (PMID:31368599)
• Ubiquitylation of MITOL at K268 by Parkin is required for p97/VCP-dependent redistribution from mitochondria to peroxisomes. (PMID:31602805)
• Mitochondria ubiquitin ligase, MARCH5 resolves hepatitis B virus X protein aggregates in the liver pathogenesis. (PMID:31819032)
• Dual targeting of RIG-I and MAVS by MARCH5 mitochondria ubiquitin ligase in innate immunity. (PMID:31881323)
• MARCH5-dependent degradation of MCL1/NOXA complexes defines susceptibility to antimitotic drug treatment. (PMID:32015503)
• MARCH5 requires MTCH2 to coordinate proteasomal turnover of the MCL1:NOXA complex. (PMID:32094511)
• MARCH5 mediates NOXA-dependent MCL1 degradation driven by kinase inhibitors and integrated stress response activation. (PMID:32484436)
• MARCH5 restores endothelial cell function against ischaemic/hypoxia injury via Akt/eNOS pathway. (PMID:33611830)
• MITOL-dependent ubiquitylation negatively regulates the entry of PolgammaA into mitochondria. (PMID:33657094)
• The XBP1MARCH5MFN2 Axis Confers Endoplasmic Reticulum Stress Resistance by Coordinating Mitochondrial Fission and Mitophagy in Melanoma. (PMID:34048729)
• Ubiquitin ligase MARCH5 localizes to peroxisomes to regulate pexophagy. (PMID:34747980)
• A decrease of mitochondrial ubiquitin ligase increases the secretion of matrix metalloproteinase-1 by dermal fibroblasts through the induction of ER stress. (PMID:37337400)
• Hyperubiquitylation of DNA helicase RECQL4 by E3 ligase MITOL prevents mitochondrial entry and potentiates mitophagy. (PMID:37495109)
• PD-1 signaling negatively regulates the common cytokine receptor gamma chain via MARCH5-mediated ubiquitination and degradation to suppress anti-tumor immunity. (PMID:37932447)
• MARCH5-mediated downregulation of ACC2 promotes fatty acid oxidation and tumor progression in ovarian cancer. (PMID:38211832)
• MARCH5 promotes hepatocellular carcinoma progression by inducing p53 ubiquitination degradation. (PMID:38861187)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	marchf5	ENSDARG00000032552
mus_musculus	Marchf5	ENSMUSG00000023307
rattus_norvegicus	Marchf5	ENSRNOG00000017396
drosophila_melanogaster	CG16781	FBGN0029661
drosophila_melanogaster	CG10761	FBGN0030015
drosophila_melanogaster	CG9855	FBGN0037242
drosophila_melanogaster	CG17991	FBGN0039498
caenorhabditis_elegans		WBGENE00010913

Protein

Protein identifiers

E3 ubiquitin-protein ligase MARCHF5 — Q9NX47 (reviewed: Q9NX47)

Alternative names: Membrane-associated RING finger protein 5, Membrane-associated RING-CH protein V, Mitochondrial ubiquitin ligase, RING finger protein 153, RING-type E3 ubiquitin transferase MARCHF5

All UniProt accessions (1): Q9NX47

UniProt curated annotations — full annotation on UniProt →

Function. Mitochondrial E3 ubiquitin-protein ligase that plays a crucial role in the control of mitochondrial morphology by acting as a positive regulator of mitochondrial fission and as an important regulator of immune response. Plays a crucial role in maintaining mitochondrial homeostasis by regulating the dynamics of mitochondria through the ubiquitination of key proteins involved in fission and fusion such as FIS1, DNM1L and MFN1. Acts as a critical determinant of mitotic apoptosis through both MCL1-dependent and -independent pathways. Turns off persistent immune signaling by degrading oligomeric complexes of retinoic acid-inducible gene I/DDX58 and mitochondrial antiviral-signaling protein/MAVS formed upon RNA virus infection. Promotes STING-mediated type-I interferon production via ‘Lys-63’-linked ubiquitination of STING1 thereby preserving its activity and preventing the formation of inactive STING1 polymers. Plays also an essential role in the formation of PEX3-containing vesicles in the de novo biogenesis of peroxisomes from mitochondria. Acts as a regulator of NLRP3 inflammasome activation on the mitochondria by mediating the ‘Lys-27’-linked polyubiquitination of NLRP3, positively regulating the NLRP3-NEK7 complex formation and NLRP3 oligomerization. (Microbial infection) Plays a positive role in Japanese encephalitis virus infection by catalyzing the ‘Lys-27’-linked polyubiquitination of viral E protein to facilitate efficient viral attachment.

Subunit / interactions. Monomer and homodimer. Interacts with MFN1, MFN2, DNM1L and FIS1.

Subcellular location. Mitochondrion outer membrane. Endoplasmic reticulum membrane. Peroxisome membrane.

Tissue specificity. Expressed in brain, heart, liver, lung, spleen, stomach, testis, skeletal and muscle.

Post-translational modifications. Autoubiquitinated leading to degradation (short half-life).

Domain organisation. The RING-CH-type zinc finger domain is required for E3 ligase activity.

Pathway. Protein modification; protein ubiquitination.

Miscellaneous. By binding to and ubiquitinating two ALS1 variants of SOD1 (mSOD1 variants Arg-86 and Ala-94) it attenuates their cytotoxicity.

RefSeq proteins (1): NP_060294* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011016	Znf_RING-CH	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily

Pfam: PF12906

UniProt features (17 total): binding site 8, transmembrane region 4, mutagenesis site 3, chain 1, zinc finger region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NX47-F1	85.75	0.54

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 (8): 43; 46; 65; 68; 14; 17; 33; 35

Mutagenesis-validated functional residues (3):

Position	Phenotype
43	loss of ubiquitin ligase activity, formation of highly interconnected mitochondria, change in mitochondria morphology th
65	loss of e3 ubiquitin ligase activity. formation of highly interconnected mitochondria and perinuclear accumulation; when
68	loss of e3 ubiquitin ligase activity. formation of highly interconnected mitochondria and perinuclear accumulation; when

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 258 (showing top): GOBP_POSITIVE_REGULATION_OF_MITOCHONDRIAL_FISSION, GOBP_INFLAMMATORY_RESPONSE, SP3_Q3, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, AP4_Q6, GOMF_GTPASE_BINDING, GOBP_POSITIVE_REGULATION_OF_ORGANELLE_ORGANIZATION, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, CAGCTG_AP4_Q5, MONNIER_POSTRADIATION_TUMOR_ESCAPE_UP, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, GOBP_POSITIVE_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS, GOBP_REGULATION_OF_MITOCHONDRION_ORGANIZATION, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GOBP_POSITIVE_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS

GO Biological Process (15): protein polyubiquitination (GO:0000209), negative regulation of cytoplasmic pattern recognition receptor signaling pathway (GO:0039532), protein K27-linked ubiquitination (GO:0044314), protein autoubiquitination (GO:0051865), protein K63-linked ubiquitination (GO:0070534), protein localization to mitochondrion (GO:0070585), protein K48-linked ubiquitination (GO:0070936), regulation of mitochondrial fission (GO:0090140), positive regulation of mitochondrial fission (GO:0090141), positive regulation of cGAS/STING signaling pathway (GO:0141111), positive regulation of NLRP3 inflammasome complex assembly (GO:1900227), cytoplasmic pattern recognition receptor signaling pathway (GO:0002753), protein ubiquitination (GO:0016567), NLRP3 inflammasome complex assembly (GO:0044546), cGAS/STING signaling pathway (GO:0140896)

GO Molecular Function (6): zinc ion binding (GO:0008270), GTPase binding (GO:0051020), ubiquitin protein ligase activity (GO:0061630), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (7): mitochondrion (GO:0005739), mitochondrial outer membrane (GO:0005741), peroxisomal membrane (GO:0005778), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), membrane (GO:0016020), peroxisome (GO:0005777)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein polyubiquitination	3
protein ubiquitination	2
cytoplasmic pattern recognition receptor signaling pathway	2
regulation of cytoplasmic pattern recognition receptor signaling pathway	2
mitochondrial fission	2
cytoplasm	2
intracellular membrane-bounded organelle	2
negative regulation of immune system process	1
negative regulation of intracellular signal transduction	1
protein localization to organelle	1
regulation of mitochondrion organization	1
regulation of anatomical structure morphogenesis	1
positive regulation of organelle organization	1
positive regulation of developmental process	1
regulation of mitochondrial fission	1
positive regulation of pattern recognition receptor signaling pathway	1
cGAS/STING signaling pathway	1
positive regulation of intracellular signal transduction	1
positive regulation of protein-containing complex assembly	1
NLRP3 inflammasome complex assembly	1
positive regulation of inflammasome-mediated signaling pathway	1
regulation of NLRP3 inflammasome complex assembly	1
positive regulation of cytokine production	1
pattern recognition receptor signaling pathway	1
intracellular receptor signaling pathway	1
protein modification by small protein conjugation	1
canonical inflammasome complex assembly	1
transition metal ion binding	1
enzyme binding	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
binding	1
catalytic activity	1
cation binding	1
mitochondrial membrane	1
organelle outer membrane	1
peroxisome	1
microbody membrane	1
endomembrane system	1
organelle membrane	1

Protein interactions and networks

STRING

1196 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MARCHF5	MFN2	O95140	995
MARCHF5	FIS1	Q9Y3D6	953
MARCHF5	DNM1L	O00429	951
MARCHF5	MARCHF2	Q9P0N8	853
MARCHF5	MFN1	Q8IWA4	816
MARCHF5	MUL1	Q969V5	786
MARCHF5	FUNDC1	Q8IVP5	779
MARCHF5	TANK	Q92844	746
MARCHF5	UBE2E1	P51965	695
MARCHF5	MAVS	Q7Z434	684
MARCHF5	UBE2E3	Q969T4	672
MARCHF5	MIEF2	Q96C03	663
MARCHF5	USP30	Q70CQ3	651
MARCHF5	BCAP31	P51572	622
MARCHF5	WSB2	Q9NYS7	616

IntAct

111 interactions, top by confidence:

A	B	Type	Score
MARCHF5	UBE2W	psi-mi:“MI:0915”(physical association)	0.740
UBE2W	MARCHF5	psi-mi:“MI:0915”(physical association)	0.740
MARCHF5	UBE2W	psi-mi:“MI:0915”(physical association)	0.720
UBE2W	MARCHF5	psi-mi:“MI:0915”(physical association)	0.720
MARCHF5	FATE1	psi-mi:“MI:0915”(physical association)	0.670
FATE1	MARCHF5	psi-mi:“MI:0915”(physical association)	0.670
MARCHF5	MFN2	psi-mi:“MI:0914”(association)	0.670
MFN2	MARCHF5	psi-mi:“MI:0915”(physical association)	0.670
DENR	MARCHF5	psi-mi:“MI:0915”(physical association)	0.590
MARCHF5	DSC3	psi-mi:“MI:0915”(physical association)	0.560
MARCHF5	TMEM14B	psi-mi:“MI:0915”(physical association)	0.560
MARCHF5	ANKS6	psi-mi:“MI:0915”(physical association)	0.560
MARCHF5	HSD17B13	psi-mi:“MI:0915”(physical association)	0.560
MARCHF5	CGRRF1	psi-mi:“MI:0915”(physical association)	0.560
PTPN5	MARCHF5	psi-mi:“MI:0915”(physical association)	0.560
BIK	MARCHF5	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (314): UBE2W (Two-hybrid), FATE1 (Two-hybrid), UBE2D2 (Reconstituted Complex), MIA3 (Affinity Capture-MS), MFN2 (Affinity Capture-MS), MARCH5 (Affinity Capture-MS), MARCH5 (Affinity Capture-RNA), MARCH5 (Two-hybrid), MARCH5 (Affinity Capture-Western), SLC25A38 (Affinity Capture-Western), MARCH5 (Affinity Capture-Western), MARCH5 (Affinity Capture-Western), SLC25A26 (Affinity Capture-Western), MARCH5 (Affinity Capture-Western), FUNDC1 (Biochemical Activity)

ESM2 similar proteins: A0A8I3PI99, A0M8U1, A7Y521, B5DEN9, C5HGF3, O88544, O94973, P13666, P17427, P18484, P38024, Q00765, Q0VCK5, Q0X0A5, Q13098, Q1RLU8, Q28635, Q2PG42, Q3KNM2, Q3SZA0, Q3T0N3, Q3T126, Q3T178, Q3ZC24, Q4R5E6, Q5F418, Q5I0H4, Q5M7T4, Q5R648, Q5R9B0, Q5R9M4, Q5RE33, Q5ZJ41, Q5ZJD7, Q6DGW9, Q6GM44, Q6NRT5, Q7TQ48, Q8C407, Q8R1Z9

Diamond homologs: A0JN69, A6NNE9, A6P320, F4JKK0, O60103, O60337, P40318, Q0IH10, Q0P496, Q0VD59, Q0X0A5, Q1LVZ2, Q28EX7, Q28IK8, Q32L65, Q3KNM2, Q3TZ87, Q3ZC24, Q5I0I2, Q5PQ35, Q5R9W1, Q5R9W2, Q5T0T0, Q5XH39, Q5XI50, Q5XIE5, Q5ZJ41, Q68FA7, Q6GM44, Q6NYK8, Q6NZQ8, Q6ZQ89, Q80TE3, Q86UD3, Q86YJ5, Q8BRX9, Q8CBH7, Q8TCQ1, Q99M02, Q9DBD2

SIGNOR signaling

15 interactions.

A	Effect	B	Mechanism
Ub:E2	“up-regulates activity”	MARCHF5	ubiquitination
MARCHF5	“down-regulates quantity by destabilization”	DNM1L	polyubiquitination
MARCHF5	“down-regulates quantity by destabilization”	MARCHF5	polyubiquitination
MARCHF5	“down-regulates quantity by destabilization”	FIS1	polyubiquitination
MARCHF5	“down-regulates quantity by destabilization”	MFN1	ubiquitination
MARCHF5	“down-regulates quantity by destabilization”	FIS1	ubiquitination
MARCHF5	“up-regulates activity”	MFN2	ubiquitination
MARCHF5	“down-regulates quantity by destabilization”	PRKN	ubiquitination
MARCHF5	“down-regulates activity”	ERN1	ubiquitination
MARCHF5	“down-regulates quantity”	SOD1	ubiquitination
MARCHF5	“down-regulates quantity by destabilization”	MCL1	ubiquitination
MARCHF5	“down-regulates quantity”	PMAIP1	ubiquitination
MARCHF5	“down-regulates quantity by destabilization”	SOD1	ubiquitination

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	11
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1300 predictions. Top by Δscore:

Variant	Effect	Δscore
10:92311133:A:AG	acceptor_gain	1.0000
10:92311134:G:GC	acceptor_gain	1.0000
10:92311134:GA:G	acceptor_gain	1.0000
10:92311134:GAA:G	acceptor_gain	1.0000
10:92311134:GAAGT:G	acceptor_gain	1.0000
10:92340828:A:AG	donor_gain	1.0000
10:92349345:ACAG:A	acceptor_gain	1.0000
10:92349347:AG:A	acceptor_gain	1.0000
10:92349348:GG:G	acceptor_gain	1.0000
10:92349348:GGTT:G	acceptor_gain	1.0000
10:92349528:TCCAG:T	donor_loss	1.0000
10:92349529:CCAG:C	donor_loss	1.0000
10:92349530:CAGG:C	donor_loss	1.0000
10:92349531:AGGT:A	donor_loss	1.0000
10:92349532:GGTAA:G	donor_loss	1.0000
10:92349533:GT:G	donor_loss	1.0000
10:92349534:T:A	donor_loss	1.0000
10:92349784:GTTG:G	donor_gain	1.0000
10:92351089:AG:A	acceptor_gain	1.0000
10:92351090:GG:G	acceptor_gain	1.0000
10:92291526:ACAG:A	donor_loss	0.9900
10:92291527:CAGGT:C	donor_loss	0.9900
10:92291528:AGGTA:A	donor_loss	0.9900
10:92291529:GGTAC:G	donor_loss	0.9900
10:92291531:T:A	donor_loss	0.9900
10:92311126:A:AG	acceptor_gain	0.9900
10:92311130:TACA:T	acceptor_loss	0.9900
10:92311334:TTGGG:T	donor_loss	0.9900
10:92311336:GG:G	donor_gain	0.9900
10:92311336:GGGT:G	donor_loss	0.9900

AlphaMissense

1804 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:92311139:T:C	C14R	1.000
10:92311141:C:G	C14W	1.000
10:92311144:G:C	W15C	1.000
10:92311144:G:T	W15C	1.000
10:92311148:T:C	C17R	1.000
10:92311150:T:G	C17W	1.000
10:92311184:T:A	W29R	1.000
10:92311184:T:C	W29R	1.000
10:92311186:G:C	W29C	1.000
10:92311186:G:T	W29C	1.000
10:92311196:T:A	C33S	1.000
10:92311196:T:C	C33R	1.000
10:92311197:G:A	C33Y	1.000
10:92311197:G:C	C33S	1.000
10:92311198:C:G	C33W	1.000
10:92311202:T:A	C35S	1.000
10:92311202:T:C	C35R	1.000
10:92311203:G:A	C35Y	1.000
10:92311203:G:C	C35S	1.000
10:92311220:T:A	W41R	1.000
10:92311220:T:C	W41R	1.000
10:92311226:C:G	H43D	1.000
10:92311235:T:A	C46S	1.000
10:92311235:T:C	C46R	1.000
10:92311236:G:A	C46Y	1.000
10:92311236:G:C	C46S	1.000
10:92311237:T:G	C46W	1.000
10:92311247:T:A	W50R	1.000
10:92311247:T:C	W50R	1.000
10:92311249:G:C	W50C	1.000

dbSNP variants (sampled 300 via entrez): RS1000000952 (10:92324528 AT>A,ATT), RS1000035340 (10:92339243 G>A), RS1000115527 (10:92317105 TTTA>T), RS1000117911 (10:92325002 A>C), RS1000141835 (10:92332071 T>G), RS1000212448 (10:92330593 A>G), RS1000235329 (10:92293325 A>G), RS1000254516 (10:92344484 T>C), RS1000255721 (10:92325319 G>A), RS1000314207 (10:92337778 A>G), RS1000409916 (10:92317611 A>C), RS1000424135 (10:92310565 C>A,G), RS1000456015 (10:92326372 C>G,T), RS1000531219 (10:92312921 A>C), RS1000586885 (10:92344042 T>C)

Disease associations

OMIM: gene MIM:610637 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol F	increases expression, affects cotreatment, decreases expression	2
Valproic Acid	affects expression, decreases expression	2
GSK-J4	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
arsenite	affects binding, increases reaction	1
methylparaben	increases expression	1
sodium arsenite	increases expression	1
cobaltous chloride	increases expression	1
Resveratrol	increases expression, affects cotreatment	1
Acetaminophen	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Atrazine	decreases expression	1
Carbamazepine	affects expression	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Dexamethasone	affects cotreatment, decreases expression	1
Indomethacin	affects cotreatment, decreases expression	1
Ivermectin	decreases expression	1
Methyl Methanesulfonate	increases expression	1
Plant Extracts	affects cotreatment, increases expression	1
Thiram	increases expression	1
Tobacco Smoke Pollution	increases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, decreases expression	1
Cyclosporine	increases expression	1
Copper Sulfate	increases expression	1
Lactic Acid	decreases expression	1
Particulate Matter	increases abundance, decreases expression	1

Clinical trials (associated diseases)

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