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): 241 total — 3 pathogenic, 1 likely-pathogenic
• MANE Select transcript: NM_001104

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: 5 — 4 protein_coding, 1 nonsense_mediated_decay

ENST00000502692, ENST00000511191, ENST00000513398, ENST00000968415, ENST00000968416

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
ENSE00002077699	66563035	66563334
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

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.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
115346	2.2926	169

Top tissues by expression

273 total, 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

Single-cell (SCXA)

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

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

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

5 targeting ACTN3, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

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

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)

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): Q08043, A0A087WSZ2, D6RH00

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 (41 total): helix 13, binding site 6, sequence variant 5, domain 4, turn 4, repeat 4, strand 2, chain 1, modified residue 1, region of interest 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
1WKU	X-RAY DIFFRACTION	1.6
1TJT	X-RAY DIFFRACTION	2.19
3LUE	ELECTRON MICROSCOPY	15

Predicted structure (AlphaFold)

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

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): 773; 777; 779; 784; 809; 811

Post-translational modifications (1): 1

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

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

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

Rollup of top-2 pathways:

Category	Pathways
Cell-Cell communication	1
Muscle contraction	1

GO top-level categories

Rollup of top GO terms by namespace:

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

Protein interactions and networks

STRING

1468 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ACTN3	TNNT3	P45378	826
ACTN3	MYOT	Q9UBF9	817
ACTN3	ACTA1	P02568	717
ACTN3	MYH1	P12882	703
ACTN3	TPM3	P06753	682
ACTN3	MYBPC2	Q14324	673
ACTN3	MYL1	P05976	651
ACTN3	ACE	P12821	644
ACTN3	TNNI1	P19237	631
ACTN3	TNNT1	P13805	620
ACTN3	MYPN	Q86TC9	615
ACTN3	AMPD1	P23109	604
ACTN3	TNNC2	P02585	601
ACTN3	MYOZ1	Q9NP98	600
ACTN3	CDC73	Q6P1J9	591

IntAct

183 interactions, top by confidence:

A	B	Type	Score
PDLIM1	ACTN4	psi-mi:“MI:0914”(association)	0.800
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
ACTN3	RTP5	psi-mi:“MI:0915”(physical association)	0.560
HGS	ACTN3	psi-mi:“MI:0915”(physical association)	0.560
CIMAP1B	ACTN3	psi-mi:“MI:0915”(physical association)	0.560
ACTN3	MYOZ1	psi-mi:“MI:0915”(physical association)	0.560
CADPS	ACTN3	psi-mi:“MI:0915”(physical association)	0.560
ACTN3	MYOT	psi-mi:“MI:0915”(physical association)	0.560
ACTN3	C2CD6	psi-mi:“MI:0915”(physical association)	0.560
ACTN3	SYNPO2L	psi-mi:“MI:0915”(physical association)	0.560
ACTN3	MICALL2	psi-mi:“MI:0915”(physical association)	0.560
HSF2BP	ACTN3	psi-mi:“MI:0915”(physical association)	0.560
CTAG1A	ACTN3	psi-mi:“MI:0915”(physical association)	0.560
ACTN3	NKAPD1	psi-mi:“MI:0915”(physical association)	0.560
USP2	ACTN3	psi-mi:“MI:0915”(physical association)	0.560
ACTN3	FAM90A1	psi-mi:“MI:0915”(physical association)	0.560
MAGEA6	ACTN3	psi-mi:“MI:0915”(physical association)	0.560
ACTN3	ACTN3	psi-mi:“MI:0915”(physical association)	0.560
ACTN3	LNX1	psi-mi:“MI:0915”(physical association)	0.560
ACTN3	LHX3	psi-mi:“MI:0915”(physical association)	0.560
ACTN3	TRAF1	psi-mi:“MI:0915”(physical association)	0.560
SNAI1	ACTN3	psi-mi:“MI:0915”(physical association)	0.560
ACTN1	ACTN3	psi-mi:“MI:0915”(physical association)	0.560
PCCB	ACTN3	psi-mi:“MI:0915”(physical association)	0.560
ACTN3	GLIS2	psi-mi:“MI:0915”(physical association)	0.560
ACTN3	PPP1R18	psi-mi:“MI:0915”(physical association)	0.560
ACTN3	PTK6	psi-mi:“MI:0915”(physical association)	0.560
ACTN4	ACTN3	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (121): ACTN3 (Two-hybrid), ACTN3 (Two-hybrid), ACTN3 (Two-hybrid), REL (Two-hybrid), TRAF1 (Two-hybrid), TRAF2 (Two-hybrid), NEBL (Two-hybrid), ABI3 (Two-hybrid), RNF111 (Two-hybrid), PLEKHG2 (Two-hybrid), C1orf94 (Two-hybrid), KCTD6 (Two-hybrid), SUMO1P1 (Two-hybrid), BRCA1 (Two-hybrid), ACTN3 (Affinity Capture-MS)

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

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

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	1
Uncertain significance	200
Likely benign	19
Benign	17

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
154814	GRCh38/hg38 11q13.1-13.2(chr11:65741431-67705669)x1	Pathogenic
2684646	GRCh37/hg19 11q12.2-13.5(chr11:59923608-76272324)x3	Pathogenic
59757	GRCh38/hg38 11q13.2(chr11:66193502-67890770)x3	Pathogenic
443398	GRCh37/hg19 11q13.1-13.2(chr11:64501919-67129258)x3	Likely pathogenic

SpliceAI

2553 predictions. Top by Δscore:

Variant	Effect	Δscore
11:66547080:GGAAA:G	donor_gain	1.0000
11:66547081:GAAA:G	donor_gain	1.0000
11:66547081:GAAAG:G	donor_gain	1.0000
11:66547082:A:T	donor_gain	1.0000
11:66547084:AG:A	donor_loss	1.0000
11:66547085:G:GG	donor_gain	1.0000
11:66547085:G:T	donor_loss	1.0000
11:66551520:A:AG	acceptor_gain	1.0000
11:66551523:C:G	acceptor_gain	1.0000
11:66551525:CAGG:C	acceptor_loss	1.0000
11:66551643:TGAAG:T	donor_loss	1.0000
11:66551645:AAG:A	donor_loss	1.0000
11:66551647:GGTGA:G	donor_loss	1.0000
11:66551648:GT:G	donor_loss	1.0000
11:66551649:T:G	donor_loss	1.0000
11:66554044:GAGA:G	acceptor_gain	1.0000
11:66554127:GGAAG:G	donor_gain	1.0000
11:66554128:GAAG:G	donor_gain	1.0000
11:66554128:GAAGG:G	donor_gain	1.0000
11:66554129:AAGGT:A	donor_loss	1.0000
11:66554130:AGG:A	donor_loss	1.0000
11:66554131:GGTG:G	donor_loss	1.0000
11:66554132:G:GG	donor_gain	1.0000
11:66554528:C:A	acceptor_gain	1.0000
11:66554532:CCAGA:C	acceptor_loss	1.0000
11:66554534:A:AG	acceptor_gain	1.0000
11:66554535:G:GA	acceptor_loss	1.0000
11:66554535:G:GG	acceptor_gain	1.0000
11:66555123:T:A	acceptor_gain	1.0000
11:66555127:CAG:C	acceptor_gain	1.0000

AlphaMissense

5941 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:66547078:G:C	Q47H	1.000
11:66547078:G:T	Q47H	1.000
11:66551242:T:C	F51L	1.000
11:66551244:C:A	F51L	1.000
11:66551244:C:G	F51L	1.000
11:66551251:T:A	W54R	1.000
11:66551251:T:C	W54R	1.000
11:66551253:G:C	W54C	1.000
11:66551253:G:T	W54C	1.000
11:66551256:C:G	C55W	1.000
11:66551267:T:C	L59P	1.000
11:66551317:G:C	G76R	1.000
11:66551318:G:A	G76D	1.000
11:66551318:G:T	G76V	1.000
11:66551327:T:C	L79P	1.000
11:66551336:T:C	L82P	1.000
11:66551339:T:C	L83P	1.000
11:66551569:C:G	H102D	1.000
11:66551583:C:A	N106K	1.000
11:66551583:C:G	N106K	1.000
11:66551597:T:C	L111P	1.000
11:66554051:T:A	V130D	1.000
11:66554075:T:C	L138P	1.000
11:66554077:G:C	G139R	1.000
11:66554078:G:A	G139D	1.000
11:66554086:T:A	W142R	1.000
11:66554086:T:C	W142R	1.000
11:66554088:G:C	W142C	1.000
11:66554088:G:T	W142C	1.000
11:66554099:T:C	L146P	1.000

dbSNP variants (sampled 300 via entrez): RS1000000655 (11:66547539 G>A), RS1000177456 (11:66552531 G>A), RS1000307730 (11:66558754 A>G), RS1000357812 (11:66548215 G>A,T), RS1000428445 (11:66561055 G>A), RS1000575360 (11:66547144 C>T), RS1001409414 (11:66548339 T>A), RS1001519411 (11:66547262 G>T), RS1001571411 (11:66554012 A>C), RS1001602495 (11:66553375 G>A), RS1001859227 (11:66548663 T>A), RS1002114256 (11:66559409 C>T), RS1002179439 (11:66563512 G>A), RS1002212039 (11:66563199 A>G), RS1002538186 (11:66547490 G>A,T)

Disease associations

OMIM: gene MIM:102574 | disease phenotypes: MIM:610329, MIM:613759

GenCC curated gene-disease

Mondo (2): Aicardi-Goutieres syndrome 3 (MONDO:0012471), FADD-related immunodeficiency (MONDO:0013408)

Orphanet (2): FADD-related immunodeficiency (Orphanet:306550), Aicardi-Goutières syndrome (Orphanet:51)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST001241_12	Bipolar disorder	2.000000e-07
GCST006148_9	Frontotemporal dementia with GRN mutation	5.000000e-06

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C563683	Aicardi-Goutieres Syndrome 3 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

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	decreases expression, affects cotreatment	2
mercuric bromide	affects cotreatment, decreases expression	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	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, affects cotreatment	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)

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