FMN2

Summary

FMN2 (formin 2, HGNC:14074) is a protein-coding gene on chromosome 1q43, encoding Formin-2 (Q9NZ56). Actin-binding protein that is involved in actin cytoskeleton assembly and reorganization.

This gene is a member of the formin homology protein family. The encoded protein is thought to have essential roles in organization of the actin cytoskeleton and in cell polarity. This protein mediates the formation of an actin mesh that positions the spindle during oogenesis and also regulates the formation of actin filaments in the nucleus. This protein also forms a perinuclear actin/focal-adhesion system that regulates the shape and position of the nucleus during cell migration. Mutations in this gene have been associated with infertility and also with an autosomal recessive form of intellectual disability (MRT47). Alternatively spliced transcript variants have been identified.

Source: NCBI Gene 56776 — RefSeq curated summary.

At a glance

• Gene–disease (curated): intellectual disability, autosomal recessive 47 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 20
• Clinical variants (ClinVar): 610 total — 7 pathogenic, 10 likely-pathogenic
• Phenotypes (HPO): 9
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 1 cancer types
• MANE Select transcript: NM_020066

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14074
Approved symbol	FMN2
Name	formin 2
Location	1q43
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000155816
Ensembl biotype	protein_coding
OMIM	606373
Entrez	56776

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 7 protein_coding, 7 protein_coding_CDS_not_defined, 3 nonsense_mediated_decay, 1 retained_intron

ENST00000319653, ENST00000441342, ENST00000447095, ENST00000463398, ENST00000496950, ENST00000543681, ENST00000545751, ENST00000679390, ENST00000679646, ENST00000679725, ENST00000679980, ENST00000681131, ENST00000681210, ENST00000681296, ENST00000681741, ENST00000681743, ENST00000681805, ENST00000681824

RefSeq mRNA: 3 — MANE Select: NM_020066 NM_001305424, NM_001348094, NM_020066

CCDS: CCDS31069

Canonical transcript exons

ENST00000319653 — 18 exons

Exon	Start	End
ENSE00001022869	240392511	240392562
ENSE00001069187	240188207	240188262
ENSE00001069190	240206799	240208732
ENSE00001069193	240177921	240178068
ENSE00001240295	240334109	240334229
ENSE00001348680	240438061	240438210
ENSE00001348683	240355816	240355908
ENSE00001442045	240211091	240211235
ENSE00001552702	240091883	240093724
ENSE00001818349	240474128	240475187
ENSE00003469062	240329339	240329468
ENSE00003537811	240257945	240258032
ENSE00003566254	240123179	240123345
ENSE00003574817	240472372	240472453
ENSE00003622469	240294822	240294883
ENSE00003660692	240329076	240329167
ENSE00003729266	240330603	240330749
ENSE00003737423	240333887	240333946

Expression profiles

Bgee: expression breadth ubiquitous, 187 present calls, max score 95.53.

FANTOM5 (CAGE): breadth broad, TPM avg 7.2325 / max 620.4743, expressed in 825 samples.

FANTOM5 promoters (16 alternative TSS)

Promoter ID	TPM avg	Samples expressed
9336	2.8992	628
9338	2.0280	518
9337	0.6682	235
9349	0.6218	125
9334	0.2672	8
9352	0.1174	44
9341	0.1148	57
9346	0.1109	58
9347	0.1072	31
9353	0.1036	34

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	95.53	gold quality
prefrontal cortex	UBERON:0000451	94.47	gold quality
Brodmann (1909) area 9	UBERON:0013540	93.65	gold quality
anterior cingulate cortex	UBERON:0009835	93.36	gold quality
right frontal lobe	UBERON:0002810	93.17	gold quality
sural nerve	UBERON:0015488	93.10	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	93.08	gold quality
frontal cortex	UBERON:0001870	92.98	gold quality
neocortex	UBERON:0001950	92.94	gold quality
caudate nucleus	UBERON:0001873	92.11	gold quality
amygdala	UBERON:0001876	91.88	gold quality
cerebral cortex	UBERON:0000956	91.81	gold quality
superior frontal gyrus	UBERON:0002661	91.31	gold quality
ganglionic eminence	UBERON:0004023	91.30	gold quality
nucleus accumbens	UBERON:0001882	91.03	gold quality
postcentral gyrus	UBERON:0002581	91.00	gold quality
putamen	UBERON:0001874	90.94	gold quality
hypothalamus	UBERON:0001898	90.67	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	90.58	gold quality
primary visual cortex	UBERON:0002436	90.46	gold quality
forebrain	UBERON:0001890	90.30	gold quality
cerebellar hemisphere	UBERON:0002245	90.13	gold quality
cerebellar cortex	UBERON:0002129	90.11	gold quality
ventricular zone	UBERON:0003053	90.06	gold quality
right hemisphere of cerebellum	UBERON:0014890	90.05	gold quality
brain	UBERON:0000955	89.85	gold quality
stromal cell of endometrium	CL:0002255	89.73	gold quality
temporal lobe	UBERON:0001871	89.60	gold quality
Ammon’s horn	UBERON:0001954	89.41	gold quality
cerebellum	UBERON:0002037	89.18	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-GEOD-124858	yes	243.27
E-HCAD-35	yes	84.56
E-CURD-119	yes	34.11
E-GEOD-81547	yes	10.96
E-ANND-3	yes	7.10
E-GEOD-137537	yes	5.73

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CTNNBL1, E2F1, RELA

miRNA regulators (miRDB)

64 targeting FMN2, 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-4795-3P	100.00	74.62	4024
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-8067	99.86	69.59	2260
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-4719	99.73	72.10	3329
HSA-MIR-1283	99.69	72.42	3009
HSA-MIR-580-3P	99.67	69.23	1841
HSA-MIR-29B-2-5P	99.67	68.98	1726
HSA-MIR-545-5P	99.66	70.18	2308
HSA-MIR-452-5P	99.65	69.63	1762
HSA-MIR-4676-3P	99.65	69.31	1733
HSA-MIR-892C-3P	99.65	69.38	1745
HSA-MIR-587	99.64	70.86	2611

Literature-anchored findings (GeneRIF, showing 16)

• FMN2 was characterized at human chromosome 1q43. (PMID:15289902)
• It is likely that FMN2 has the same function as Fmn2 in the mouse, i.e., maintenance of the meiotic spindle. Identification of patients with meiosis I arrest is necessary to determine whether FMN2 mutations are a cause of unexplained infertility. (PMID:15866570)
• both mammalian Spir proteins, Spir-1 and Spir-2, interact with mammalian Fmn subgroup proteins formin-1 and formin-2 (PMID:19605360)
• analysis of the molecular basis of the Spir1/formin-2 interaction (PMID:21705804)
• results identify FMN2 as a crucial component in the regulation of p21 and consequent oncogene/stress-induced cell-cycle arrest in human cells. (PMID:23375502)
• FMN2 is a crucial protein involved in the control of p21. (PMID:23839046)
• miR-335 regulates the expression of at least five formin family members, three of which are validated, FMNL3, FMN2 and DAAM2. (PMID:24223803)
• FMN2 mutations link intellectual disability either directly or indirectly to the regulation of actin-mediated synaptic spine density. (PMID:25480035)
• We therefore characterized co-expressed Spir-2 and Fmn-2 fluorescent protein fusions . The data corroborate a model according to which Spir-2 exists in two different states, a cytosolic monomeric conformation and a membrane-bound state (PMID:25564607)
• This DNA damage-induced nuclear actin assembly requires two biologically and physically linked nucleation factors: Formin-2 and Spire-1/Spire-2. (PMID:26287480)
• Overexpressing FMN2 reversed the inhibitory effects of miR-144-upregulation on acute lymphoblastic leukemia proliferation and cell-cycle transition (PMID:27556228)
• Fmn2 mutant mice develop accelerated age-associated memory decline that is further increased in the presence of additional risk factors and is mechanistically linked to a loss of transcriptional homeostasis. (PMID:28768717)
• FMN2 promoter hypermethylation may be an important early event in colorectal cancer, most likely playing a critical role in cancer initiation, and can serve as an ideal diagnostic biomarker in elderly patients with early-stage colon cancer. (PMID:30510376)
• Heterozygous FMN2 missense variant found in a family case of premature ovarian insufficiency. (PMID:35227295)
• Exosomal Circ_FMN2 Derived from the Serum of Colorectal Cancer Patients Promotes Cancer Progression by miR-338-3p/MSI1 Axis. (PMID:36995659)
• Mechanism of tumor-derived extracellular vesicles in prostatic cancer progression through the circFMN2/KLF2/RNF128 axis. (PMID:37452271)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
mus_musculus	Fmn2	ENSMUSG00000028354
rattus_norvegicus	Fmn2	ENSRNOG00000061764
drosophila_melanogaster	form3	FBGN0053556
caenorhabditis_elegans	fhod-1	WBGENE00016735
caenorhabditis_elegans		WBGENE00018976

Paralogs (18): DAAM1 (ENSG00000100592), FNBP4 (ENSG00000109920), DIAPH1 (ENSG00000131504), FHOD3 (ENSG00000134775), FHOD1 (ENSG00000135723), FHDC1 (ENSG00000137460), DIAPH3 (ENSG00000139734), DAAM2 (ENSG00000146122), DIAPH2 (ENSG00000147202), FMNL2 (ENSG00000157827), FMNL3 (ENSG00000161791), FMNL1 (ENSG00000184922), FAM47A (ENSG00000185448), SHTN1 (ENSG00000187164), FAM47B (ENSG00000189132), FAM47C (ENSG00000198173), INF2 (ENSG00000203485), GRID2IP (ENSG00000215045)

Protein

Protein identifiers

Formin-2 — Q9NZ56 (reviewed: Q9NZ56)

All UniProt accessions (10): Q9NZ56, A0A0A0MTF8, A0A7P0T8C5, A0A7P0T8F6, A0A7P0T994, A0A7P0T9J5, A0A7P0TA49, A0A7P0Z432, B0QZA8, B0QZD5

UniProt curated annotations — full annotation on UniProt →

Function. Actin-binding protein that is involved in actin cytoskeleton assembly and reorganization. Acts as an actin nucleation factor and promotes assembly of actin filaments together with SPIRE1 and SPIRE2. Involved in intracellular vesicle transport along actin fibers, providing a novel link between actin cytoskeleton dynamics and intracellular transport. Required for asymmetric spindle positioning, asymmetric oocyte division and polar body extrusion during female germ cell meiosis. Plays a role in responses to DNA damage, cellular stress and hypoxia by protecting CDKN1A against degradation, and thereby plays a role in stress-induced cell cycle arrest. Also acts in the nucleus: together with SPIRE1 and SPIRE2, promotes assembly of nuclear actin filaments in response to DNA damage in order to facilitate movement of chromatin and repair factors after DNA damage. Protects cells against apoptosis by protecting CDKN1A against degradation.

Subunit / interactions. Interacts with SPIRE1. Binds actin. Interacts with CDKN1A.

Subcellular location. Cytoplasm. Cytoskeleton. Cytosol. Perinuclear region. Nucleus. Nucleolus. Cell membrane. Cytoplasmic vesicle membrane. Cell cortex.

Tissue specificity. Expressed almost exclusively in the developing and mature central nervous system.

Disease relevance. Intellectual developmental disorder, autosomal recessive 47 (MRT47) [MIM:616193] A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRT47 patients show delayed development, with cognition and speech more affected than motor skills. The disease is caused by variants affecting the gene represented in this entry.

Induction. Up-regulated in response to cellular stress, hypoxia and DNA damage via NF-kappa-B.

Similarity. Belongs to the formin homology family. Cappuccino subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9NZ56-1	1	yes
Q9NZ56-2	2

RefSeq proteins (3): NP_001292353, NP_001335023, NP_064450* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000591	DEP_dom	Domain
IPR015425	FH2_Formin	Domain
IPR042201	FH2_Formin_sf	Homologous_superfamily

Pfam: PF02181

UniProt features (44 total): compositionally biased region 15, region of interest 6, coiled-coil region 4, mutagenesis site 4, modified residue 3, sequence variant 3, sequence conflict 3, domain 2, chain 1, splice variant 1, strand 1, helix 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
2YLE	X-RAY DIFFRACTION	1.8
3R7G	X-RAY DIFFRACTION	2.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NZ56-F1	51.48	0.15

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 (3): 93, 482, 516

Mutagenesis-validated functional residues (4):

Position	Phenotype
444–446	blocks accumulation in the nucleus in response to dna damage.
1715	abolishes interaction with spire1.
1717	strongly reduces interaction with spire1.
1721	strongly reduces interaction with spire1.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 185 (showing top): GOBP_MEIOTIC_CHROMOSOME_SEGREGATION, GOBP_REGULATION_OF_DOUBLE_STRAND_BREAK_REPAIR, GOBP_ACTIN_FILAMENT_BUNDLE_ORGANIZATION, TTTGTAG_MIR520D, GOBP_SPINDLE_LOCALIZATION, GOBP_CHROMOSOME_LOCALIZATION, GOBP_OOGENESIS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, KEGG_DORSO_VENTRAL_AXIS_FORMATION, GOBP_VESICLE_MEDIATED_TRANSPORT, ACEVEDO_LIVER_CANCER_WITH_H3K27ME3_UP, GOBP_REGULATION_OF_DNA_REPAIR, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_CATABOLIC_PROCESS, ATGTTAA_MIR302C, MARTORIATI_MDM4_TARGETS_NEUROEPITHELIUM_DN

GO Biological Process (19): DNA damage response (GO:0006974), protein transport (GO:0015031), vesicle-mediated transport (GO:0016192), cell migration (GO:0016477), actin cytoskeleton organization (GO:0030036), intracellular signal transduction (GO:0035556), polar body extrusion after meiotic divisions (GO:0040038), negative regulation of protein catabolic process (GO:0042177), negative regulation of apoptotic process (GO:0043066), intracellular transport (GO:0046907), oogenesis (GO:0048477), establishment of meiotic spindle localization (GO:0051295), homologous chromosome movement towards spindle pole in meiosis I anaphase (GO:0051758), formin-nucleated actin cable assembly (GO:0070649), cellular response to hypoxia (GO:0071456), positive regulation of double-strand break repair (GO:2000781), meiotic chromosome movement towards spindle pole (GO:0016344), actin nucleation (GO:0045010), actin filament bundle assembly (GO:0051017)

GO Molecular Function (3): actin binding (GO:0003779), molecular_function (GO:0003674), microtubule binding (GO:0008017)

GO Cellular Component (18): nucleus (GO:0005634), nucleolus (GO:0005730), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), spindle (GO:0005819), cytosol (GO:0005829), plasma membrane (GO:0005886), microvillus (GO:0005902), cell cortex (GO:0005938), actin cytoskeleton (GO:0015629), cytoplasmic vesicle membrane (GO:0030659), perinuclear region of cytoplasm (GO:0048471), cytoplasm (GO:0005737), cytoskeleton (GO:0005856), actin filament (GO:0005884), membrane (GO:0016020), cytoplasmic vesicle (GO:0031410), cell periphery (GO:0071944)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	5
cellular anatomical structure	5
transport	3
intracellular anatomical structure	3
intracellular membraneless organelle	3
cellular response to stress	2
meiotic cell cycle	2
meiotic cell cycle process	2
intracellular membrane-bounded organelle	2
cell periphery	2
intracellular protein localization	1
establishment of protein localization	1
cellular process	1
cell motility	1
cytoskeleton organization	1
actin filament-based process	1
signal transduction	1
female meiotic nuclear division	1
meiotic cytokinesis	1
negative regulation of catabolic process	1
protein catabolic process	1
regulation of protein catabolic process	1
negative regulation of protein metabolic process	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
cellular localization	1
establishment of localization in cell	1
germ cell development	1
female gamete generation	1
establishment of spindle localization	1
meiotic chromosome movement towards spindle pole	1
homologous chromosome segregation	1
parallel actin filament bundle assembly	1
formin-nucleated actin cable organization	1
response to hypoxia	1
cellular response to decreased oxygen levels	1
double-strand break repair	1
positive regulation of DNA repair	1
regulation of double-strand break repair	1

Protein interactions and networks

STRING

1862 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FMN2	SPIRE1	Q08AE8	925
FMN2	SPIRE2	Q8WWL2	909
FMN2	MYO5B	Q9ULV0	694
FMN2	PFN4	Q8NHR9	657
FMN2	ACTR3	P32391	592
FMN2	PFN3	P60673	566
FMN2	WDR17	Q8IZU2	564
FMN2	RAB11A	P24410	549
FMN2	PFN1	P07737	541
FMN2	JMY	Q8N9B5	538
FMN2	GRID2IP	A4D2P6	523
FMN2	FMN1	Q68DA7	522
FMN2	FMNL1	O95466	511
FMN2	FHDC1	Q9C0D6	502
FMN2	CFL2	Q9Y281	492

IntAct

44 interactions, top by confidence:

A	B	Type	Score
CEP19	CEP43	psi-mi:“MI:0914”(association)	0.770
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
IMP3	MPHOSPH10	psi-mi:“MI:0914”(association)	0.670
PTP4A2	PTP4A3	psi-mi:“MI:0914”(association)	0.640
ALDH3B1	UBA6	psi-mi:“MI:0914”(association)	0.530
BTN2A1	POTEF	psi-mi:“MI:0914”(association)	0.530
KPTN	EIF4G3	psi-mi:“MI:0914”(association)	0.530
TGFBR2	PIK3R2	psi-mi:“MI:0914”(association)	0.530
SLC31A1	C2orf72	psi-mi:“MI:0914”(association)	0.530
CAPN2	MYO9A	psi-mi:“MI:0914”(association)	0.530
NRBP1	TBC1D4	psi-mi:“MI:0914”(association)	0.530
FMN2	MANF	psi-mi:“MI:0915”(physical association)	0.400
RAB2B	UBA6	psi-mi:“MI:0914”(association)	0.350
GATD1		psi-mi:“MI:0914”(association)	0.350
SPATA5L1	HSPA8	psi-mi:“MI:0914”(association)	0.350
APBB2	APBB1	psi-mi:“MI:0914”(association)	0.350
BOD1	BPGM	psi-mi:“MI:0914”(association)	0.350
CASP1	KIF11	psi-mi:“MI:0914”(association)	0.350
RIMS1	KIF2A	psi-mi:“MI:0914”(association)	0.350
ACTG1	ENAH	psi-mi:“MI:0914”(association)	0.350
PFN1	WASL	psi-mi:“MI:0914”(association)	0.350
AVPR1B	KLRG2	psi-mi:“MI:0914”(association)	0.350

BioGRID (89): FMN2 (Affinity Capture-MS), FMN2 (Affinity Capture-MS), FMN2 (Affinity Capture-MS), FMN2 (Affinity Capture-MS), FMN2 (Affinity Capture-MS), FMN2 (Affinity Capture-MS), FMN2 (Proximity Label-MS), FMN2 (Affinity Capture-MS), FMN2 (Affinity Capture-MS), FMN2 (Affinity Capture-MS), FMN2 (Affinity Capture-MS), FMN2 (Affinity Capture-MS), FMN2 (Affinity Capture-MS), FMN2 (Affinity Capture-MS), FMN2 (Affinity Capture-MS)

ESM2 similar proteins: A1L1I3, A5D7F8, A5D8S5, D3ZEN0, E9Q0S6, G5E5X0, O08919, O35615, O54967, O70405, O75385, P00519, P19419, P48382, Q07912, Q17R13, Q28E95, Q3TN34, Q498M5, Q498S6, Q4KMP7, Q5RBI7, Q5RBR0, Q5U2X5, Q63767, Q69ZB8, Q69ZI1, Q6GQX6, Q6NRD3, Q71F54, Q7TT28, Q7Z6J0, Q80Z36, Q8BHL3, Q8BZT2, Q8C120, Q8IY33, Q8N1G0, Q8TEC5, Q8TEJ3

Diamond homologs: P78621, Q05858, Q5AAF4, Q9JL04, Q9NZ56, Q05860, Q24120, Q5TJ55, Q68DA7, Q8GX37, A0A1D5P556, Q1ZXK2, Q5AL52, Q9TYU9, A2XUA1, O22824, O23373, P41832, Q0D5P3, Q69MT2, Q7XUV2, Q8H8K7, Q8S0F0, Q9FJX6, P0C5K3, P0C5K5, Q54SP2, Q54WH2, Q6K8Z4, Q6ZCX3, Q7G6K7, Q7XWS7, Q84ZL0, Q9C6S1, Q9FF15, Q9FLQ7, Q9JL26, Q9LH02, Q9LVN1, Q9SK28

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 54 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Translocation of SLC2A4 (GLUT4) to the plasma membrane	5	18.8×	2e-03
RHO GTPase Effectors	5	8.3×	6e-03
Membrane Trafficking	7	6.3×	4e-03
Vesicle-mediated transport	7	5.9×	4e-03
Signaling by Rho GTPases	7	5.8×	4e-03
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	7	5.7×	4e-03

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 1 cancer types — PAAD.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	7
Likely pathogenic	10
Uncertain significance	235
Likely benign	290
Benign	30

Top pathogenic / likely-pathogenic (17)

Variant ID	HGVS	Classification
1028639	NM_020066.5(FMN2):c.1618C>T (p.Arg540Ter)	Pathogenic
162607	NM_020066.5(FMN2):c.1394dup (p.Ala466fs)	Pathogenic
162608	NM_020066.5(FMN2):c.2515del (p.Thr839fs)	Pathogenic
2612470	NM_020066.5(FMN2):c.4414G>T (p.Glu1472Ter)	Pathogenic
280455	NM_020066.5(FMN2):c.2363_2364del (p.Ile788fs)	Pathogenic
3064678	NM_020066.5(FMN2):c.2233C>T (p.Gln745Ter)	Pathogenic
687934	GRCh37/hg19 1q43(chr1:240224262-240317038)x1	Pathogenic
1254882	NM_020066.5(FMN2):c.1948dup (p.Ser650fs)	Likely pathogenic
1324420	NM_020066.5(FMN2):c.1861C>T (p.Arg621Ter)	Likely pathogenic
2580492	NM_020066.5(FMN2):c.1097G>A (p.Trp366Ter)	Likely pathogenic
2690601	NM_020066.5(FMN2):c.874C>T (p.Gln292Ter)	Likely pathogenic
3253156	NM_020066.5(FMN2):c.1803G>A (p.Trp601Ter)	Likely pathogenic
372820	NM_020066.5(FMN2):c.4348C>T (p.Arg1450Ter)	Likely pathogenic
3779672	NM_020066.5(FMN2):c.2840del (p.Pro947fs)	Likely pathogenic
429780	NM_020066.5(FMN2):c.547A>T (p.Ile183Phe)	Likely pathogenic
4813787	NM_020066.5(FMN2):c.4510G>T (p.Gly1504Ter)	Likely pathogenic
4813788	NM_020066.5(FMN2):c.4604T>A (p.Leu1535Ter)	Likely pathogenic

SpliceAI

5590 predictions. Top by Δscore:

Variant	Effect	Δscore
1:240123173:CTGCA:C	acceptor_loss	1.0000
1:240123174:TGCAG:T	acceptor_loss	1.0000
1:240123175:GCAG:G	acceptor_loss	1.0000
1:240123176:CAGG:C	acceptor_loss	1.0000
1:240123177:A:AG	acceptor_gain	1.0000
1:240123177:AG:A	acceptor_gain	1.0000
1:240123177:AGGG:A	acceptor_loss	1.0000
1:240123177:AGGGC:A	acceptor_gain	1.0000
1:240123178:G:C	acceptor_loss	1.0000
1:240123178:G:GG	acceptor_gain	1.0000
1:240123178:GG:G	acceptor_gain	1.0000
1:240123178:GGGC:G	acceptor_gain	1.0000
1:240123178:GGGCG:G	acceptor_gain	1.0000
1:240123342:TGATG:T	donor_loss	1.0000
1:240123343:GAT:G	donor_gain	1.0000
1:240123343:GATGT:G	donor_loss	1.0000
1:240123344:AT:A	donor_gain	1.0000
1:240123345:TG:T	donor_loss	1.0000
1:240123346:G:GA	donor_loss	1.0000
1:240123346:G:GG	donor_gain	1.0000
1:240123347:TA:T	donor_loss	1.0000
1:240123348:A:AC	donor_loss	1.0000
1:240123349:A:AC	donor_loss	1.0000
1:240177914:A:G	acceptor_gain	1.0000
1:240188205:A:AG	acceptor_gain	1.0000
1:240188206:G:GG	acceptor_gain	1.0000
1:240188206:GA:G	acceptor_gain	1.0000
1:240206794:TTCA:T	acceptor_loss	1.0000
1:240206796:CA:C	acceptor_loss	1.0000
1:240206797:A:AC	acceptor_loss	1.0000

AlphaMissense

11013 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:240092696:T:C	L196P	1.000
1:240092705:T:A	I199N	1.000
1:240092713:G:C	A202P	1.000
1:240123272:T:C	L570P	1.000
1:240177939:T:A	W601R	1.000
1:240177939:T:C	W601R	1.000
1:240177941:G:C	W601C	1.000
1:240177941:G:T	W601C	1.000
1:240206869:T:C	L686P	1.000
1:240208704:T:A	W1298R	1.000
1:240208704:T:C	W1298R	1.000
1:240208706:G:C	W1298C	1.000
1:240208706:G:T	W1298C	1.000
1:240211113:T:A	W1315R	1.000
1:240211113:T:C	W1315R	1.000
1:240211115:G:C	W1315C	1.000
1:240211115:G:T	W1315C	1.000
1:240211153:T:C	F1328S	1.000
1:240257958:T:C	L1360S	1.000
1:240257971:A:C	R1364S	1.000
1:240257971:A:T	R1364S	1.000
1:240257978:G:C	A1367P	1.000
1:240257982:T:A	V1368D	1.000
1:240257984:G:A	G1369R	1.000
1:240257984:G:C	G1369R	1.000
1:240257985:G:A	G1369E	1.000
1:240257988:T:A	I1370K	1.000
1:240257988:T:C	I1370T	1.000
1:240257988:T:G	I1370R	1.000
1:240257991:T:A	L1371Q	1.000

dbSNP variants (sampled 300 via entrez): RS1000017783 (1:240119023 G>A), RS1000060908 (1:240276539 T>A), RS1000063823 (1:240440968 A>T), RS1000063946 (1:240229749 C>A,T), RS1000079541 (1:240121283 C>T), RS1000091685 (1:240276824 G>A), RS1000106480 (1:240434431 C>G), RS1000111662 (1:240355482 A>G), RS1000113911 (1:240316440 C>T), RS1000118972 (1:240422820 T>C), RS1000124686 (1:240112237 G>A,T), RS1000125742 (1:240231398 A>G), RS1000132773 (1:240167307 G>C), RS1000140117 (1:240394988 A>T), RS1000152832 (1:240158366 C>T)

Disease associations

OMIM: gene MIM:606373 | disease phenotypes: MIM:616193, MIM:142623

GenCC curated gene-disease

Disease	Classification	Inheritance
intellectual disability, autosomal recessive 47	Strong	Autosomal recessive
autosomal recessive non-syndromic intellectual disability	Supportive	Autosomal recessive

Mondo (5): intellectual disability, autosomal recessive 47 (MONDO:0014524), primary ovarian failure (MONDO:0005387), Hirschsprung disease (MONDO:0018309), intellectual disability (MONDO:0001071), autosomal recessive non-syndromic intellectual disability (MONDO:0019502)

Orphanet (4): Autosomal recessive non-syndromic intellectual disability (Orphanet:88616), Hirschsprung disease (Orphanet:388), NON RARE IN EUROPE: Primary ovarian failure (Orphanet:619), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

9 total (9 of 9 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000750	Delayed speech and language development
HP:0001249	Intellectual disability
HP:0001263	Global developmental delay
HP:0001290	Generalized hypotonia
HP:0001634	Mitral valve prolapse
HP:0002384	Focal impaired awareness seizure
HP:0002465	Poor speech
HP:0003593	Infantile onset

GWAS associations

20 associations (top):

Study	Trait	p-value
GCST001870_7	Bone mineral density	2.000000e-09
GCST001915_2	Alzheimer’s disease (cognitive decline)	7.000000e-08
GCST002324_14	Anger	9.000000e-06
GCST002828_4	Urate levels in obese individuals	8.000000e-06
GCST003654_4	Bone mineral density (Ward’s triangle area)	1.000000e-08
GCST006288_180	Heel bone mineral density	3.000000e-39
GCST006288_262	Heel bone mineral density	5.000000e-48
GCST006288_567	Heel bone mineral density	1.000000e-87
GCST006979_905	Heel bone mineral density	3.000000e-275
GCST006988_80	Blond vs. brown/black hair color	2.000000e-08
GCST007014_3	Lumbar spine bone mineral density (trabecular)	1.000000e-11
GCST007015_12	Lumbar spine bone mineral density (integral)	1.000000e-07
GCST007203_11	Total cholesterol levels	8.000000e-06
GCST007425_3	Carotid plaques in rheumatoid arthritis	5.000000e-06
GCST007470_1	Rapid automatized naming of letters	4.000000e-06
GCST007935_10	Medication use (drugs affecting bone structure and mineralization)	2.000000e-08
GCST011940_8	Bullous pemphigoid	3.000000e-06
GCST90002400_547	Plateletcrit	8.000000e-12
GCST90002402_268	Platelet count	3.000000e-09
GCST90011900_36	Serum alkaline phosphatase levels	2.000000e-10

EFO canonical traits (13, from GWAS)

EFO ID	Trait name
EFO:0003015	aggressive behavior
EFO:0004531	urate measurement
EFO:0007785	femoral neck bone mineral density
EFO:0009270	heel bone mineral density
EFO:0003924	hair color
EFO:0007620	volumetric bone mineral density
EFO:0004574	total cholesterol measurement
EFO:0009783	carotid atherosclerosis
EFO:0005301	reading and spelling ability
EFO:0009936	Drugs affecting bone structure and mineralization use measurement
EFO:0007985	platelet crit
EFO:0004309	platelet count
EFO:0004533	alkaline phosphatase measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D006627	Hirschsprung Disease	C06.198.439; C06.405.469.158.701.439; C16.131.314.439
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D016649	Primary Ovarian Insufficiency	C12.050.351.500.056.630.750; C12.100.250.056.630.750; C19.391.630.750

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
trichostatin A	affects cotreatment, decreases expression, increases expression	3
Valproic Acid	affects expression, increases expression	3
sodium arsenite	decreases expression, increases expression	2
Vorinostat	affects cotreatment, decreases expression	2
Benzo(a)pyrene	affects methylation, increases methylation	2
Silicon Dioxide	decreases expression, increases expression	2
Aflatoxin B1	decreases methylation	2
FR900359	increases phosphorylation	1
daidzein	affects cotreatment, increases expression	1
bisphenol A	affects cotreatment, affects methylation	1
2,5,2’,5’-tetrachlorobiphenyl	decreases expression	1
arsenite	affects binding, decreases reaction	1
butyraldehyde	decreases expression	1
benzo(e)pyrene	decreases methylation	1
potassium chromate(VI)	increases expression	1
cupric chloride	increases expression	1
perfluorooctane sulfonic acid	decreases expression	1
glycitein	increases expression, affects cotreatment	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
2,2’,4,4’,5-brominated diphenyl ether	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	decreases expression, increases reaction	1
Decitabine	decreases expression, decreases reaction	1
Arsenic Trioxide	increases expression	1
Fulvestrant	affects cotreatment, affects methylation	1
Arsenic	affects methylation	1
Cisplatin	decreases expression, increases reaction	1
Diethylhexyl Phthalate	decreases expression	1
Chlordecone	affects response to substance	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00417066	PHASE4	COMPLETED	Flexible GnRH Antagonist vs Flare up GnRH Agonist Protocol in Poor Responders
NCT00732693	PHASE4	COMPLETED	Evaluation of Physiologic and Standard Sex Steroid Replacement Regimens in Women With Premature Ovarian Failure
NCT00837616	PHASE4	COMPLETED	Estrogen Dosing in Turner Syndrome: Pharmacology and Metabolism
NCT01853501	PHASE4	UNKNOWN	Effects of ADSC Therapy in Women With POF
NCT02783937	PHASE4	COMPLETED	Filgrastim for Premature Ovarian Insufficiency
NCT03535480	PHASE4	UNKNOWN	Autologous Bone Marrow Stem Cell Ovarian Transplantation to Restore Ovarian Function in Premature Ovarian Failure
NCT02343562	PHASE4	UNKNOWN	Probiotics for Prophylaxis of Postoperative Hirschsprungs Associated Enterocolitis
NCT07186647	PHASE4	COMPLETED	Laparoscopic-Assisted Transanal Pull-Through for Hirschsprung Disease in Pediatric:Short and Intermediate Outcomes of Two Different Techniques
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT00140998	PHASE3	COMPLETED	Estrogen Treatment (Oral vs. Patches) in Turner Syndrome
NCT03660176	PHASE3	UNKNOWN	Effects of Butyrate Enemas on Postoperative Intestinal Mobility Disorders in Hirschsprung’s Disease
NCT04904081	PHASE3	UNKNOWN	Feasibility of Use of Indocyanine Green in Pediatric Colorectal Surgery
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT00001951	PHASE2	COMPLETED	Hormone Replacement in Young Women With Premature Ovarian Failure
NCT00370019	PHASE2	WITHDRAWN	Effects of an Estrogen Replacement Therapy Skin Patch on Ovulation in Women With Premature Ovarian Failure
NCT00429494	PHASE2	COMPLETED	GnRH Analogue for Ovarian Function Preservation in Hematopoietic Stem Cell Transplantation Patients
NCT03816852	PHASE2	SUSPENDED	The Safety and Efficiency Study of Mesenchymal Stem Cell (19#iSCLife®-POI) in Premature Ovarian Insufficiency
NCT04536467	PHASE2	UNKNOWN	Prevention of Chemotherapy-Induced Ovarian Failure With Goserelin in Premenopausal Lymphoma Patients
NCT06117982	PHASE2	COMPLETED	The Impact of Granulocyte Colony Stimulating Factor on Premature Ovarian Insufficiency
NCT00630838	PHASE2	COMPLETED	Probiotic Prophylaxis of Hirschprung’s Disease Associated Enterocolitis (HAEC)
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT02912104	PHASE1	COMPLETED	A Therapeutic Trial of Human Amniotic Epithelial Cells Transplantation for Primary Ovarian Failure
NCT03178695	PHASE1	COMPLETED	Inovium Ovarian Rejuvenation Trials
NCT04815213	PHASE1	ACTIVE_NOT_RECRUITING	The Use of Expandeded Mesenchymal Stromal Cells (MSC) in Premature Ovarian Failure (POF) in Adult Humans
NCT05138367	PHASE1	COMPLETED	Effects of UCA-PSCs in Women With POF
NCT06132542	PHASE1	UNKNOWN	Autologous ADMSC Transplantation in Patients With POI
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT00948857	PHASE2/PHASE3	TERMINATED	Dehydroepiandrosterone (DHEA) Treatment and Premature Ovarian Failure (POF)
NCT04031456	PHASE2/PHASE3	RECRUITING	Autologous PRP Infusion May Restore Ovarian Function and May Promote Folliculogenesis in POI Patients
NCT02043743	PHASE1/PHASE2	UNKNOWN	Autologous Stem Cells Transplantation in Patients With Idiopathic and Drug Induced Premature Ovarian Failure