FIG4

Summary

FIG4 (FIG4 phosphoinositide 5-phosphatase, HGNC:16873) is a protein-coding gene on chromosome 6q21, encoding Polyphosphoinositide phosphatase (Q92562). Dual specificity phosphatase component of the PI(3,5)P2 regulatory complex which regulates both the synthesis and turnover of phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2).

The protein encoded by this gene belongs to the SAC domain-containing protein gene family. The SAC domain, approximately 400 amino acids in length and consisting of seven conserved motifs, has been shown to possess phosphoinositide phosphatase activity. The yeast homolog, Sac1p, is involved in the regulation of various phosphoinositides, and affects diverse cellular functions such as actin cytoskeleton organization, Golgi function, and maintenance of vacuole morphology. Membrane-bound phosphoinositides function as signaling molecules and play a key role in vesicle trafficking in eukaryotic cells. Mutations in this gene have been associated with Charcot-Marie-Tooth disease, type 4J.

Source: NCBI Gene 9896 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Charcot-Marie-Tooth disease (Definitive, ClinGen) — +5 more curated relationships
• GWAS associations: 7
• Clinical variants (ClinVar): 1,168 total — 74 pathogenic, 43 likely-pathogenic
• Phenotypes (HPO): 255
• MANE Select transcript: NM_014845

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16873
Approved symbol	FIG4
Name	FIG4 phosphoinositide 5-phosphatase
Location	6q21
Locus type	gene with protein product
Status	Approved
Aliases	SAC3, hSac3, dJ249I4.1, ALS11, CMT4J
Ensembl gene	ENSG00000112367
Ensembl biotype	protein_coding
OMIM	609390
Entrez	9896

Gene structure

Transcript identifiers

Ensembl transcripts: 64 — 23 protein_coding, 23 nonsense_mediated_decay, 11 retained_intron, 7 protein_coding_CDS_not_defined

ENST00000230124, ENST00000368941, ENST00000415980, ENST00000419951, ENST00000454215, ENST00000458693, ENST00000674532, ENST00000674557, ENST00000674569, ENST00000674571, ENST00000674573, ENST00000674575, ENST00000674614, ENST00000674641, ENST00000674644, ENST00000674649, ENST00000674657, ENST00000674744, ENST00000674778, ENST00000674783, ENST00000674830, ENST00000674884, ENST00000674930, ENST00000674933, ENST00000674956, ENST00000675002, ENST00000675004, ENST00000675009, ENST00000675096, ENST00000675115, ENST00000675122, ENST00000675153, ENST00000675254, ENST00000675272, ENST00000675284, ENST00000675301, ENST00000675311, ENST00000675426, ENST00000675516, ENST00000675523, ENST00000675552, ENST00000675606, ENST00000675681, ENST00000675714, ENST00000675726, ENST00000675772, ENST00000675831, ENST00000675834, ENST00000675844, ENST00000675847, ENST00000675849, ENST00000675879, ENST00000675887, ENST00000675954, ENST00000675973, ENST00000675991, ENST00000675994, ENST00000676021, ENST00000676037, ENST00000676136, ENST00000676246, ENST00000676435, ENST00000676442, ENST00000922531

RefSeq mRNA: 1 — MANE Select: NM_014845 NM_014845

CCDS: CCDS5078

Canonical transcript exons

ENST00000230124 — 23 exons

Exon	Start	End
ENSE00000919028	109766729	109766895
ENSE00000975482	109776922	109777060
ENSE00000975483	109784970	109785028
ENSE00000975484	109786302	109786449
ENSE00000975485	109789594	109789677
ENSE00000975487	109792582	109792664
ENSE00000975488	109796765	109796851
ENSE00001837291	109825088	109825426
ENSE00001943194	109691296	109691501
ENSE00002238882	109741444	109741544
ENSE00002249687	109765013	109765161
ENSE00002254480	109732637	109732687
ENSE00002262351	109727109	109727265
ENSE00002267048	109763937	109763982
ENSE00002268215	109762091	109762207
ENSE00002293983	109716445	109716568
ENSE00002300571	109735150	109735298
ENSE00002310689	109743110	109743272
ENSE00002311712	109743675	109743772
ENSE00002324219	109760250	109760383
ENSE00003601740	109715078	109715176
ENSE00003785944	109738325	109738453
ENSE00003787581	109791376	109791571

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 96.11.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 16.1303 / max 217.9673, expressed in 1786 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
69242	16.1303	1786

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
middle temporal gyrus	UBERON:0002771	96.11	gold quality
endothelial cell	CL:0000115	94.80	gold quality
lateral nuclear group of thalamus	UBERON:0002736	94.26	gold quality
monocyte	CL:0000576	93.26	gold quality
Brodmann (1909) area 23	UBERON:0013554	93.25	gold quality
mononuclear cell	CL:0000842	93.23	gold quality
leukocyte	CL:0000738	92.89	gold quality
substantia nigra pars compacta	UBERON:0001965	92.63	gold quality
substantia nigra pars reticulata	UBERON:0001966	91.95	gold quality
parotid gland	UBERON:0001831	91.41	gold quality
calcaneal tendon	UBERON:0003701	90.92	gold quality
cervix squamous epithelium	UBERON:0006922	90.68	gold quality
nucleus accumbens	UBERON:0001882	90.45	gold quality
lateral globus pallidus	UBERON:0002476	90.31	gold quality
prefrontal cortex	UBERON:0000451	90.23	gold quality
putamen	UBERON:0001874	89.97	gold quality
caudate nucleus	UBERON:0001873	89.85	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	89.80	gold quality
Brodmann (1909) area 9	UBERON:0013540	89.78	gold quality
Brodmann (1909) area 10	UBERON:0013541	89.65	gold quality
bone marrow cell	CL:0002092	89.54	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	89.39	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	89.32	gold quality
frontal cortex	UBERON:0001870	89.26	gold quality
primary visual cortex	UBERON:0002436	89.23	gold quality
neocortex	UBERON:0001950	89.10	gold quality
cortical plate	UBERON:0005343	88.97	gold quality
granulocyte	CL:0000094	88.94	gold quality
entorhinal cortex	UBERON:0002728	88.87	gold quality
Brodmann (1909) area 46	UBERON:0006483	88.83	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.06

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

2 targeting FIG4, 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-542-3P	99.34	67.58	1270
HSA-MIR-8083	95.93	67.55	694

Literature-anchored findings (GeneRIF, showing 25)

• We identified pathogenic mutations of human FIG4 (KIAA0274) on chromosome 6q21 in four unrelated patients with hereditary motor and sensory neuropathy. (PMID:17572665)
• The authors data indicate that the PAS complex is organized to provide optimal PIKfyve functionality and is maintained via ArPIKfyve homomeric and heteromeric interactions. (PMID:18950639)
• Heterozygosity for a deleterious allele of FIG4 appears to be a risk factor for ALS and PLS, extending the list of known ALS genes and increasing the clinical spectrum of FIG4-related diseases (PMID:19118816)
• PIKfyve-ArPIKfyve-Sac3 core complex: contact sites and their consequence for Sac3 phosphatase activity and endocytic membrane homeostasis (PMID:19840946)
• a novel regulatory mechanism whereby ArPIKfyve enhances Sac3 abundance by attenuating Sac3 proteasome-dependent degradation and suggest that a failure of this mechanism could be the primary molecular defect in the pathogenesis of CMT4J. (PMID:20630877)
• This study demonistrated that CMT4J is a clinically distinct form of Charcot-Marie-Tooth disease with mutations in the PI(3,5)P phosphatase FIG4. (PMID:21705420)
• Genetic variations in the FIG4 gene were not found to cause ALS in Italian patients. (PMID:23336365)
• Yunis-Varon syndrome is caused by mutations in FIG4, encoding a phosphoinositide phosphatase. (PMID:23623387)
• The findings suggest that FIG4 may have a common role in the formation or degradation of neuronal cytoplasmic and nuclear inclusions in several neurodegenerative diseases. (PMID:23888880)
• results uncover an unexpected role for Sac3 phosphatase in triple-negative breast cancer cell proliferation (PMID:24070605)
• FIG4 mutations were identified in autosomal-dominant Amyotrophic lateral sclerosis. (PMID:24085347)
• Identified novel biallelic FIG4 mutations. (PMID:24088667)
• Phenotypes associated with FIG4 mutations include cortical malformation associated with seizures and psychiatric manifestations, in addition to the Charcot-Marie-Tooth disease type 4J and Yunis-Varon syndrome. (PMID:24598713)
• data identify a novel role of the ArPIKfyve-Sac3 complex in the mechanisms controlling aggregate formation of Sph1 and suggest that Sac3 protein deficiency or overproduction may facilitate aggregation of aggregation-prone proteins (PMID:26405034)
• These results suggest that FIG4 binds to hepatitis C virus and modulates particle formation in a cholesteryl ester-related manner. (PMID:26519381)
• A rare heterozygous FIG4 frameshift variant was identified in a German family. Sequence analysis of FIG4 in 200 ALS cases revealed five rare heterozygous FIG4 missense variants predicted to be deleterious. FIG4 is an ALS risk gene in a central European cohort. (PMID:28051077)
• These findings strongly indicate a critical dependence of FIG4 for the normal functions of peripheral nerve myelin. (PMID:29518270)
• in the adult PNS Fig4 is required to protect myelinated axons from Wallerian degeneration. In the adult CNS, Fig4 is dispensable for fiber stability and nerve conduction, but is required for the timely repair of damaged white matter. The greater vulnerability of the PNS to Fig4 deficiency in the mouse is consistent with clinical observations in patients with Charcot-Marie-Tooth disease. (PMID:29688489)
• we identified four families with novel FIG4 genotypes and CNS white matter disease varying from severe hypomyelination to mild undermyelination, in addition to peripheral neuropathy. Impaired FIG4 function was revealed by the presence of large vacuoles in cultured patient fibroblasts (PMID:30740813)
• Severe Consequences SAC3/FIG4 Phosphatase Deficiency to Phosphoinositides in Patients with Charcot-Marie-Tooth Disease Type-4J. (PMID:31313076)
• Clinical and radiological characterization of novel FIG4-related combined system disease with neuropathy. (PMID:32385905)
• Clinical features of homozygous FIG4-p.Ile41Thr Charcot-Marie-Tooth 4J patients. (PMID:33405357)
• Proximity Interactome Map of the Vac14-Fig4 Complex Using BioID. (PMID:34554760)
• PROK2, HRNR, and FIG4 as potential genetic biomarkers of high bleeding propensity in East Asian patients with acute coronary syndrome using ticagrelor. (PMID:36263704)
• Clinical and genetic features of patients suffering from CMT4J. (PMID:37950760)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	FIG4	ENSDARG00000107912
		ENSDARG00000115982
mus_musculus	Fig4	ENSMUSG00000038417
rattus_norvegicus	Fig4	ENSRNOG00000000312
drosophila_melanogaster	FIG4	FBGN0031611
caenorhabditis_elegans	figo-1	WBGENE00007912

Paralogs (13): SYNJ2 (ENSG00000078269), OCRL (ENSG00000122126), INPP5K (ENSG00000132376), INPP5E (ENSG00000148384), SYNJ1 (ENSG00000159082), INPPL1 (ENSG00000165458), INPP5D (ENSG00000168918), SH2D1A (ENSG00000183918), INPP5J (ENSG00000185133), SH2D1B (ENSG00000198574), INPP5F (ENSG00000198825), INPP5B (ENSG00000204084), SACM1L (ENSG00000211456)

Protein

Protein identifiers

Polyphosphoinositide phosphatase — Q92562 (reviewed: Q92562)

Alternative names: Phosphatidylinositol 3,5-bisphosphate 5-phosphatase, SAC domain-containing protein 3, Serine-protein phosphatase FIG4

All UniProt accessions (33): Q92562, A0A6Q8PF04, A0A6Q8PF27, A0A6Q8PF62, A0A6Q8PF70, A0A6Q8PF86, A0A6Q8PF90, A0A6Q8PFJ3, A0A6Q8PFK7, A0A6Q8PG49, A0A6Q8PG59, A0A6Q8PG61, A0A6Q8PGB4, A0A6Q8PGC1, A0A6Q8PGL0, A0A6Q8PGM1, A0A6Q8PGP1, A0A6Q8PGP4, A0A6Q8PGW0, A0A6Q8PGW5, A0A6Q8PGY4, A0A6Q8PGY7, A0A6Q8PH92, A0A6Q8PHA1, A0A6Q8PHB4, A0A6Q8PHC7, A0A6Q8PHH5, A0A6Q8PHK3, A0A6Q8PHM5, A0A6Q8PHP5, H0Y6G7, Q5TCS4, Q5TCS5

UniProt curated annotations — full annotation on UniProt →

Function. Dual specificity phosphatase component of the PI(3,5)P2 regulatory complex which regulates both the synthesis and turnover of phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2). Catalyzes the dephosphorylation of phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2) to form phosphatidylinositol 3-phosphate. Has serine-protein phosphatase activity acting on PIKfyve to stimulate its lipid kinase activity, its catalytically activity being required for maximal PI(3,5)P2 production. In vitro, hydrolyzes all three D5-phosphorylated polyphosphoinositide and although displaying preferences for PtdIns(3,5)P2, it is capable of hydrolyzing PtdIns(3,4,5)P3 and PtdIns(4,5)P2, at least in vitro.

Subunit / interactions. Component of the PI(3,5)P2 regulatory complex/PAS complex, at least composed of PIKFYVE, FIG4 and VAC14. VAC14 nucleates the assembly of the complex and serves as a scaffold by pentamerizing into a star-shaped structure, which can bind a single copy each of PIKFYVE and FIG4 and coordinates their activities.

Subcellular location. Endosome membrane.

Disease relevance. Charcot-Marie-Tooth disease, demyelinating, type 4J (CMT4J) [MIM:611228] A recessive demyelinating form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Demyelinating neuropathies are characterized by severely reduced nerve conduction velocities (less than 38 m/sec), segmental demyelination and remyelination with onion bulb formations on nerve biopsy, slowly progressive distal muscle atrophy and weakness, absent deep tendon reflexes, and hollow feet. By convention autosomal recessive forms of demyelinating Charcot-Marie-Tooth disease are designated CMT4. The disease is caused by variants affecting the gene represented in this entry. Amyotrophic lateral sclerosis 11 (ALS11) [MIM:612577] A neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, resulting in fatal paralysis. Sensory abnormalities are absent. The pathologic hallmarks of the disease include pallor of the corticospinal tract due to loss of motor neurons, presence of ubiquitin-positive inclusions within surviving motor neurons, and deposition of pathologic aggregates. The etiology of amyotrophic lateral sclerosis is likely to be multifactorial, involving both genetic and environmental factors. The disease is inherited in 5-10% of the cases. The disease is caused by variants affecting the gene represented in this entry. Yunis-Varon syndrome (YVS) [MIM:216340] A severe autosomal recessive disorder characterized by skeletal defects, including cleidocranial dysplasia and digital anomalies, and severe neurologic involvement with neuronal loss. Enlarged cytoplasmic vacuoles are found in neurons, muscle, and cartilage. The disorder is usually lethal in infancy. The disease is caused by variants affecting the gene represented in this entry. Polymicrogyria, bilateral temporooccipital (BTOP) [MIM:612691] A disease characterized by temporo-occipital polymicrogyria, psychiatric manifestations, and epilepsy. The disease is caused by variants affecting the gene represented in this entry.

RefSeq proteins (1): NP_055660* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002013	SAC_dom	Domain
IPR043573	Fig4-like	Family

Pfam: PF02383

Catalyzed reactions (Rhea), 4 shown:

• O-phospho-L-seryl-[protein] + H2O = L-seryl-[protein] + phosphate (RHEA:20629)
• a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-4,5-bisphosphate) + H2O = a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol 4-phosphate) + phosphate (RHEA:22764)
• a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-3,4,5-trisphosphate) + H2O = a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-3,4-bisphosphate) + phosphate (RHEA:25528)
• a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-3,5-bisphosphate) + H2O = a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-3-phosphate) + phosphate (RHEA:32955)

UniProt features (23 total): sequence variant 14, sequence conflict 3, mutagenesis site 2, chain 1, domain 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
7K1W	ELECTRON MICROSCOPY	5.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q92562-F1	80.65	0.50

Functional residue map

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

Mutagenesis-validated functional residues (2):

Position	Phenotype
486	loss of phosphatase activity on pikfyve.
488	loss of activity.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-1660514	Synthesis of PIPs at the Golgi membrane
R-HSA-1660516	Synthesis of PIPs at the early endosome membrane
R-HSA-1660517	Synthesis of PIPs at the late endosome membrane

MSigDB gene sets: 738 (showing top): GOBP_LIPID_MODIFICATION, GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, GOBP_PHOSPHATIDYLINOSITOL_METABOLIC_PROCESS, GOBP_BEHAVIOR, MORF_MSH3, GOBP_VACUOLE_ORGANIZATION, GOCC_VACUOLAR_MEMBRANE, GCANCTGNY_MYOD_Q6, GOBP_PHOSPHOLIPID_DEPHOSPHORYLATION, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, MORF_BRCA1, MORF_ATRX, GOBP_NEGATIVE_REGULATION_OF_NERVOUS_SYSTEM_PROCESS, GOBP_NEUROGENESIS, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS

GO Biological Process (12): phosphatidylinositol biosynthetic process (GO:0006661), vacuole organization (GO:0007033), locomotory behavior (GO:0007626), positive regulation of neuron projection development (GO:0010976), negative regulation of myelination (GO:0031642), myelin assembly (GO:0032288), pigmentation (GO:0043473), phosphatidylinositol dephosphorylation (GO:0046856), neuron development (GO:0048666), phosphatidylinositol-3-phosphate biosynthetic process (GO:0036092), myelination (GO:0042552), phosphatidylinositol metabolic process (GO:0046488)

GO Molecular Function (10): phosphatidylinositol-3-phosphate phosphatase activity (GO:0004438), phosphatidylinositol-4,5-bisphosphate 5-phosphatase activity (GO:0004439), protein serine/threonine phosphatase activity (GO:0004722), phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase activity (GO:0034485), phosphatidylinositol-4-phosphate phosphatase activity (GO:0043812), phosphatidylinositol-3,5-bisphosphate 5-phosphatase activity (GO:0043813), protein binding (GO:0005515), hydrolase activity (GO:0016787), phosphatase activity (GO:0016791), phosphatidylinositol bisphosphate phosphatase activity (GO:0034593)

GO Cellular Component (9): Golgi membrane (GO:0000139), lipid droplet (GO:0005811), endosome membrane (GO:0010008), early endosome membrane (GO:0031901), late endosome membrane (GO:0031902), recycling endosome (GO:0055037), endosome (GO:0005768), endomembrane system (GO:0012505), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
PI Metabolism	3

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
phosphatidylinositol phosphate 5-phosphatase activity	3
phosphatidylinositol metabolic process	2
myelination	2
phosphatidylinositol monophosphate phosphatase activity	2
bounding membrane of organelle	2
endosome	2
endosome membrane	2
cellular anatomical structure	2
biosynthetic process	1
organelle organization	1
behavior	1
regulation of neuron projection development	1
neuron projection development	1
positive regulation of cell projection organization	1
regulation of myelination	1
negative regulation of nervous system process	1
negative regulation of cellular process	1
cellular component assembly involved in morphogenesis	1
biological_process	1
phospholipid dephosphorylation	1
neuron differentiation	1
cell development	1
phosphatidylinositol phosphate biosynthetic process	1
axon ensheathment	1
phosphorus metabolic process	1
phosphatidylinositol-4,5-bisphosphate phosphatase activity	1
phosphoprotein phosphatase activity	1
phosphatidylinositol trisphosphate phosphatase activity	1
phosphatidylinositol phosphate 4-phosphatase activity	1
phosphatidylinositol-3-phosphate biosynthetic process	1
phosphatidylinositol-3,5-bisphosphate phosphatase activity	1
binding	1
catalytic activity	1
phosphoric ester hydrolase activity	1
phosphatidylinositol phosphate phosphatase activity	1
Golgi apparatus	1
intracellular membraneless organelle	1
cytoplasmic vesicle membrane	1
early endosome	1
late endosome	1

Protein interactions and networks

STRING

1190 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FIG4	VAC14	Q08AM6	999
FIG4	PIKFYVE	Q9Y2I7	999
FIG4	ALS2	Q96Q42	854
FIG4	VAPB	O95292	843
FIG4	NAAA	Q02083	839
FIG4	TARDBP	Q13148	835
FIG4	WIPI1	Q5MNZ9	833
FIG4	LAMP2	P13473	820
FIG4	SETX	Q7Z333	815
FIG4	DCTN1	Q14203	772
FIG4	MTMR2	Q13614	771
FIG4	CHMP2B	Q9UQN3	765
FIG4	SQSTM1	Q13501	755
FIG4	SH3TC2	Q8TF17	740
FIG4	SOD1	P00441	739

IntAct

26 interactions, top by confidence:

A	B	Type	Score
VAC14	FIG4	psi-mi:“MI:0915”(physical association)	0.800
FIG4	VAC14	psi-mi:“MI:0914”(association)	0.800
FIG4	GORASP2	psi-mi:“MI:0915”(physical association)	0.560
PIKFYVE	FIG4	psi-mi:“MI:0915”(physical association)	0.560
PSME1	POLR3A	psi-mi:“MI:0914”(association)	0.530
ANK1	PIKFYVE	psi-mi:“MI:0914”(association)	0.350
VAC14	PIKFYVE	psi-mi:“MI:0914”(association)	0.350
FIG4	PIKFYVE	psi-mi:“MI:0914”(association)	0.350
	HLA-C	psi-mi:“MI:0914”(association)	0.350
CAPZB	ENAH	psi-mi:“MI:0914”(association)	0.350
PTGES3	SBNO1	psi-mi:“MI:0914”(association)	0.350
NPTN	RTL8C	psi-mi:“MI:0914”(association)	0.350
VAC14	NUDT19	psi-mi:“MI:0914”(association)	0.350
FIG4	YEATS4	psi-mi:“MI:0914”(association)	0.350
ANK1	VAC14	psi-mi:“MI:0914”(association)	0.350
VAC14	MGST3	psi-mi:“MI:0914”(association)	0.350
SLC7A9	CDC7	psi-mi:“MI:0914”(association)	0.350
SLC9A7	NBAS	psi-mi:“MI:0914”(association)	0.350
	MYO1C	psi-mi:“MI:0914”(association)	0.350
INSR	RIMOC1	psi-mi:“MI:0914”(association)	0.350
FIG4	VAC14	psi-mi:“MI:0915”(physical association)	0.000
FIG4	GORASP2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (41): VAC14 (Affinity Capture-MS), MYO18A (Affinity Capture-MS), PIKFYVE (Affinity Capture-MS), CMAS (Affinity Capture-MS), TWISTNB (Affinity Capture-MS), FIG4 (Affinity Capture-MS), PIKFYVE (Affinity Capture-MS), FIG4 (Affinity Capture-MS), SNX27 (Affinity Capture-MS), FIG4 (Affinity Capture-MS), FIG4 (Affinity Capture-MS), FIG4 (Reconstituted Complex), FIG4 (Two-hybrid), GORASP2 (Two-hybrid), FIG4 (Affinity Capture-MS)

ESM2 similar proteins: A0A1D5AG16, A0JND4, A3KN83, A4H7G5, A4HVU6, A8NS89, B0B8S7, B0BAF6, B4GH42, B6EU02, B7F7B9, D3ZKV9, D8WUA4, F4IAE9, F4IF36, G2WR64, O22243, O84707, Q00681, Q2QMH2, Q36795, Q3KKZ3, Q41062, Q4DCH3, Q4QFY1, Q57X81, Q580W5, Q5B7V0, Q5BJL5, Q5F371, Q64749, Q689Z5, Q6FLD4, Q6GZW6, Q6P158, Q7TNB8, Q7XZU0, Q8TGA2, Q91WF7, Q92562

Diamond homologs: A1L244, A6QL88, O60162, P42837, Q5R921, Q6GM29, Q7XZU1, Q7XZU2, Q7XZU3, Q7Z9H9, Q8RW97, Q91WF7, Q92562, Q94A27, Q9EP69, Q9ES21, Q9NTJ5, Q9W0I6, A4VCH0, A8E7C5, G5ECL2, O15056, O18964, O43001, O43426, O55207, P32368, P50942, Q55AW9, Q62910, Q7X911, Q8CDA1, Q8CHC4, Q96328, Q9C5G5, Q9D2G5, Q9Y2H2, Q9USQ6

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
FIG4	“form complex”	“PAS complex”	binding
FIG4	“up-regulates activity”	MCOLN1
VAC14	“up-regulates quantity by stabilization”	FIG4	binding
FIG4	“down-regulates quantity”	1,2-dioctanoyl-sn-glycero-3-phospho-(1D-myo-inositol-3,5-bisphosphate)(5-)	“chemical modification”

Disease & clinical

Clinical variants and AI predictions

ClinVar

1168 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	74
Likely pathogenic	43
Uncertain significance	467
Likely benign	420
Benign	69

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1070629	NM_014845.6(FIG4):c.531T>G (p.Tyr177Ter)	Pathogenic
1073202	NM_014845.6(FIG4):c.2161del (p.Thr721fs)	Pathogenic
1073230	NM_014845.6(FIG4):c.1445_1452del (p.Leu482fs)	Pathogenic
1075927	NM_014845.6(FIG4):c.783del (p.Ile262fs)	Pathogenic
1299662	NM_014845.6(FIG4):c.2174dup (p.Leu726fs)	Pathogenic
1355256	NM_014845.6(FIG4):c.1688G>A (p.Trp563Ter)	Pathogenic
1383668	NM_014845.6(FIG4):c.1538del (p.Gly513fs)	Pathogenic
1427728	NM_014845.6(FIG4):c.1327A>T (p.Lys443Ter)	Pathogenic
1431306	NM_014845.6(FIG4):c.1_18del (p.Met1_Ala6del)	Pathogenic
1446731	NM_014845.6(FIG4):c.1762C>T (p.Gln588Ter)	Pathogenic
1454104	NM_014845.6(FIG4):c.2302G>T (p.Glu768Ter)	Pathogenic
1457285	NM_014845.6(FIG4):c.1412_1413del (p.Val471fs)	Pathogenic
1458878	NC_000006.11:g.(?110048292)(110098283_?)del	Pathogenic
1459446	NM_014845.6(FIG4):c.1096C>T (p.Gln366Ter)	Pathogenic
1459809	NC_000006.11:g.(?110012639)(110064995_?)del	Pathogenic
1460151	NC_000006.11:g.(?110048292)(110053276_?)del	Pathogenic
1722	NM_014845.6(FIG4):c.294del (p.Phe98fs)	Pathogenic
1724	NM_014845.6(FIG4):c.1043_1050del (p.Asp348fs)	Pathogenic
1917074	NM_014845.6(FIG4):c.21del (p.Ile8fs)	Pathogenic
1940123	NM_014845.6(FIG4):c.1808_1811dup (p.Pro605fs)	Pathogenic
1952309	NM_014845.6(FIG4):c.156del (p.Ile52fs)	Pathogenic
1996895	NM_014845.6(FIG4):c.557del (p.Leu186fs)	Pathogenic
2020290	NM_014845.6(FIG4):c.184G>T (p.Glu62Ter)	Pathogenic
2091633	NM_014845.6(FIG4):c.2180+1del	Pathogenic
2133903	NM_014845.6(FIG4):c.463C>T (p.Gln155Ter)	Pathogenic
217228	NM_014845.6(FIG4):c.1141C>T (p.Arg381Ter)	Pathogenic
2202635	NM_014845.6(FIG4):c.2071dup (p.Cys691fs)	Pathogenic
2431047	NM_014845.6(FIG4):c.1049C>T (p.Ala350Val)	Pathogenic
245747	NM_014845.6(FIG4):c.1207C>T (p.Gln403Ter)	Pathogenic
246120	NM_014845.6(FIG4):c.2459+1G>A	Pathogenic

SpliceAI

4553 predictions. Top by Δscore:

Variant	Effect	Δscore
6:109691497:GAGCT:G	donor_gain	1.0000
6:109691499:GCT:G	donor_gain	1.0000
6:109691502:G:GG	donor_gain	1.0000
6:109715073:TATA:T	acceptor_loss	1.0000
6:109715075:T:G	acceptor_gain	1.0000
6:109715075:TA:T	acceptor_loss	1.0000
6:109715075:TAGA:T	acceptor_gain	1.0000
6:109715076:A:AG	acceptor_gain	1.0000
6:109715076:A:AT	acceptor_loss	1.0000
6:109715076:AGAGA:A	acceptor_gain	1.0000
6:109715077:G:GA	acceptor_gain	1.0000
6:109715077:GA:G	acceptor_gain	1.0000
6:109715077:GAGA:G	acceptor_gain	1.0000
6:109715077:GAGAT:G	acceptor_gain	1.0000
6:109715172:ACAGG:A	donor_gain	1.0000
6:109715173:CAGG:C	donor_gain	1.0000
6:109715174:AGG:A	donor_gain	1.0000
6:109715175:GG:G	donor_gain	1.0000
6:109715175:GGG:G	donor_gain	1.0000
6:109715175:GGGTA:G	donor_loss	1.0000
6:109715176:GG:G	donor_gain	1.0000
6:109715177:G:GG	donor_gain	1.0000
6:109715177:GT:G	donor_loss	1.0000
6:109715178:T:A	donor_loss	1.0000
6:109716443:A:AG	acceptor_gain	1.0000
6:109716444:G:GG	acceptor_gain	1.0000
6:109716444:GC:G	acceptor_gain	1.0000
6:109716444:GCA:G	acceptor_gain	1.0000
6:109716444:GCAT:G	acceptor_gain	1.0000
6:109716567:GG:G	donor_gain	1.0000

AlphaMissense

5983 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:109715093:G:T	G28W	1.000
6:109715094:G:A	G28E	1.000
6:109715121:G:C	R37P	1.000
6:109715139:G:C	R43T	1.000
6:109715140:A:C	R43S	1.000
6:109715140:A:T	R43S	1.000
6:109738366:T:A	W230R	1.000
6:109738366:T:C	W230R	1.000
6:109738414:T:A	W246R	1.000
6:109738414:T:C	W246R	1.000
6:109738435:G:A	G253R	1.000
6:109738435:G:C	G253R	1.000
6:109738435:G:T	G253W	1.000
6:109738436:G:A	G253E	1.000
6:109741489:G:C	R274T	1.000
6:109741489:G:T	R274I	1.000
6:109741490:A:C	R274S	1.000
6:109741490:A:T	R274S	1.000
6:109741493:A:C	R275S	1.000
6:109741493:A:T	R275S	1.000
6:109741509:G:C	G281R	1.000
6:109741510:G:A	G281D	1.000
6:109741510:G:T	G281V	1.000
6:109741515:C:A	R283S	1.000
6:109741515:C:G	R283G	1.000
6:109741518:T:A	F284I	1.000
6:109741518:T:C	F284L	1.000
6:109741518:T:G	F284V	1.000
6:109741519:T:C	F284S	1.000
6:109741519:T:G	F284C	1.000

dbSNP variants (sampled 300 via entrez): RS1000000196 (6:109817842 G>C), RS1000034573 (6:109706495 T>G), RS1000040181 (6:109798279 T>A,C), RS1000041043 (6:109756527 A>C), RS1000059274 (6:109811096 C>T), RS1000098762 (6:109752035 G>A), RS1000178044 (6:109766032 A>G), RS1000184263 (6:109791437 C>A,T), RS1000186737 (6:109746577 C>A), RS1000228508 (6:109701822 C>A,T), RS1000287981 (6:109772388 C>T), RS1000305163 (6:109731556 CTG>C), RS1000317494 (6:109739190 A>G,T), RS1000349345 (6:109753635 G>C), RS1000359450 (6:109804268 C>G,T)

Disease associations

OMIM: gene MIM:609390 | disease phenotypes: MIM:612691, MIM:611228, MIM:216340, MIM:612577, MIM:118220, MIM:612557, MIM:182960

GenCC curated gene-disease

Disease	Classification	Inheritance
Charcot-Marie-Tooth disease type 4J	Definitive	Autosomal recessive
Charcot-Marie-Tooth disease	Definitive	Autosomal recessive
amyotrophic lateral sclerosis type 11	Strong	Autosomal dominant
Yunis-Varon syndrome	Strong	Autosomal recessive
bilateral parasagittal parieto-occipital polymicrogyria	Moderate	Autosomal recessive
amyotrophic lateral sclerosis	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
Charcot-Marie-Tooth disease	Definitive	AR
amyotrophic lateral sclerosis type 11	Limited	AD

Mondo (10): Charcot-Marie-Tooth disease type 4 (MONDO:0018995), bilateral parasagittal parieto-occipital polymicrogyria (MONDO:0012986), Charcot-Marie-Tooth disease type 4J (MONDO:0012640), Yunis-Varon syndrome (MONDO:0008995), amyotrophic lateral sclerosis type 11 (MONDO:0012945), amyotrophic lateral sclerosis (MONDO:0004976), Charcot-Marie-Tooth disease (MONDO:0015626), leukemia, chronic lymphocytic, susceptibility to, 3 (MONDO:0012934), neuronopathy, distal hereditary motor, autosomal dominant (MONDO:0015362), Charcot-Marie-Tooth disease type 1 (MONDO:0019011)

Orphanet (9): Charcot-Marie-Tooth disease type 4 (Orphanet:64749), Bilateral parasagittal parieto-occipital polymicrogyria (Orphanet:208441), Charcot-Marie-Tooth disease type 4J (Orphanet:139515), Yunis-Varon syndrome (Orphanet:3472), Amyotrophic lateral sclerosis (Orphanet:803), Charcot-Marie-Tooth disease/Hereditary motor and sensory neuropathy (Orphanet:166), B-cell chronic lymphocytic leukemia (Orphanet:67038), Autosomal dominant distal hereditary motor neuropathy (Orphanet:140465), Charcot-Marie-Tooth disease type 1 (Orphanet:65753)

HPO phenotypes

255 total (30 of 255 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000047	Hypospadias
HP:0000054	Micropenis
HP:0000059	Hypoplastic labia majora
HP:0000162	Glossoptosis
HP:0000174	Abnormal palate morphology
HP:0000187	Broad alveolar ridges
HP:0000188	Short upper lip
HP:0000216	Broad secondary alveolar ridge
HP:0000217	Xerostomia
HP:0000218	High palate
HP:0000219	Thin upper lip vermilion
HP:0000233	Thin vermilion border
HP:0000238	Hydrocephalus
HP:0000239	Large fontanelles
HP:0000242	Parietal bossing
HP:0000252	Microcephaly
HP:0000256	Macrocephaly
HP:0000268	Dolichocephaly
HP:0000286	Epicanthus
HP:0000316	Hypertelorism
HP:0000322	Short philtrum
HP:0000331	Short chin
HP:0000347	Micrognathia
HP:0000348	High forehead
HP:0000365	Hearing impairment
HP:0000369	Low-set ears
HP:0000377	Abnormal pinna morphology

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST004570_9	Iron status biomarkers (iron levels)	1.000000e-06
GCST006427_18	Depression in smokers	3.000000e-06
GCST007576_334	Chronotype	3.000000e-10
GCST008163_440	Height	3.000000e-06
GCST010243_55	Apolipoprotein B levels	2.000000e-08
GCST90002404_268	Red cell distribution width	2.000000e-15
GCST90020028_614	Hip circumference adjusted for BMI	6.000000e-09

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0008328	chronotype measurement
EFO:0004615	apolipoprotein B measurement
EFO:0009188	Red cell distribution width
EFO:0008039	BMI-adjusted hip circumference

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D000690	Amyotrophic Lateral Sclerosis	C10.228.854.139; C10.574.562.250; C10.574.950.050; C10.668.467.250; C18.452.845.800.050
D002607	Charcot-Marie-Tooth Disease	C10.500.300.200; C10.574.500.495.200; C10.668.829.800.300.200; C16.131.666.300.200; C16.320.400.375.200
C567244	Amyotrophic Lateral Sclerosis 11 (supp.)
C566984	Charcot-Marie-Tooth Disease, Type 4j (supp.)
C567201	Polymicrogyria, Bilateral Occipital (supp.)
C536719	Yunis Varon syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases methylation, increases expression	3
trichostatin A	affects cotreatment, decreases expression	2
sodium arsenite	affects cotreatment, decreases expression, increases abundance, increases expression	2
Arsenic	affects methylation, affects cotreatment, decreases expression, increases abundance	2
Benzo(a)pyrene	decreases expression	2
Particulate Matter	increases abundance, decreases expression	2
aristolochic acid I	decreases expression	1
bisphenol A	affects cotreatment, decreases methylation	1
butyraldehyde	decreases expression	1
manganese chloride	decreases expression, increases abundance, affects cotreatment	1
di-n-butylphosphoric acid	affects expression	1
deguelin	decreases expression	1
4-chloro-N-((4-(1,1-dimethylethyl)phenyl)methyl)-3-ethyl-1-methyl-1H-pyrazole-5-carboxamide	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	increases expression, increases reaction	1
Resveratrol	increases expression, affects cotreatment	1
Sunitinib	increases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Air Pollutants	decreases expression, increases abundance	1
Air Pollutants, Occupational	decreases expression	1
Antimycin A	decreases expression	1
Vehicle Emissions	decreases expression, increases abundance	1
Carbamazepine	affects expression	1
Cisplatin	increases expression, increases reaction	1
Doxorubicin	decreases expression	1
Endosulfan	increases expression	1
Manganese	decreases expression, increases abundance, affects cotreatment	1
Nickel	decreases expression	1
Plant Extracts	affects cotreatment, increases expression	1

Cellosaurus cell lines

6 cell lines: 3 induced pluripotent stem cell, 2 cancer cell line, 1 finite cell line

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

Cellosaurus	Name	Category	Sex
CVCL_E4FU	CENSOi068-A	Induced pluripotent stem cell	Male
CVCL_JX02	NYSCF-AG0011-01-MR	Induced pluripotent stem cell	Male
CVCL_SN57	HAP1 FIG4 (-) 1	Cancer cell line	Male
CVCL_SN58	HAP1 FIG4 (-) 2	Cancer cell line	Male
CVCL_T863	ND35669	Induced pluripotent stem cell	Female
CVCL_T864	ND39025	Finite cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00542412	PHASE4	COMPLETED	CARE Canadian ALS Riluzole Evaluation
NCT00560287	PHASE4	UNKNOWN	Non-Invasive Ventilation in Amyotrophic Lateral Sclerosis
NCT00613899	PHASE4	COMPLETED	Feasibility of Telesurveillance and Home Cough Assistance for Amyotrophic Lateral Patients (ALS)
NCT04997954	PHASE4	UNKNOWN	EMERALD TRIAL Open Label Extension Study
NCT06849115	PHASE4	COMPLETED	Effects of L-Carnitine in Amyotrophic Lateral Sclerosis Patients With CHCHD10 Mutations
NCT07223723	PHASE4	RECRUITING	A Study to Learn More About the Long-Term Safety of Tofersen (Qalsody) in Chinese Participants With SOD-1 Amyotrophic Lateral Sclerosis (ALS)
NCT04762758	PHASE3	UNKNOWN	Phase III Trial Assessing the Efficacy and Safety of PXT3003 in CMT1A Patients
NCT00021697	PHASE3	COMPLETED	Safety/Efficacy of AVP-923 in the Treatment of Emotional Lability (Uncontrolled Crying & Laughing) in Patients With ALS
NCT00035815	PHASE3	COMPLETED	Insulin-like Growth Factor-1 in Amyotrophic Lateral Sclerosis (ALS) Trial
NCT00047723	PHASE3	COMPLETED	Minocycline to Treat Amyotrophic Lateral Sclerosis
NCT00069186	PHASE3	UNKNOWN	Study of Creatine Monohydrate in Patients With Amyotrophic Lateral Sclerosis
NCT00136110	PHASE3	COMPLETED	Trial of Sodium Valproate in Amyotrophic Lateral Sclerosis
NCT00330681	PHASE3	COMPLETED	Efficacy and Safety Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis (ALS)
NCT00349622	PHASE3	COMPLETED	Clinical Trial Ceftriaxone in Subjects With ALS
NCT00372879	PHASE3	COMPLETED	Clinical Trial of Vitamin E to Treat Muscular Cramps in Patients With ALS
NCT00415519	PHASE3	COMPLETED	Efficacy and Safety Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis (ALS) Who Met Severity Classification III
NCT00424463	PHASE3	COMPLETED	Expanded Controlled Study of Safety and Efficacy of MCI-186 in Patients With Amyotrophic Lateral Sclerosis (ALS)
NCT00839033	PHASE3	TERMINATED	Evaluation of a Mechanical Device During Acute Respiratory Failure in Patients With Neuromuscular Disorders
NCT00868166	PHASE3	COMPLETED	Safety and Efficacy of TRO19622 as add-on Therapy to Riluzole Versus Placebo in Treatment of Patients Suffering From ALS
NCT00965497	PHASE3	COMPLETED	Escitalopram (Lexapro) for Depression MS or ALS
NCT01016522	PHASE3	TERMINATED	Safety and Tolerability of the Ketogenic Diet in Amyotrophic Lateral Sclerosis (ALS)
NCT01160263	PHASE3	COMPLETED	Study of Dopamine and Serotonin Transporters in Patients With Amyotrophic Lateral Sclerosis and Controls
NCT01281189	PHASE3	COMPLETED	Phase 3 Study of Dexpramipexole in ALS
NCT01492686	PHASE3	COMPLETED	Phase 3 Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis
NCT01583088	PHASE3	TERMINATED	Early Stage Amyotrophic Lateral Sclerosis Phrenic Stimulation
NCT01622088	PHASE3	TERMINATED	Phase 3 Extension Study of Dexpramipexole in ALS
NCT02496767	PHASE3	COMPLETED	Ventilatory Investigation of Tirasemtiv and Assessment of Longitudinal Indices After Treatment for a Year
NCT02623699	PHASE3	COMPLETED	An Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of BIIB067 (Tofersen) in Adults With Inherited Amyotrophic Lateral Sclerosis (ALS)
NCT02936635	PHASE3	COMPLETED	A Study for Patients Who Completed VITALITY-ALS (CY 4031)
NCT03127267	PHASE3	RECRUITING	Efficacy and Safety of Masitinib Versus Placebo in the Treatment of ALS Patients
NCT03280056	PHASE3	COMPLETED	Safety and Efficacy of Repeated Administrations of NurOwn® in ALS Patients
NCT03491462	PHASE3	COMPLETED	Arimoclomol in Amyotropic Lateral Sclerosis
NCT03505021	PHASE3	COMPLETED	Effects of Oral Levosimendan (ODM-109) on Respiratory Function in Patients With ALS
NCT03548311	PHASE3	COMPLETED	Clinical Trial of Ultra-high Dose Methylcobalamin for ALS
NCT03690791	PHASE3	UNKNOWN	Efficacy of Cannabinoids in Amyotrophic Lateral Sclerosis or Motor Neurone Disease
NCT03800524	PHASE3	UNKNOWN	Safety and Efficacy of TUDCA as add-on Treatment in Patients Affected by ALS
NCT03836716	PHASE3	TERMINATED	Arimoclomol in Amyotropic Lateral Sclerosis - Open Label Extension Trial
NCT03948178	PHASE3	TERMINATED	Effects of Oral Levosimendan on Respiratory Function in Patients With Amyotrophic Lateral Sclerosis (ALS): Open-Label Extension
NCT04165824	PHASE3	COMPLETED	Safety Study of Oral Edaravone Administered in Subjects With ALS
NCT04248465	PHASE3	TERMINATED	An Efficacy and Safety Study of Ravulizumab in ALS Participants