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28 sources retrieved Β· Most recent: April 2026 Β· Index updated 14 days ago
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ACTN4
actinin alpha 4
Chromosome 19 Β· 19q13.2
NCBI Gene: 81Ensembl: ENSG00000130402.14HGNC: HGNC:166UniProt: A0A0S2Z3G9
414PubMed Papers
21Diseases
0Drugs
17Pathogenic Variants
FUNCTIONAL ROLE
Highly ConstrainedHub GeneTransporter
RESEARCH IMPACT
Highly StudiedTrending
CLINICAL
OMIM Disease Gene
DATA QUALITY
βœ“ Experimental GO Evidenceβœ“ Swiss-Prot Reviewed
nucleusRNA polymerase II transcription regulatory region sequence-specific DNA bindingnucleoside bindingtranscription coactivator activityfocal segmental glomerulosclerosis 1familial idiopathic steroid-resistant nephrotic syndromeneurodegenerative diseasefocal segmental glomerulosclerosis
✦AI Summary

ACTN4 (actinin alpha 4) is a non-muscle F-actin cross-linking protein that anchors actin to intracellular structures and functions as an actin bundling protein. Primary functions include cytoskeletal organization, with roles in vesicular trafficking via the CART complex for transferrin receptor recycling, and tight junction assembly in epithelial cells 1. ACTN4 also possesses transcriptional coactivator activity, stimulating nuclear hormone receptor-mediated transcription 2, and regulates immune synapse formation through IGSF8 interaction, required for T-cell activation 3. Mechanistically, ACTN4 regulates multiple signaling pathways. It interacts with HDAC5, which deacetylates ACTN4 at K417 to enable nuclear translocation and modulation of YBX1 transcriptional activity during wound healing 4. In cancer contexts, ACTN4 promotes tumor progression through epithelial-mesenchymal transition and metastasis 5. The CCT3/ACTN4/TFRC axis regulates ferroptosis in hepatocellular carcinoma by controlling iron endocytosis 6, while PDLIM1 competitively binds ACTN4 to regulate Hippo signaling and suppress HCC metastasis 7. CircACTN4 promotes intrahepatic cholangiocarcinoma through miR-424-5p sponging and YBX1-mediated FZD7 transcription 8. Clinically, ACTN4 variants associate with preeclampsia and hypertensive pregnancy disorders, linking to placental development, spiral artery remodeling, and kidney function 9. ACTN4 is also implicated in aortic aneurysm pathogenesis through vascular smooth muscle cell gene expression 10.

Sources cited
1
Primary functions include cytoskeletal organization, with roles in vesicular trafficking via the CART complex for transferrin receptor recycling, and tight junction assembly in epithelial cells .
PMID: 15772161
2
ACTN4 also possesses transcriptional coactivator activity, stimulating nuclear hormone receptor-mediated transcription , and regulates immune synapse formation through IGSF8 interaction, required for T-cell activation .
PMID: 22351778
3
ACTN4 also possesses transcriptional coactivator activity, stimulating nuclear hormone receptor-mediated transcription , and regulates immune synapse formation through IGSF8 interaction, required for T-cell activation .
PMID: 22689882
4
It interacts with HDAC5, which deacetylates ACTN4 at K417 to enable nuclear translocation and modulation of YBX1 transcriptional activity during wound healing .
PMID: 41442502
5
In cancer contexts, ACTN4 promotes tumor progression through epithelial-mesenchymal transition and metastasis .
PMID: 31766144
6
The CCT3/ACTN4/TFRC axis regulates ferroptosis in hepatocellular carcinoma by controlling iron endocytosis , while PDLIM1 competitively binds ACTN4 to regulate Hippo signaling and suppress HCC metastasis .
PMID: 39210442
7
The CCT3/ACTN4/TFRC axis regulates ferroptosis in hepatocellular carcinoma by controlling iron endocytosis , while PDLIM1 competitively binds ACTN4 to regulate Hippo signaling and suppress HCC metastasis .
PMID: 31509262
8
CircACTN4 promotes intrahepatic cholangiocarcinoma through miR-424-5p sponging and YBX1-mediated FZD7 transcription .
PMID: 34509526
9
Clinically, ACTN4 variants associate with preeclampsia and hypertensive pregnancy disorders, linking to placental development, spiral artery remodeling, and kidney function .
PMID: 37285119
10
ACTN4 is also implicated in aortic aneurysm pathogenesis through vascular smooth muscle cell gene expression .
PMID: 36172868
Disease Associationsβ“˜21
focal segmental glomerulosclerosis 1Open Targets
0.78Strong
familial idiopathic steroid-resistant nephrotic syndromeOpen Targets
0.39Weak
neurodegenerative diseaseOpen Targets
0.28Weak
focal segmental glomerulosclerosisOpen Targets
0.20Weak
genetic disorderOpen Targets
0.19Weak
kidney diseaseOpen Targets
0.15Weak
hypertension, pregnancy-inducedOpen Targets
0.15Weak
preeclampsiaOpen Targets
0.14Weak
nephrotic syndromeOpen Targets
0.13Weak
chronic kidney diseaseOpen Targets
0.12Weak
Transient global amnesiaOpen Targets
0.12Weak
breast cancerOpen Targets
0.10Suggestive
hepatocellular carcinomaOpen Targets
0.10Suggestive
neoplasmOpen Targets
0.08Suggestive
posterior cortical atrophyOpen Targets
0.08Suggestive
osteosarcomaOpen Targets
0.08Suggestive
salivary gland carcinomaOpen Targets
0.08Suggestive
pulmonary arterial hypertensionOpen Targets
0.07Suggestive
nail-patella-like renal diseaseOpen Targets
0.06Suggestive
nephrotic syndrome, type 20Open Targets
0.06Suggestive
Focal segmental glomerulosclerosis 1UniProt
Pathogenic Variants17
NM_004924.6(ACTN4):c.763A>G (p.Lys255Glu)Pathogenic
Focal segmental glomerulosclerosis 1|not provided
β˜…β˜…β˜†β˜†2024β†’ Residue 255
NM_004924.6(ACTN4):c.773T>C (p.Met258Thr)Likely pathogenic
Focal segmental glomerulosclerosis 1
β˜…β˜†β˜†β˜†2026β†’ Residue 258
NM_004924.6(ACTN4):c.214G>C (p.Glu72Gln)Likely pathogenic
not provided
β˜…β˜†β˜†β˜†2025β†’ Residue 72
NM_004924.6(ACTN4):c.757G>A (p.Asp253Asn)Likely pathogenic
Focal segmental glomerulosclerosis 1
β˜…β˜†β˜†β˜†2025β†’ Residue 253
NM_004924.6(ACTN4):c.718A>G (p.Met240Val)Likely pathogenic
Focal segmental glomerulosclerosis 1
β˜…β˜†β˜†β˜†2024β†’ Residue 240
NM_004924.6(ACTN4):c.517T>C (p.Cys173Arg)Likely pathogenic
Focal segmental glomerulosclerosis 1
β˜…β˜†β˜†β˜†2024β†’ Residue 173
NM_004924.6(ACTN4):c.445ATC[1] (p.Ile150del)Pathogenic
not provided
β˜…β˜†β˜†β˜†2023β†’ Residue 150
NM_004924.6(ACTN4):c.584G>T (p.Gly195Val)Pathogenic
Focal segmental glomerulosclerosis 1
β˜…β˜†β˜†β˜†2022β†’ Residue 195
NM_004924.6(ACTN4):c.175T>C (p.Trp59Arg)Likely pathogenic
Focal segmental glomerulosclerosis 1
β˜…β˜†β˜†β˜†2020β†’ Residue 59
NM_004924.6(ACTN4):c.776C>T (p.Thr259Ile)Pathogenic
Focal segmental glomerulosclerosis 1|not provided
β˜…β˜†β˜†β˜†2019β†’ Residue 259
NM_004924.6(ACTN4):c.493G>A (p.Ala165Thr)Likely pathogenic
Focal segmental glomerulosclerosis 1
β˜…β˜†β˜†β˜†β†’ Residue 165
NM_004924.6(ACTN4):c.608A>C (p.His203Pro)Likely pathogenic
ACTN4-related disorder
β˜†β˜†β˜†β˜†2024β†’ Residue 203
NM_004924.6(ACTN4):c.506T>G (p.Leu169Arg)Likely pathogenic
ACTN4-related disorder
β˜†β˜†β˜†β˜†2023β†’ Residue 169
NM_004924.6(ACTN4):c.458T>C (p.Phe153Ser)Likely pathogenic
Focal segmental glomerulosclerosis 1
β˜†β˜†β˜†β˜†2018β†’ Residue 153
NM_004924.6(ACTN4):c.510_512del (p.Leu171del)Likely pathogenic
Focal segmental glomerulosclerosis 1
β˜†β˜†β˜†β˜†2018β†’ Residue 171
NM_004924.6(ACTN4):c.584G>A (p.Gly195Asp)Pathogenic
Focal segmental glomerulosclerosis 1
β˜†β˜†β˜†β˜†2017β†’ Residue 195
NM_004924.6(ACTN4):c.784T>C (p.Ser262Pro)Pathogenic
Focal segmental glomerulosclerosis 1
β˜†β˜†β˜†β˜†2000β†’ Residue 262
View on ClinVar β†—
Related Genes
ACTBProtein interaction100%ACTG1Protein interaction100%CTNNA1Protein interaction100%ZYXProtein interaction100%TPM2Protein interaction100%VCLProtein interaction100%
Tissue Expression6 tissues
Lung
100%
Ovary
50%
Bone Marrow
47%
Brain
45%
Liver
43%
Heart
37%
Gene Interaction Network
Click a node to explore
ACTN4ACTBACTG1CTNNA1ZYXTPM2VCL
PROTEIN STRUCTURE
Preparing viewer…
PDB6OA6 Β· 1.37 Γ… Β· X-ray
View on RCSB β†—
Constraintβ“˜
LOEUFβ“˜
0.24Highly Constrained
pLIβ“˜
1.00Intolerant
Observed/Expected LoF0.16 [0.11–0.24]
RankingsWhere ACTN4 stands among ~20K protein-coding genes
  • #689of 20,598
    Most Researched414 Β· top 5%
  • #2,311of 5,498
    Most Pathogenic Variants17
  • #686of 17,882
    Most Constrained (LOEUF)0.24 Β· top 5%
Genes detectedACTN4
Sources retrieved28 papers
Response timeβ€”
πŸ“„ Sources
28β–Ό
1
Genetic Risk Factors Associated With Preeclampsia and Hypertensive Disorders of Pregnancy.
PMID: 37285119
JAMA Cardiol Β· 2023
1.00
2
Chitinase-3 like-protein-1 promotes glioma progression via the NF-ΞΊB signaling pathway and tumor microenvironment reprogramming.
PMID: 36276655
Theranostics Β· 2022
0.90
3
HDAC5 deacetylates cytosolic ACTN4 during skin reepithelialization and represents a therapeutic target for chronic wound healing.
PMID: 41442502
Sci Transl Med Β· 2025
0.80
4
The FSGS protein actinin-4 interacts with NKCC2 to regulate thick ascending limb NaCl reabsorption.
PMID: 39446130
Am J Physiol Renal Physiol Β· 2024
0.80
5
ACTN4 Gene Amplification and Actinin-4 Protein Expression for Osimertinib Efficacy in EGFR-Mutant NSCLC.
PMID: 41074261
Cancer Sci Β· 2025
0.72