ACTN3

Summary

ACTN3 (actinin alpha 3, HGNC:165) is a protein-coding gene on chromosome 11q13.2, encoding Alpha-actinin-3 (Q08043). F-actin cross-linking protein which is thought to anchor actin to a variety of intracellular structures.

This gene encodes a member of the alpha-actin binding protein gene family. The encoded protein is primarily expressed in skeletal muscle and functions as a structural component of sarcomeric Z line. This protein is involved in crosslinking actin containing thin filaments. An allelic polymorphism in this gene results in both coding and non-coding variants; the reference genome represents the coding allele. The non-functional allele of this gene is associated with elite athlete status.

Source: NCBI Gene 89 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 256 total — 3 pathogenic, 2 likely-pathogenic
• GTEx eGene: eQTL in 31 tissues, sQTL in 2 (q < 0.05)
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 0.94 (unconstrained)
• MANE Select transcript: NM_001104
• Notable: 256 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:165
Approved symbol	ACTN3
Name	actinin alpha 3
Location	11q13.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000248746
Ensembl biotype	protein_coding
OMIM	102574
Entrez	89

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 4 protein_coding, 4 nonsense_mediated_decay

MANE Select: ENST00000513398

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

ENST00000513398, ENST00000502692, ENST00000511191, ENST00000968415, ENST00000968416, ENST00001035400, ENST00001035401, ENST00001087961

RefSeq mRNA: 2 — MANE Select: NM_001104 NM_001104, NM_001258371

CCDS: CCDS53663, CCDS76439

Canonical transcript exons

ENST00000513398 — 21 exons

Exon	Start	End
ENSE00002024928	66558027	66558174
ENSE00002029405	66546903	66547084
ENSE00002034197	66559236	66559386
ENSE00002036344	66562257	66562322
ENSE00002047828	66562796	66562954
ENSE00002048744	66559968	66560076
ENSE00002055836	66556145	66556230
ENSE00002064960	66560573	66560755
ENSE00002065625	66561227	66561361
ENSE00002066762	66560171	66560311
ENSE00002078726	66561458	66561637
ENSE00002084177	66557133	66557225
ENSE00002449334	66551239	66551353
ENSE00002449997	66554536	66554623
ENSE00002486281	66557699	66557929
ENSE00002505409	66555130	66555208
ENSE00002512334	66555286	66555367
ENSE00002515453	66562022	66562168
ENSE00003613315	66551528	66551647
ENSE00003640449	66554045	66554131
ENSE00004787902	66563035	66563334

Expression profiles

Bgee: expression breadth ubiquitous, 146 present calls, max score 99.72.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 2.2926 / max 760.8658, expressed in 169 samples.

Highest expression (Bgee): skeletal muscle tissue of rectus abdominis, skeletal muscle tissue of biceps brachii, diaphragm, vastus lateralis, biceps brachii.

Genetic regulation across tissues (GTEx eQTL / sQTL)

ACTN3 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 31 tissues and its splicing (sQTL) in 2 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 33 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Muscle Skeletal	eqtl	1.1e-134	-0.73	11:66560624:C:T
Testis	eqtl	4.5e-47	-0.57	11:66560624:C:T
Thyroid	eqtl	9.7e-44	+0.66	11:66561023:G:GTTA
Esophagus Muscularis	eqtl	5.5e-35	-0.64	11:66560624:C:T
Artery Aorta	eqtl	1.1e-29	-0.71	11:66560624:C:T
Artery Tibial	eqtl	1.6e-28	-0.53	11:66560624:C:T
Nerve Tibial	eqtl	4.8e-28	+0.57	11:66561023:G:GTTA
Adipose Subcutaneous	eqtl	3.0e-26	-0.55	11:66560624:C:T
Colon Sigmoid	eqtl	9.8e-26	+0.66	11:66561023:G:GTTA
Cells Cultured fibroblasts	eqtl	9.4e-23	+0.49	11:66561023:G:GTTA
Esophagus Gastroesophageal Junction	eqtl	6.6e-22	-0.64	11:66560624:C:T
Adipose Visceral Omentum	eqtl	1.4e-21	-0.53	11:66560624:C:T
Muscle Skeletal	sqtl	8.1e-21	-0.53	11:66560624:C:T
Breast Mammary Tissue	eqtl	1.2e-19	+0.56	11:66561023:G:GTTA
Colon Transverse	eqtl	2.0e-19	+0.49	11:66560202:G:A
Heart Atrial Appendage	eqtl	2.4e-13	-0.51	11:66560624:C:T
Skin Not Sun Exposed Suprapubic	eqtl	6.8e-09	+0.37	11:66562261:A:G
Skin Sun Exposed Lower leg	eqtl	9.8e-09	+0.33	11:66562261:A:G
Esophagus Mucosa	eqtl	3.5e-08	-0.36	11:66560624:C:T
Artery Coronary	eqtl	9.1e-07	+0.46	11:66568077:A:G

FANTOM5 promoters

1 alternative TSS:

Promoter ID	TPM avg	Samples expressed
115346	2.2926	169

Top tissues by expression

showing 100 of 273 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	99.72	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	98.98	gold quality
diaphragm	UBERON:0001103	98.84	gold quality
vastus lateralis	UBERON:0001379	96.69	gold quality
biceps brachii	UBERON:0001507	96.62	gold quality
quadriceps femoris	UBERON:0001377	96.34	gold quality
skeletal muscle tissue	UBERON:0001134	96.24	gold quality
hindlimb stylopod muscle	UBERON:0004252	95.18	gold quality
gastrocnemius	UBERON:0001388	93.63	gold quality
muscle organ	UBERON:0001630	93.41	gold quality
triceps brachii	UBERON:0001509	93.08	gold quality
muscle of leg	UBERON:0001383	92.31	gold quality
muscle tissue	UBERON:0002385	88.56	gold quality
deltoid	UBERON:0001476	87.59	gold quality
tibialis anterior	UBERON:0001385	82.69	gold quality
gluteal muscle	UBERON:0002000	81.38	gold quality
sperm	CL:0000019	67.22	gold quality
oocyte	CL:0000023	66.81	silver quality
right testis	UBERON:0004534	66.58	gold quality
left testis	UBERON:0004533	66.50	gold quality
trabecular bone tissue	UBERON:0002483	66.46	gold quality
male germ cell	CL:0000015	65.93	gold quality
secondary oocyte	CL:0000655	64.93	gold quality
synovial joint	UBERON:0002217	64.82	gold quality
testis	UBERON:0000473	64.36	gold quality
body of tongue	UBERON:0011876	63.40	gold quality
vena cava	UBERON:0004087	62.08	gold quality
pancreatic ductal cell	CL:0002079	59.76	silver quality
decidua	UBERON:0002450	59.03	gold quality
tongue	UBERON:0001723	58.66	silver quality
apex of heart	UBERON:0002098	58.58	gold quality
jejunum	UBERON:0002115	57.50	gold quality
granulocyte	CL:0000094	56.92	gold quality
endometrium epithelium	UBERON:0004811	56.87	gold quality
endothelial cell	CL:0000115	56.72	gold quality
pharyngeal mucosa	UBERON:0000355	54.85	gold quality
myocardium	UBERON:0002349	53.77	gold quality
bone marrow cell	CL:0002092	53.74	gold quality
epithelium of esophagus	UBERON:0001976	53.49	gold quality
esophagus squamous epithelium	UBERON:0006920	53.31	gold quality
cerebellar hemisphere	UBERON:0002245	53.05	gold quality
cerebellar cortex	UBERON:0002129	52.81	gold quality
cerebellum	UBERON:0002037	52.58	gold quality
hair follicle	UBERON:0002073	52.43	gold quality
parotid gland	UBERON:0001831	52.41	gold quality
ileal mucosa	UBERON:0000331	52.11	gold quality
layer of synovial tissue	UBERON:0007616	51.81	silver quality
superior surface of tongue	UBERON:0007371	51.48	silver quality
right hemisphere of cerebellum	UBERON:0014890	51.36	gold quality
lateral nuclear group of thalamus	UBERON:0002736	51.28	gold quality
stromal cell of endometrium	CL:0002255	51.16	silver quality
epithelial cell of pancreas	CL:0000083	51.15	gold quality
squamous epithelium	UBERON:0006914	50.81	gold quality
popliteal artery	UBERON:0002250	50.70	gold quality
tibial artery	UBERON:0007610	50.65	gold quality
frontal pole	UBERON:0002795	50.41	gold quality
middle frontal gyrus	UBERON:0002702	50.30	gold quality
lower esophagus muscularis layer	UBERON:0035833	50.24	gold quality
lower esophagus	UBERON:0013473	50.20	gold quality
paraflocculus	UBERON:0005351	50.18	gold quality
Brodmann (1909) area 10	UBERON:0013541	50.18	gold quality
muscle layer of sigmoid colon	UBERON:0035805	50.17	gold quality
aorta	UBERON:0000947	50.15	gold quality
Brodmann (1909) area 46	UBERON:0006483	49.89	gold quality
right ovary	UBERON:0002118	49.76	gold quality
metanephric glomerulus	UBERON:0004736	49.61	gold quality
left coronary artery	UBERON:0001626	49.59	gold quality
coronary artery	UBERON:0001621	49.50	gold quality
ascending aorta	UBERON:0001496	49.48	gold quality
thymus	UBERON:0002370	49.48	gold quality
thoracic aorta	UBERON:0001515	49.43	gold quality
mucosa of stomach	UBERON:0001199	49.30	gold quality
cerebellar vermis	UBERON:0004720	49.25	gold quality
cervix squamous epithelium	UBERON:0006922	49.20	gold quality
cervix epithelium	UBERON:0004801	48.94	gold quality
oviduct epithelium	UBERON:0004804	48.93	gold quality
olfactory bulb	UBERON:0002264	48.92	gold quality
type B pancreatic cell	CL:0000169	48.83	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	48.75	gold quality
blood	UBERON:0000178	48.70	gold quality
cardiac muscle of right atrium	UBERON:0003379	48.55	gold quality
sigmoid colon	UBERON:0001159	48.51	gold quality
CA1 field of hippocampus	UBERON:0003881	48.50	gold quality
embryo	UBERON:0000922	48.46	gold quality
medial globus pallidus	UBERON:0002477	48.41	gold quality
left ventricle myocardium	UBERON:0006566	48.24	gold quality
orbitofrontal cortex	UBERON:0004167	48.20	gold quality
kidney epithelium	UBERON:0004819	48.11	gold quality
upper arm skin	UBERON:0004263	48.06	gold quality
urinary bladder	UBERON:0001255	48.00	gold quality
tongue squamous epithelium	UBERON:0006919	47.92	gold quality
myometrium	UBERON:0001296	47.83	gold quality
mucosa of urinary bladder	UBERON:0001259	47.80	gold quality
fundus of stomach	UBERON:0001160	47.72	gold quality
descending thoracic aorta	UBERON:0002345	47.63	gold quality
nasal cavity epithelium	UBERON:0005384	47.56	gold quality
nephron tubule	UBERON:0001231	47.30	gold quality
bone marrow	UBERON:0002371	47.29	gold quality
heart left ventricle	UBERON:0002084	47.26	gold quality
anatomical system	UBERON:0000467	47.24	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	2.93

HPA expression

RNA tissue specificity: Tissue enriched

29 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM
Skeletal muscle	tissue	1567.3
Tongue	tissue	21.7
Testis	tissue	2.2
Esophagus	tissue	1.1
Nucleus accumbens	tissue	1.1
Locus coeruleus	tissue	0.8
Hippocampus	tissue	0.8
Frontal cortex	tissue	0.6
Postcentral gyrus	tissue	0.5
Prostate	tissue	0.4
Caudate putamen	tissue	0.3
Retina	tissue	0.2
Vagina	tissue	0.2
Choroid plexus	tissue	0.2
Prefrontal cortex	tissue	0.1
Cerebral cortex	tissue	0.1
Seminal vesicle	tissue	0.1
Medulla oblongata	tissue	0.1
Thalamus	tissue	0.1
Hypothalamus	tissue	0.1
Superior colliculi	tissue	0.1
Cerebellum	tissue	0.1
Gallbladder	tissue	0.1
Spinal cord	tissue	0.1
Hippocampal formation	tissue	0.1
Periaqueductal gray	tissue	0.1
Olfactory bulb	tissue	0.1
Septum	tissue	0.1
Appendix	tissue	0.1

Brain sub-regions (HPA Brain Atlas): detected in 186; highest nTPM — Flocculonodular lobe (3.0), Cerebellar cortex (2.8), Vermis (2.7), Parieto-temporal junction (white matter) (1.8), Temporal white matter (1.7).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

Targeting ACTN3 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

5 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-92B-5P	99.36	63.29	110
HSA-MIR-3925-5P	99.21	67.90	1466
HSA-MIR-892C-5P	99.16	70.56	2116
HSA-MIR-153-3P	98.96	72.51	1644
HSA-MIR-4691-3P	98.11	66.83	1204

Functional genomics

gnomAD constraint: pLI 1.16e-24, LOEUF 0.944, missense Z -0.338 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000513398 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
11:66,546,938–66,554,588	239 / 231.8	1.03	no
11:66,554,589–66,555,359	48 / 83.4	0.58	no
11:66,555,360–66,563,190	934 / 899.9	1.04	no

Literature-anchored findings (GeneRIF, showing 40)

• REIVIEW: function and evolutionary history of the ACTN3 gene and other alpha-actinin family members (PMID:15221860)
• ACTN3 is one of many genes contributing to genetic variation in muscle performance and adaptation to exercise. (PMID:15718405)
• Data report the crystal structure of the actin binding domain of human muscle alpha-actinin-3, which is formed by two consecutive calponin homology domains arranged in a “closed” conformation. (PMID:15808860)
• Subjects possessing the ACTN3-deficient genotype (XX) had lower baseline CK compared with the heterozygotes (P = 0.035). (PMID:15817725)
• We determined mitochondrial DNA (mtDNA) and ACTN3 genotypes in Finnish elite endurance (n = 52) and sprint (n = 89) athletes, and found that the frequencies of mtDNA haplogroups differed significantly between the two groups (PMID:15886711)
• In a study of adolescent Greeks there is a significant association between the ACTN3 R577X polymorphism and 40 m sprint time in males that accounts for phenotypic variance, with the 577R allele contributing to faster times in an additive manner. (PMID:17033684)
• the ACTN3 R577X polymorphism influences the response of quadriceps muscle power to strength training in older adults (PMID:17339648)
• In women with McArdle’s disease, ACTN3 genotypes might partly explain the large individual variability that exists in the phenotypic manifestation of this disorder (PMID:17560787)
• the R577X polymorphism within the ACTN3 gene was not associated with ultra-endurance performance in the 2000 and 2001 South African Ironman Triathlons (PMID:17627799)
• The mechanism by which the ACTN3 polymorphism has its effect on muscle power, relies on a control function of fiber type proportions. (PMID:17848603)
• alpha-actinin-3 deficiency is not a major influence on performance in African athletes (PMID:17986906)
• results indicate that the ACTN3 R577X nonsense allele (X) is under-represented in elite strength athletes, consistent with previous reports indicating that alpha-actinin-3 deficiency appears to impair muscle performance (PMID:18043716)
• ACTN3 R577X polymorphism was associated with power athlete status in Russians. (PMID:18470530)
• the shift towards more efficient aerobic muscle metabolism associated with alpha-actinin-3 deficiency also underlies the adaptive benefit of the 577X allele (PMID:18637739)
• in world-class cyclists, we only found an association between ACTN3 genotypes and ventilatory threshold and peak power output, and between ACTN3/ACE genotype combinations and respiratory compensation threshold (PMID:18651373)
• Knee extensor functional and contractile properties, including high-velocity strength, were not influenced by ACE and ACTN3 polymorphisms in a cohort of United Kingdom Caucasian males. (PMID:18676575)
• actinin-3 participate in sequestering parafibromin in the cytoplasmic compartment (PMID:18687124)
• data suggest that alpha-actinin-3 deficiency may negatively influence sports performance in Russian endurance athletes. (PMID:18718976)
• ACTN3 genotype is associated with muscle phenotypes in women across the adult age span. (PMID:18756004)
• The authors observed that Opc-expressing bacteria interacted with a 100 kDa protein in whole-cell lysates of human endothelial and epithelial cells. The identity of the protein was established as alpha-actinin by mass spectrometry. (PMID:19016781)
• The ACTN3 polymorphism may influence declines in certain measures of physical performance with aging but the influence of the ACTN3 R577X polymorphism does not appear to have a strong effect on skeletal muscle-related phenotypes. (PMID:19038838)
• ACTN3 genotype may modulate responsiveness to exercise training. (PMID:19150855)
• Association between the ACTN3 R577X polymorphism and artistic gymnastic performance in Italy is reported. (PMID:19405879)
• the ACTN3 R allele is associated with top-level sprint performance and the X allele and XX genotypes may not be critical but rather additive to endurance performance (PMID:19544227)
• The main finding of our study was that the ACTN3 R577X polymorphism does not seem to influence the ability to produce peak (explosive) power in nonathletic, young adults of both genders. (PMID:19807896)
• sprinter performance is determined by the interaction between the wild-type HIF1A Pro/Pro genotype and ACTN3 RR genotype (PMID:20005538)
• ACTN3 XX genotype is negatively associated with elite sprint athlete status, the underlying low frequency in these populations eliminates the possibility of replicating this association in Jamaican and US African American sprinters. (PMID:20010124)
• data suggest that ACE ID/ ACTN3 R577X genotype combination is associated with sprint ability. However, ACE ID/ ACTN3 R577X genotype combination is not related to the level of performance (PMID:20013558)
• ACTN3 R/X polymorphisms were not associated with muscle function or muscularity phenotypes in older Caucasian men. (PMID:20069311)
• We propose that the alteration in GPh activity in the absence of alpha-actinin-3 is a fundamental mechanistic link in the association between ACTN3 genotype and human performance. (PMID:20089531)
• The researchers found no significant evidence that genetic polymorphisms, such as ACTN3, significantly influence muscle phenotypes in a group of nonagenarians. (PMID:20148371)
• The results show that ACTN3 R577X polymorphism influences the size of the thigh muscles of older women. (PMID:20222007)
• Study suggests a protective role of alpha-actinin-3 protein in muscle damage after eccentric training and an improved stress-sensor signaling, although effects are small. (PMID:20507967)
• Examined the association of R577X polymorphism (rs1815739) in the alpha-actinin-3 (ACTN3) gene with “explosive” leg muscle power performance. Findings suggest that the ACTN3 R577X polymorphism does not influence explosive leg muscle power. (PMID:20561285)
• The presence of alpha-actinin-3 protein is associated with improved sprint/power performance in athletes and the general population–REVIEW (PMID:20699471)
• Though the ACE I/D polymorphism is a strong candidate to modulate some exercise-related phenotypes, alone or in combination with the ACTN3 R577X polymorphism, does not seem to exert a major influence in the muscle power, as assessed during exercise tests. (PMID:20734058)
• in recreationally active individuals, the ACTN3 R577X polymorphism is not associated with muscle performance phenotypes, supporting recent findings that R577X may only be important for predicting performance in elite athletes (PMID:20830656)
• In conclusion, our findings indicate that ACTN3 R577X and other SNPs in ACTN3 are not genetic determinants of endurance performance in Caucasian males. (PMID:20845221)
• results indicated that ACTN3 R577X polymorphism was associated with endurance performance in female athletes but not male athletes in China (PMID:20936592)
• functional ACTN3 R577X genotype represents a genetic risk factor for falling in older females. (PMID:20966103)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	actn3b	ENSDARG00000001431
danio_rerio	actn3a	ENSDARG00000013755
mus_musculus	Actn3	ENSMUSG00000006457
rattus_norvegicus	Actn3	ENSRNOG00000019745
caenorhabditis_elegans		WBGENE00000228

Paralogs (36): SYNE2 (ENSG00000054654), SPTB (ENSG00000070182), ACTN1 (ENSG00000072110), ACTN2 (ENSG00000077522), DSP (ENSG00000096696), DRP2 (ENSG00000102385), SPTBN1 (ENSG00000115306), MACF1 (ENSG00000127603), FLNC (ENSG00000128591), ACTN4 (ENSG00000130402), SYNE1 (ENSG00000131018), MICAL2 (ENSG00000133816), DTNA (ENSG00000134769), MICAL1 (ENSG00000135596), FLNB (ENSG00000136068), SPTBN5 (ENSG00000137877), DTNB (ENSG00000138101), GAS2L3 (ENSG00000139354), DST (ENSG00000151914), UTRN (ENSG00000152818), SPTBN4 (ENSG00000160460), SPTA1 (ENSG00000163554), CLMN (ENSG00000165959), PKHD1 (ENSG00000170927), SPTBN2 (ENSG00000173898), SYNE3 (ENSG00000176438), PLEC (ENSG00000178209), SMTNL2 (ENSG00000188176), FLNA (ENSG00000196924), SPTAN1 (ENSG00000197694), DMD (ENSG00000198947), PKHD1L1 (ENSG00000205038), DYTN (ENSG00000232125), MICAL3 (ENSG00000243156), EPPK1 (ENSG00000261150), GAS2L2 (ENSG00000270765)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:99678) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 3 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal skeletal muscle morphology	1
abnormal muscle physiology	1
increased aerobic running capacity	1

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
DPP3-DT	ncRNA	101928069
PELI3	protein-coding	246330
ZDHHC24	protein-coding	254359
BBS1	protein-coding	582
DPP3	protein-coding	10072
CCDC87	protein-coding	55231
CTSF	protein-coding	8722
CCS	protein-coding	9973

Protein

Protein identifiers

Alpha-actinin-3 — Q08043 (reviewed: Q08043)

Alternative names: Alpha-actinin skeletal muscle isoform 3, F-actin cross-linking protein

All UniProt accessions (3): A0A087WSZ2, D6RH00, Q08043

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.

Subunit / interactions. Homodimer; antiparallel. Also forms heterodimers with ACTN2. Interacts with MYOZ1.

Tissue specificity. Expression restricted to fast (type 2) skeletal muscle fibers (at protein level).

Polymorphism. A common variant at position 577 creates a stop codon at position 577, leading to ACTN3 deficiency. The presence of this variant is not associated with any disease phenotype [MIM:617749]. It has a global frequency of almost 44% in the human population according to the Genome Aggregation Database (gnomAD v4.1.0). It is thought that the variant p.Arg577Ter became more frequent as humans migrated out of Africa into the colder climates of central and northern Europe, as individuals carrying this variant are superior in maintaining core body temperature during cold-water immersion due to changes in skeletal muscle thermogenesis. The variant p.Arg577Ter at the homozygous state is underrepresented in elite sprint/power athletes and overrepresented in endurance athletes, suggesting that ACT3 deficiency increases muscle endurance at the cost of power generation.

Similarity. Belongs to the alpha-actinin family.

RefSeq proteins (2): NP_001095, NP_001245300 (=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
IPR036872	CH_dom_sf	Homologous_superfamily

Pfam: PF00307, PF00435, PF08726

UniProt features (42 total): helix 15, binding site 6, sequence variant 5, domain 4, repeat 4, turn 3, strand 2, chain 1, modified residue 1, region of interest 1

Structure

Experimental structures (PDB)

3 structures by resolution:

PDB	Title	Method	Resolution (Å)
1WKU	High resolution structure of the human alpha-actinin isoform 3	X-RAY DIFFRACTION	1.6
1TJT	X-ray structure of the human alpha-actinin isoform 3 at 2.2A resolution	X-RAY DIFFRACTION	2.19
3LUE	Model of alpha-actinin CH1 bound to F-actin	ELECTRON MICROSCOPY	15

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q08043-F1	84.61	0.44

Human Protein Atlas

Protein class: Predicted intracellular proteins, Plasma proteins

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 uncertain · 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 (6)

Position	Role
773	Ca(2+)
777	Ca(2+)
779	Ca(2+)
784	Ca(2+)
809	Ca(2+)
811	Ca(2+)

Post-translational modifications (1)

Type	Positions
N-acetylmethionine	1

Function

Pathways and Gene Ontology

Reactome pathways

1 curated (TAS) of 4; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

4 pathways:

ID	Pathway	Evidence
R-HSA-390522	Striated Muscle Contraction	curated
R-HSA-1500931	Cell-Cell communication	—
R-HSA-397014	Muscle contraction	—
R-HSA-373753	Nephrin family interactions	electronic

MSigDB gene sets: 295 (showing top): CREL_01, GOBP_NUCLEOSIDE_DIPHOSPHATE_METABOLIC_PROCESS, GOBP_REGULATION_OF_SKELETAL_MUSCLE_TISSUE_DEVELOPMENT, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_REGULATION_OF_CALCIUM_MEDIATED_SIGNALING, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_REGULATION_OF_DEVELOPMENTAL_GROWTH, GOBP_POSITIVE_REGULATION_OF_MUSCLE_CELL_DIFFERENTIATION, GOBP_SKELETAL_MUSCLE_ADAPTATION, GCANCTGNY_MYOD_Q6, GOBP_FOCAL_ADHESION_ASSEMBLY, GOBP_GROWTH, GAUSSMANN_MLL_AF4_FUSION_TARGETS_C_UP, GOBP_STRIATED_MUSCLE_CELL_DIFFERENTIATION, GOBP_CARBOHYDRATE_DERIVATIVE_CATABOLIC_PROCESS

GO Biological Process (21): regulation of the force of skeletal muscle contraction (GO:0014728), skeletal muscle atrophy (GO:0014732), transition between fast and slow fiber (GO:0014883), response to denervation involved in regulation of muscle adaptation (GO:0014894), actin cytoskeleton organization (GO:0030036), positive regulation of fast-twitch skeletal muscle fiber contraction (GO:0031448), regulation of apoptotic process (GO:0042981), negative regulation of glycolytic process (GO:0045820), focal adhesion assembly (GO:0048041), positive regulation of skeletal muscle tissue growth (GO:0048633), positive regulation of skeletal muscle fiber development (GO:0048743), muscle cell development (GO:0055001), bone morphogenesis (GO:0060349), negative regulation of calcineurin-NFAT signaling cascade (GO:0070885), negative regulation of oxidative phosphorylation (GO:0090324), negative regulation of cold-induced thermogenesis (GO:0120163), positive regulation of bone mineralization involved in bone maturation (GO:1900159), negative regulation of relaxation of muscle (GO:1901078), regulation of aerobic respiration (GO:1903715), positive regulation of glucose catabolic process to lactate via pyruvate (GO:1904025), regulation of muscle system process (GO:0090257)

GO Molecular Function (9): integrin binding (GO:0005178), calcium ion binding (GO:0005509), structural constituent of muscle (GO:0008307), identical protein binding (GO:0042802), transmembrane transporter binding (GO:0044325), actin filament binding (GO:0051015), actin binding (GO:0003779), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (14): cytosol (GO:0005829), actin filament (GO:0005884), plasma membrane (GO:0005886), brush border (GO:0005903), focal adhesion (GO:0005925), Z disc (GO:0030018), cell junction (GO:0030054), cortical actin cytoskeleton (GO:0030864), pseudopodium (GO:0031143), cell projection (GO:0042995), extracellular exosome (GO:0070062), cytoplasm (GO:0005737), actin cytoskeleton (GO:0015629), sarcomere (GO:0030017)

Reactome top-level categories

2 top-level categories:

Category	Pathways
Cell-Cell communication	1
Muscle contraction	1

GO top-level categories

showing 60 of 79 GO namespaces:

Category	Terms
cellular anatomical structure	6
positive regulation of skeletal muscle tissue development	2
negative regulation of multicellular organismal process	2
protein-containing complex binding	2
protein binding	2
actin cytoskeleton	2
regulation of skeletal muscle contraction by chemo-mechanical energy conversion	1
striated muscle atrophy	1
skeletal muscle adaptation	1
regulation of skeletal muscle adaptation	1
response to muscle inactivity	1
regulation of muscle adaptation	1
cytoskeleton organization	1
actin filament-based process	1
fast-twitch skeletal muscle fiber contraction	1
regulation of fast-twitch skeletal muscle fiber contraction	1
positive regulation of striated muscle contraction	1
apoptotic process	1
regulation of programmed cell death	1
glycolytic process	1
regulation of glycolytic process	1
negative regulation of purine nucleotide catabolic process	1
negative regulation of carbohydrate metabolic process	1
negative regulation of ATP metabolic process	1
cell-substrate junction assembly	1
cell-matrix adhesion	1
skeletal muscle tissue growth	1
regulation of skeletal muscle tissue growth	1
positive regulation of developmental growth	1
positive regulation of cell development	1
skeletal muscle fiber development	1
regulation of skeletal muscle fiber development	1
positive regulation of striated muscle cell differentiation	1
muscle cell differentiation	1
cell development	1
animal organ morphogenesis	1
skeletal system morphogenesis	1
bone development	1
calcineurin-NFAT signaling cascade	1
regulation of calcineurin-NFAT signaling cascade	1
negative regulation of calcineurin-mediated signaling	1
regulation of oxidative phosphorylation	1
oxidative phosphorylation	1
negative regulation of cellular respiration	1
cold-induced thermogenesis	1
regulation of cold-induced thermogenesis	1
positive regulation of bone mineralization	1
bone mineralization involved in bone maturation	1
relaxation of muscle	1
regulation of relaxation of muscle	1
aerobic respiration	1
regulation of cellular respiration	1
positive regulation of catabolic process	1
pyruvate fermentation to lactate	1
positive regulation of small molecule metabolic process	1
regulation of glucose catabolic process to lactate via pyruvate	1
signaling receptor binding	1
cell adhesion molecule binding	1
metal ion binding	1
structural molecule activity	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 5 of 44 annotations. The rest are phylogenetic / computational / electronic (IEA).

5 experimentally-supported GO terms:

GO term	NS	Evidence
focal adhesion assembly	BP	mutant phenotype
extracellular exosome	CC	high-throughput assay
focal adhesion	CC	mutant phenotype
identical protein binding	MF	physical interaction
transmembrane transporter binding	MF	physical interaction

Protein interactions and networks

STRING

showing 16 of 1,160 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ACTN3	MYOT	Q9UBF9	767
ACTN3	ACTA1	P02568	715
ACTN3	TNNC2	P02585	697
ACTN3	ACE	P12821	622
ACTN3	TNNT1	P13805	618
ACTN3	MYOZ1	Q9NP98	610
ACTN3	CASQ1	P31415	593
ACTN3	TNNI2	P48788	586
ACTN3	AMPD1	P23109	585
ACTN3	TNNT3	P45378	573
ACTN3	NEB	P20929	573
ACTN3	MYH1	P12882	555
ACTN3	MYL11	Q96A32	548
ACTN3	MYH4	Q9Y623	545
ACTN3	TCAP	O15273	544
ACTN3	CAPN3	P20807	544

IntAct

Human interaction partners of ACTN3 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

showing 30 of 54 partners by confidence:

Partner	Interaction type	MIscore	Records
CTAG1A	physical association	0.560	5
LHX3	physical association	0.560	5
ACTN1	physical association	0.560	3
ACTN4	physical association	0.560	3
ASB9	physical association	0.560	3
ATP23	physical association	0.560	3
C2CD6	physical association	0.560	3
CADPS	physical association	0.560	3
CIMAP1B	physical association	0.560	3
CIMIP1	physical association	0.560	3
CTDSP1	physical association	0.560	3
CXCL5	physical association	0.560	3
DDAH2	physical association	0.560	3
ECM1	physical association	0.560	3
FAM90A1	physical association	0.560	3
GLIS2	physical association	0.560	3
HGS	physical association	0.560	3
HOXD12	physical association	0.560	3
HSF2BP	physical association	0.560	3
IVD	physical association	0.560	3
KRT6C	physical association	0.560	3
LNX1	physical association	0.560	3
MAGEA6	physical association	0.560	3
MICALL2	physical association	0.560	3
MYOT	physical association	0.560	3
MYOZ1	physical association	0.560	3
NDUFAB1	physical association	0.560	3
NKAPD1	physical association	0.560	3
PCCB	physical association	0.560	3
PKP2	physical association	0.560	3

BioGRID (125 interactions; top human partners by supporting records): ACTN2 (Far Western; 7 records), ACTN1 (Two-hybrid; 3 records), ACTN4 (Two-hybrid; 3 records), CDC73 (Two-hybrid; 3 records), PDLIM1 (Affinity Capture-MS; 3 records), AKAP17A (Affinity Capture-MS; 2 records), BCHE (Affinity Capture-MS; 2 records), LRRCC1 (Affinity Capture-MS; 2 records), PLEKHG2 (Two-hybrid; 2 records), TRAF1 (Two-hybrid; 2 records), ABI3 (Two-hybrid), AGO2 (Affinity Capture-RNA), ALS2CR11 (Two-hybrid), ANLN (Affinity Capture-MS), ASB9 (Two-hybrid)

Disease & clinical

Genetic variants

Variant evidence for ACTN3: 256 ClinVar records (5 pathogenic / likely pathogenic); 2 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	2
Uncertain significance	201
Likely benign	33
Benign	16

Top pathogenic / likely-pathogenic (5)

Showing all 5 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
59757	GRCh38/hg38 11q13.2(chr11:66193502-67890770)x3	Pathogenic	criteria provided, single submitter	1
2684646	GRCh37/hg19 11q12.2-13.5(chr11:59923608-76272324)x3	Pathogenic	criteria provided, single submitter	1
3063215	GRCh37/hg19 11q12.1-13.3(chr11:56895955-69295402)x3	Likely pathogenic	criteria provided, single submitter	1
154814	GRCh38/hg38 11q13.1-13.2(chr11:65741431-67705669)x1	Pathogenic	no assertion criteria provided	1
443398	GRCh37/hg19 11q13.1-13.2(chr11:64501919-67129258)x3	Likely pathogenic	no assertion criteria provided	1

Per-variant reference — Sugi Variant

Explore ACTN3’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; 25 predictions of 1,259):

Position(s)	Effect	Δscore	Sites
11:66547082	donor_gain	1.0000
11:66547085	donor_loss	1.0000	2
11:66551523	acceptor_gain	1.0000
11:66551527	acceptor_loss	1.0000
11:66551648–66551649	donor_loss	1.0000	5
11:66554132–66554133	donor_loss	1.0000	3
11:66554528	acceptor_gain	1.0000
11:66555123	acceptor_gain	1.0000
11:66555128–66555129	acceptor_loss	1.0000	6
11:66555209–66555210	donor_loss	1.0000	4

AlphaMissense

2,430 missense substitutions predicted likely pathogenic (of 5,941 scored), across 627 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
M136	9	0.959	0.999
M235	9	0.941	0.998
M99	9	0.910	0.996
M253	9	0.877	0.996
D131	8	0.995	0.999
F51	8	0.994	1.000
H102	8	0.994	1.000
F148	8	0.992	1.000
D248	8	0.992	0.998
F183	8	0.988	0.999
H261	8	0.980	0.998
D40	8	0.979	0.993
N106	8	0.978	1.000
D72	8	0.977	0.996
F842	8	0.963	0.996
H58	8	0.956	0.999
F772	8	0.956	0.998
F263	8	0.950	0.992
N56	8	0.930	0.998
S186	8	0.928	0.999

HPA cancer prognostics

RNA cancer specificity: Not detected

Disease associations

OMIM: gene MIM:102574 | disease phenotypes:

GWAS associations

2 associations:

Study	Trait	p-value
GCST001241_12	Bipolar disorder	2e-7
GCST006148_9	Frontotemporal dementia with GRN mutation	5e-6

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

22 total (human), top 22 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression	7
bisphenol A	increases methylation, affects cotreatment, affects expression, increases abundance	2
trichostatin A	affects cotreatment, decreases expression	2
mercuric bromide	decreases expression, affects cotreatment	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
aristolochic acid I	increases expression	1
ginger extract	affects cotreatment, affects expression, increases abundance	1
methylmercuric chloride	decreases expression	1
CGP 52608	increases reaction, affects binding	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
licochalcone B	increases expression	1
Sunitinib	decreases expression	1
Arsenic Trioxide	decreases expression	1
Benzo(a)pyrene	decreases methylation	1
Cisplatin	decreases response to substance, increases expression	1
Doxorubicin	decreases expression	1
Oils, Volatile	affects cotreatment, affects expression, increases abundance	1
Smoke	decreases expression	1
Tretinoin	decreases expression	1
Triclosan	decreases expression	1
1-Methyl-4-phenylpyridinium	decreases expression	1

Clinical trials (associated diseases)

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