ACTN4

gene
On this page

Summary

ACTN4 (actinin alpha 4, HGNC:166) is a protein-coding gene on chromosome 19q13.2, encoding Alpha-actinin-4 (O43707). F-actin cross-linking protein which is thought to anchor actin to a variety of intracellular structures.

Alpha actinins belong to the spectrin gene superfamily which represents a diverse group of cytoskeletal proteins, including the alpha and beta spectrins and dystrophins. Alpha actinin is an actin-binding protein with multiple roles in different cell types. In nonmuscle cells, the cytoskeletal isoform is found along microfilament bundles and adherens-type junctions, where it is involved in binding actin to the membrane. In contrast, skeletal, cardiac, and smooth muscle isoforms are localized to the Z-disc and analogous dense bodies, where they help anchor the myofibrillar actin filaments. This gene encodes a nonmuscle, alpha actinin isoform which is concentrated in the cytoplasm, and thought to be involved in metastatic processes. Mutations in this gene have been associated with focal and segmental glomerulosclerosis.

Source: NCBI Gene 81 — RefSeq curated summary.

At a glance

  • Gene–disease (curated): focal segmental glomerulosclerosis 1 (Strong, GenCC) — +1 more curated relationship
  • GWAS associations: 9
  • Clinical variants (ClinVar): 596 total — 6 pathogenic, 11 likely-pathogenic
  • Phenotypes (HPO): 27
  • Druggable target: yes — 1 molecules with ChEMBL bioactivity
  • MANE Select transcript: NM_004924

Identifiers

Gene identifiers

FieldValue
HGNC IDHGNC:166
Approved symbolACTN4
Nameactinin alpha 4
Location19q13.2
Locus typegene with protein product
StatusApproved
Ensembl geneENSG00000130402
Ensembl biotypeprotein_coding
OMIM604638
Entrez81

Gene structure

Transcript identifiers

Ensembl transcripts: 29 — 24 protein_coding, 4 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000252699, ENST00000390009, ENST00000424234, ENST00000440400, ENST00000477174, ENST00000489451, ENST00000495553, ENST00000497637, ENST00000588618, ENST00000589528, ENST00000697712, ENST00000871324, ENST00000871325, ENST00000871326, ENST00000871327, ENST00000871328, ENST00000871329, ENST00000871330, ENST00000871331, ENST00000871332, ENST00000871333, ENST00000871334, ENST00000871335, ENST00000871336, ENST00000871337, ENST00000924368, ENST00000924369, ENST00000924370, ENST00000924371

RefSeq mRNA: 3 — MANE Select: NM_004924 NM_001322033, NM_001411143, NM_004924

CCDS: CCDS12518, CCDS92610, CCDS92611

Canonical transcript exons

ENST00000252699 — 21 exons

ExonStartEnd
ENSE000008957743872794638728026
ENSE000008957773872443138724565
ENSE000008957783872415738724339
ENSE000008957793872393738724077
ENSE000008957803872361438723722
ENSE000008957813872153838721688
ENSE000019099083864764938647907
ENSE000022567943872572438725903
ENSE000025298683872695738727103
ENSE000034787163870811738708195
ENSE000035210503871792738718074
ENSE000035422533870100238701121
ENSE000035638413870939538709476
ENSE000035904433870604438706131
ENSE000036052233870060038700714
ENSE000036127413871025738710342
ENSE000036160793872899638729154
ENSE000036229213871446938714561
ENSE000036288963870493438705020
ENSE000037908553871708638717316
ENSE000038428353872927438731589

Expression profiles

Bgee: expression breadth ubiquitous, 145 present calls, max score 99.48.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 97.8361 / max 1000.0509, expressed in 1827 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter IDTPM avgSamples expressed
17564559.67541824
17564637.44621803
1756500.6088365
1756540.105747

Top tissues by expression

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

TissueAnatomy IDExpression scoreQuality
popliteal arteryUBERON:000225099.48gold quality
tibial arteryUBERON:000761099.48gold quality
smooth muscle tissueUBERON:000113599.43gold quality
right coronary arteryUBERON:000162599.43gold quality
arteryUBERON:000163799.43gold quality
aortaUBERON:000094799.41gold quality
stromal cell of endometriumCL:000225599.39gold quality
ascending aortaUBERON:000149699.33gold quality
thoracic aortaUBERON:000151599.32gold quality
placentaUBERON:000198799.30gold quality
body of uterusUBERON:000985399.27gold quality
islet of LangerhansUBERON:000000699.26gold quality
myometriumUBERON:000129699.18gold quality
lower esophagus mucosaUBERON:003583499.11gold quality
descending thoracic aortaUBERON:000234599.07gold quality
left coronary arteryUBERON:000162699.04gold quality
duodenumUBERON:000211499.04gold quality
fallopian tubeUBERON:000388998.99gold quality
vermiform appendixUBERON:000115498.96gold quality
esophagus mucosaUBERON:000246998.96gold quality
metanephros cortexUBERON:001053398.95gold quality
vaginaUBERON:000099698.94gold quality
left uterine tubeUBERON:000130398.94gold quality
ectocervixUBERON:001224998.94gold quality
right lungUBERON:000216798.91gold quality
skin of legUBERON:000151198.90gold quality
upper lobe of left lungUBERON:000895298.90gold quality
esophagusUBERON:000104398.88gold quality
transverse colonUBERON:000115798.88gold quality
rectumUBERON:000105298.86gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 5.

ExperimentMarker?Max mean expression
E-HCAD-11yes18.97
E-HCAD-10yes18.91
E-HCAD-13yes7.47
E-GEOD-137537yes6.11
E-CURD-112no2.51
E-ANND-3no0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): HDAC7

miRNA regulators (miRDB)

125 targeting ACTN4, 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-3613-3P100.0076.367965
HSA-MIR-5011-5P100.0083.465820
HSA-MIR-190A-3P100.0080.355520
HSA-MIR-4692100.0067.322066
HSA-MIR-5692B100.0071.322622
HSA-MIR-5692C100.0071.322622
HSA-MIR-6758-5P100.0066.211470
HSA-MIR-6856-5P100.0065.471298
HSA-MIR-371B-5P99.9975.344759
HSA-MIR-548C-3P99.9974.017587
HSA-MIR-451499.9967.101870
HSA-MIR-373-5P99.9875.364753
HSA-MIR-616-5P99.9875.584775
HSA-MIR-6825-5P99.9669.813431
HSA-MIR-55999.9572.283609
HSA-MIR-548AB99.9571.313488
HSA-MIR-185-3P99.9567.011743
HSA-MIR-548A-5P99.9471.273482
HSA-MIR-548AD-5P99.9471.233502
HSA-MIR-548AE-5P99.9471.233502
HSA-MIR-548AK99.9471.243488
HSA-MIR-548AM-5P99.9471.243488
HSA-MIR-548AP-5P99.9471.143489
HSA-MIR-548AQ-5P99.9471.343426
HSA-MIR-548AR-5P99.9471.283515
HSA-MIR-548AS-5P99.9471.223482
HSA-MIR-548AU-5P99.9471.243488
HSA-MIR-548AY-5P99.9471.233502
HSA-MIR-548B-5P99.9471.233502
HSA-MIR-548BB-5P99.9471.273509

Literature-anchored findings (GeneRIF, showing 40)

  • interaction with tight junction protein MAGI-1 (PMID:12042308)
  • isolated two anti-alpha-actinin-4 T cell clones from the same patient TIL and from his peripheral blood lymphocytes (PBLs) by using tetramers of soluble HLA-A2 molecules loaded with the mutated peptide (PMID:12093915)
  • Sporadic FSGS is a heterogeneous disease, since ACTN4 and podocin genes are not found in our patients with sporadic FSGS. (PMID:12617336)
  • ACTN4 has a role promoting tumorigenicity and regulating cell motility (PMID:15048094)
  • Actinin alpha-4 is mainly present intracellularly and is involved in cellular motility via interaction with the actin cytoskeleton, thus probably affecting the metastatic potential of tumor cells. (PMID:15493875)
  • Results suggest that humanin is a novel binding partner of the alpha-actinin-4 R1-R4 domain in podocytes. (PMID:15619032)
  • the endosome-associated protein hrs is a subunit of a protein complex containing actinin-4, BERP, and myosin V that is necessary for efficient TfR recycling but not for EGFR degradation (PMID:15772161)
  • No mutations detected in Japanese congenital nephrotic synddrome patients. (PMID:15780077)
  • ACTN4 mutations accounts for about 3.5% of familial focal glomerulosclerosis. (PMID:16251236)
  • Interaction of alpha 4 actinin with ICAM-1 is required for leukocyte extravasation. (PMID:16951376)
  • The role of ACTN4 in MEF2A transcription via HDAC7 antagonism is reported. (PMID:16980305)
  • A critical regulator of AKT1 localization and function. (PMID:17018644)
  • Cytokine activation of MAPK14 and apoptosis is opposed by ACTN4 targeting of protein phosphatase 2A for site-specific dephosphorylation of MEK3. (PMID:17438131)
  • actinin-4…could be a novel prognostic indicator for patients with ovarian carcinomas. (PMID:17873890)
  • exposure of a buried actin-binding site 1 in mutant alpha-actinin-4 causes an increase in its actin-binding affinity (PMID:17901210)
  • common variants in LRRC7, KIRREL, NPHS2 and ACTN4 do not appeear to contribute to susceptibility to diabetic nephropathy in Finnish patients with type 1 diabetes (PMID:17968527)
  • Crystal structure of the actin-binding domain of alpha-actininin-4 Lys255Glu mutant implicated in focal segmental glomerulosclerosis. (PMID:18164029)
  • eNOS activity in vascular endothelial cells is tonically and dynamically regulated by competitive interaction with alpha-actinin-4 and calmodulin. (PMID:18180332)
  • alpha-actinin-4 is important for the NF-kappaB nuclear translocation and its functions inside the nucleus. (PMID:18215660)
  • Motility-related ACTN4 is associated with advanced and metastatic ovarian carcinoma. (PMID:18362906)
  • A novel ACTN4 mutation, p.Ser262Phe, was detected in the patients, and their father was found to have a germline mosaicism for the mutation in these patients with familial focal segmental glomerulosclerosis (PMID:18436095)
  • low expression levels of alpha-actinin-4 mRNA and protein are linked to the progression of glomerulopathy and proteinuria in human diabetic nephropathy (PMID:18552466)
  • Actinin-4 contributes to the invasive growth of pancreatic ductal carcinoma, and ACTN4 is one of the candidate oncogenes in this chromosome locus. (PMID:18765526)
  • Mutations and single nucleotide polymorphisms of the ACTN4 gene may be associated with Chinese idiopathic focal segmental glomerulosclerosis. (PMID:19142020)
  • The actinin-4 gene may serve as a predictor of poor outcome and tumor chemoresistance in patients with advanced-stage ovarian cancers. (PMID:19151661)
  • Mutations in ACTN4, the gene encoding the actin-binding protein alpha-actinin-4, are a cause of focal segmental glomerulosclerosis. (PMID:19357256)
  • Heterozygous mutations in the promoters of the ACTN4 and SYNPO genes are found in patients with idiopathic focal segmental glomerulosclerosis. (PMID:19666657)
  • Data show that actinin-4 expression levels significantly correlate with worse survival after PDAC resection. (PMID:19672209)
  • expression of alpha-actinin-4 was significantly associated with invasion potential defined by the Matrigel invasion assay. Cancer cell lines with higher alpha-actinin-4 expression had greater invasive potential. (PMID:19913389)
  • EGF regulates the actin binding activity of ACTN4 by inducing tyrosyl-directed phosphorylation (PMID:19920151)
  • The absence of mutations of ACTN4 in this study suggests that there are other genetic causes of steroid-resistant nephrotic syndrome (PMID:19956976)
  • Both alpha-actinin-1 and alpha-actinin-4 make critical and distinct contributions to cytoskeletal organization, rigidity-sensing, and motility of glioma cells. (PMID:20037648)
  • Alpha-actinin 1 and 4 are differentially regulated during the development and progression of astrocytomas because each of these isoforms uniquely contributes to distinct malignant properties of astrocytoma cells. (PMID:20156433)
  • The association of ACTN4 with different ribonucleoproteins suggests that a major function of nuclear ACTN4 may be regulation of mRNA metabolism and signaling. (PMID:20519146)
  • Levels of eEF1A2 and alpha-actinin-4 mRNA appeared to be unrelated to breast tumour size, except for a significant down-regulation of alpha-actinin-4 mRNA in T3 cases. (PMID:20819441)
  • The actin-binding protein, actinin alpha 4 (ACTN4), is a nuclear receptor coactivator that promotes proliferation of MCF-7 breast cancer cells. (PMID:21078666)
  • Epothilone B antagonizes glioma cell motility associated with reorganization of the actin-binding protein alpha-actinin 4. (PMID:21234524)
  • The results suggest that the interaction between HAMLET and alpha-actinins promotes tumor cell detachment. (PMID:21408150)
  • The urinary mRNA profiles of synaptopodin, podocalyxin, CD2-AP, alpha-actin4, and podocin were found to increase with the progression of diabetic nephropathy. (PMID:21655212)
  • Alpha-actinin-4 and CLP36 protein deficiencies contribute to podocyte defects in multiple human glomerulopathies (PMID:21680739)

Cross-species orthologs

2 orthologs

OrganismSymbolGene ID
mus_musculusActn4ENSMUSG00000054808
rattus_norvegicusActn4ENSRNOG00000020433

Paralogs (36): SYNE2 (ENSG00000054654), SPTB (ENSG00000070182), ACTN1 (ENSG00000072110), ACTN2 (ENSG00000077522), DSP (ENSG00000096696), DRP2 (ENSG00000102385), SPTBN1 (ENSG00000115306), MACF1 (ENSG00000127603), FLNC (ENSG00000128591), 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), FLNA (ENSG00000196924), SPTAN1 (ENSG00000197694), DMD (ENSG00000198947), PKHD1L1 (ENSG00000205038), DYTN (ENSG00000232125), MICAL3 (ENSG00000243156), ACTN3 (ENSG00000248746), EPPK1 (ENSG00000261150), GAS2L2 (ENSG00000270765)

Protein

Protein identifiers

Alpha-actinin-4O43707 (reviewed: O43707)

Alternative names: Non-muscle alpha-actinin 4

All UniProt accessions (6): O43707, A0A0S2Z3G9, A0A8V8TL71, F5GXS2, H7C144, K7EP19

UniProt curated annotations — full annotation on UniProt →

Function. F-actin cross-linking protein which is thought to anchor actin to a variety of intracellular structures. This is a bundling protein. Probably involved in vesicular trafficking via its association with the CART complex. The CART complex is necessary for efficient transferrin receptor recycling but not for EGFR degradation. Involved in tight junction assembly in epithelial cells probably through interaction with MICALL2. Links MICALL2 to the actin cytoskeleton and recruits it to the tight junctions. May also function as a transcriptional coactivator, stimulating transcription mediated by the nuclear hormone receptors PPARG and RARA. Association with IGSF8 regulates the immune synapse formation and is required for efficient T-cell activation.

Subunit / interactions. Homodimer; antiparallel. Binds TRIM3 at the N-terminus. Interacts with MICALL2 (preferentially in opened conformation); stimulated by RAB13 activation. Identified in a complex with CASK, IQGAP1, MAGI2, NPHS1, SPTAN1 and SPTBN1. Identified in a IGF2BP1-dependent mRNP granule complex containing untranslated mRNAs. Component of the CART complex, at least composed of ACTN4, HGS/HRS, MYO5B and TRIM3. Interacts with MAGI1. Interacts with PDLIM2. Interacts with PPARG and RARA. Binds to VCL; this interaction triggers VCL conformational changes. Interacts with SEPTIN14. Interacts with IGSF8.

Subcellular location. Nucleus. Cytoplasm. Cell junction. Cytoskeleton. Stress fiber. Perinuclear region.

Tissue specificity. Widely expressed.

Disease relevance. Focal segmental glomerulosclerosis 1 (FSGS1) [MIM:603278] A renal pathology defined by the presence of segmental sclerosis in glomeruli and resulting in proteinuria, reduced glomerular filtration rate and progressive decline in renal function. Renal insufficiency often progresses to end-stage renal disease, a highly morbid state requiring either dialysis therapy or kidney transplantation. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Contains one Leu-Xaa-Xaa-Leu-Leu (LXXLL) motif that mediates interaction with nuclear receptors.

Miscellaneous. Does not colocalize with actin cytoskeleton structures.

Similarity. Belongs to the alpha-actinin family.

Isoforms (3)

UniProt IDNamesCanonical?
O43707-11yes
O43707-2ACTN4ISO
O43707-33

RefSeq proteins (3): NP_001308962, NP_001398072, NP_004915* (*=MANE)

Domains & families (InterPro)

IDNameType
IPR001589Actinin_actin-bd_CSConserved_site
IPR001715CH_domDomain
IPR002017Spectrin_repeatRepeat
IPR002048EF_hand_domDomain
IPR011992EF-hand-dom_pairHomologous_superfamily
IPR014837EF-hand_Ca_insenDomain
IPR018159Spectrin/alpha-actininRepeat
IPR018247EF_Hand_1_Ca_BSBinding_site
IPR036872CH_dom_sfHomologous_superfamily

Pfam: PF00307, PF00435, PF08726

UniProt features (85 total): helix 18, sequence variant 17, sequence conflict 13, modified residue 10, region of interest 6, domain 4, repeat 4, binding site 3, strand 3, splice variant 2, turn 2, chain 1, short sequence motif 1, mutagenesis site 1

Structure

Experimental structures (PDB)

5 structures.

PDBMethodResolution (Å)
6OA6X-RAY DIFFRACTION1.37
6O31X-RAY DIFFRACTION1.51
1YDIX-RAY DIFFRACTION1.8
2R0OX-RAY DIFFRACTION2.2
1WLXSOLUTION NMR

Predicted structure (AlphaFold)

ModelpLDDTFraction very-high
AF-O43707-F184.660.48

Functional residue map

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

Ligand- & substrate-binding residues (3): 778; 780; 789

Post-translational modifications (10): 31, 114, 214, 249, 592, 625, 696, 779, 859, 909

Mutagenesis-validated functional residues (1):

PositionPhenotype
87–88reduced interaction with rara. loss of the transcriptional coac tivator activity toward rara.

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

IDPathway
R-HSA-114608Platelet degranulation
R-HSA-373753Nephrin family interactions
R-HSA-109582Hemostasis
R-HSA-1500931Cell-Cell communication
R-HSA-76002Platelet activation, signaling and aggregation
R-HSA-76005Response to elevated platelet cytosolic Ca2+

MSigDB gene sets: 437 (showing top): TSENG_IRS1_TARGETS_UP, GOBP_VESICLE_LOCALIZATION, GOBP_RESPONSE_TO_PEPTIDE, GOCC_SECRETORY_GRANULE, GOBP_SODIUM_ION_TRANSMEMBRANE_TRANSPORT, REACTOME_PLATELET_ACTIVATION_SIGNALING_AND_AGGREGATION, ENK_UV_RESPONSE_KERATINOCYTE_UP, GOBP_POSITIVE_REGULATION_OF_TRANSPORTER_ACTIVITY, TATTATA_MIR374, THEILGAARD_NEUTROPHIL_AT_SKIN_WOUND_DN, KYNG_DNA_DAMAGE_DN, KEGG_TIGHT_JUNCTION, GHO_ATF5_TARGETS_DN, GOBP_POSITIVE_REGULATION_OF_SODIUM_ION_TRANSPORT, CTATGCA_MIR153

GO Biological Process (13): protein transport (GO:0015031), actin cytoskeleton organization (GO:0030036), vesicle transport along actin filament (GO:0030050), positive regulation of cell migration (GO:0030335), positive regulation of sodium:proton antiporter activity (GO:0032417), tumor necrosis factor-mediated signaling pathway (GO:0033209), peroxisome proliferator activated receptor signaling pathway (GO:0035357), regulation of apoptotic process (GO:0042981), positive regulation of transcription by RNA polymerase II (GO:0045944), retinoic acid receptor signaling pathway (GO:0048384), muscle cell development (GO:0055001), negative regulation of substrate adhesion-dependent cell spreading (GO:1900025), positive regulation of non-canonical NF-kappaB signal transduction (GO:1901224)

GO Molecular Function (16): RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), nucleoside binding (GO:0001882), transcription coactivator activity (GO:0003713), RNA binding (GO:0003723), actin binding (GO:0003779), integrin binding (GO:0005178), calcium ion binding (GO:0005509), nuclear receptor binding (GO:0016922), chromatin DNA binding (GO:0031490), protein homodimerization activity (GO:0042803), nuclear retinoic acid receptor binding (GO:0042974), transmembrane transporter binding (GO:0044325), actin filament binding (GO:0051015), protein binding (GO:0005515), identical protein binding (GO:0042802), metal ion binding (GO:0046872)

GO Cellular Component (21): stress fiber (GO:0001725), extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), nucleus (GO:0005634), cytoplasm (GO:0005737), plasma membrane (GO:0005886), focal adhesion (GO:0005925), actin cytoskeleton (GO:0015629), Z disc (GO:0030018), cell junction (GO:0030054), cortical actin cytoskeleton (GO:0030864), platelet alpha granule lumen (GO:0031093), pseudopodium (GO:0031143), protein-containing complex (GO:0032991), cell projection (GO:0042995), perinuclear region of cytoplasm (GO:0048471), extracellular exosome (GO:0070062), postsynaptic actin cytoskeleton (GO:0098871), ribonucleoprotein complex (GO:1990904), cytoskeleton (GO:0005856), anchoring junction (GO:0070161)

Reactome top-level categories

Rollup of top-4 pathways:

CategoryPathways
Response to elevated platelet cytosolic Ca2+1
Cell-Cell communication1
Hemostasis1
Platelet activation, signaling and aggregation1

GO top-level categories

Rollup of top GO terms by namespace:

CategoryTerms
cellular anatomical structure6
nuclear receptor-mediated signaling pathway2
positive regulation of DNA-templated transcription2
protein-containing complex binding2
protein binding2
actin cytoskeleton2
transport1
intracellular protein localization1
establishment of protein localization1
cytoskeleton organization1
actin filament-based process1
actin filament-based movement1
actin filament-based transport1
vesicle cytoskeletal trafficking1
cell migration1
regulation of cell migration1
positive regulation of cell motility1
sodium:proton antiporter activity1
positive regulation of sodium ion transmembrane transporter activity1
cytokine-mediated signaling pathway1
cellular response to tumor necrosis factor1
apoptotic process1
regulation of programmed cell death1
regulation of transcription by RNA polymerase II1
transcription by RNA polymerase II1
hormone-mediated signaling pathway1
muscle cell differentiation1
cell development1
negative regulation of cell-substrate adhesion1
substrate adhesion-dependent cell spreading1
regulation of substrate adhesion-dependent cell spreading1
non-canonical NF-kappaB signal transduction1
regulation of non-canonical NF-kappaB signal transduction1
positive regulation of intracellular signal transduction1
transcription cis-regulatory region binding1
carbohydrate derivative binding1
heterocyclic compound binding1
transcription coregulator activity1
nucleic acid binding1
cytoskeletal protein binding1

Protein interactions and networks

STRING

2468 interactions, top by confidence (×1000):

Protein AProtein BPartner UniProtScore
ACTN4NPHS1O60500988
ACTN4SYNPOQ8N3V7979
ACTN4NPHS2Q9NP85971
ACTN4VCLP18206965
ACTN4CD2APQ9Y5K6939
ACTN4INF2Q27J81929
ACTN4MAGI1Q96QZ7922
ACTN4TRPC6Q9Y210904
ACTN4TRIM3O75382879
ACTN4TJP1Q07157873
ACTN4TLN1Q9Y490859
ACTN4MYH9P35579840
ACTN4PLCE1Q9P212824
ACTN4PDLIM1O00151821
ACTN4PDLIM2Q96JY6794

IntAct

283 interactions, top by confidence:

ABTypeScore
ACTN4MYOZ2psi-mi:“MI:0915”(physical association)0.930
MYOZ2ACTN4psi-mi:“MI:0915”(physical association)0.930
PDLIM1ACTN4psi-mi:“MI:0914”(association)0.800
ACTN4PDLIM1psi-mi:“MI:0915”(physical association)0.800
CFTRESYT2psi-mi:“MI:0914”(association)0.710
CTNNB1ACTN4psi-mi:“MI:0914”(association)0.680
ACTN4CTNNB1psi-mi:“MI:0915”(physical association)0.680
ACTN4CTNNB1psi-mi:“MI:0403”(colocalization)0.680

BioGRID (552): ACTN4 (Affinity Capture-MS), ACTN3 (Two-hybrid), BMP7 (Two-hybrid), MYOZ2 (Two-hybrid), ACTN4 (Affinity Capture-MS), ACTN4 (Affinity Capture-MS), ACTN4 (Affinity Capture-MS), ACTN4 (Affinity Capture-MS), ACTN4 (Two-hybrid), ACTN4 (Affinity Capture-MS), ACTN4 (Affinity Capture-Western), RARA (Reconstituted Complex), ACTN4 (Affinity Capture-MS), MYOZ2 (Two-hybrid), MYOZ1 (Two-hybrid)

ESM2 similar proteins: A5D7D1, L7UZ85, O43707, O88990, P05094, P11277, P12814, P15508, P18091, P20111, P26232, P30997, P35609, P46940, P57780, Q00078, Q00963, Q01082, Q08043, Q0E908, Q0III9, Q13576, Q2PFV7, Q3B7N2, Q3UQ44, Q3ZC55, Q4QR29, Q4WVG0, Q5M7J9, Q5R416, Q5RCS6, Q61301, Q62018, Q62261, Q6DEU9, Q6INS3, Q6NXC0, Q6PD62, Q7G188, Q7PKQ5

Diamond homologs: A5D7D1, D3ZEN0, D3ZHA0, D3ZHV2, D3ZQL6, E1BBG2, F1MF74, F1RA39, F6QZ15, G3MWR8, G3V7L1, L7UZ85, M9MRD1, O13728, O15020, O43707, O75369, O76329, O88990, O94851, O97592, P05094, P05095, P07751, P11277, P11530, P11531, P11532, P11533, P12814, P13395, P13466, P15508, P16086, P16546, P18091, P20111, P21333, P30427, P35609

SIGNOR signaling

3 interactions.

AEffectBMechanism
PTK2up-regulatesACTN4phosphorylation
PTK2down-regulatesACTN4phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 141 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
FCGR3A-mediated phagocytosis511.0×1e-02
RHOQ GTPase cycle510.7×1e-02
Regulation of PLK1 Activity at G2/M Transition69.0×7e-03
RHO GTPase Effectors86.4×7e-03
Signaling by Rho GTPases, Miro GTPases and RHOBTB3124.7×5e-03
Signaling by Rho GTPases114.4×7e-03

GO biological processes:

GO termPartnersFoldFDR
epidermal growth factor receptor signaling pathway510.9×1e-02
actin cytoskeleton organization139.0×3e-06
protein phosphorylation95.4×5e-03
negative regulation of apoptotic process134.0×5e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

ClassificationCount (floor)
Pathogenic6
Likely pathogenic11
Uncertain significance255
Likely benign169
Benign59

Top pathogenic / likely-pathogenic (17)

Variant IDHGVSClassification
235864NM_004924.6(ACTN4):c.584G>A (p.Gly195Asp)Pathogenic
2500724NM_004924.6(ACTN4):c.584G>T (p.Gly195Val)Pathogenic
2736886NM_004924.6(ACTN4):c.445ATC[1] (p.Ile150del)Pathogenic
5420NM_004924.6(ACTN4):c.763A>G (p.Lys255Glu)Pathogenic
5421NM_004924.6(ACTN4):c.776C>T (p.Thr259Ile)Pathogenic
5422NM_004924.6(ACTN4):c.784T>C (p.Ser262Pro)Pathogenic
1028308NM_004924.6(ACTN4):c.175T>C (p.Trp59Arg)Likely pathogenic
2572429NM_004924.6(ACTN4):c.493G>A (p.Ala165Thr)Likely pathogenic
3035302NM_004924.6(ACTN4):c.608A>C (p.His203Pro)Likely pathogenic
3061635NM_004924.6(ACTN4):c.506T>G (p.Leu169Arg)Likely pathogenic
3068392NM_004924.6(ACTN4):c.517T>C (p.Cys173Arg)Likely pathogenic
3236342NM_004924.6(ACTN4):c.718A>G (p.Met240Val)Likely pathogenic
3900730NM_004924.6(ACTN4):c.757G>A (p.Asp253Asn)Likely pathogenic
4084962NM_004924.6(ACTN4):c.214G>C (p.Glu72Gln)Likely pathogenic
4796795NM_004924.6(ACTN4):c.773T>C (p.Met258Thr)Likely pathogenic
599063NM_004924.6(ACTN4):c.510_512del (p.Leu171del)Likely pathogenic
599130NM_004924.6(ACTN4):c.458T>C (p.Phe153Ser)Likely pathogenic

SpliceAI

4101 predictions. Top by Δscore:

VariantEffectΔscore
19:38647905:AAGGT:Adonor_loss1.0000
19:38647906:AGGTG:Adonor_loss1.0000
19:38647907:GGTG:Gdonor_loss1.0000
19:38647908:G:GGdonor_gain1.0000
19:38647908:GT:Gdonor_loss1.0000
19:38700589:T:TAacceptor_gain1.0000
19:38700594:CCCCA:Cacceptor_loss1.0000
19:38700596:CCA:Cacceptor_loss1.0000
19:38700598:A:AGacceptor_gain1.0000
19:38700598:A:Cacceptor_loss1.0000
19:38700599:G:GAacceptor_gain1.0000
19:38700599:GA:Gacceptor_gain1.0000
19:38700599:GAC:Gacceptor_gain1.0000
19:38700599:GACC:Gacceptor_gain1.0000
19:38700599:GACCT:Gacceptor_gain1.0000
19:38700711:TCAG:Tdonor_loss1.0000
19:38700715:G:Tdonor_loss1.0000
19:38700988:T:TAacceptor_gain1.0000
19:38700990:T:TAacceptor_gain1.0000
19:38700993:A:AGacceptor_gain1.0000
19:38700994:C:Gacceptor_gain1.0000
19:38701000:A:AGacceptor_gain1.0000
19:38701000:AG:Aacceptor_gain1.0000
19:38701000:AGG:Aacceptor_gain1.0000
19:38701000:AGGG:Aacceptor_gain1.0000
19:38701001:G:GAacceptor_gain1.0000
19:38701001:GG:Gacceptor_gain1.0000
19:38701001:GGG:Gacceptor_gain1.0000
19:38701001:GGGG:Gacceptor_gain1.0000
19:38701001:GGGGA:Gacceptor_gain1.0000

AlphaMissense

6111 scored. Top likely-pathogenic:

VariantProtein changeam_pathogenicity
19:38647887:T:AW48R1.000
19:38647887:T:CW48R1.000
19:38647889:G:CW48C1.000
19:38647889:G:TW48C1.000
19:38647900:A:CQ52P1.000
19:38647901:G:CQ52H1.000
19:38647901:G:TQ52H1.000
19:38647903:G:CR53P1.000
19:38700603:T:AF56I1.000
19:38700603:T:CF56L1.000
19:38700604:T:CF56S1.000
19:38700604:T:GF56C1.000
19:38700605:C:AF56L1.000
19:38700605:C:GF56L1.000
19:38700612:T:AW59R1.000
19:38700612:T:CW59R1.000
19:38700613:G:CW59S1.000
19:38700614:G:CW59C1.000
19:38700614:G:TW59C1.000
19:38700615:T:CC60R1.000
19:38700616:G:AC60Y1.000
19:38700617:C:GC60W1.000
19:38700621:T:CS62P1.000
19:38700624:C:GH63D1.000
19:38700628:T:AL64Q1.000
19:38700628:T:CL64P1.000
19:38700678:G:AG81R1.000
19:38700678:G:CG81R1.000
19:38700678:G:TG81W1.000
19:38700679:G:AG81E1.000

dbSNP variants (sampled 300 via entrez): RS1000043704 (19:38699663 G>A,T), RS1000116175 (19:38672359 G>T), RS1000140544 (19:38689761 C>T), RS1000150687 (19:38699181 T>C), RS1000201936 (19:38654067 A>C), RS1000215632 (19:38658727 G>A,C), RS1000254141 (19:38654328 G>A), RS1000348394 (19:38682020 G>A), RS1000372966 (19:38719783 A>C), RS1000395227 (19:38647598 G>A,T), RS1000524619 (19:38693504 C>G,T), RS1000526476 (19:38678162 G>A), RS1000538274 (19:38715314 T>A), RS1000561245 (19:38655301 C>T), RS1000597214 (19:38698431 G>T)

Disease associations

OMIM: gene MIM:604638 | disease phenotypes: MIM:603278, MIM:614607

GenCC curated gene-disease

DiseaseClassificationInheritance
focal segmental glomerulosclerosis 1StrongAutosomal dominant
familial idiopathic steroid-resistant nephrotic syndromeSupportiveAutosomal dominant

Mondo (7): focal segmental glomerulosclerosis 1 (MONDO:0011303), focal segmental glomerulosclerosis (MONDO:0100313), kidney disorder (MONDO:0005240), intellectual disability, autosomal dominant 14 (MONDO:0013819), chronic kidney disease (MONDO:0005300), nephrotic syndrome (MONDO:0005377), familial idiopathic steroid-resistant nephrotic syndrome (MONDO:0019006)

Orphanet (3): Hereditary steroid-resistant nephrotic syndrome (Orphanet:656), Coffin-Siris syndrome (Orphanet:1465), OBSOLETE: Familial idiopathic steroid-resistant nephrotic syndrome with focal segmental hyalinosis (Orphanet:93213)

HPO phenotypes

27 total (27 of 27 shown, HPO-id order):

HPOTerm
HP:0000006Autosomal dominant inheritance
HP:0000093Proteinuria
HP:0000097Focal segmental glomerulosclerosis
HP:0000707Abnormality of the nervous system
HP:0000737Irritability
HP:0000822Hypertension
HP:0000969Edema
HP:0001541Ascites
HP:0001903Anemia
HP:0001945Fever
HP:0001967Diffuse mesangial sclerosis
HP:0002027Abdominal pain
HP:0002202Pleural effusion
HP:0002315Headache
HP:0002586Peritonitis
HP:0003073Hypoalbuminemia
HP:0003077Hyperlipidemia
HP:0003677Slowly progressive
HP:0003774Stage 5 chronic kidney disease
HP:0003829Typified by incomplete penetrance
HP:0004719Hyperechogenic kidneys
HP:0005565Reduced renal corticomedullary differentiation
HP:0011947Respiratory tract infection
HP:0012579Minimal change glomerulonephritis
HP:0012622Chronic kidney disease
HP:0031504Foamy urine
HP:0100539Periorbital edema

GWAS associations

9 associations (top):

StudyTraitp-value
GCST001969_30Heart rate2.000000e-06
GCST006999_4Logical memory (immediate recall) in mild cognitive impairment4.000000e-07
GCST008151_16Waist circumference7.000000e-06
GCST008160_61Waist circumference7.000000e-06
GCST009422_1Retinal venular tortuosity2.000000e-13
GCST010703_256Brain morphology (MOSTest)8.000000e-14
GCST012047_17Fasting glucose7.000000e-07
GCST90002387_53Immature fraction of reticulocytes1.000000e-09
GCST90002395_411Mean platelet volume1.000000e-14

EFO canonical traits (3, from GWAS)

EFO IDTrait name
EFO:0004874memory performance
EFO:0010554retinal vasculature measurement
EFO:0004346neuroimaging measurement

MeSH disease descriptors (5)

DescriptorNameTree numbers
D005923Glomerulosclerosis, Focal SegmentalC12.050.351.968.419.570.363.640; C12.200.777.419.570.363.660; C12.950.419.570.363.640
D007674Kidney DiseasesC12.050.351.968.419; C12.200.777.419; C12.950.419
D007676Kidney Failure, ChronicC12.050.351.968.419.780.750.500; C12.200.777.419.780.750.500; C12.950.419.780.750.500; C23.550.291.500.906.500
D009404Nephrotic SyndromeC12.050.351.968.419.630.643; C12.200.777.419.630.643; C12.950.419.630.643
C538457Segmental glomerulosclerosis (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5724737 (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

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

pChemblTypeValueUnitMolecule
6.92Kd120.3nMCHEMBL5653589
6.92ED50120.3nMCHEMBL5653589
6.28IC50530nMMOLIBRESIB
5.40Kd4006nMCHEMBL3752910
5.40ED504006nMCHEMBL3752910

PubChem BioAssay actives

3 with measured affinity, of 10 total; 3 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

CompoundAssayTypeValueUnit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide2147797: Binding affinity to human ACTN4 incubated for 45 mins by Kinobead based pull down assaykd0.1203uM
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide2178896: Inhibition of ACTN4 (unknown origin) incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysisic500.5300uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide2147797: Binding affinity to human ACTN4 incubated for 45 mins by Kinobead based pull down assaykd4.0058uM

CTD chemical–gene interactions

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

ChemicalActions (top 5)PubMed papers
bisphenol Aaffects cotreatment, increases methylation, decreases methylation, increases expression, affects expression4
Tobacco Smoke Pollutionaffects expression, decreases expression, increases expression3
Aflatoxin B1decreases expression, increases methylation, affects cotreatment3
Air Pollutantsdecreases expression, increases abundance, increases expression2
Particulate Matterdecreases expression, increases abundance, affects cotreatment, increases expression2
aristolochic acid Iincreases expression1
FR900359increases phosphorylation1
triphenyl phosphateaffects expression1
sodium arsenatedecreases expression1
pyrogallol 1,3-dimethyl etherdecreases expression, affects localization, increases expression, affects cotreatment1
quercitrinaffects expression1
beta-lapachoneincreases expression1
arseniteaffects binding, increases reaction1
sodium arsenitedecreases expression1
cobaltous chloridedecreases expression1
4-hydroxy-2-nonenalaffects binding1
aflatoxin B2increases methylation1
cupric oxideincreases expression1
beta-methylcholineaffects expression1
perfluorooctane sulfonic aciddecreases expression1
2,3,5-(triglutathion-S-yl)hydroquinoneincreases ADP-ribosylation1
CGP 52608affects binding, increases reaction1
chloropicrinincreases expression1
K 7174decreases expression1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamideaffects cotreatment, decreases expression1
bisphenol Bincreases expression1
bromovaninincreases expression1
bisphenol Sincreases expression1
LDN 193189affects cotreatment, decreases expression1
(+)-JQ1 compoundincreases expression1

ChEMBL screening assays

7 unique, capped per target: 7 binding

Representative assays (with source publication via chembl_document):

Assay IDTypeDescriptionSource paper
CHEMBL5650839BindingBinding affinity to human ACTN4 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

2 cell lines: 2 cancer cell line

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

CellosaurusNameCategorySex
CVCL_SB30HAP1 ACTN4 (-) 1Cancer cell lineMale
CVCL_XL02HAP1 ACTN4 (-) 2Cancer cell lineMale

Clinical trials (associated diseases)

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

TrialPhaseStatusTitle
NCT01129557PHASE4TERMINATEDAldosterone Breakthrough During Diovan, Tekturna, and Combination Therapy in Patients With Proteinuric Kidney Disease
NCT02399462PHASE4WITHDRAWNActhar for Treatment of Post-transplant FSGS
NCT02585804PHASE4COMPLETEDTreating to Reduce Albuminuria and Normalize Hemodynamic Function in Focal ScLerosis With dApagliflozin Trial Effects
NCT02633046PHASE4COMPLETEDActhar for Treatment-Resistant or Treatment-Intolerant Proteinuria
NCT07219121PHASE4RECRUITINGSparsentan in Posttransplant Immunoglobulin A Nephropathy or Focal Segmental Glomerulosclerosis
NCT00067990PHASE4COMPLETEDAngiotensin II Blockade for Chronic Allograft Nephropathy
NCT00117078PHASE4COMPLETEDAranesp® Monthly Preference Study - 2
NCT00117130PHASE4COMPLETEDStudy to Evaluate Effectiveness of Aranesp®
NCT00132431PHASE4COMPLETEDSTART: Sensipar Treatment Algorithm to Reach K/DOQI Targets in Chronic Kidney Disease Subjects With Secondary Hyperparathyroidism
NCT00140985PHASE4COMPLETEDAntiproteinuric Efficacy of Losartan Potassium in Patients With Non-Diabetic Proteinuric Renal Diseases (0954-213)
NCT00246129PHASE4COMPLETEDCamTac Trial:Campath-Tacrolimus vs IL2R MoAb/Tacrolimus/MMF in Renal Transplantation
NCT00275535PHASE4COMPLETEDThe Comparison of Tacrolimus and Sirolimus Immunosuppression Based Drug Regimens in Kidney Transplant Recipients
NCT00282217PHASE4COMPLETEDStudy Evaluating Sirolimus in the Treatment of Kidney Transplant
NCT00289614PHASE4COMPLETEDPatients With Renal Impairment and Diabetes Undergoing Computed Tomography (CT)
NCT00290069PHASE4UNKNOWNRenal Function Optimization With Mycophenolate Mofetil (MMF) Immunosuppressor Regimes (ALHAMBRA)
NCT00338468PHASE4TERMINATEDA Study to Assess Disability in Anemic Elderly Patients With Kidney Disease Receiving PROCRIT (Epoetin Alfa)
NCT00368901PHASE4COMPLETEDSTAAR-2 Clinical Study
NCT00369733PHASE4COMPLETEDSTAAR-3 Clinical Study
NCT00369772PHASE4COMPLETEDSTAAR-1 Clinical Study
NCT00379899PHASE4COMPLETEDADVANCE: Study to Evaluate Cinacalcet Plus Low Dose Vitamin D on Vascular Calcification in Subjects With Chronic Kidney Disease Receiving Hemodialysis
NCT00443508PHASE4UNKNOWNReduction or Discontinuation of CNI’s With Conversion to Everolimus-Based Immunosuppresion
NCT00452478PHASE4TERMINATEDConversion From Standard Phosphate Binder Therapy to Fosrenol® (Lanthanum Carbonate) in Chronic Kidney Disease Stage 5
NCT00492518PHASE4COMPLETEDAcetylcysteine, Theophylline, and a Combination of Both in the Prophylaxis of Contrast-Induced Nephropathy
NCT00505102PHASE4UNKNOWNSafe Renal Function In Long Term Heart Transplanted Patients
NCT00526331PHASE4COMPLETEDEvaluation of Arterial Pressure Based Cardiac Output for Goal-Directed Perioperative Therapy
NCT00688480PHASE4COMPLETEDDo Xanthine Oxidase Inhibitors Reduce Both Left Ventricular Hypertrophy and Endothelial Dysfunction in Cardiovascular Patients With Renal Dysfunction?
NCT00863707PHASE4COMPLETEDA Study of the Safety and Tolerance of Regadenoson in Subjects With Renal Impairment
NCT01101698PHASE4UNKNOWNVitamin K2 and Vessel Calcification in Chronic Kidney Disease Patients
NCT01150201PHASE4COMPLETEDAliskiren Combined With Losartan in Proteinuric, Non-diabetic Chronic Kidney Disease
NCT01155141PHASE4COMPLETEDIdiopathic Focal Segmental Glomerulosclerosis (FSGS) and Treatment With ACTH
NCT01228279PHASE4COMPLETEDSympathetic Activity in Patients With End-stage Renal Disease on Peritoneal Dialysis
NCT01334333PHASE4COMPLETEDComparison of Medication Adherence Between Once and Twice Daily Tacrolimus in Stable Renal Transplant Recipients
NCT01437943PHASE4TERMINATEDEffect of Short Term Aliskiren Treatment in Kidney Transplant Patients
NCT01545479PHASE4COMPLETEDIncreased Renal Oxygenation and Angiotensin Converting Enzyme Inhibition
NCT01614431PHASE4COMPLETEDN Acetyl Cysteine for Cystinosis Patients
NCT01631149PHASE4COMPLETEDEffect of Deep BLock on Intraoperative Surgical Conditions
NCT01722513PHASE4UNKNOWNEfficacy and Safety of Alprostadil Prevent Contrast Induced Nephropathy
NCT01985360PHASE4COMPLETEDISCHEMIA-Chronic Kidney Disease Trial
NCT02311010PHASE4UNKNOWNPractical Use of Advagraf de Novo After Kidney Transplantation According to Recipient Genetic Polymorphism
NCT02413073PHASE4COMPLETEDWhole Body Vibration in Kidney Disease