ACTN4

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): 619 total — 6 pathogenic, 13 likely-pathogenic (top 5% of genes corpus-wide)
• GTEx eGene: eQTL in 24 tissues, sQTL in 30 (q < 0.05)
• Phenotypes (HPO): 27
• ChEMBL bioactivity: 1 clinical-phase molecule tested; no curated mechanism-of-action drug
• Constraint (gnomAD): pLI 1.00 (loss-of-function intolerant), LOEUF 0.24 (highly constrained)
• MANE Select transcript: NM_004924
• Interaction hub: 2,276 STRING partners (top 5% of genes corpus-wide)

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:166
Approved symbol	ACTN4
Name	actinin alpha 4
Location	19q13.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000130402
Ensembl biotype	protein_coding
OMIM	604638
Entrez	81

Gene structure

Transcript identifiers

Ensembl transcripts: 36 — 24 protein_coding, 7 nonsense_mediated_decay, 4 retained_intron, 1 protein_coding_CDS_not_defined

MANE Select: ENST00000252699

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 4, TSL 2: 2, TSL 3: 2, TSL 5: 2

ENST00000252699, ENST00000390009, ENST00000424234, ENST00000440400, ENST00000477174, ENST00000489451, ENST00000495553, ENST00000497637, ENST00000588618, ENST00000589528, ENST00000697712, ENST00000871324, ENST00000871325, ENST00000871326, ENST00000871327, ENST00000871328, ENST00000871329, ENST00000871330, ENST00000871331, ENST00000871332, ENST00000871333, ENST00000871334, ENST00000871335, ENST00000871336, ENST00000924368, ENST00000924369, ENST00000924370, ENST00000924371, ENST00000995584, ENST00001008846, ENST00001008848, ENST00001060825, ENST00001060826, ENST00001060827, ENST00001060828, ENST00001134039

RefSeq mRNA: 7 — MANE Select: NM_004924 NM_001322033, NM_001411143, NM_001440296, NM_001440298, NM_001440299, NM_001440300, NM_004924

CCDS: CCDS12518, CCDS92610, CCDS92611

Canonical transcript exons

ENST00000252699 — 21 exons

Exon	Start	End
ENSE00000895774	38727946	38728026
ENSE00000895777	38724431	38724565
ENSE00000895778	38724157	38724339
ENSE00000895779	38723937	38724077
ENSE00000895780	38723614	38723722
ENSE00000895781	38721538	38721688
ENSE00001909908	38647649	38647907
ENSE00002256794	38725724	38725903
ENSE00002529868	38726957	38727103
ENSE00003478716	38708117	38708195
ENSE00003521050	38717927	38718074
ENSE00003542253	38701002	38701121
ENSE00003563841	38709395	38709476
ENSE00003590443	38706044	38706131
ENSE00003605223	38700600	38700714
ENSE00003612741	38710257	38710342
ENSE00003616079	38728996	38729154
ENSE00003622921	38714469	38714561
ENSE00003628896	38704934	38705020
ENSE00003790855	38717086	38717316
ENSE00003842835	38729274	38731589

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.

Highest expression (Bgee): popliteal artery, tibial artery, smooth muscle tissue, coronary artery, artery.

Genetic regulation across tissues (GTEx eQTL / sQTL)

ACTN4 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 24 tissues and its splicing (sQTL) in 30 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 54 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Whole Blood	sqtl	5.2e-38	+0.64	19:38704443:C:G
Nerve Tibial	sqtl	3.6e-33	+0.56	19:38742506:A:G
Colon Transverse	sqtl	1.0e-30	+0.72	19:38697424:C:G
Skin Sun Exposed Lower leg	sqtl	1.2e-30	+0.46	19:38695589:T:C
Thyroid	sqtl	1.2e-29	+0.58	19:38704443:C:G
Muscle Skeletal	sqtl	1.8e-24	+0.54	19:38706945:A:G
Adipose Subcutaneous	sqtl	3.2e-24	+0.43	19:38694182:T:G
Esophagus Mucosa	sqtl	1.4e-23	+0.54	19:38708981:T:C
Muscle Skeletal	eqtl	1.3e-21	+0.19	19:38653604:C:T
Cells EBV-transformed lymphocytes	sqtl	2.6e-21	-0.85	19:38704443:C:G
Artery Tibial	eqtl	2.6e-17	+0.13	19:38659595:A:G
Lung	sqtl	3.5e-17	+0.40	19:38704674:T:G
Heart Atrial Appendage	sqtl	2.2e-15	+0.49	19:38742506:A:G
Artery Aorta	sqtl	3.2e-14	+0.39	19:38696745:A:G
Adipose Subcutaneous	eqtl	2.0e-12	+0.16	19:38677120:T:C
Breast Mammary Tissue	sqtl	2.4e-12	+0.39	19:38691272:A:G
Cells Cultured fibroblasts	eqtl	3.5e-12	+0.13	19:38659595:A:G
Small Intestine Terminal Ileum	sqtl	1.3e-10	-0.73	19:38742506:A:G
Spleen	sqtl	2.8e-10	+0.71	19:38749579:C:T
Heart Atrial Appendage	eqtl	3.0e-10	+0.18	19:38756336:G:A

FANTOM5 promoters

4 alternative TSS:

Promoter ID	TPM avg	Samples expressed
175645	59.6754	1824
175646	37.4462	1803
175650	0.6088	365
175654	0.1057	47

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
popliteal artery	UBERON:0002250	99.48	gold quality
tibial artery	UBERON:0007610	99.48	gold quality
smooth muscle tissue	UBERON:0001135	99.43	gold quality
right coronary artery	UBERON:0001625	99.43	gold quality
artery	UBERON:0001637	99.43	gold quality
aorta	UBERON:0000947	99.41	gold quality
stromal cell of endometrium	CL:0002255	99.39	gold quality
ascending aorta	UBERON:0001496	99.33	gold quality
thoracic aorta	UBERON:0001515	99.32	gold quality
placenta	UBERON:0001987	99.30	gold quality
body of uterus	UBERON:0009853	99.27	gold quality
islet of Langerhans	UBERON:0000006	99.26	gold quality
myometrium	UBERON:0001296	99.18	gold quality
lower esophagus mucosa	UBERON:0035834	99.11	gold quality
descending thoracic aorta	UBERON:0002345	99.07	gold quality
left coronary artery	UBERON:0001626	99.04	gold quality
duodenum	UBERON:0002114	99.04	gold quality
fallopian tube	UBERON:0003889	98.99	gold quality
vermiform appendix	UBERON:0001154	98.96	gold quality
esophagus mucosa	UBERON:0002469	98.96	gold quality
metanephros cortex	UBERON:0010533	98.95	gold quality
vagina	UBERON:0000996	98.94	gold quality
left uterine tube	UBERON:0001303	98.94	gold quality
ectocervix	UBERON:0012249	98.94	gold quality
right lung	UBERON:0002167	98.91	gold quality
skin of leg	UBERON:0001511	98.90	gold quality
upper lobe of left lung	UBERON:0008952	98.90	gold quality
esophagus	UBERON:0001043	98.88	gold quality
transverse colon	UBERON:0001157	98.88	gold quality
rectum	UBERON:0001052	98.86	gold quality
zone of skin	UBERON:0000014	98.85	gold quality
right uterine tube	UBERON:0001302	98.81	gold quality
left adrenal gland	UBERON:0001234	98.80	gold quality
left adrenal gland cortex	UBERON:0035825	98.79	gold quality
gall bladder	UBERON:0002110	98.78	gold quality
lower esophagus	UBERON:0013473	98.78	gold quality
lower esophagus muscularis layer	UBERON:0035833	98.78	gold quality
skin of abdomen	UBERON:0001416	98.77	gold quality
adrenal gland	UBERON:0002369	98.75	gold quality
subcutaneous adipose tissue	UBERON:0002190	98.74	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	98.73	gold quality
right adrenal gland	UBERON:0001233	98.72	gold quality
small intestine	UBERON:0002108	98.72	gold quality
nerve	UBERON:0001021	98.71	gold quality
tibial nerve	UBERON:0001323	98.71	gold quality
small intestine Peyer’s patch	UBERON:0003454	98.71	gold quality
uterine cervix	UBERON:0000002	98.70	gold quality
lung	UBERON:0002048	98.69	gold quality
mucosa of transverse colon	UBERON:0004991	98.69	gold quality
right adrenal gland cortex	UBERON:0035827	98.67	gold quality
cortex of kidney	UBERON:0001225	98.66	gold quality
urinary bladder	UBERON:0001255	98.65	gold quality
mammary gland	UBERON:0001911	98.65	gold quality
thoracic mammary gland	UBERON:0005200	98.65	gold quality
sural nerve	UBERON:0015488	98.64	gold quality
adipose tissue	UBERON:0001013	98.63	gold quality
minor salivary gland	UBERON:0001830	98.63	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	98.63	gold quality
saliva-secreting gland	UBERON:0001044	98.62	gold quality
mucosa of stomach	UBERON:0001199	98.60	gold quality
adult mammalian kidney	UBERON:0000082	98.57	gold quality
intestine	UBERON:0000160	98.56	gold quality
colon	UBERON:0001155	98.56	gold quality
kidney	UBERON:0002113	98.54	gold quality
colonic epithelium	UBERON:0000397	98.52	gold quality
endocervix	UBERON:0000458	98.50	gold quality
fundus of stomach	UBERON:0001160	98.49	gold quality
omental fat pad	UBERON:0010414	98.46	gold quality
adrenal tissue	UBERON:0018303	98.45	gold quality
body of stomach	UBERON:0001161	98.40	gold quality
prostate gland	UBERON:0002367	98.40	gold quality
stomach	UBERON:0000945	98.37	gold quality
right lobe of thyroid gland	UBERON:0001119	98.30	gold quality
apex of heart	UBERON:0002098	98.23	gold quality
thyroid gland	UBERON:0002046	98.21	gold quality
spleen	UBERON:0002106	98.20	gold quality
muscle layer of sigmoid colon	UBERON:0035805	98.18	gold quality
left lobe of thyroid gland	UBERON:0001120	98.16	gold quality
tonsil	UBERON:0002372	98.03	gold quality
pancreas	UBERON:0001264	98.01	gold quality
ovary	UBERON:0000992	97.99	gold quality
granulocyte	CL:0000094	97.95	gold quality
left ovary	UBERON:0002119	97.91	gold quality
monocyte	CL:0000576	97.89	gold quality
leukocyte	CL:0000738	97.89	gold quality
right ovary	UBERON:0002118	97.88	gold quality
adenohypophysis	UBERON:0002196	97.70	gold quality
lymph node	UBERON:0000029	97.65	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	97.62	gold quality
pituitary gland	UBERON:0000007	97.61	gold quality
primary visual cortex	UBERON:0002436	97.51	gold quality
right atrium auricular region	UBERON:0006631	97.51	gold quality
material anatomical entity	UBERON:0000465	97.44	gold quality
multicellular organism	UBERON:0000468	97.44	gold quality
anatomical system	UBERON:0000467	97.43	gold quality
heart	UBERON:0000948	97.36	gold quality
bone marrow	UBERON:0002371	97.35	gold quality
bone element	UBERON:0001474	97.34	gold quality
body of pancreas	UBERON:0001150	97.32	gold quality
blood	UBERON:0000178	97.29	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-HCAD-11	yes	18.97
E-HCAD-10	yes	18.91
E-HCAD-13	yes	7.47
E-GEOD-137537	yes	6.11
E-CURD-112	no	2.51
E-ANND-3	no	0.00

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 79 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Choroid plexus	tissue	182.6
Vagina	tissue	170.5	low
Duodenum	tissue	157.9	medium
Small intestine	tissue	156.8	medium
Esophagus	tissue	130.5	low
Corpus callosum	tissue	120.9
Putamen	tissue	111.3
Placenta	tissue	110.7	high
Spleen	tissue	110.1	medium
Spinal cord	tissue	110.1
Superior colliculi	tissue	107.4
Frontal cortex	tissue	105.5
Smooth muscle	tissue	101.5	medium
Basal ganglia	tissue	100.9	not detected
Cerebral cortex	tissue	99.9	medium
Motor cortex	tissue	99.9
Substantia nigra	tissue	97.9
Somatosensory cortex	tissue	97.2
Salivary gland	tissue	96.5	medium
Colon	tissue	96.2	high
Prefrontal cortex	tissue	93.8
Medulla oblongata	tissue	93.4
Nucleus accumbens	tissue	93.3
Midbrain	tissue	93.3
Lung	tissue	93.1	high
Occipital cortex	tissue	92.7
Stomach 1	tissue	92.2	medium
Pancreas	tissue	89.7	medium
Postcentral gyrus	tissue	87.6
Bone marrow	tissue	87.0
Temporal cortex	tissue	85.4
Thalamus	tissue	84.9
Locus coeruleus	tissue	84.5
Insular cortex	tissue	84.4
Ventral forebrain	tissue	83.7
Retrosplenial and cingulate cortex	tissue	83.5
Hippocampal formation	tissue	83.1
Entorhinal cortex	tissue	83.1
Retrosplenial cortex	tissue	83.0
Adrenal gland	tissue	81.2	medium
Adipose tissue	tissue	80.5	not detected
Urinary bladder	tissue	78.7	high
Skin 1	tissue	77.9	medium
Pons	tissue	77.6
Olfactory bulb	tissue	77.5
Seminal vesicle	tissue	77.1	medium
Endometrium 1	tissue	77.1	medium
Appendix	tissue	76.8	medium
Fallopian tube	tissue	76.3	medium
Caudate putamen	tissue	74.5
Pituitary gland	tissue	74.4
Kidney	tissue	70.1	medium
Periaqueductal gray	tissue	69.1
Hippocampus	tissue	67.3	not detected
Hypothalamus	tissue	63.0
Ovary	tissue	62.9	low
Septum	tissue	58.6
Gallbladder	tissue	58.4	medium
Rectum	tissue	57.5	medium
Parathyroid gland	tissue	56.6	low

Brain sub-regions (HPA Brain Atlas): detected in 191; highest nTPM — Blood vessel (539.7), Parieto-temporal junction (white matter) (179.5), Temporal white matter (162.7), Corpus callosum, splenium (white matter) (161.1), Cerebellar white matter (154.8).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): HDAC7

miRNA regulators (miRDB)

Targeting ACTN4 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 125 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509

Functional genomics

gnomAD constraint: pLI 1, LOEUF 0.238, missense Z 5.69 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000252699 splits into 3 regions with different missense tolerance; 0 are missense-constrained. Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
19:38,647,746–38,647,903	72 / 75.6	0.95	no
19:38,647,904–38,714,511	127 / 311.3	0.41	no
19:38,714,512–38,729,429	523 / 875.9	0.60	no

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

Organism	Symbol	Gene ID
mus_musculus	Actn4	ENSMUSG00000054808
rattus_norvegicus	Actn4	ENSRNOG00000020433

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)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1890773) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 64 distinct phenotype terms.

Mouse phenotype (MP)	Records
albuminuria	2
overriding aortic valve	1
double outlet right ventricle	1
abnormal atrioventricular cushion morphology	1
short snout	1
cortical renal glomerulopathies	1
dilated liver sinusoidal space	1
abnormal forebrain morphology	1
absent superior cervical ganglion	1
small superior cervical ganglion	1
weight loss	1
abnormal retina morphology	1
postnatal growth retardation	1
premature death	1
dilated renal tubule	1
abnormal vein morphology	1
increased heart weight	1
increased urine microalbumin level	1
increased urine protein level	1
small kidney	1
abnormal lens epithelium morphology	1
biliary cyst	1
kidney failure	1
abnormal eye muscle morphology	1
abnormal Mullerian duct morphology	1

+39 more (showing top 25).

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Macaca fascicularis	Q2PFV7	99.9%	Diamond
Pongo abelii	Q5RCS6	99.8%	Diamond
Pan troglodytes	Q2KNA1	99.7%	Diamond
Bos taurus	Q3B7N2	99.6%	Diamond
Gallus gallus	P05094	98.3%	Diamond
Cricetulus griseus	Q9JI55	94.7%	Diamond
Canis lupus familiaris	O97592	94.6%	Diamond
Sus scrofa	Q5GN48	94.6%	Diamond
Drosophila melanogaster	Q9VDW6	91.8%	Diamond
Anopheles gambiae	Q7PKQ5	90.1%	Diamond
Takifugu rubripes	Q2KN94	89.2%	Diamond
Tetraodon nigroviridis	Q2KN95	89.2%	Diamond
Dermatophagoides farinae	L7UZ85	80.5%	Diamond
Dictyostelium discoideum	Q550R2	79.0%	Diamond
Heterostelium album PN500	Q9Y0T3	79.0%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
MAP4K1	protein-coding	11184
RASGRP4	protein-coding	115727
TSLIG3C	protein-coding	147965
EIF3K	protein-coding	27335
RYR1	protein-coding	6261
MAP4K1-AS1	ncRNA	105372397
CAPN12	protein-coding	147968
LGALS7	protein-coding	3963
LGALS7B	protein-coding	653499

Protein

Protein identifiers

Alpha-actinin-4 — O43707 (reviewed: O43707)

Alternative names: Non-muscle alpha-actinin 4

All UniProt accessions (6): A0A0S2Z3G9, A0A8V8TL71, F5GXS2, O43707, 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 ID	Names	Canonical?
O43707-1	1	yes
O43707-2	ACTN4ISO
O43707-3	3

RefSeq proteins (7): NP_001308962, NP_001398072, NP_001427225, NP_001427227, NP_001427228, NP_001427229, NP_004915* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001589	Actinin_actin-bd_CS	Conserved_site
IPR001715	CH_dom	Domain
IPR002017	Spectrin_repeat	Repeat
IPR002048	EF_hand_dom	Domain
IPR011992	EF-hand-dom_pair	Homologous_superfamily
IPR014837	EF-hand_Ca_insen	Domain
IPR018159	Spectrin/alpha-actinin	Repeat
IPR018247	EF_Hand_1_Ca_BS	Binding_site
IPR036872	CH_dom_sf	Homologous_superfamily

Pfam: PF00307, PF00435, PF08726

UniProt features (86 total): helix 20, 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, chain 1, short sequence motif 1, mutagenesis site 1, turn 1

Structure

Experimental structures (PDB)

5 structures by resolution:

PDB	Title	Method	Resolution (Å)
6OA6	CRYSTAL STRUCTURE OF THE ACTIN-BINDING DOMAIN OF HUMAN ALPHA-ACTININ-4	X-RAY DIFFRACTION	1.37
6O31	CRYSTAL STRUCTURE OF THE ACTIN-BINDING DOMAIN OF HUMAN ALPHA-ACTININ-4	X-RAY DIFFRACTION	1.51
1YDI	Human Vinculin Head Domain (VH1, 1-258) in Complex with Human Alpha-Actinin’s …	X-RAY DIFFRACTION	1.8
2R0O	Crystal structure of the actin-binding domain of human alpha-actinin-4 mutant(K255E)	X-RAY DIFFRACTION	2.2
1WLX	Solution structure of the third spectrin repeat of alpha-actinin-4	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43707-F1	84.66	0.48

Human Protein Atlas

Protein class: Predicted intracellular proteins, Plasma proteins, Disease related genes, Human disease related genes

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): actin filaments; focal adhesion sites; cytosol; primary cilium; primary cilium transition zone

Antibody reliability (HPA): IH supported · IF approved

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)

Position	Role
778	Ca(2+)
780	Ca(2+)
789	Ca(2+)

Post-translational modifications (10)

Type	Positions
Phosphotyrosine	31
N6-acetyllysine	114, 214, 592, 625, 779, 859
Phosphothreonine	249
Phosphoserine	696, 909

Mutagenesis-validated functional residues (1)

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

Function

Pathways and Gene Ontology

Reactome pathways

1 curated (TAS) of 6; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

6 pathways:

ID	Pathway	Evidence
R-HSA-114608	Platelet degranulation	curated
R-HSA-1500931	Cell-Cell communication	—
R-HSA-109582	Hemostasis	—
R-HSA-373753	Nephrin family interactions	electronic
R-HSA-76002	Platelet activation, signaling and aggregation	—
R-HSA-76005	Response 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 (19): stress fiber (GO:0001725), extracellular region (GO:0005576), 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), anchoring junction (GO:0070161)

Reactome top-level categories

4 top-level categories:

Category	Pathways
Response to elevated platelet cytosolic Ca2+	1
Cell-Cell communication	1
Hemostasis	1
Platelet activation, signaling and aggregation	1

GO top-level categories

showing 60 of 72 GO namespaces:

Category	Terms
cellular anatomical structure	6
nuclear receptor-mediated signaling pathway	2
positive regulation of DNA-templated transcription	2
protein-containing complex binding	2
protein binding	2
actin cytoskeleton	2
transport	1
intracellular protein localization	1
establishment of protein localization	1
cytoskeleton organization	1
actin filament-based process	1
actin filament-based movement	1
actin filament-based transport	1
vesicle cytoskeletal trafficking	1
cell migration	1
regulation of cell migration	1
positive regulation of cell motility	1
sodium:proton antiporter activity	1
positive regulation of sodium ion transmembrane transporter activity	1
cytokine-mediated signaling pathway	1
cellular response to tumor necrosis factor	1
apoptotic process	1
regulation of programmed cell death	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
hormone-mediated signaling pathway	1
muscle cell differentiation	1
cell development	1
negative regulation of cell-substrate adhesion	1
substrate adhesion-dependent cell spreading	1
regulation of substrate adhesion-dependent cell spreading	1
non-canonical NF-kappaB signal transduction	1
regulation of non-canonical NF-kappaB signal transduction	1
positive regulation of intracellular signal transduction	1
transcription cis-regulatory region binding	1
carbohydrate derivative binding	1
heterocyclic compound binding	1
transcription coregulator activity	1
nucleic acid binding	1
cytoskeletal protein binding	1
signaling receptor binding	1
cell adhesion molecule binding	1
metal ion binding	1
RNA polymerase II-specific DNA-binding transcription factor binding	1
DNA binding	1
chromatin binding	1
identical protein binding	1
protein dimerization activity	1
nuclear receptor binding	1
actin binding	1
binding	1
cation binding	1
actomyosin	1
contractile actin filament bundle	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
membrane	1
cell periphery	1
cell-substrate junction	1
cytoskeleton	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 27 of 49 annotations. The rest are phylogenetic / computational / electronic (IEA).

27 experimentally-supported GO terms:

GO term	NS	Evidence
negative regulation of substrate adhesion-dependent cell spreading	BP	mutant phenotype
peroxisome proliferator activated receptor signaling pathway	BP	direct assay
positive regulation of cell migration	BP	mutant phenotype
positive regulation of non-canonical NF-kappaB signal transduction	BP	mutant phenotype
positive regulation of transcription by RNA polymerase II	BP	mutant phenotype
retinoic acid receptor signaling pathway	BP	direct assay
tumor necrosis factor-mediated signaling pathway	BP	direct assay
vesicle transport along actin filament	BP	mutant phenotype
actin cytoskeleton	CC	direct assay
cytoplasm	CC	direct assay
extracellular exosome	CC	high-throughput assay
focal adhesion	CC	high-throughput assay
nucleus	CC	direct assay
perinuclear region of cytoplasm	CC	direct assay
postsynaptic actin cytoskeleton	CC	direct assay
protein-containing complex	CC	direct assay
ribonucleoprotein complex	CC	direct assay
RNA binding	MF	high-throughput assay
RNA polymerase II transcription regulatory region sequence-specific DNA binding	MF	direct assay
actin filament binding	MF	direct assay
chromatin DNA binding	MF	direct assay
nuclear receptor binding	MF	physical interaction
nuclear retinoic acid receptor binding	MF	physical interaction
nucleoside binding	MF	direct assay
protein homodimerization activity	MF	physical interaction
transcription coactivator activity	MF	mutant phenotype
transmembrane transporter binding	MF	physical interaction

Protein interactions and networks

STRING

showing 15 of 2,276 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ACTN4	SYNPO	Q8N3V7	925
ACTN4	NPHS1	O60500	919
ACTN4	CD2AP	Q9Y5K6	885
ACTN4	INF2	Q27J81	879
ACTN4	NPHS2	Q9NP85	875
ACTN4	TRPC6	Q9Y210	830
ACTN4	PLCE1	Q9P212	815
ACTN4	TRIM3	O75382	796
ACTN4	FSCN1	Q16658	790
ACTN4	CAPN12	Q6ZSI9	786
ACTN4	WT1	P19544	773
ACTN4	MAGI1	Q96QZ7	769
ACTN4	PDLIM1	O00151	761
ACTN4	MYH9	P35579	740
ACTN4	VCL	P18206	726

IntAct

Human interaction partners of ACTN4 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

showing 30 of 51 partners by confidence:

Partner	Interaction type	MIscore	Records
MYOZ2	physical association	0.930	16
PDLIM1	association	0.800	5
CTNNB1	association	0.680	7
SORBS2	physical association	0.600	4
TJP1	association	0.600	4
IQGAP1	colocalization	0.600	3
NP	physical association	0.590	12
ACTN3	physical association	0.560	3
BMP7	physical association	0.560	3
C14orf119	physical association	0.560	3
LCMT2	physical association	0.560	3
LNX1	physical association	0.560	3
MEOX2	physical association	0.560	3
MICALL2	physical association	0.560	3
EGFR	physical association	0.550	2
PDLIM7	association	0.530	1
NHERF2	association	0.510	2
CDH1	physical association	0.500	2
TXN	physical association	0.440	2
RARA	physical association	0.400	1
SCRIB	physical association	0.400	1
YWHAZ	physical association	0.400	1
ECE1	physical association	0.370	3
ATXN7	physical association	0.370	1
HSPB1	physical association	0.370	1
KPNA2	physical association	0.370	1
MAPK7	physical association	0.370	1
MYOZ1	physical association	0.370	1
NOS3	physical association	0.370	1
POT1	physical association	0.370	1

BioGRID (567 interactions; top human partners by supporting records): ACTN1 (Affinity Capture-MS; 15 records), PDLIM1 (Affinity Capture-MS; 7 records), ACTN2 (Cross-Linking-MS (XL-MS); 6 records), MYOZ2 (Two-hybrid; 6 records), HGS (Co-localization; 5 records), EGFR (Two-hybrid; 4 records), MEF2A (Affinity Capture-Western; 4 records), TRIM3 (Affinity Capture-MS; 4 records), ACTB (Proximity Label-MS; 3 records), ACTN3 (Two-hybrid; 3 records), ANLN (Affinity Capture-MS; 3 records), DDX39B (Affinity Capture-MS; 3 records), HDAC7 (Two-hybrid; 3 records), ISG15 (Affinity Capture-MS; 3 records), RNF38 (Affinity Capture-Western; 3 records)

SIGNOR signaling

showing 2 of 3 signaling interactions:

A	Effect	B	Mechanism
PTK2	up-regulates	ACTN4	phosphorylation
PTK2	down-regulates	ACTN4	phosphorylation

Protein complexes (CORUM) (12)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

12 complexes by size:

Complex	Subunits	Members
★ P2X7 receptor signalling complex	12	ACTB, ACTN4, HSP90AB1, HSPA1A, PI4KA, PTPRB, SVIL, HSPA8, ITGB2, LAMA3, MPP3, P2RX7
CART complex	4	HGS, MYO5B, TRIM3, ACTN4
Ternary complex (ACTN4, CAMK2A, LRRC7)	3	CAMK2A, LRRC7, ACTN4
★ ACTN4-NHERF2-SLC9A3 complex	3	ACTN4, NHERF2, SLC9A3
★ ACTN4-HDAC7 complex	2	ACTN4, HDAC7
★ ACTN4-HDAC4 complex	2	ACTN4, HDAC4
★ ACTN4-HDAC5 complex	2	ACTN4, HDAC5
SLC9A3R1-ACTN4 complex	2	ACTN4, NHERF1
★ ACTN4-PPARG complex	2	ACTN4, PPARG
★ ACTN4-RARA complex	2	ACTN4, RARA
★ ACTN4-VDR complex	2	ACTN4, VDR
★ ACTN4-ESR1 complex	2	ESR1, ACTN4

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 51 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Signaling by Interleukins	5	8.7×	7e-03
Cytokine Signaling in Immune system	7	7.7×	2e-03
Signaling by Rho GTPases	7	6.5×	3e-03
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	7	6.3×	4e-03

GO biological processes:

GO term	Partners	Fold	FDR
epidermal growth factor receptor signaling pathway	5	26.4×	5e-04
actin cytoskeleton organization	7	11.8×	6e-04
cell-cell adhesion	5	10.8×	6e-03
negative regulation of cell population proliferation	7	6.3×	7e-03
negative regulation of apoptotic process	8	5.9×	5e-03

Disease & clinical

Genetic variants

Variant evidence for ACTN4: 619 ClinVar records (19 pathogenic / likely pathogenic); 9 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	13
Uncertain significance	258
Likely benign	182
Benign	55

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 19 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
5420	NM_004924.6(ACTN4):c.763A>G (p.Lys255Glu)	Pathogenic	criteria provided, multiple submitters, no conflicts	3
5421	NM_004924.6(ACTN4):c.776C>T (p.Thr259Ile)	Pathogenic	criteria provided, single submitter	2
2500724	NM_004924.6(ACTN4):c.584G>T (p.Gly195Val)	Pathogenic	criteria provided, single submitter	1
2736886	NM_004924.6(ACTN4):c.445ATC[1] (p.Ile150del)	Pathogenic	criteria provided, single submitter	1
1028308	NM_004924.6(ACTN4):c.175T>C (p.Trp59Arg)	Likely pathogenic	criteria provided, single submitter	1
2572429	NM_004924.6(ACTN4):c.493G>A (p.Ala165Thr)	Likely pathogenic	criteria provided, single submitter	1
3068392	NM_004924.6(ACTN4):c.517T>C (p.Cys173Arg)	Likely pathogenic	criteria provided, single submitter	1
3236342	NM_004924.6(ACTN4):c.718A>G (p.Met240Val)	Likely pathogenic	criteria provided, single submitter	1
3900730	NM_004924.6(ACTN4):c.757G>A (p.Asp253Asn)	Likely pathogenic	criteria provided, single submitter	1
4084962	NM_004924.6(ACTN4):c.214G>C (p.Glu72Gln)	Likely pathogenic	criteria provided, single submitter	1
4796795	NM_004924.6(ACTN4):c.773T>C (p.Met258Thr)	Likely pathogenic	criteria provided, single submitter	1
4876734	NM_004924.6(ACTN4):c.2338-5G>A	Likely pathogenic	criteria provided, single submitter	1
4942209	NM_004924.6(ACTN4):c.494C>T (p.Ala165Val)	Likely pathogenic	criteria provided, single submitter	1
5422	NM_004924.6(ACTN4):c.784T>C (p.Ser262Pro)	Pathogenic	no assertion criteria provided	1
235864	NM_004924.6(ACTN4):c.584G>A (p.Gly195Asp)	Pathogenic	no assertion criteria provided	1

Per-variant reference — Sugi Variant

Explore ACTN4’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 31 predictions of 1,980):

Position(s)	Effect	Δscore	Sites
19:38647908	donor_loss	1.0000
19:38700589	acceptor_gain	1.0000
19:38700598–38700599	acceptor_loss	1.0000	5
19:38700715–38700716	donor_loss	1.0000	5
19:38700994	acceptor_gain	1.0000
19:38701000–38701001	acceptor_loss	1.0000	5
19:38701001	acceptor_gain	1.0000
19:38701122–38701123	donor_loss	1.0000	5
19:38704925	acceptor_gain	1.0000
19:38704932–38704933	acceptor_loss	1.0000	6

AlphaMissense

3,697 missense substitutions predicted likely pathogenic (of 6,111 scored), across 763 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M141	9	0.985	1.000
M258	9	0.979	1.000
M240	9	0.977	1.000
M295	9	0.956	0.993
M104	9	0.939	0.999
M883	9	0.934	0.998
M145	9	0.897	1.000
M835	9	0.854	0.984
F56	8	0.999	1.000
D136	8	0.999	1.000
D253	8	0.999	1.000
F188	8	0.998	1.000
F153	8	0.997	1.000
D45	8	0.996	0.998
H205	8	0.996	1.000
H266	8	0.996	1.000
H107	8	0.995	1.000
N111	8	0.995	1.000
N187	8	0.994	1.000
H189	8	0.994	0.999

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

1 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	7.31e-09

Disease associations

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

GenCC curated gene-disease

2 curated gene-disease records:

Disease	Classification	Inheritance	Records
focal segmental glomerulosclerosis 1	Strong	Autosomal dominant	3
familial idiopathic steroid-resistant nephrotic syndrome	Supportive	Autosomal dominant

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (3 panels, 3 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

3 panels:

Panel	Rating
Proteinuric renal disease	green
Unexplained kidney failure in young people	green
Unexplained young onset end-stage renal disease	green

Mondo (2): focal segmental glomerulosclerosis 1 (MONDO:0011303), familial idiopathic steroid-resistant nephrotic syndrome (MONDO:0019006)

Orphanet (2): Hereditary steroid-resistant nephrotic syndrome (Orphanet:656), OBSOLETE: Familial idiopathic steroid-resistant nephrotic syndrome with focal segmental hyalinosis (Orphanet:93213)

HPO phenotypes

27 phenotypes (HPO-id order):

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

GWAS associations

9 associations:

Study	Trait	p-value
GCST90002395_321	Mean platelet volume	1e-14
GCST010703_208	Brain morphology (MOSTest)	8e-14
GCST009422_1	Retinal venular tortuosity	2e-13
GCST90002387_20	Immature fraction of reticulocytes	1e-9
GCST006999_4	Logical memory (immediate recall) in mild cognitive impairment	4e-7
GCST012047_17	Fasting glucose	7e-7
GCST001969_30	Heart rate	2e-6
GCST008151_16	Waist circumference	7e-6
GCST008160_68	Waist circumference	7e-6

EFO canonical traits (from GWAS)

3 canonical traits:

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

MeSH disease descriptors

1 disease descriptors:

Descriptor	Name	Tree numbers
C538457	Segmental glomerulosclerosis *(supp.)*

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5724737 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,601 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

1 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL1232461	MOLIBRESIB	2	1,601

PharmGKB: 1 entry (CPIC guideline: no)

Binding affinities (BindingDB)

1 measured of 1 human assays (3 total across all organisms); most potent 1 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
CHEMBL5653589	KD	1440 nM

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
6.92	Kd	120.3	nM	CHEMBL5653589
6.92	ED50	120.3	nM	CHEMBL5653589
6.28	IC50	530	nM	MOLIBRESIB
5.40	Kd	4006	nM	CHEMBL3752910
5.40	ED50	4006	nM	CHEMBL3752910

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.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147797: Binding affinity to human ACTN4 incubated for 45 mins by Kinobead based pull down assay	kd	0.1203	uM
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2178896: Inhibition of ACTN4 (unknown origin) incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	ic50	0.5300	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147797: Binding affinity to human ACTN4 incubated for 45 mins by Kinobead based pull down assay	kd	4.0058	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, affects cotreatment, increases methylation, decreases methylation, increases expression	4
Tobacco Smoke Pollution	affects expression, decreases expression, increases expression	3
Aflatoxin B1	affects cotreatment, decreases expression, increases methylation	3
Particulate Matter	decreases expression, increases abundance, affects cotreatment, increases expression, affects expression	3
Air Pollutants	decreases expression, increases abundance, increases expression	2
aristolochic acid I	increases expression	1
FR900359	increases phosphorylation	1
triphenyl phosphate	affects expression	1
sodium arsenate	decreases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, decreases expression, affects localization, increases expression	1
quercitrin	affects expression	1
beta-lapachone	increases expression	1
arsenite	affects binding, increases reaction	1
sodium arsenite	decreases expression	1
cobaltous chloride	decreases expression	1
4-hydroxy-2-nonenal	affects binding	1
aflatoxin B2	increases methylation	1
cupric oxide	increases expression	1
beta-methylcholine	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
2,3,5-(triglutathion-S-yl)hydroquinone	increases ADP-ribosylation	1
CGP 52608	affects binding, increases reaction	1
chloropicrin	increases expression	1
K 7174	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
bisphenol B	increases expression	1
bromovanin	increases expression	1
bisphenol S	increases expression	1
LDN 193189	affects cotreatment, decreases expression	1
(+)-JQ1 compound	increases expression	1

ChEMBL screening assays

7 unique, capped per target: 7 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5650839	Binding	Binding affinity to human ACTN4 incubated for 45 mins by Kinobead based pull down assay	NVP-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):

Cellosaurus	Name	Category	Sex
CVCL_SB30	HAP1 ACTN4 (-) 1	Cancer cell line	Male
CVCL_XL02	HAP1 ACTN4 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

showing 60 of 300 trials:

NCT	Phase	Status	Title
NCT01129557	Phase 4	TERMINATED	Aldosterone Breakthrough During Diovan, Tekturna, and Combination Therapy in Patients With Proteinuric Kidney Disease
NCT02399462	Phase 4	WITHDRAWN	Acthar for Treatment of Post-transplant FSGS
NCT02585804	Phase 4	COMPLETED	Treating to Reduce Albuminuria and Normalize Hemodynamic Function in Focal ScLerosis With dApagliflozin Trial Effects
NCT02633046	Phase 4	COMPLETED	Acthar for Treatment-Resistant or Treatment-Intolerant Proteinuria
NCT07219121	Phase 4	ACTIVE_NOT_RECRUITING	Sparsentan in Posttransplant Immunoglobulin A Nephropathy or Focal Segmental Glomerulosclerosis
NCT00067990	Phase 4	COMPLETED	Angiotensin II Blockade for Chronic Allograft Nephropathy
NCT00117078	Phase 4	COMPLETED	Aranesp® Monthly Preference Study - 2
NCT00117130	Phase 4	COMPLETED	Study to Evaluate Effectiveness of Aranesp®
NCT00132431	Phase 4	COMPLETED	START: Sensipar Treatment Algorithm to Reach K/DOQI Targets in Chronic Kidney Disease Subjects With Secondary Hyperparathyroidism
NCT00140985	Phase 4	COMPLETED	Antiproteinuric Efficacy of Losartan Potassium in Patients With Non-Diabetic Proteinuric Renal Diseases (0954-213)
NCT00246129	Phase 4	COMPLETED	CamTac Trial:Campath-Tacrolimus vs IL2R MoAb/Tacrolimus/MMF in Renal Transplantation
NCT00275535	Phase 4	COMPLETED	The Comparison of Tacrolimus and Sirolimus Immunosuppression Based Drug Regimens in Kidney Transplant Recipients
NCT00282217	Phase 4	COMPLETED	Study Evaluating Sirolimus in the Treatment of Kidney Transplant
NCT00289614	Phase 4	COMPLETED	Patients With Renal Impairment and Diabetes Undergoing Computed Tomography (CT)
NCT00290069	Phase 4	UNKNOWN	Renal Function Optimization With Mycophenolate Mofetil (MMF) Immunosuppressor Regimes (ALHAMBRA)
NCT00338468	Phase 4	TERMINATED	A Study to Assess Disability in Anemic Elderly Patients With Kidney Disease Receiving PROCRIT (Epoetin Alfa)
NCT00368901	Phase 4	COMPLETED	STAAR-2 Clinical Study
NCT00369733	Phase 4	COMPLETED	STAAR-3 Clinical Study
NCT00369772	Phase 4	COMPLETED	STAAR-1 Clinical Study
NCT00379899	Phase 4	COMPLETED	ADVANCE: Study to Evaluate Cinacalcet Plus Low Dose Vitamin D on Vascular Calcification in Subjects With Chronic Kidney Disease Receiving Hemodialysis
NCT00443508	Phase 4	UNKNOWN	Reduction or Discontinuation of CNI’s With Conversion to Everolimus-Based Immunosuppresion
NCT00452478	Phase 4	TERMINATED	Conversion From Standard Phosphate Binder Therapy to Fosrenol® (Lanthanum Carbonate) in Chronic Kidney Disease Stage 5
NCT00492518	Phase 4	COMPLETED	Acetylcysteine, Theophylline, and a Combination of Both in the Prophylaxis of Contrast-Induced Nephropathy
NCT00505102	Phase 4	UNKNOWN	Safe Renal Function In Long Term Heart Transplanted Patients
NCT00526331	Phase 4	COMPLETED	Evaluation of Arterial Pressure Based Cardiac Output for Goal-Directed Perioperative Therapy
NCT00688480	Phase 4	COMPLETED	Do Xanthine Oxidase Inhibitors Reduce Both Left Ventricular Hypertrophy and Endothelial Dysfunction in Cardiovascular Patients With Renal Dysfunction?
NCT00863707	Phase 4	COMPLETED	A Study of the Safety and Tolerance of Regadenoson in Subjects With Renal Impairment
NCT01101698	Phase 4	UNKNOWN	Vitamin K2 and Vessel Calcification in Chronic Kidney Disease Patients
NCT01150201	Phase 4	COMPLETED	Aliskiren Combined With Losartan in Proteinuric, Non-diabetic Chronic Kidney Disease
NCT01155141	Phase 4	COMPLETED	Idiopathic Focal Segmental Glomerulosclerosis (FSGS) and Treatment With ACTH
NCT01228279	Phase 4	COMPLETED	Sympathetic Activity in Patients With End-stage Renal Disease on Peritoneal Dialysis
NCT01334333	Phase 4	COMPLETED	Comparison of Medication Adherence Between Once and Twice Daily Tacrolimus in Stable Renal Transplant Recipients
NCT01437943	Phase 4	TERMINATED	Effect of Short Term Aliskiren Treatment in Kidney Transplant Patients
NCT01545479	Phase 4	COMPLETED	Increased Renal Oxygenation and Angiotensin Converting Enzyme Inhibition
NCT01614431	Phase 4	COMPLETED	N Acetyl Cysteine for Cystinosis Patients
NCT01631149	Phase 4	COMPLETED	Effect of Deep BLock on Intraoperative Surgical Conditions
NCT01722513	Phase 4	UNKNOWN	Efficacy and Safety of Alprostadil Prevent Contrast Induced Nephropathy
NCT01985360	Phase 4	COMPLETED	ISCHEMIA-Chronic Kidney Disease Trial
NCT02311010	Phase 4	UNKNOWN	Practical Use of Advagraf de Novo After Kidney Transplantation According to Recipient Genetic Polymorphism
NCT02413073	Phase 4	COMPLETED	Whole Body Vibration in Kidney Disease
NCT02444013	Phase 4	UNKNOWN	Folic Acid for Prevention of Contrast Induced Nephropathy
NCT02663713	Phase 4	COMPLETED	A Randomized, Pharmacodynamic Comparison of Low Dose Ticagrelor to Clopidogrel in Patients With Prior Myocardial Infarction
NCT02707809	Phase 4	COMPLETED	Effects of Dexmedetomidine on Microcirculation of Kidney Transplant Recipient
NCT02761577	Phase 4	COMPLETED	A Prospective Study on Incidence and Prevention of Contrast-induced Nephropathy in Croatia
NCT03029351	Phase 4	TERMINATED	GLP-1 Receptor Agonist Therapy and Albuminuria in Patients With Type 2 Diabetes
NCT03160729	Phase 4	TERMINATED	High vs Low Dose Dexamethasone on Complications in the Immediate Postoperative Phase After Nephrectomy
NCT03387826	Phase 4	COMPLETED	Low Dose Ticagrelor Versus Low Dose Prasugrel in Patients With Prior Myocardial Infarction
NCT03623568	Phase 4	WITHDRAWN	Direct Acting Antiviral Therapy in Donor HCV-positive to Recipient HCV-negative Kidney Transplant
NCT04080076	Phase 4	WITHDRAWN	Comparative and Efficacy Study of ACTHar Gel Alone or in Combination With Tacrolimus in Fibrillary Glomerulopathy
NCT04539418	Phase 4	COMPLETED	Vitamin K2 Supplementation and Vascular Calcification
NCT04653779	Phase 4	UNKNOWN	A Clinical Trial to Evaluate the Preference Regarding Convenience of Medication and Efficacy/Safety of SUGAMET®XR Tablet 5/1000mg
NCT04839536	Phase 4	UNKNOWN	Comparing Sevoflurane With Propofol Sedation in ESRF Patients
NCT05030974	Phase 4	COMPLETED	RECOVAC Repeated Vaccination Study
NCT05096195	Phase 4	ACTIVE_NOT_RECRUITING	PRevEnting FracturEs in REnal Disease - 1
NCT05700903	Phase 4	TERMINATED	Contributions to Hypertension With Androgen Deprivation Therapy
NCT06291077	Phase 4	RECRUITING	Comparison of the Effects of Belatacept and Anticalcineurins on Endothelial Function in Renal Transplant Patients -
NCT06625073	Phase 4	RECRUITING	Randomized Trial of SGLT2i in Heart Transplant Recipients
NCT06642623	Phase 4	RECRUITING	A Prospective Trial of Enavogliflozin to Evaluate Cardio-renal Outcome in Type 2 Diabetes Mellitus Patients
NCT07138521	Phase 4	NOT_YET_RECRUITING	Optimizing Linezolid Dosing in Patients With Advanced Renal Impairment: a Therapeutic Drug Monitoring-based Evaluation
NCT07182422	Phase 4	RECRUITING	AST-120 (Kremezin®) for the Renal Protection and Attenuation of Decline in Acute Kidney Disease

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for ACTN4 across ~30M SureChEMBL compounds — explore on Sugi Predict.