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FLNA

gene
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Also known as ABP-280

Summary

FLNA (filamin A, HGNC:3754) is a protein-coding gene on chromosome Xq28, encoding Filamin-A (P21333). Promotes orthogonal branching of actin filaments and links actin filaments to membrane glycoproteins. It is haploinsufficient (ClinGen: sufficient evidence).

The protein encoded by this gene is an actin-binding protein that crosslinks actin filaments and links actin filaments to membrane glycoproteins. The encoded protein is involved in remodeling the cytoskeleton to effect changes in cell shape and migration. This protein interacts with integrins, transmembrane receptor complexes, and second messengers. Defects in this gene are a cause of several syndromes, including periventricular nodular heterotopias (PVNH1, PVNH4), otopalatodigital syndromes (OPD1, OPD2), frontometaphyseal dysplasia (FMD), Melnick-Needles syndrome (MNS), and X-linked congenital idiopathic intestinal pseudoobstruction (CIIPX). Two transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 2316 — RefSeq curated summary.

At a glance

  • Gene–disease (curated): periventricular nodular heterotopia (Definitive, ClinGen) — +14 more curated relationships
  • GWAS associations: 2
  • Clinical variants (ClinVar): 4,402 total — 212 pathogenic, 110 likely-pathogenic
  • Phenotypes (HPO): 356
  • Druggable target: yes — 1 molecules with ChEMBL bioactivity
  • Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
  • MANE Select transcript: NM_001110556

Identifiers

Gene identifiers

FieldValue
HGNC IDHGNC:3754
Approved symbolFLNA
Namefilamin A
LocationXq28
Locus typegene with protein product
StatusApproved
AliasesABP-280
Ensembl geneENSG00000196924
Ensembl biotypeprotein_coding
OMIM300017
Entrez2316

Gene structure

Transcript identifiers

Ensembl transcripts: 31 — 17 protein_coding, 8 retained_intron, 4 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000360319, ENST00000369850, ENST00000369856, ENST00000415241, ENST00000420627, ENST00000422373, ENST00000438732, ENST00000444578, ENST00000462590, ENST00000465144, ENST00000466319, ENST00000466325, ENST00000474072, ENST00000474358, ENST00000490936, ENST00000498411, ENST00000498491, ENST00000610817, ENST00000673639, ENST00000676696, ENST00000678304, ENST00000888338, ENST00000888339, ENST00000888340, ENST00000888341, ENST00000888342, ENST00000888343, ENST00000888344, ENST00000934717, ENST00000964813, ENST00000964814

RefSeq mRNA: 2 — MANE Select: NM_001110556 NM_001110556, NM_001456

CCDS: CCDS44021, CCDS48194

Canonical transcript exons

ENST00000369850 — 48 exons

ExonStartEnd
ENSE00001451045154370873154371361
ENSE00001593508154367397154367544
ENSE00001600780154367641154367738
ENSE00001609326154366308154366470
ENSE00001611867154365136154365259
ENSE00001666330154366024154366224
ENSE00001761667154367842154368090
ENSE00001766993154366732154366850
ENSE00001785883154366562154366639
ENSE00001801647154365349154365486
ENSE00003469485154361979154362148
ENSE00003481024154361670154361787
ENSE00003487826154364259154364372
ENSE00003499067154353554154353727
ENSE00003507155154354825154355072
ENSE00003521034154362242154362332
ENSE00003522996154362418154362578
ENSE00003529019154364526154364719
ENSE00003531396154364821154364957
ENSE00003546501154361308154361570
ENSE00003546981154349649154349867
ENSE00003547693154352181154352447
ENSE00003548613154359990154360587
ENSE00003548939154352772154352924
ENSE00003553638154359484154359646
ENSE00003557849154357251154357274
ENSE00003575553154350909154351041
ENSE00003603013154358445154358568
ENSE00003611143154353915154354043
ENSE00003621135154350031154350207
ENSE00003626883154352553154352675
ENSE00003635672154359732154359905
ENSE00003639210154357434154357623
ENSE00003643791154358199154358355
ENSE00003651081154359246154359406
ENSE00003655364154351884154352021
ENSE00003657633154358984154359154
ENSE00003659753154353001154353204
ENSE00003661051154364022154364165
ENSE00003663711154354381154354483
ENSE00003663935154349362154349565
ENSE00003671291154362661154362784
ENSE00003694696154354616154354711
ENSE00003713256154354151154354291
ENSE00003790175154351581154351696
ENSE00003791200154353296154353457
ENSE00003844438154374506154374634
ENSE00003886404154348531154349036

Expression profiles

Bgee: expression breadth ubiquitous, 285 present calls, max score 99.96.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 576.0610 / max 5937.7460, expressed in 1822 samples.

FANTOM5 promoters (28 alternative TSS)

Promoter IDTPM avgSamples expressed
201000373.29391821
201001113.98011812
20100558.93831634
20100412.17821430
2009982.80431338
2009872.33031162
2009841.4215842
2009771.2479749
2009891.2253752
2009991.1179746

Top tissues by expression

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

TissueAnatomy IDExpression scoreQuality
right coronary arteryUBERON:000162599.96gold quality
popliteal arteryUBERON:000225099.96gold quality
tibial arteryUBERON:000761099.96gold quality
aortaUBERON:000094799.95gold quality
ascending aortaUBERON:000149699.95gold quality
thoracic aortaUBERON:000151599.95gold quality
descending thoracic aortaUBERON:000234599.94gold quality
lower esophagusUBERON:001347399.94gold quality
lower esophagus muscularis layerUBERON:003583399.94gold quality
esophagogastric junction muscularis propriaUBERON:003584199.93gold quality
saphenous veinUBERON:000731899.92gold quality
body of uterusUBERON:000985399.92gold quality
mucosa of stomachUBERON:000119999.91gold quality
coronary arteryUBERON:000162199.91gold quality
left coronary arteryUBERON:000162699.91gold quality
muscle layer of sigmoid colonUBERON:003580599.91gold quality
left uterine tubeUBERON:000130399.88gold quality
blood vessel layerUBERON:000479799.87gold quality
stromal cell of endometriumCL:000225599.82gold quality
lower esophagus mucosaUBERON:003583499.81gold quality
myometriumUBERON:000129699.78gold quality
endocervixUBERON:000045899.74gold quality
urethraUBERON:000005799.73gold quality
right ovaryUBERON:000211899.69gold quality
upper lobe of left lungUBERON:000895299.69gold quality
fundus of stomachUBERON:000116099.68gold quality
granulocyteCL:000009499.66gold quality
colonic epitheliumUBERON:000039799.66gold quality
smooth muscle tissueUBERON:000113599.66gold quality
upper lobe of lungUBERON:000894899.65gold quality

Single-cell (SCXA)

Detected in 22 experiment(s), a significant marker in 19.

ExperimentMarker?Max mean expression
E-ANND-2yes5028.17
E-GEOD-84465yes431.05
E-MTAB-10287yes78.95
E-CURD-114yes72.90
E-CURD-122yes56.37
E-HCAD-1yes37.66
E-MTAB-8410yes35.85
E-MTAB-9467yes35.35
E-GEOD-135922yes28.98
E-GEOD-81547yes22.55
E-CURD-112yes20.20
E-CURD-46yes11.31
E-MTAB-9067yes10.96
E-HCAD-11yes10.26
E-MTAB-6678yes9.94

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CUX1, PAX1, SP1, SREBF1

miRNA regulators (miRDB)

27 targeting FLNA, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNAMax scoreAvg scoremiRNA target_count
HSA-MIR-146A-5P99.9668.93988
HSA-MIR-146B-5P99.9669.13977
HSA-MIR-6825-5P99.9669.813431
HSA-MIR-185-3P99.9567.011743
HSA-MIR-7153-5P99.9468.891006
HSA-MIR-607999.8468.541170
HSA-MIR-451699.6167.783390
HSA-MIR-18A-3P99.5665.681092
HSA-MIR-6828-5P99.3169.211433
HSA-MIR-450599.2767.812678
HSA-MIR-578799.2267.862628
HSA-MIR-3925-5P99.2167.901466
HSA-MIR-443499.1067.011984
HSA-MIR-570399.1067.092053
HSA-MIR-6829-5P98.8665.121480
HSA-MIR-448398.0964.121642
HSA-MIR-6842-3P98.0766.331325
HSA-MIR-365297.7165.431890
HSA-MIR-443097.4765.611813
HSA-MIR-10398-5P97.1264.941051
HSA-MIR-191397.0766.201417
HSA-MIR-2276-5P96.2765.85937
HSA-MIR-129396.1664.69916
HSA-MIR-6734-5P95.7065.56950
HSA-MIR-744-5P93.7865.29230
HSA-MIR-10396A-5P93.4965.54172
HSA-MIR-4781-5P88.2264.40100

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

  • Cell death and mechanoprotection by filamin a in connective tissues after challenge by applied tensile forces (PMID:11909861)
  • Two new pedigrees of bilateral periventricular nodular heterotopia are reported with a mutation of FLN1 and a deletion in its C-terminus causing a distal protein truncation. (PMID:11914408)
  • FLNa may be essential for Pak1-induced cytoskeletal reorganization (PMID:12198493)
  • there is a mechanically coupled transcriptional circuit from p38 that induces filamin-A expression [filamin A] (PMID:12324467)
  • an important role for filamin in the endocytic sorting and recycling of the internalized CTR (PMID:12531889)
  • PH domain of ROCK binds to the carboxy-terminal region of filamin-A containing the last 24th repeat. ROCK co-localized with filamin-A at the protrusive cell membranes of HeLa cells. (PMID:12589795)
  • filamin A has a role in signaling pathways that mediate organogenesis in multiple systems during embryonic development (PMID:12612583)
  • FLNa interfered with androgen receptor (AR) interdomain interactions and competed with the coactivator transcriptional intermediary factor 2 to specifically down-regulate AR function. (PMID:12682292)
  • Filamin A was identified as a direct binding partner of protein kinase Calpha; two binding sites were identified on filamin A; a Ca2+ and phospholipid-dependent association of the regulatory domain of protein kinase C with these sites was revealed. (PMID:12704190)
  • Interaction of filamin A with the insulin receptor alters insulin-dependent activation of the mitogen-activated protein kinase pathway. (PMID:12734206)
  • Filamin A binding to PSMA reduces the internalization rate of PSMA and its N-acelylated-alpha linked-acidic dipeptidase activity. (PMID:12750292)
  • shear-dependent VWF-induced platelet activation affects filamin A binding to GpIb-IX-V, and filamin A binding to the cytoplasmic tail of GpIbalpha regulates proaggregatory tyrosine kinase signaling. (PMID:12791664)
  • filamin-A was found to have no effect on Kir2.1 channel behavior but, rather, increased the number of functional channels resident within the membrane (PMID:12923176)
  • filamin-A has a role in the recovery from G2 arrest and subsequent mitotic cell death after DNA damage (PMID:14660646)
  • A woman with complex partial seizures and periventricular nodular heterotopia (PNH) had an amino acid exchange, a transition of guanine to adenine at the first position of intron 13 (IVS13 + 1 G -> A) causing a splice site mutation (2022 + 1 G -> A) (PMID:14718723)
  • Dual phenotype of periventricular nodular heterotopia and frontometaphyseal dysplasia in one patient is caused by two functionally different, aberrant filamin A proteins (PMID:14988809)
  • Data provide substantial evidence that ribosomal S6 kinase (RSK) phosphorylates filamin A, and suggest a novel role for RSK in the regulation of the actin cytoskeleton. (PMID:15024089)
  • Filamin-A interacts with c-mip/Tc-mip in a new T-cell signaling pathway. (PMID:15128042)
  • FLNA has diverse roles in embryonic, fetal and postnatal development [review] (PMID:15194946)
  • Periventricular nodular heterotopia caused by FLN1 mutations in men has a wide clinical spectrum and is caused by different genetic mechanisms, including somatic mosaicism. (PMID:15249610)
  • FLN1 mutations may have a role in periventricular heterotopia (PMID:15459826)
  • Interaction with filamin A increases cellular CaR by preventing CaR degradation, thereby facilitating CaR signaling. (PMID:15657061)
  • 3 filamin A mutations were identified in periventricular heterotopia/Ehlers-Danlos patients: a 2762 delG, a C116 point mutation causing A39G, & a 4147 delG. (PMID:15668422)
  • D3R, filamin A, and beta-arrestin form a signaling complex that is destabilized by agonist- or expression-mediated increases in GRK2/3 activity (PMID:15687500)
  • G12, Rho, filamin-A, and the actin cytoskeleton are required for amino acid-stimulated Ca2+ oscillations produced by the Ca2+-sensing receptor (PMID:15837785)
  • familial Ehlers-Danlos syndrome and periventricular nodular heterotopia is associated with an amino acid substition sssisns FLNA. (PMID:15994863)
  • calmodulin and calcium regulate the binding of filamin A to actin filaments (PMID:16030015)
  • A purified C-terminal region of filamin is a suitable substrate for calcineurin in vitro and in vivo (PMID:16442073)
  • beta-arrestins and FLNA cooperate to regulate ERK activation and actin cytoskeleton reorganization. (PMID:16611986)
  • Mutations in FLNA result in frontometaphyseal dysplasia and phenotypic diversity. (PMID:16835913)
  • A novel role is revealed for filamin A in the T cell receptor/CD28 signaling pathway leading to transcription factor activation and interleukin-2 production via the inducible interaction with protein kinase C theta. (PMID:16849481)
  • This suggests that the titin Z2-Zis1 domain can link filamins and alpha-actinin together in the periphery of the Z-line/dense bodies in a fashion that is conserved in smooth and striated muscles. (PMID:16949617)
  • Data indicate that filamin A binding to CD28 is required to induce the T-cell cytoskeletal rearrangements leading to recruitment of lipid microdomains and signalling mediators into the immunological synapse. (PMID:17060905)
  • filamin A is the first gene known to cause isolated nonsyndromic valvular heart disease. (PMID:17190868)
  • In cells, filamin A tethered plasma membrane CFTR to the underlying actin network. This interaction stabilized CFTR at the cell surface and regulated the plasma membrane dynamics and confinement of the channel. (PMID:17235394)
  • Filamin A is mutated in X-linked chronic idiopathic intestinal pseudo-obstruction with central nervous system involvement. (PMID:17357080)
  • expression of FLNa regulates constitutive activation of the Ras/ERK pathway partly through a Ras-GRF1 mechanism to modulate the production of MMP-9. (PMID:17389601)
  • Our results suggest a role for cyclin B1/Cdk1 in FLNa-dependent actin remodelling. (PMID:17408621)
  • FlnA restored Casodex anticaner sensitivity in C4-2 prostatic cancer cells by decreasing Akt phosphorylation. (PMID:17420725)
  • A novel mutation, 629G>T, in FLNA that had arisen de novo in the mother lead to Otopalatodigital syndrome type 2. (PMID:17431908)

Cross-species orthologs

2 orthologs

OrganismSymbolGene ID
mus_musculusFlnaENSMUSG00000031328
rattus_norvegicusFlnaENSRNOG00000054890

Paralogs (36): SYNE2 (ENSG00000054654), SPTB (ENSG00000070182), ACTN1 (ENSG00000072110), ACTN2 (ENSG00000077522), DSP (ENSG00000096696), DRP2 (ENSG00000102385), SPTBN1 (ENSG00000115306), MACF1 (ENSG00000127603), FLNC (ENSG00000128591), ACTN4 (ENSG00000130402), SYNE1 (ENSG00000131018), MICAL2 (ENSG00000133816), DTNA (ENSG00000134769), MICAL1 (ENSG00000135596), FLNB (ENSG00000136068), SPTBN5 (ENSG00000137877), DTNB (ENSG00000138101), GAS2L3 (ENSG00000139354), DST (ENSG00000151914), UTRN (ENSG00000152818), SPTBN4 (ENSG00000160460), SPTA1 (ENSG00000163554), CLMN (ENSG00000165959), PKHD1 (ENSG00000170927), SPTBN2 (ENSG00000173898), SYNE3 (ENSG00000176438), PLEC (ENSG00000178209), SMTNL2 (ENSG00000188176), SPTAN1 (ENSG00000197694), DMD (ENSG00000198947), PKHD1L1 (ENSG00000205038), DYTN (ENSG00000232125), MICAL3 (ENSG00000243156), ACTN3 (ENSG00000248746), EPPK1 (ENSG00000261150), GAS2L2 (ENSG00000270765)

Protein

Protein identifiers

Filamin-A — P21333 (reviewed: P21333)

Alternative names: Actin-binding protein 280, Alpha-filamin, Endothelial actin-binding protein, Filamin-1, Non-muscle filamin

All UniProt accessions (10): A0A087WWY3, A0A669KBC6, A0A7I2V3E6, A0A7P0NMY4, P21333, F8WE98, H0Y5C6, H0Y5F3, H7C2E7, Q60FE5

UniProt curated annotations — full annotation on UniProt →

Function. Promotes orthogonal branching of actin filaments and links actin filaments to membrane glycoproteins. Anchors various transmembrane proteins to the actin cytoskeleton and serves as a scaffold for a wide range of cytoplasmic signaling proteins. Interaction with FLNB may allow neuroblast migration from the ventricular zone into the cortical plate. Tethers cell surface-localized furin, modulates its rate of internalization and directs its intracellular trafficking. Involved in ciliogenesis. Plays a role in cell-cell contacts and adherens junctions during the development of blood vessels, heart and brain organs. Plays a role in platelets morphology through interaction with SYK that regulates ITAM- and ITAM-like-containing receptor signaling, resulting in by platelet cytoskeleton organization maintenance. During the axon guidance process, required for growth cone collapse induced by SEMA3A-mediated stimulation of neurons.

Subunit / interactions. Homodimer. Interacts with PDLIM2. Interacts with RFLNA and RFLNB. Interacts with FCGR1A, FLNB, FURIN, HSPB7, INPPL1, KCND2, MYOT, MYOZ1, ARHGAP24, PSEN1, PSEN2 and ECSCR. Also interacts with various other binding partners in addition to filamentous actin. Interacts (via N-terminus) with MIS18BP1 (via N-terminus). Interacts (via N-terminus) with TAF1B. Interacts with TMEM67 (via C-terminus) and MKS1. Interacts (via actin-binding domain) with MICALL2 (via CH domain). Interacts (via filamin repeat 5) with SYK; docks SYK to the plasma membrane. Interacts (via filamin repeats 19 and 21) with DRD3; increased PKA-mediated phosphorylation at Ser-2152. Interacts (via filamin repeat 21) with MAS1, AGTR1 and ADRA1D; increases PKA-mediated phosphorylation of FLNA at Ser-2152. Interacts (via filamin repeats 4, 9, 12, 17, 19, 21, and 23) with GP1BA (high affinity), ITGB7, ITGB2 and FBLIM1. Interacts with CEACAM1 (via cytoplasmic domain); inhibits cell migration and cell scattering by interfering with the interaction between FLNA and RALA. Interacts with FOXC1. Interacts (via calponin-homology (CH) domain 1 and filamin repeat 24) with CRMP1; the interaction alters FLNA ternary structure and thus promotes FLNA dissociation from F-actin. Interacts with DPYSL3/CRMP3 and DPYSL4/CRMP4. Interacts with integrin ITGB1 isoform 1/beta-1A and isoform 5/beta-1D. Interacts with LUZP1; the interaction is not necessary for colocalization of LUZP1 with F-actin.

Subcellular location. Cytoplasm. Cell cortex. Cytoskeleton. Perikaryon. Cell projection. Growth cone. Podosome.

Tissue specificity. Ubiquitous.

Post-translational modifications. Phosphorylation at Ser-2152 is negatively regulated by the autoinhibited conformation of filamin repeats 19-21. Ligand binding induces a conformational switch triggering phosphorylation at Ser-2152 by PKA. Phosphorylation extent changes in response to cell activation. Polyubiquitination in the CH1 domain by a SCF-like complex containing ASB2 leads to proteasomal degradation. Prior dissociation from actin may be required to expose the target lysines. Ubiquitinated in endothelial cells by RNF213 downstream of the non-canonical Wnt signaling pathway, leading to its degradation by the proteasome.

Disease relevance. Periventricular nodular heterotopia 1 (PVNH1) [MIM:300049] A developmental disorder characterized by the presence of periventricular nodules of cerebral gray matter, resulting from a failure of neurons to migrate normally from the lateral ventricular proliferative zone, where they are formed, to the cerebral cortex. PVNH1 is an X-linked dominant form. Heterozygous females have normal intelligence but suffer from seizures and various manifestations outside the central nervous system, especially related to the vascular system. Hemizygous affected males die in the prenatal or perinatal period. The disease is caused by variants affecting the gene represented in this entry. Otopalatodigital syndrome 1 (OPD1) [MIM:311300] X-linked dominant multiple congenital anomalies disease mainly characterized by a generalized skeletal dysplasia, mild intellectual disability, hearing loss, cleft palate, and typical facial anomalies. OPD1 belongs to a group of X-linked skeletal dysplasias known as oto-palato-digital syndrome spectrum disorders that also include OPD2, Melnick-Needles syndrome (MNS), and frontometaphyseal dysplasia (FMD). Remodeling of the cytoskeleton is central to the modulation of cell shape and migration. FLNA is a widely expressed protein that regulates re-organization of the actin cytoskeleton by interacting with integrins, transmembrane receptor complexes and second messengers. Males with OPD1 have cleft palate, malformations of the ossicles causing deafness and milder bone and limb defects than those associated with OPD2. Obligate female carriers of mutations causing both OPD1 and OPD2 have variable (often milder) expression of a similar phenotypic spectrum. The disease is caused by variants affecting the gene represented in this entry. Otopalatodigital syndrome 2 (OPD2) [MIM:304120] Congenital bone disorder that is characterized by abnormally modeled, bowed bones, small or absent first digits and, more variably, cleft palate, posterior fossa brain anomalies, omphalocele and cardiac defects. The disease is caused by variants affecting the gene represented in this entry. Frontometaphyseal dysplasia 1 (FMD1) [MIM:305620] An X-linked disease characterized by generalized skeletal dysplasia, deafness, and urogenital defects. The disease is caused by variants affecting the gene represented in this entry. Melnick-Needles syndrome (MNS) [MIM:309350] Severe congenital bone disorder characterized by typical facies (exophthalmos, full cheeks, micrognathia and malalignment of teeth), flaring of the metaphyses of long bones, s-like curvature of bones of legs, irregular constrictions in the ribs, and sclerosis of base of skull. The disease is caused by variants affecting the gene represented in this entry. Intestinal pseudoobstruction, neuronal, chronic idiopathic, X-linked (CIIPX) [MIM:300048] A disease characterized by a severe abnormality of gastrointestinal motility due to primary qualitative defects of enteric ganglia and nerve fibers. Affected individuals manifest recurrent signs of intestinal obstruction in the absence of any mechanical lesion. The disease is caused by variants affecting the gene represented in this entry. FG syndrome 2 (FGS2) [MIM:300321] FG syndrome (FGS) is an X-linked disorder characterized by intellectual disability, relative macrocephaly, hypotonia and constipation. The disease is caused by variants affecting the gene represented in this entry. Terminal osseous dysplasia (TOD) [MIM:300244] A rare X-linked dominant male-lethal disease characterized by skeletal dysplasia of the limbs, pigmentary defects of the skin and recurrent digital fibroma during infancy. A significant phenotypic variability is observed in affected females. The disease is caused by variants affecting the gene represented in this entry. Cardiac valvular dysplasia, X-linked (CVDPX) [MIM:314400] A rare X-linked heart disease characterized by mitral and/or aortic valve regurgitation. The histologic features include fragmentation of collagenous bundles within the valve fibrosa and accumulation of proteoglycans, which produces excessive valve tissue leading to billowing of the valve leaflets. The disease is caused by variants affecting the gene represented in this entry. Defects in FLNA may be a cause of macrothrombocytopenia, a disorder characterized by subnormal levels of blood platelets. Blood platelets are abnormally enlarged. Congenital short bowel syndrome, X-linked (CSBSX) [MIM:300048] A disease characterized by a shortened small intestine, and malabsorption. The mean length of the small intestine in affected individuals is approximately 50 cm, compared with a normal length at birth of 190-280 cm. It is associated with significant mortality and morbidity. Infants usually present with failure to thrive, recurrent vomiting, and diarrhea. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Comprised of a NH2-terminal actin-binding domain, 24 immunoglobulin-like internally homologous repeats and two hinge regions. Repeat 24 and the second hinge domain are important for dimer formation. Filamin repeat 20 interacts with filamin repeat 21 masking the ligand binding site on filamin repeat 21, resulting in an autoinhibited conformation. The autoinhibition can be relieved by ligands like ITGB7 or FBLIM1. Filamin repeats 19 and 21 can simultaneously engage ligands.

Similarity. Belongs to the filamin family.

Isoforms (3)

UniProt IDNamesCanonical?
P21333-11yes
P21333-22
P21333-33, VAR-1

RefSeq proteins (2): NP_001104026, NP_001447 (=MANE)

Domains & families (InterPro)

IDNameType
IPR001298Filamin/ABP280_rptRepeat
IPR001589Actinin_actin-bd_CSConserved_site
IPR001715CH_domDomain
IPR013783Ig-like_foldHomologous_superfamily
IPR014756Ig_E-setHomologous_superfamily
IPR017868Filamin/ABP280_rpt-likeRepeat
IPR036872CH_dom_sfHomologous_superfamily
IPR044801FilaminFamily

Pfam: PF00307, PF00630

UniProt features (285 total): strand 98, sequence variant 48, modified residue 48, helix 31, repeat 24, region of interest 8, turn 7, cross-link 5, sequence conflict 4, mutagenesis site 3, domain 2, compositionally biased region 2, splice variant 2, initiator methionine 1, chain 1, site 1

Structure

Experimental structures (PDB)

26 structures.

PDBMethodResolution (Å)
3CNKX-RAY DIFFRACTION1.65
4M9PX-RAY DIFFRACTION1.72
7SC4X-RAY DIFFRACTION1.85
2W0PX-RAY DIFFRACTION1.9
4P3WX-RAY DIFFRACTION2
2BRQX-RAY DIFFRACTION2.1
2JF1X-RAY DIFFRACTION2.2
9LWXX-RAY DIFFRACTION2.29
3HOCX-RAY DIFFRACTION2.3
3HOPX-RAY DIFFRACTION2.3
6EW1X-RAY DIFFRACTION2.31
2BP3X-RAY DIFFRACTION2.32
3RGHX-RAY DIFFRACTION2.44
9LXGX-RAY DIFFRACTION2.46
2J3SX-RAY DIFFRACTION2.5
3HORX-RAY DIFFRACTION2.7
3ISWX-RAY DIFFRACTION2.8
2WFNX-RAY DIFFRACTION3.2
6D8CELECTRON MICROSCOPY3.54
2AAVSOLUTION NMR
2K3TSOLUTION NMR
2K7PSOLUTION NMR
2K7QSOLUTION NMR
2MTPSOLUTION NMR
5XR1SOLUTION NMR
7SFTSOLUTION NMR

Predicted structure (AlphaFold)

ModelpLDDTFraction very-high
AF-P21333-F177.370.11

Functional residue map

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

Catalytic / active sites (1): 1761–1762 (cleavage; by calpain)

Post-translational modifications (53): 2, 11, 376, 508, 700, 781, 837, 865, 906, 968, 1055, 1071, 1071, 1081, 1084, 1089, 1301, 1338, 1372, 1459 …

Mutagenesis-validated functional residues (3):

PositionPhenotype
42abrogates asb2alpha-mediated degradation without altering asb2alpha binding; when associated with r-43 and r-135.
43abrogates asb2alpha-mediated degradation without altering asb2alpha binding; when associated with r-42 and r-135.
135abrogates asb2alpha-mediated degradation without altering asb2alpha binding; when associated with r-42 and r-43.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

IDPathway
R-HSA-114608Platelet degranulation
R-HSA-430116GP1b-IX-V activation signalling
R-HSA-446353Cell-extracellular matrix interactions
R-HSA-5627123RHO GTPases activate PAKs
R-HSA-8983711OAS antiviral response

MSigDB gene sets: 1227 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GSE45365_NK_CELL_VS_CD11B_DC_DN, GOBP_POTASSIUM_ION_TRANSPORT, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_CHROMOSOME_ORGANIZATION, GOBP_HINDBRAIN_DEVELOPMENT, MODULE_52, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, BORCZUK_MALIGNANT_MESOTHELIOMA_UP, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_EPITHELIUM_DEVELOPMENT, HORIUCHI_WTAP_TARGETS_DN, GOBP_PROTEIN_ACTIVATION_CASCADE, GOBP_ACTIN_FILAMENT_BUNDLE_ORGANIZATION

GO Biological Process (39): adenylate cyclase-inhibiting dopamine receptor signaling pathway (GO:0007195), blood coagulation, intrinsic pathway (GO:0007597), positive regulation of platelet activation (GO:0010572), negative regulation of transcription by RNA polymerase I (GO:0016479), formation of radial glial scaffolds (GO:0021943), cerebral cortex development (GO:0021987), actin cytoskeleton organization (GO:0030036), regulation of cell migration (GO:0030334), positive regulation of actin filament bundle assembly (GO:0032233), protein localization to cell surface (GO:0034394), megakaryocyte development (GO:0035855), negative regulation of protein catabolic process (GO:0042177), positive regulation of protein import into nucleus (GO:0042307), mRNA transcription by RNA polymerase II (GO:0042789), negative regulation of apoptotic process (GO:0043066), receptor clustering (GO:0043113), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), obsolete negative regulation of DNA-binding transcription factor activity (GO:0043433), wound healing, spreading of cells (GO:0044319), establishment of protein localization (GO:0045184), protein stabilization (GO:0050821), release of sequestered calcium ion into cytosol (GO:0051209), actin crosslink formation (GO:0051764), cilium assembly (GO:0060271), platelet aggregation (GO:0070527), semaphorin-plexin signaling pathway (GO:0071526), protein localization to plasma membrane (GO:0072659), tubulin deacetylation (GO:0090042), mitotic spindle assembly (GO:0090307), establishment of Sertoli cell barrier (GO:0097368), positive regulation of substrate adhesion-dependent cell spreading (GO:1900026), positive regulation of potassium ion transmembrane transport (GO:1901381), protein localization to bicellular tight junction (GO:1902396), regulation of membrane repolarization during atrial cardiac muscle cell action potential (GO:1905000), regulation of membrane repolarization during cardiac muscle cell action potential (GO:1905031), positive regulation of neural precursor cell proliferation (GO:2000179), positive regulation of integrin-mediated signaling pathway (GO:2001046), positive regulation of neuron migration (GO:2001224), cell projection organization (GO:0030030)

GO Molecular Function (17): G protein-coupled receptor binding (GO:0001664), RNA binding (GO:0003723), potassium channel regulator activity (GO:0015459), kinase binding (GO:0019900), small GTPase binding (GO:0031267), Fc-gamma receptor I complex binding (GO:0034988), protein homodimerization activity (GO:0042803), transmembrane transporter binding (GO:0044325), cadherin binding (GO:0045296), SMAD binding (GO:0046332), actin filament binding (GO:0051015), GTPase binding (GO:0051020), DNA-binding transcription factor binding (GO:0140297), protein sequestering activity (GO:0140311), actin binding (GO:0003779), protein binding (GO:0005515), protein-containing complex binding (GO:0044877)

GO Cellular Component (29): podosome (GO:0002102), extracellular region (GO:0005576), nucleus (GO:0005634), nucleolus (GO:0005730), cytoplasm (GO:0005737), cytosol (GO:0005829), actin filament (GO:0005884), plasma membrane (GO:0005886), cell-cell junction (GO:0005911), focal adhesion (GO:0005925), actin cytoskeleton (GO:0015629), membrane (GO:0016020), Z disc (GO:0030018), growth cone (GO:0030426), cortical cytoskeleton (GO:0030863), Myb complex (GO:0031523), dendritic shaft (GO:0043198), perikaryon (GO:0043204), perinuclear region of cytoplasm (GO:0048471), extracellular exosome (GO:0070062), apical dendrite (GO:0097440), postsynapse (GO:0098794), glutamatergic synapse (GO:0098978), glycoprotein Ib-IX-V complex (GO:1990779), cytoskeleton (GO:0005856), cell cortex (GO:0005938), cell projection (GO:0042995), neuronal cell body (GO:0043025), anchoring junction (GO:0070161)

Reactome top-level categories

Rollup of top-5 pathways:

CategoryPathways
Response to elevated platelet cytosolic Ca2+1
Platelet activation, signaling and aggregation1
Cell junction organization1
RHO GTPase Effectors1
Antimicrobial mechanism of IFN-stimulated genes1

GO top-level categories

Rollup of top GO terms by namespace:

CategoryTerms
cellular anatomical structure8
protein binding3
cell migration2
enzyme binding2
protein-containing complex binding2
binding2
cytoplasm2
cytoskeleton2
adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway1
G protein-coupled dopamine receptor signaling pathway1
protein activation cascade1
blood coagulation, fibrin clot formation1
regulation of platelet activation1
platelet activation1
positive regulation of cell activation1
regulation of transcription by RNA polymerase I1
transcription by RNA polymerase I1
negative regulation of DNA-templated transcription1
cell morphogenesis1
hindbrain radial glia guided cell migration1
pallium development1
anatomical structure development1
cytoskeleton organization1
actin filament-based process1
regulation of cell motility1
regulation of actin filament bundle assembly1
positive regulation of cellular component biogenesis1
actin filament bundle assembly1
positive regulation of cytoskeleton organization1
positive regulation of supramolecular fiber organization1
intracellular protein localization1
megakaryocyte differentiation1
myeloid cell development1
negative regulation of catabolic process1
protein catabolic process1
regulation of protein catabolic process1
negative regulation of protein metabolic process1
protein import into nucleus1
regulation of protein import into nucleus1
positive regulation of nucleocytoplasmic transport1

Protein interactions and networks

STRING

4116 interactions, top by confidence (×1000):

Protein AProtein BPartner UniProtScore
FLNATLN1Q9Y490997
FLNATLN2Q9Y4G6997
FLNAVCLP18206995
FLNAFBLIM1Q8WUP2995
FLNAPXNP49023988
FLNAGP1BAP07359987
FLNAARHGAP24Q8N264985
FLNAFILIP1Q7Z7B0974
FLNABRCA2P51587970
FLNACDC42P21181955
FLNAHSPB7Q9UBY9940
FLNAIQGAP1P46940937
FLNARHOAP06749929
FLNARALAP11233906
FLNACALM1P02593903

IntAct

343 interactions, top by confidence:

ABTypeScore
RNF146TNKSpsi-mi:“MI:0914”(association)0.790
CFTRESYT2psi-mi:“MI:0914”(association)0.710
CFTRESYT2psi-mi:“MI:2364”(proximity)0.710
TANC2TAX1BP3psi-mi:“MI:0914”(association)0.690
ARHGAP24FLNApsi-mi:“MI:0915”(physical association)0.640
ITGB3FLNApsi-mi:“MI:0407”(direct interaction)0.610
FLNAITGA2Bpsi-mi:“MI:0407”(direct interaction)0.610
FLNAITGB3psi-mi:“MI:0915”(physical association)0.610
TJP1ACTN4psi-mi:“MI:0914”(association)0.600
FLNAOPRM1psi-mi:“MI:0915”(physical association)0.600
OPRM1FLNApsi-mi:“MI:0915”(physical association)0.600
FLNAOPRM1psi-mi:“MI:0403”(colocalization)0.600
FLNALPAR1psi-mi:“MI:2364”(proximity)0.580
LPAR1FLNApsi-mi:“MI:2364”(proximity)0.580
FLNALPAR1psi-mi:“MI:0914”(association)0.580
LPAR1FLNApsi-mi:“MI:0914”(association)0.580
MRTFAFLNApsi-mi:“MI:2364”(proximity)0.570

BioGRID (862): FLNA (Two-hybrid), FLNA (Affinity Capture-MS), FLNA (Two-hybrid), REL (Two-hybrid), TCF4 (Two-hybrid), HSPB7 (Two-hybrid), ADAMTSL4 (Two-hybrid), LGALS14 (Two-hybrid), KLHL12 (Two-hybrid), FAM101A (Two-hybrid), FLNA (Affinity Capture-MS), FLNA (Affinity Capture-MS), FLNA (Affinity Capture-MS), FLNA (Affinity Capture-MS), FLNA (Affinity Capture-MS)

ESM2 similar proteins: A0A087WV53, A1CS92, A2ABU4, A2Q908, A2RUH7, A4QZL9, D3ZHA0, O01761, O70468, O75369, O88599, P05548, P11275, P11730, P11798, P13466, P21333, P56276, P56741, P70402, P79280, Q05623, Q13177, Q13203, Q13557, Q14315, Q2GM53, Q2HJF7, Q2URB7, Q5FW53, Q5PQM4, Q5RCC4, Q5VTT5, Q5ZJJ9, Q5ZKI0, Q62422, Q63518, Q6C1H8, Q6P686, Q6PHZ2

Diamond homologs: A4IF63, A5D7F8, A5D8S5, D2GXS7, D3ZHA0, D3ZQG6, F7H9X2, O70277, O75369, O75382, P13466, P21333, Q14315, Q1XHU0, Q28E95, Q3UIW8, Q5RBR0, Q60953, Q69ZI1, Q6NRD3, Q71F54, Q7Z6J0, Q80X90, Q80XJ2, Q8BTM8, Q8C120, Q8TEJ3, Q8VHX6, Q9C040, Q9ESN6, Q9HCM9, Q9R1R2, Q9VEN1, A5D7D1, D3ZEN0, D3ZHV2, D3ZQL6, E1BBG2, F1MF74, F1RA39

SIGNOR signaling

23 interactions.

AEffectBMechanism
RPS6KA1up-regulatesFLNAphosphorylation
PRKACAup-regulatesFLNAphosphorylation
PPP3CAdown-regulatesFLNAdephosphorylation
ROR2up-regulatesFLNAbinding
PPP3CB“down-regulates quantity by destabilization”FLNAdephosphorylation
PPP3CC“down-regulates quantity by destabilization”FLNAdephosphorylation
Calcineurindown-regulatesFLNAdephosphorylation
RPS6Kup-regulatesFLNAphosphorylation
FLNA“up-regulates activity”MAPK8
MAS1“up-regulates activity”FLNAbinding
FLNA“up-regulates activity”MAP2K7binding
FLNA“up-regulates activity”MAP2K4binding
calcium(2+)“down-regulates activity”FLNA“chemical inhibition”
“GPIb-IX-V complex”“up-regulates activity”FLNArelocalization
FLNA“up-regulates quantity by stabilization”F-actin_assemblybinding
PP2B“down-regulates quantity by destabilization”FLNAdephosphorylation
ASB2“down-regulates quantity by destabilization”FLNApolyubiquitination
STK38L“up-regulates activity”FLNAphosphorylation
FLNAup-regulatesMAP2K4binding
PAK1up-regulatesFLNAphosphorylation
FBLIM1“up-regulates activity”FLNAbinding
FLNA“up-regulates activity”KCND2binding
CAMK2GunknownFLNAphosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 189 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:

PathwayPartnersFoldFDR
Downstream signal transduction616.1×1e-04
Signaling by RAS mutants514.9×8e-04
CD28 dependent PI3K/Akt signaling513.9×9e-04
Activation of AMPK downstream of NMDARs513.4×1e-03
DAP12 signaling513.0×1e-03
Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells512.6×1e-03
FCERI mediated MAPK activation512.2×1e-03
Parasite infection512.2×1e-03

GO biological processes:

GO termPartnersFoldFDR
signal transduction in response to DNA damage524.0×1e-03
stimulatory C-type lectin receptor signaling pathway521.9×1e-03
Fc-epsilon receptor signaling pathway521.9×1e-03
ephrin receptor signaling pathway612.4×2e-03
cellular response to reactive oxygen species512.3×7e-03
positive regulation of substrate adhesion-dependent cell spreading511.2×9e-03
positive regulation of fibroblast proliferation610.6×4e-03
substrate adhesion-dependent cell spreading510.3×9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

4402 variants total. Per-class counts are floors (≥ shown; pagination cap):

ClassificationCount (floor)
Pathogenic212
Likely pathogenic110
Uncertain significance1421
Likely benign1449
Benign172

Top pathogenic / likely-pathogenic (30)

Variant IDHGVSClassification
1012290NM_001110556.2(FLNA):c.5796del (p.Asp1931_Tyr1932insTer)Pathogenic
1012298NM_001110556.2(FLNA):c.2527dup (p.Ala843fs)Pathogenic
1012677NM_001110556.2(FLNA):c.705G>A (p.Trp235Ter)Pathogenic
1031981NM_001110556.2(FLNA):c.5162del (p.Val1721fs)Pathogenic
1069630NM_001110556.2(FLNA):c.334_335insGAGAACGTGTCGG (p.Glu112fs)Pathogenic
1070215NM_001110556.2(FLNA):c.812del (p.Pro271fs)Pathogenic
1070361NM_001110556.2(FLNA):c.2947dup (p.Val983fs)Pathogenic
1071106NM_001110556.2(FLNA):c.6677dup (p.Gln2227fs)Pathogenic
1071650NM_001110556.2(FLNA):c.829_835del (p.Arg276_Pro277insTer)Pathogenic
1072111NM_001110556.2(FLNA):c.577C>T (p.Gln193Ter)Pathogenic
1072754NM_001110556.2(FLNA):c.6329_6330del (p.Glu2110fs)Pathogenic
1073243NM_001110556.2(FLNA):c.5146del (p.Gln1716fs)Pathogenic
1075551NM_001110556.2(FLNA):c.2965C>T (p.Gln989Ter)Pathogenic
1075693NM_001110556.2(FLNA):c.4138dup (p.Thr1380fs)Pathogenic
11747NM_001110556.2(FLNA):c.544C>T (p.Gln182Ter)Pathogenic
11748NM_001110556.2(FLNA):c.720+2T>CPathogenic
11750NM_001110556.2(FLNA):c.373+1G>APathogenic
11751NM_001110556.2(FLNA):c.287_291del (p.Arg96fs)Pathogenic
11753NM_001110556.2(FLNA):c.6915C>G (p.Tyr2305Ter)Pathogenic
11754NM_001110556.2(FLNA):c.245A>T (p.Glu82Val)Pathogenic
11757NM_001110556.2(FLNA):c.3476A>C (p.Asp1159Ala)Pathogenic
11760NM_001110556.2(FLNA):c.7315C>A (p.Leu2439Met)Pathogenic
11762NM_001110556.2(FLNA):c.4904_4912del (p.Arg1635_Val1637del)Pathogenic
11763NM_001110556.2(FLNA):c.2762del (p.Arg921fs)Pathogenic
11764NM_001110556.2(FLNA):c.4147del (p.Ala1383fs)Pathogenic
11765NM_001110556.2(FLNA):c.116C>G (p.Ala39Gly)Pathogenic
11766NM_001110556.2(FLNA):c.607G>T (p.Asp203Tyr)Pathogenic
1176611NM_001110556.2(FLNA):c.6163C>T (p.Gln2055Ter)Pathogenic
11767NM_001110556.2(FLNA):c.383C>T (p.Ala128Val)Pathogenic
11768NM_001110556.2(FLNA):c.5182G>T (p.Gly1728Cys)Pathogenic

SpliceAI

6507 predictions. Top by Δscore:

VariantEffectΔscore
X:154349037:C:CCacceptor_gain1.0000
X:154349357:CCCA:Cdonor_loss1.0000
X:154349358:CCAC:Cdonor_loss1.0000
X:154349359:CAC:Cdonor_loss1.0000
X:154349360:A:ATdonor_loss1.0000
X:154349643:GCTCA:Gdonor_loss1.0000
X:154349644:CTCA:Cdonor_loss1.0000
X:154349645:TCAC:Tdonor_loss1.0000
X:154349646:CACC:Cdonor_loss1.0000
X:154349647:A:Tdonor_loss1.0000
X:154349648:C:CAdonor_loss1.0000
X:154349700:A:ACdonor_gain1.0000
X:154349701:C:CCdonor_gain1.0000
X:154349864:TTCC:Tacceptor_gain1.0000
X:154349865:TCC:Tacceptor_gain1.0000
X:154349866:CC:Cacceptor_gain1.0000
X:154349866:CCC:Cacceptor_gain1.0000
X:154349867:CC:Cacceptor_gain1.0000
X:154349868:C:CCacceptor_gain1.0000
X:154349868:C:Tacceptor_gain1.0000
X:154349868:CT:Cacceptor_loss1.0000
X:154350027:TTAC:Tdonor_loss1.0000
X:154350028:TA:Tdonor_loss1.0000
X:154350030:CCTGT:Cdonor_loss1.0000
X:154350180:C:CTacceptor_gain1.0000
X:154350180:C:Tacceptor_gain1.0000
X:154350181:G:Tacceptor_gain1.0000
X:154350203:CTTAT:Cacceptor_gain1.0000
X:154350207:TCTGA:Tacceptor_loss1.0000
X:154350208:C:CCacceptor_gain1.0000

AlphaMissense

17282 scored. Top likely-pathogenic:

VariantProtein changeam_pathogenicity
X:154349742:A:CY2487D1.000
X:154349852:A:GF2450S1.000
X:154350153:A:TV2404D1.000
X:154350183:G:TP2394H1.000
X:154351001:A:TV2355D1.000
X:154351007:A:GF2353S1.000
X:154352315:A:TV2212D1.000
X:154352835:A:CY2106D1.000
X:154352895:C:GG2086R1.000
X:154353024:A:GF2068S1.000
X:154353704:C:GG1904R1.000
X:154353944:A:GF1886S1.000
X:154354864:A:CF1726L1.000
X:154354864:A:TF1726L1.000
X:154354866:A:GF1726L1.000
X:154354868:C:GR1725P1.000
X:154357444:G:CC1645W1.000
X:154357446:A:GC1645R1.000
X:154357550:G:TP1610Q1.000
X:154358209:A:TV1582D1.000
X:154358245:A:TI1570N1.000
X:154358251:A:GF1568S1.000
X:154359272:A:TV1426D1.000
X:154359285:A:CY1422D1.000
X:154359302:G:TP1416H1.000
X:154359309:A:GY1414H1.000
X:154359314:A:TV1412D1.000
X:154359321:A:GC1410R1.000
X:154359369:C:GG1394R1.000
X:154359498:G:CF1376L1.000

dbSNP variants (sampled 300 via entrez): RS1000274605 (X:154376133 C>T), RS1000527605 (X:154355271 C>G), RS1000580094 (X:154355519 G>T), RS1000809697 (X:154362879 G>A), RS1000839676 (X:154368907 C>G,T), RS1000971846 (X:154369297 G>A), RS1001333218 (X:154358244 G>A,T), RS1001468370 (X:154358865 C>G,T), RS1001493815 (X:154373859 G>A), RS1002868204 (X:154350333 C>G,T), RS1002888365 (X:154360974 G>A), RS1003077041 (X:154356719 C>T), RS1003442569 (X:154371482 G>A,C,T), RS1003944569 (X:154357074 C>G,T), RS1003972996 (X:154371938 G>A,C)

Disease associations

OMIM: gene MIM:300017 | disease phenotypes: MIM:300049, MIM:304120, MIM:309350, MIM:305620, MIM:607086, MIM:300048, MIM:300244, MIM:300321, MIM:311300, MIM:314400, MIM:607411, MIM:119530, MIM:130000, MIM:607087, MIM:134500, MIM:306700, MIM:601086, MIM:194200, MIM:154700, MIM:160700, MIM:614429, MIM:300673, MIM:255200, MIM:100100

GenCC curated gene-disease

DiseaseClassificationInheritance
heterotopia, periventricular, X-linked dominantDefinitiveX-linked
periventricular nodular heterotopiaDefinitiveX-linked
otopalatodigital syndrome type 2DefinitiveX-linked
intestinal pseudoobstruction, neuronal, chronic idiopathic, X-linkedDefinitiveX-linked
terminal osseous dysplasia-pigmentary defects syndromeDefinitiveX-linked
Melnick-Needles syndromeDefinitiveX-linked
genetic developmental and epileptic encephalopathyDefinitiveX-linked
frontometaphyseal dysplasia 1DefinitiveX-linked
cardiac valvular dysplasia, X-linkedStrongX-linked
otopalatodigital syndromeStrongX-linked
frontometaphyseal dysplasiaSupportiveAutosomal dominant
congenital short bowel syndromeSupportiveAutosomal recessive
X-linked Ehlers-Danlos syndromeSupportiveX-linked
otopalatodigital syndrome type 1SupportiveX-linked
familial thoracic aortic aneurysm and aortic dissectionLimitedUnknown

ClinGen Gene-Disease Validity (2)

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

DiseaseClassificationInheritance
periventricular nodular heterotopiaDefinitiveXL
familial thoracic aortic aneurysm and aortic dissectionLimitedXL

Mondo (50): heterotopia, periventricular, X-linked dominant (MONDO:0010233), otopalatodigital syndrome type 2 (MONDO:0010571), Melnick-Needles syndrome (MONDO:0010650), frontometaphyseal dysplasia (MONDO:0015942), familial thoracic aortic aneurysm and aortic dissection (MONDO:0019625), intestinal pseudoobstruction, neuronal, chronic idiopathic, X-linked (MONDO:0010232), terminal osseous dysplasia-pigmentary defects syndrome (MONDO:0010279), FG syndrome 2 (MONDO:0010297), otopalatodigital syndrome type 1 (MONDO:0010704), cardiac valvular dysplasia, X-linked (MONDO:0010753), frontometaphyseal dysplasia 1 (MONDO:0024550), periventricular nodular heterotopia (MONDO:0020341), cleft palate (MONDO:0016064), conductive hearing loss disorder (MONDO:0020679), otopalatodigital syndrome spectrum disorder (MONDO:0018233)

Orphanet (37): Frontometaphyseal dysplasia (Orphanet:1826), Nodular neuronal heterotopia (Orphanet:2149), Melnick-Needles syndrome (Orphanet:2484), OBSOLETE: Otopalatodigital syndrome (Orphanet:669), Ehlers-Danlos syndrome with periventricular heterotopia (Orphanet:82004), Otopalatodigital syndrome type 2 (Orphanet:90652), Familial thoracic aortic aneurysm and aortic dissection (Orphanet:91387), OBSOLETE: Congenital valvular dysplasia (Orphanet:1864), Congenital short bowel syndrome (Orphanet:2301), FLNA-related X-linked myxomatous valvular dysplasia (Orphanet:555877), X-linked Ehlers-Danlos syndrome (Orphanet:75497), Terminal osseous dysplasia-pigmentary defects syndrome (Orphanet:88630), Otopalatodigital syndrome type 1 (Orphanet:90650), Periventricular nodular heterotopia (Orphanet:98892), Cleft palate (Orphanet:2014)

HPO phenotypes

356 total (30 of 356 shown, HPO-id order):

HPOTerm
HP:0000023Inguinal hernia
HP:0000028Cryptorchidism
HP:0000047Hypospadias
HP:0000071Ureteral stenosis
HP:0000072Hydroureter
HP:0000076Vesicoureteral reflux
HP:0000126Hydronephrosis
HP:0000160Narrow mouth
HP:0000162Glossoptosis
HP:0000175Cleft palate
HP:0000179Thick lower lip vermilion
HP:0000189Narrow palate
HP:0000191Accessory oral frenulum
HP:0000193Bifid uvula
HP:0000201Pierre-Robin sequence
HP:0000218High palate
HP:0000238Hydrocephalus
HP:0000239Large fontanelles
HP:0000260Wide anterior fontanel
HP:0000269Prominent occiput
HP:0000270Delayed cranial suture closure
HP:0000272Malar flattening
HP:0000274Small face
HP:0000280Coarse facial features
HP:0000283Broad face
HP:0000286Epicanthus
HP:0000293Full cheeks
HP:0000307Pointed chin
HP:0000316Hypertelorism
HP:0000319Smooth philtrum

GWAS associations

2 associations (top):

StudyTraitp-value
GCST90002387_186Immature fraction of reticulocytes3.000000e-22
GCST90002407_383White blood cell count4.000000e-20

MeSH disease descriptors (35)

DescriptorNameTree numbers
D002972Cleft PalateC05.500.460.185; C05.660.207.540.460.185; C07.320.440.185; C07.465.525.185; C07.650.500.460.185; C07.650.525.185; C16.131.621.207.540.460.185; C16.131.850.500.460.185; C16.131.850.525.185
D003240Connective Tissue DiseasesC17.300
D012734Disorders of Sex DevelopmentC12.050.351.875.253; C12.200.706.316; C12.800.316; C16.131.939.316; C19.391.119
D004374Ductus Arteriosus, PatentC14.240.400.340; C14.280.400.340; C16.131.240.400.340
D004535Ehlers-Danlos SyndromeC14.907.454.240; C15.378.463.515.240; C16.131.831.428; C16.320.850.260; C17.300.200.310; C17.800.804.428; C17.800.827.260
D054092Foramen Ovale, PatentC14.240.400.560.375.258; C14.280.400.560.375.258; C16.131.240.400.560.375.258
D034381Hearing LossC09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341
D006330Heart Defects, CongenitalC14.240.400; C14.280.400; C16.131.240.400
D006345Heart Septal Defects, VentricularC14.240.400.560.540; C14.280.400.560.540; C16.131.240.400.560.540
D006467Hemophilia AC15.378.100.100.500; C15.378.100.141.500; C15.378.463.500; C16.320.099.500
D018197HepatoblastomaC04.557.435.380
D061325Hereditary Breast and Ovarian Cancer SyndromeC04.588.180.483; C04.588.322.455.431; C04.700.517; C12.050.351.500.056.630.705.431; C12.050.351.937.418.685.431; C12.100.250.056.630.705.431; C12.900.418.685.431; C16.320.700.517; C17.800.090.500.483; C19.344.410.431; C19.391.630.705.431
D006869HydronephrosisC12.050.351.968.419.307; C12.200.777.419.307; C12.950.419.307
D008607Intellectual DisabilityC10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D008382Marfan SyndromeC05.116.099.674; C14.240.400.725; C14.280.400.725; C16.131.077.550; C16.131.240.400.720; C16.320.540; C17.300.500
D008831MicrocephalyC05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
D020325Migraine with AuraC10.228.140.546.399.750.250
D009216MyopiaC11.744.636
D065886Neurodevelopmental DisordersF03.625
D054091Periventricular Nodular HeterotopiaC10.500.507.450.750; C16.131.666.507.450.750
D011535Prune Belly SyndromeC16.131.077.745
D012600ScoliosisC05.116.900.800.875
D013921ThrombocytopeniaC15.378.140.855; C15.378.243.937
D014927Wolff-Parkinson-White SyndromeC14.280.067.780.977; C14.280.123.750.977; C16.131.240.400.980
D000083143X-Linked Emery-Dreifuss Muscular DystrophyC05.651.534.500.350.500; C10.668.491.175.500.350.500; C16.320.322.625.500; C16.320.577.350.500
C564627Aortic Aneurysm, Familial Thoracic 2 (supp.)
C535576Cardiac valvular dysplasia, X-linked (supp.)
C535532Congenital idiopathic intestinal pseudoobstruction (supp.)
C536197Ehlers-Danlos syndrome type 5 (supp.)
C566878Encephalopathy, Neonatal Severe, Due To Mecp2 Mutations (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4804243 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,538 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

MoleculeNamePhasePatents
CHEMBL1232461MOLIBRESIB21,538

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

ChEMBL bioactivities

3 potent at pChembl≥5 of 5 total, top 3 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChemblTypeValueUnitMolecule
6.68IC50210nMMOLIBRESIB
5.10Kd7875nMCHEMBL3752910
5.10ED507875nMCHEMBL3752910

PubChem BioAssay actives

2 with measured affinity, of 10 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

CompoundAssayTypeValueUnit
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide2178731: Inhibition of FLNA (unknown origin) incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysisic500.2100uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide2148393: Binding affinity to human FLNA incubated for 45 mins by Kinobead based pull down assaykd7.8754uM

CTD chemical–gene interactions

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

ChemicalActions (top 5)PubMed papers
bisphenol Aincreases expression, affects expression, decreases expression, decreases methylation4
sodium arsenitedecreases expression, increases abundance, increases expression3
Estradiolaffects cotreatment, increases expression3
Cadmium Chlorideincreases expression, decreases expression, increases abundance3
Particulate Matterdecreases expression, increases abundance, affects cotreatment, increases expression3
cobaltous chloridedecreases expression, increases expression2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamideaffects cotreatment, decreases expression, increases expression2
Benzo(a)pyreneaffects methylation, decreases methylation, increases expression2
Doxorubicinaffects expression2
Phenylmercuric Acetateaffects cotreatment, increases expression2
Tetrachlorodibenzodioxinaffects expression, increases expression2
Tobacco Smoke Pollutionincreases expression, affects expression2
Valproic Aciddecreases expression, increases expression, increases methylation2
Cyclosporineincreases expression2
FR900359affects phosphorylation1
bisphenol Fincreases expression1
TAK-243decreases sumoylation1
dicrotophosincreases expression1
triphenyl phosphateaffects expression1
propionaldehydeincreases expression1
lead acetateincreases expression1
pyrogallol 1,3-dimethyl etheraffects cotreatment, affects localization, decreases expression, increases expression1
beta-lapachoneincreases expression1
arseniteaffects binding, increases reaction1
trimellitic anhydridedecreases expression1
afimoxifeneincreases expression1
benzo(e)pyreneincreases methylation1
potassium chromate(VI)decreases expression1
ferrous chlorideincreases expression1
aflatoxin B2increases methylation1

ChEMBL screening assays

7 unique, capped per target: 7 binding

Representative assays (with source publication via chembl_document):

Assay IDTypeDescriptionSource paper
CHEMBL5651435BindingBinding affinity to human FLNA incubated for 45 mins by Kinobead based pull down assayNVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

9 cell lines: 6 cancer cell line, 1 transformed cell line, 1 embryonic stem cell, 1 induced pluripotent stem cell

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

CellosaurusNameCategorySex
CVCL_3486M2A7Cancer cell lineSex unspecified
CVCL_A2VSGM26147Transformed cell lineFemale
CVCL_C9J7WAe009-A-PEmbryonic stem cellFemale
CVCL_D4YGM2A5Cancer cell lineSex unspecified
CVCL_D8LHUbigene HCT 116 FLNA KOCancer cell lineMale
CVCL_E0D4Ubigene HeLa FLNA KOCancer cell lineFemale
CVCL_SN72HAP1 FLNA (-) 1Cancer cell lineMale
CVCL_XN80HAP1 FLNA (-) 2Cancer cell lineMale
CVCL_YM34ZZUNEUi008-AInduced pluripotent stem cellMale

Clinical trials (associated diseases)

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

TrialPhaseStatusTitle
NCT05857085PHASE4COMPLETEDNovel Therapeutics and Endothelial Dysfunction in T1DM Patients
NCT02422056PHASE4COMPLETEDAcid Tranexamic Effectiveness in Reducing the Intraoperative Bleeding in Palatoplasty
NCT02915042PHASE4WITHDRAWNDexmedetomidine vs Placebo for Pediatric Cleft Palate Repair
NCT02953145PHASE4WITHDRAWNThe Use of Fibrin Sealant to Reduce Post Operative Pain in Cleft Palate Surgery
NCT03632044PHASE4ACTIVE_NOT_RECRUITINGEvaluation of Trigeminal Nerve Blockade
NCT06962306PHASE4RECRUITINGOptimizing Perioperative Analgesia to Lower Pain Following Cleft Palate Surgery
NCT00393159PHASE4UNKNOWNThe Influence of The Ear Popper on Serous Otitis Media and on the Accompanying Conductive Hearing Loss in Children
NCT01264510PHASE4WITHDRAWNEvaluation of the Effectiveness of Bone-anchored Hearing Aids (Baha)
NCT01042158PHASE4COMPLETEDA Clinical Trial of Ambrisentan and Tadalafil in Pulmonary Arterial Hypertension Associated With Systemic Sclerosis
NCT03688191PHASE4UNKNOWNStudy of Sirolimus in CTD-TP in China
NCT04169100PHASE4UNKNOWNNovel Form of Acquired Long QT Syndrome
NCT04197050PHASE4UNKNOWNEffect of Sacubitril/Valsartan on Reduced Right Ventricular Ejection Fraction in Patients With CTD
NCT04928586PHASE4UNKNOWNImmunosuppressant Combined With Pirfenidone in CTD-ILD
NCT05440240PHASE4RECRUITINGPercutaneous Needle Fasciotomy +/- Corticosteroid Injection for Dupuytren’s Contracture
NCT05505409PHASE4UNKNOWNEfficacy and Safety of Pirfenidone in CTD-ILD
NCT06499233PHASE4RECRUITINGEfficacy and Safety of Prophylactic Treatment for Pneumocystis Jirovecii Pneumonia in Patients With Autoimmune Inflammatory Rheumatic Disease
NCT00668824PHASE4UNKNOWNImproved Diagnosis of Congenital Heart Disease by Magnetic Resonance Imaging Using Vasovist
NCT01368705PHASE4COMPLETEDNitrogen Balance in Infants After Post Cardiothoracic Surgery
NCT01619982PHASE4COMPLETEDPre-operative Prophylaxis With Vancomycin and Cefazolin in Pediatric Cardiovascular Surgery Patients
NCT02122679PHASE4WITHDRAWNTranexamic Acid Effect on Platelet Aggregation Following Infant Cardiopulmonary Bypass
NCT02527811PHASE4UNKNOWNUlinastatin Injection in in Pediatric Patients Undergoing Open Heart Surgery
NCT03014700PHASE4COMPLETEDFibrinogen Concentrate vs Cryoprecipitate
NCT03408340PHASE4TERMINATEDParavertebral Nerve Blocks in Neonates
NCT03630796PHASE4UNKNOWNEffect of Sevoflurane in Postoperative Troponin I Levels in Children Undergoing Congenital Heart Defects Surgery
NCT03667703PHASE4COMPLETEDStress Ulcer Prophylaxis Versus Placebo in Critically Ill Infants With Congenital Heart Disease
NCT06719141PHASE3RECRUITINGA Study to Investigate LP352 in Children and Adults With Developmental and Epileptic Encephalopathies (DEE)
NCT06908226PHASE3ENROLLING_BY_INVITATIONA Study to Investigate LP352 in Children and Adults With Developmental and Epileptic Encephalopathy (DEE)
NCT00098319PHASE3COMPLETEDOral Cleft Prevention Trial in Brazil
NCT00397917PHASE3COMPLETEDOral Cleft Prevention Program
NCT04928352PHASE3RECRUITINGNebulized Bupivacaine Analgesia for Cleft Palate Repair
NCT04928391PHASE3COMPLETEDA Single Bolus of Dexmedetomidine Versus Normal Saline in Postoperative Agitation
NCT00864201PHASE3UNKNOWNA Study to Evaluate the Use of Bosentan in Patients With Exercise Induced Pulmonary Arterial Hypertension Associated With Connective Tissue Disease
NCT01196091PHASE3COMPLETEDA Study of LY2127399 in Participants With Systemic Lupus Erythematosus
NCT01205438PHASE3COMPLETEDA Study of LY2127399 in Participants With Systemic Lupus Erythematosus
NCT01488708PHASE3TERMINATEDOn Open-Label Study in Participants With Systemic Lupus Erythematosus
NCT03626688PHASE3COMPLETEDA Study Evaluating the Efficacy and Safety of Ralinepag to Improve Treatment Outcomes in PAH Patients
NCT03683186PHASE3ENROLLING_BY_INVITATIONA Study Evaluating the Long-Term Efficacy and Safety of Ralinepag in Subjects With PAH Via an Open-Label Extension
NCT04084678PHASE3TERMINATEDA Study of Ralinepag to Evaluate Effects on Exercise Capacity by CPET in Subjects With WHO Group 1 PH
NCT06716606PHASE3RECRUITINGA Study to Investigate the Long-term Safety and Efficacy of Belimumab in Adults With Interstitial Lung Disease (ILD) Associated With Systemic Sclerosis (SSc) and Other Connective Tissue Diseases (CTD) (BLISSconneCTD-OLE)
NCT06917690PHASE3RECRUITINGA Study to Learn About the Safety and Efficacy of the Drug Oleogel-S10 in Japanese Patients With Epidermolysis Bullosa

About this page

Generated deterministically by Sugi Atlas from primary biomedical databases via BioBTree. Every record on this page traces to a primary source.

Generated
Atlas version
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BioBTree
v2.0.2

Sources 79

This page pulls from 79 datasets indexed by BioBTree:

alphafoldalphamissenseantibodybgeebgee_evidencebindingdbbiogrid_interactionbrendabrenda_kineticsccdscellosauruschembl_activitychembl_assaychembl_documentchembl_moleculechembl_targetciviccivic_evidenceclingen_dosageclingen_gene_validityclinical_trialsclinvarcollectrictd_gene_interactiondbsnpdepmapdiamond_similarityefoensemblentrezesm2_similarityexonfantom5_genefantom5_promotergenccgenerifgogoparentgtopdbgwasgwas_studyhgnchpointactinterprointogenjasparmeshmimmirdbmondomsigdborphanetorthologparalogpatent_compoundpdbpfampharmgkb_clinicalpharmgkb_genepharmgkb_guidelinepharmgkb_variantpubchempubchem_activitypubchem_assaypubmedreactomereactomeparentrefseqrhearnacentralscxa_expressionscxa_gene_experimentsignorspliceaistring_interactiontranscriptufeatureuniprot