FIS1

Summary

FIS1 (fission, mitochondrial 1, HGNC:21689) is a protein-coding gene on chromosome 7q22.1, encoding Mitochondrial fission 1 protein (Q9Y3D6). Involved in the fragmentation of the mitochondrial network and its perinuclear clustering. It is a selective cancer dependency (DepMap: 24.4% of cell lines).

Enables identical protein binding activity; lipid binding activity; and molecular adaptor activity. Involved in several processes, including negative regulation of ATP metabolic process; negative regulation of fatty acid transport; and organelle fission. Acts upstream of or within mitochondrion organization. Located in mitochondrial outer membrane and peroxisomal membrane. Part of protein-containing complex. Biomarker of Alzheimer’s disease.

Source: NCBI Gene 51024 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 34 total
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 24.4% of screened cell lines
• MANE Select transcript: NM_016068

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21689
Approved symbol	FIS1
Name	fission, mitochondrial 1
Location	7q22.1
Locus type	gene with protein product
Status	Approved
Aliases	CGI-135, H_NH0132A01.6
Ensembl gene	ENSG00000214253
Ensembl biotype	protein_coding
OMIM	609003
Entrez	51024

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 12 protein_coding, 3 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay

ENST00000223136, ENST00000435848, ENST00000442303, ENST00000449367, ENST00000463406, ENST00000473527, ENST00000474120, ENST00000480497, ENST00000482199, ENST00000902740, ENST00000902741, ENST00000902742, ENST00000920970, ENST00000920971, ENST00000920972, ENST00000920973, ENST00000955058

RefSeq mRNA: 1 — MANE Select: NM_016068 NM_016068

CCDS: CCDS43626

Canonical transcript exons

ENST00000223136 — 5 exons

Exon	Start	End
ENSE00000881583	101244960	101245081
ENSE00003489249	101240830	101240906
ENSE00003528179	101240142	101240247
ENSE00003598790	101239472	101239903
ENSE00003610157	101244007	101244139

Expression profiles

Bgee: expression breadth ubiquitous, 284 present calls, max score 99.35.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 92.5603 / max 414.2169, expressed in 1828 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
85328	80.3712	1827
85330	6.0722	1732
85329	4.9306	1713
85327	0.7484	390
85325	0.3597	32
85324	0.0488	15
85326	0.0295	5

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
C1 segment of cervical spinal cord	UBERON:0006469	99.35	gold quality
apex of heart	UBERON:0002098	99.22	gold quality
spinal cord	UBERON:0002240	99.09	gold quality
prefrontal cortex	UBERON:0000451	98.94	gold quality
hindlimb stylopod muscle	UBERON:0004252	98.78	gold quality
adenohypophysis	UBERON:0002196	98.70	gold quality
gastrocnemius	UBERON:0001388	98.68	gold quality
anterior cingulate cortex	UBERON:0009835	98.65	gold quality
cingulate cortex	UBERON:0003027	98.64	gold quality
right frontal lobe	UBERON:0002810	98.61	gold quality
pituitary gland	UBERON:0000007	98.60	gold quality
right atrium auricular region	UBERON:0006631	98.57	gold quality
lower esophagus	UBERON:0013473	98.54	gold quality
lower esophagus muscularis layer	UBERON:0035833	98.54	gold quality
heart left ventricle	UBERON:0002084	98.53	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	98.52	gold quality
mucosa of stomach	UBERON:0001199	98.51	gold quality
left adrenal gland cortex	UBERON:0035825	98.51	gold quality
muscle of leg	UBERON:0001383	98.50	gold quality
cranial nerve II	UBERON:0000941	98.49	gold quality
tibial nerve	UBERON:0001323	98.49	gold quality
muscle layer of sigmoid colon	UBERON:0035805	98.49	gold quality
left adrenal gland	UBERON:0001234	98.45	gold quality
cardiac ventricle	UBERON:0002082	98.43	gold quality
right lobe of thyroid gland	UBERON:0001119	98.42	gold quality
metanephros cortex	UBERON:0010533	98.42	gold quality
right adrenal gland	UBERON:0001233	98.39	gold quality
amygdala	UBERON:0001876	98.39	gold quality
nucleus accumbens	UBERON:0001882	98.39	gold quality
left lobe of thyroid gland	UBERON:0001120	98.38	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-4850	no	247.30
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

18 targeting FIS1, 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-4283	100.00	66.42	2097
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-4493	99.90	66.48	977
HSA-MIR-3175	99.65	66.30	2031
HSA-MIR-4489	99.50	65.56	785
HSA-MIR-6081	99.48	66.07	1446
HSA-MIR-5589-3P	99.29	68.30	1443
HSA-MIR-4656	98.79	66.22	1306
HSA-MIR-4717-5P	98.19	67.97	894
HSA-MIR-4518	98.12	66.82	1030
HSA-MIR-1266-5P	97.71	66.92	1052
HSA-MIR-939-5P	97.10	65.80	1579
HSA-MIR-1343-5P	96.48	66.06	1506
HSA-MIR-3675-5P	95.90	65.80	474

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 24.4% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• hFis1 is part of the mammalian fission machinery and regulation of the fission processes might be involved in apoptotic mechanisms (PMID:12783892)
• regulates mitochondrial fission in mammalian cells through an interaction with the dynamin-like protein DLP1 (PMID:12861026)
• Cytosolic domain of fis1 adopts a tetratricopeptide repeat domain fold. (PMID:14705031)
• the level of Fis1 at the mitochondrial surface influences mitochondrial fission events and hence overall mitochondrial morphology within the cell (PMID:14996942)
• hFis1 induces mitochondrial fragmentation and perinuclear clustering in a state of calcium homeostasis (PMID:15024001)
• Fis1, Drp1, and Opa1 have roles in apoptosis (PMID:15356267)
• Fis1 together with dynamin-related protein (Drp1) antogonizes Bcl-2. (PMID:16010987)
• These findings provide the first evidence for a role of Fis1 in peroxisomal fission and suggest that the fission machinery of mitochondria and peroxisomes shares common components. (PMID:16107562)
• TPR region of hFis1 participates in the interaction with DLP1 or DLP1-containing complex and that the first helix (alpha1) of hFis1 is required for mitochondrial fission presumably by regulating DLP1-hFis1 interaction. (PMID:16118244)
• Direct induction of mitochondrial elongation by blocking mitochondrial fission process with Fis1-DeltaTM or Drp1-K38A was sufficient to develop senescent phenotypes with increased Reactive oxygen species production. (PMID:16883569)
• hFis1 is a bifunctional protein that independently regulates mitochondrial fragmentation and endoplasmic reticulum-mediated apoptosis. (PMID:16914522)
• Fis1 plays important roles in peroxisome division and maintenance of peroxisome morphology in mammalian cells, possibly in a concerted manner with Pex11pbeta and DLP1. (PMID:17408615)
• hFis1 and OPA1 modulate cellular senescence (PMID:17545159)
• the concave surface of the Fis1 tetratricopeptide repeat-like domain is evolutionarily conserved to bind the dynamin-like GTPase Dnm1 and not Mdv1 as previously predicted (PMID:17884824)
• Changes correlate with mitochondrial dysfunction rather than with fragmentation, as substantiated by Fis1 mutants with different effects on organelle shape and function (PMID:18515060)
• targeting of hFis1 to peroxisomes and mitochondria are independent events and support a direct, Pex19p-dependent targeting of peroxisomal tail-anchored proteins. (PMID:18782765)
• Fis1 and Mfn1 activities influence mitochondrial signal generation thereby insulin exocytosis. (PMID:18832378)
• oligomerization of hFis1 in the mitochondrial outer membrane plays a role in mitochondrial fission, potentially through participating in fission factor recruitment. (PMID:18845145)
• hFis1 can bind to multiple amino acid sequences selectively, and the tetratricopeptide repeat constitutes the main binding region of hFis1. (PMID:19864424)
• There is a Drp1- and Fis1-induced, and PINK1-mediated protection mechanism in senescent cells. (PMID:20179104)
• we observed interactions between Drp1 and Fis1 in mitochondrial fragmentation induced by increasing mitochondrial calcium (PMID:20428767)
• The mitochondrial fission protein Fission 1 homologue (Fis1) conveys an apoptosis signal from the mitochondria to the ER by interacting with Bap31 at the ER and facilitating its cleavage into the pro-apoptotic p20Bap31. (PMID:21183955)
• Fis1 and dynamin-related protein (Drp)1 levels are remarkably increased in peripheral blood lymphocytes of Alzheimer’s disease patients. (PMID:22340708)
• PEX11 proteins attract both Mff and human Fis1 (hFis1) to their site of action. (PMID:22595523)
• Fis1 activity depends on its ability to interconvert between monomer and dimer species (PMID:22789569)
• Fis1 acts as a mitochondrial recruitment factor for TBC1D15 that is involved in regulation of mitochondrial morphology. (PMID:23077178)
• Fis1 expression is significantly increased in spinal cord in a transgenic mouse model of amyotrophic lateral sclerosis. (PMID:23713734)
• Overexpression of FoxM1 and Plk1 in Fis1-depleted cells restores mitotic entry. (PMID:23907611)
• MiD49 and MiD51 can act independently of Mff and Fis1 in Drp1 recruitment and suggest that they provide specificity to the division of mitochondria. (PMID:23921378)
• PDCD7, Ang2 and FIS1 may indicate a more aggressive form and poor prognosis of acute myeloid leukemia. (PMID:24416201)
• Results show that Fis1 is significantly overexpressed in malignant oncocytomas. (PMID:25822260)
• Study revealed that a novel mitochondrial fission pathway composed of miR-483-5p and FIS1 regulates cisplatin sensitivity. (PMID:25843291)
• Fis1 depletion in osteoarthritis impairs chondrocyte survival and peroxisomal and lysosomal function. (PMID:27497958)
• inhibition of Drp1/Fis1 interaction by a selective peptide inhibitor, P110, led to a significant reduction in reactive oxygen species levels, and to improvement in mitochondrial structure and functions. (PMID:29335339)
• data suggest a model in which leukemia stem cells co-opt AMPK/FIS1-mediated mitophagy as a means to maintain stem cell properties that may be otherwise compromised by the stresses induced by oncogenic transformation (PMID:29910151)
• we found that differential expression of BAK1, FIS1, and SFN were altered across the Barrett’s disease sequence and manipulation of these genes elicited significant effects on mitochondrial membrane potential. (PMID:30404157)
• FIS1 and PDCD7 expression are considered independent risk factors and should be integrated into the current acute myeloid leukemia stratification system (PMID:30555023)
• Glomerular overproduction of Drp1, phospho-Drp1 (Ser 616) and Fis1 occurred mainly in children with membranous nephropathy. (PMID:30566949)
• Study demonstrated that the STX17 initiates mitophagy upon depletion of outer mitochondrial membrane protein Fis1. Fis1 loss results in aberrant STX17 accumulation on mitochondria, which exposes the N terminus and promotes self-oligomerization to trigger mitophagy. Findings uncover a PINK1/Parkin-independent mitophagic mechanism in which outer mitochondrial membrane protein Fis1 regulates mitochondrial quality control. (PMID:31053718)
• In human EPCs, down-regulation of Fis1 is involved in mitochondrial dysfunction and contributes to the impaired activity of EPCs during the senescence process. Enhanced expression of Fis1 in senescent EPCs restores the youthful phenotype. (PMID:31482366)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	fis1	ENSDARG00000114549
mus_musculus	Fis1	ENSMUSG00000019054
rattus_norvegicus	Fis1	ENSRNOG00000001420
drosophila_melanogaster	Fis1	FBGN0039969
caenorhabditis_elegans		WBGENE00001424
caenorhabditis_elegans		WBGENE00001425

Protein

Protein identifiers

Mitochondrial fission 1 protein — Q9Y3D6 (reviewed: Q9Y3D6)

Alternative names: FIS1 homolog, Tetratricopeptide repeat protein 11

All UniProt accessions (6): C9JXH1, F5H509, F5H8A8, F8WBT1, F8WD11, Q9Y3D6

UniProt curated annotations — full annotation on UniProt →

Function. Involved in the fragmentation of the mitochondrial network and its perinuclear clustering. Plays a minor role in the recruitment and association of the fission mediator dynamin-related protein 1 (DNM1L) to the mitochondrial surface and mitochondrial fission. May not be essential for the assembly of functional fission complexes and the subsequent membrane scission event. Also mediates peroxisomal fission. May act when the products of fission are directed toward mitochondrial homeostasis, mitophagy, or apoptosis. Can induce cytochrome c release from the mitochondrion to the cytosol, ultimately leading to apoptosis.

Subunit / interactions. Interacts with DNM1L/DLP1 through the TPR region; may form part of a larger protein complex at the endoplasmic reticulum-mitochondrial interface during mitochondrial fission. Interacts with MARCHF5. Interacts with MIEF1. Interacts with PEX11A, PEX11B and PEX11G.

Subcellular location. Mitochondrion outer membrane. Peroxisome membrane.

Post-translational modifications. Ubiquitinated by MARCHF5.

Domain organisation. The C-terminus is required for mitochondrial or peroxisomal localization, while the N-terminus is necessary for mitochondrial or peroxisomal fission, localization and regulation of the interaction with DNM1L.

Similarity. Belongs to the FIS1 family.

RefSeq proteins (1): NP_057152* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011990	TPR-like_helical_dom_sf	Homologous_superfamily
IPR016543	Fis1	Family
IPR028058	Fis1_TPR_N	Repeat
IPR028061	Fis1_TPR_C	Repeat
IPR033745	Fis1_cytosol	Domain

Pfam: PF14852, PF14853

UniProt features (27 total): mutagenesis site 8, helix 8, strand 3, topological domain 2, modified residue 2, chain 1, sequence conflict 1, transmembrane region 1, repeat 1

Structure

Experimental structures (PDB)

12 structures.

PDB	Method	Resolution (Å)
9AYD	X-RAY DIFFRACTION	1.53
7YA9	X-RAY DIFFRACTION	1.7
8U1Z	X-RAY DIFFRACTION	1.85
9AYE	X-RAY DIFFRACTION	1.9
9AVB	X-RAY DIFFRACTION	1.95
1NZN	X-RAY DIFFRACTION	2
9AVC	X-RAY DIFFRACTION	2.09
7YKA	X-RAY DIFFRACTION	2.3
9AVE	X-RAY DIFFRACTION	2.37
9AVD	X-RAY DIFFRACTION	2.51
8XWX	X-RAY DIFFRACTION	2.69
1PC2	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y3D6-F1	79.66	0.26

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): 1, 10

Mutagenesis-validated functional residues (8):

Position	Phenotype
77	less than 15% of cells display fragmented mitochondria. shows greatly reduced binding to dnm1l.
91	less than 15% of cells display fragmented mitochondria. shows greatly reduced binding to dnm1l.
110	approximately 40% of cells display fragmented mitochondria. no change in binding to dnm1l.
149	protein localizes to both mitochondrion and endoplasmic reticulum. protein localizes to endoplasmic reticulum only; when
151	protein localizes to both mitochondrion and endoplasmic reticulum. protein localizes to endoplasmic reticulum only; when
14	approximately 40% of cells display fragmented mitochondria.
42	less than 15% of cells display fragmented mitochondria.
58	less than 15% of cells display fragmented mitochondria.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9603798	Class I peroxisomal membrane protein import

MSigDB gene sets: 221 (showing top): GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_DN, GOBP_POSITIVE_REGULATION_OF_MITOCHONDRIAL_FISSION, GOBP_REGULATION_OF_ORGANIC_ACID_TRANSPORT, GOBP_RESPONSE_TO_PEPTIDE, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GOBP_CELLULAR_RESPONSE_TO_CARBOHYDRATE_STIMULUS, GOBP_PROTEIN_TARGETING, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ORGANELLE, GOBP_POSITIVE_REGULATION_OF_ORGANELLE_ORGANIZATION, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, CAGCTG_AP4_Q5, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, HERNANDEZ_MITOTIC_ARREST_BY_DOCETAXEL_1_DN

GO Biological Process (21): mitochondrial fission (GO:0000266), obsolete protein targeting to mitochondrion (GO:0006626), mitochondrion organization (GO:0007005), response to muscle activity (GO:0014850), peroxisome fission (GO:0016559), response to nutrient levels (GO:0031667), response to endoplasmic reticulum stress (GO:0034976), positive regulation of neuron apoptotic process (GO:0043525), mitochondrial fragmentation involved in apoptotic process (GO:0043653), cellular response to glucose stimulus (GO:0071333), cellular response to lipid (GO:0071396), positive regulation of mitochondrial fission (GO:0090141), cellular response to toxic substance (GO:0097237), cellular response to peptide (GO:1901653), response to fluoride (GO:1902617), negative regulation of ATP metabolic process (GO:1903579), response to flavonoid (GO:1905395), response to hypobaric hypoxia (GO:1990910), negative regulation of fatty acid transport (GO:2000192), positive regulation of intrinsic apoptotic signaling pathway (GO:2001244), apoptotic process (GO:0006915)

GO Molecular Function (4): lipid binding (GO:0008289), identical protein binding (GO:0042802), molecular adaptor activity (GO:0060090), protein binding (GO:0005515)

GO Cellular Component (7): mitochondrion (GO:0005739), mitochondrial outer membrane (GO:0005741), peroxisome (GO:0005777), peroxisomal membrane (GO:0005778), cytosol (GO:0005829), membrane (GO:0016020), protein-containing complex (GO:0032991)

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
cellular response to chemical stimulus	3
binding	3
organelle fission	2
cytoplasm	2
cellular anatomical structure	2
mitochondrion organization	1
organelle organization	1
response to activity	1
peroxisome organization	1
response to stimulus	1
cellular response to stress	1
positive regulation of apoptotic process	1
regulation of neuron apoptotic process	1
neuron apoptotic process	1
apoptotic mitochondrial changes	1
intracellular glucose homeostasis	1
response to glucose	1
cellular response to hexose stimulus	1
response to lipid	1
mitochondrial fission	1
positive regulation of organelle organization	1
positive regulation of developmental process	1
regulation of mitochondrial fission	1
response to toxic substance	1
response to peptide	1
response to chemical	1
ATP metabolic process	1
negative regulation of purine nucleotide metabolic process	1
regulation of ATP metabolic process	1
response to oxygen-containing compound	1
response to hypoxia	1
fatty acid transport	1
negative regulation of lipid transport	1
negative regulation of organic acid transport	1
regulation of fatty acid transport	1
intrinsic apoptotic signaling pathway	1
positive regulation of intracellular signal transduction	1
positive regulation of apoptotic signaling pathway	1
regulation of intrinsic apoptotic signaling pathway	1
protein binding	1

Protein interactions and networks

STRING

2390 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FIS1	DNM1L	O00429	999
FIS1	DNM1	Q05193	997
FIS1	DENR	O43583	995
FIS1	BCAP31	P51572	995
FIS1	TBC1D15	Q8TC07	994
FIS1	MFF	Q9GZY8	989
FIS1	MFN2	O95140	986
FIS1	TBC1D17	Q9HA65	962
FIS1	PEX11A	O75192	961
FIS1	VDAC1	P21796	959
FIS1	MARCHF5	Q9NX47	953
FIS1	MFN1	Q8IWA4	929
FIS1	MIEF2	Q96C03	924
FIS1	MIEF1	Q9NQG6	922
FIS1	PINK1	Q9BXM7	918

IntAct

156 interactions, top by confidence:

A	B	Type	Score
TUBA1C	TXNDC9	psi-mi:“MI:0914”(association)	0.730
MIEF1	DNM1L	psi-mi:“MI:0914”(association)	0.690
	FIS1	psi-mi:“MI:0407”(direct interaction)	0.650
FIS1		psi-mi:“MI:0407”(direct interaction)	0.650
FIS1	BCAP31	psi-mi:“MI:0915”(physical association)	0.600
BCAP31	FIS1	psi-mi:“MI:0915”(physical association)	0.600
BCAP31	FIS1	psi-mi:“MI:0403”(colocalization)	0.600
FIS1	BCAP31	psi-mi:“MI:0914”(association)	0.600
CASP8	BCAP31	psi-mi:“MI:0915”(physical association)	0.590
FIS1	KASH5	psi-mi:“MI:0915”(physical association)	0.560
KASH5	FIS1	psi-mi:“MI:0915”(physical association)	0.560
FIS1	FFAR2	psi-mi:“MI:0915”(physical association)	0.560
FIS1	SLC14A1	psi-mi:“MI:0915”(physical association)	0.560
FAM210B	FIS1	psi-mi:“MI:0915”(physical association)	0.560
TMEM14B	FIS1	psi-mi:“MI:0915”(physical association)	0.560
FFAR2	FIS1	psi-mi:“MI:0915”(physical association)	0.560
TMPPE	FIS1	psi-mi:“MI:0915”(physical association)	0.560
SLC14A1	FIS1	psi-mi:“MI:0915”(physical association)	0.560
ERGIC3	FIS1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (245): CCDC155 (Two-hybrid), FIS1 (Two-hybrid), FIS1 (Affinity Capture-MS), FIS1 (Affinity Capture-MS), FIS1 (Affinity Capture-MS), FIS1 (Affinity Capture-RNA), FIS1 (Affinity Capture-MS), FIS1 (Co-crystal Structure), DNM1L (Affinity Capture-Western), FIS1 (Affinity Capture-Western), FIS1 (Reconstituted Complex), FIS1 (Co-fractionation), FIS1 (Affinity Capture-Western), FIS1 (Two-hybrid), FIS1 (Two-hybrid)

ESM2 similar proteins: A0AVF1, A1Z6M6, A1Z8E9, B5X0I6, B7YZT2, H9IWW7, O13754, O14225, O42668, O62246, O74432, P0CN70, P0CN71, P33313, P40515, P84817, Q03560, Q20255, Q20291, Q3T0I5, Q4P7J4, Q4R7Z9, Q5AFF7, Q5FWP8, Q5U2N8, Q61LA1, Q6AHP8, Q6BLG8, Q6CFJ0, Q6CTB6, Q6CU37, Q6FIQ1, Q6GKV1, Q6INC1, Q751P7, Q75AI5, Q7RXQ1, Q8BS45, Q8NDW8, Q8SYD0

Diamond homologs: B7YZT2, P0CN70, P0CN71, P40515, P84817, Q20291, Q2H047, Q2UF96, Q3T0I5, Q4IBU4, Q4P7J4, Q4X0I8, Q5AFF7, Q5AZQ5, Q6AHP8, Q6BLG8, Q6CFJ0, Q6FIQ1, Q6WRS2, Q75AI5, Q7S8M1, Q9CQ92, Q9Y3D6, Q6CU37, Q94CK3, Q9M1J1, Q9USZ8

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
MARCHF5	“down-regulates quantity by destabilization”	FIS1	polyubiquitination
FIS1	up-regulates	Mitochondrial_fission
MARCHF5	“down-regulates quantity by destabilization”	FIS1	ubiquitination

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	27
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

884 predictions. Top by Δscore:

Variant	Effect	Δscore
7:101239899:TCCAT:T	acceptor_gain	1.0000
7:101239900:CCAT:C	acceptor_gain	1.0000
7:101239900:CCATC:C	acceptor_gain	1.0000
7:101239901:CAT:C	acceptor_gain	1.0000
7:101239901:CATC:C	acceptor_gain	1.0000
7:101239902:AT:A	acceptor_gain	1.0000
7:101239903:TC:T	acceptor_loss	1.0000
7:101239904:C:CC	acceptor_gain	1.0000
7:101240245:TTCC:T	acceptor_loss	1.0000
7:101240247:CCTGC:C	acceptor_loss	1.0000
7:101240248:CTGCG:C	acceptor_loss	1.0000
7:101240249:T:A	acceptor_loss	1.0000
7:101240825:CTCAC:C	donor_loss	1.0000
7:101240827:CACCT:C	donor_loss	1.0000
7:101240828:A:AC	donor_gain	1.0000
7:101240828:A:C	donor_loss	1.0000
7:101240829:C:CC	donor_gain	1.0000
7:101240902:CAGCT:C	acceptor_gain	1.0000
7:101240903:AGCT:A	acceptor_gain	1.0000
7:101240905:CT:C	acceptor_gain	1.0000
7:101240907:C:CA	acceptor_loss	1.0000
7:101240907:C:CC	acceptor_gain	1.0000
7:101240908:T:A	acceptor_loss	1.0000
7:101240918:C:CT	acceptor_gain	1.0000
7:101244005:AC:A	donor_gain	1.0000
7:101244006:CC:C	donor_gain	1.0000
7:101244137:CTT:C	acceptor_gain	1.0000
7:101244144:C:CT	acceptor_gain	1.0000
7:101244146:C:CT	acceptor_gain	1.0000
7:101244147:A:T	acceptor_gain	1.0000

AlphaMissense

973 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:101239846:G:T	A140D	1.000
7:101239855:G:T	A137E	1.000
7:101239861:C:T	G135D	1.000
7:101239862:C:G	G135R	1.000
7:101239867:G:T	A133D	1.000
7:101239874:C:G	G131R	1.000
7:101239876:C:T	G130E	1.000
7:101239877:C:G	G130R	1.000
7:101239877:C:T	G130R	1.000
7:101239882:A:T	I128N	1.000
7:101239885:G:T	A127D	1.000
7:101244025:C:G	G54R	1.000
7:101244060:A:G	L42P	1.000
7:101239828:G:T	A146D	0.999
7:101239834:C:T	G144E	0.999
7:101239837:A:T	I143N	0.999
7:101239843:C:T	G141E	0.999
7:101239844:C:G	G141R	0.999
7:101239844:C:T	G141R	0.999
7:101239852:C:T	G138E	0.999
7:101239853:C:G	G138R	0.999
7:101239853:C:T	G138R	0.999
7:101239864:A:C	L134R	0.999
7:101239864:A:T	L134Q	0.999
7:101239873:C:T	G131D	0.999
7:101239879:A:T	V129E	0.999
7:101239886:C:G	A127P	0.999
7:101239891:C:T	G125D	0.999
7:101239892:C:G	G125R	0.999
7:101240174:A:G	L110P	0.999

dbSNP variants (sampled 300 via entrez): RS1000034776 (7:101243397 G>A), RS1000310810 (7:101246796 C>G,T), RS1000444470 (7:101241523 A>G), RS1001297008 (7:101245295 T>A), RS1001709686 (7:101244885 G>C), RS1001890828 (7:101239546 G>A), RS1002109137 (7:101246008 C>T), RS1002270058 (7:101244747 G>GCTCA), RS1002302716 (7:101244547 T>C,G), RS1002323532 (7:101239755 G>A,C,T), RS1002466145 (7:101245610 G>A,T), RS1003276710 (7:101243349 G>C), RS1003865869 (7:101242424 C>T), RS1003895442 (7:101242637 C>A,T), RS1003925079 (7:101242966 T>C)

Disease associations

OMIM: gene MIM:609003 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST007843_12	Rheumatoid arthritis	8.000000e-09

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066466 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.15	Kd	7152	nM	CHEMBL5653589
5.15	ED50	7152	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 2 total; 1 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	2148387: Binding affinity to human FIS1 incubated for 45 mins by Kinobead based pull down assay	kd	7.1522	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Hydrogen Peroxide	increases expression, affects cotreatment, affects reaction, decreases expression, decreases reaction	3
Valproic Acid	decreases expression, increases methylation, affects cotreatment, increases expression, affects expression	3
bisphenol A	decreases expression, increases expression	2
sodium arsenite	increases expression	2
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression, increases expression	2
3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone	increases expression, decreases expression, decreases reaction	2
alpha-Chlorohydrin	decreases reaction, increases expression	2
Palmitic Acid	affects cotreatment, decreases reaction, increases expression	2
Particulate Matter	decreases expression, increases abundance, increases expression	2
aristolochic acid I	decreases expression	1
2,4,6-tribromophenol	decreases expression	1
triphenyl phosphate	affects expression	1
O,O-diethyl O-3,5,6-trichloro-2-pyridyl phosphate	affects expression, affects response to substance	1
arsenite	affects binding, increases reaction	1
sulforaphane	increases expression	1
cobaltous chloride	decreases expression	1
salvin	decreases reaction, increases expression	1
tetrabromobisphenol A	decreases expression	1
epigallocatechin gallate	affects cotreatment, affects reaction, decreases expression, decreases reaction	1
gallocatechol	affects cotreatment, affects reaction, decreases expression, decreases reaction	1
epicatechin gallate	affects reaction, decreases expression, decreases reaction, affects cotreatment	1
sarpogrelate	decreases reaction, increases expression, increases reaction	1
benzyloxycarbonylleucyl-leucyl-leucine aldehyde	affects cotreatment, decreases expression, decreases reaction	1
4-phenylbutyric acid	decreases reaction, increases expression	1
efavirenz	increases expression	1
3-N-1(spermine)-7, 24-dihydroxy-5-cholestane 24-sulfate	affects cotreatment, decreases reaction, increases expression	1
bavachin	increases expression	1
bisphenol B	increases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651429	Binding	Binding affinity to human FIS1 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

2 cell lines: 2 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_C6TX	GIBHe015-B	Embryonic stem cell	Male
CVCL_C9LB	WAe001-A-1N	Embryonic stem cell	Male

Clinical trials (associated diseases)

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