ACTG2

Summary

ACTG2 (actin gamma 2, smooth muscle, HGNC:145) is a protein-coding gene on chromosome 2p13.1, encoding Actin, gamma-enteric smooth muscle (P63267). Actins are highly conserved proteins that are involved in various types of cell motility and are ubiquitously expressed in all eukaryotic cells.

Actins are highly conserved proteins that are involved in various types of cell motility and in the maintenance of the cytoskeleton. Three types of actins, alpha, beta and gamma, have been identified in vertebrates. Alpha actins are found in muscle tissues and are a major constituent of the contractile apparatus. The beta and gamma actins co-exist in most cell types as components of the cytoskeleton and as mediators of internal cell motility. This gene encodes actin gamma 2; a smooth muscle actin found in enteric tissues. Alternative splicing results in multiple transcript variants encoding distinct isoforms. Based on similarity to peptide cleavage of related actins, the mature protein of this gene is formed by removal of two N-terminal peptides.

Source: NCBI Gene 72 — RefSeq curated summary.

At a glance

• Gene–disease (curated): visceral myopathy 1 (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 115 total — 21 pathogenic, 18 likely-pathogenic
• Phenotypes (HPO): 54
• MANE Select transcript: NM_001615

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:145
Approved symbol	ACTG2
Name	actin gamma 2, smooth muscle
Location	2p13.1
Locus type	gene with protein product
Status	Approved
Aliases	ACTSG
Ensembl gene	ENSG00000163017
Ensembl biotype	protein_coding
OMIM	102545
Entrez	72

Gene structure

Transcript identifiers

Ensembl transcripts: 27 — 23 protein_coding, 2 nonsense_mediated_decay, 2 retained_intron

ENST00000345517, ENST00000409624, ENST00000409731, ENST00000409918, ENST00000429756, ENST00000438902, ENST00000442912, ENST00000468543, ENST00000473016, ENST00000880127, ENST00000880128, ENST00000880129, ENST00000880130, ENST00000880131, ENST00000880132, ENST00000958362, ENST00000958363, ENST00000958364, ENST00000958365, ENST00000958366, ENST00000958367, ENST00000958368, ENST00000958369, ENST00000958370, ENST00000958371, ENST00000958372, ENST00000958373

RefSeq mRNA: 2 — MANE Select: NM_001615 NM_001199893, NM_001615

CCDS: CCDS1930, CCDS56124

Canonical transcript exons

ENST00000345517 — 9 exons

Exon	Start	End
ENSE00001578701	73893008	73893051
ENSE00001587209	73919432	73919865
ENSE00002534503	73902360	73902488
ENSE00003537201	73909055	73909139
ENSE00003566166	73901276	73901437
ENSE00003594003	73908673	73908783
ENSE00003603567	73916584	73916765
ENSE00003618744	73913485	73913646
ENSE00003663177	73914680	73914871

Expression profiles

Bgee: expression breadth ubiquitous, 241 present calls, max score 99.98.

FANTOM5 (CAGE): breadth broad, TPM avg 80.6591 / max 11080.0969, expressed in 808 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
20964	80.1950	800
20965	0.1470	33
20968	0.1154	39
20966	0.1130	36
20967	0.0886	32

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
seminal vesicle	UBERON:0000998	99.98	gold quality
cauda epididymis	UBERON:0004360	99.94	gold quality
saphenous vein	UBERON:0007318	99.94	gold quality
lower esophagus	UBERON:0013473	99.92	gold quality
lower esophagus muscularis layer	UBERON:0035833	99.92	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	99.88	gold quality
muscle layer of sigmoid colon	UBERON:0035805	99.87	gold quality
mucosa of stomach	UBERON:0001199	99.78	gold quality
popliteal artery	UBERON:0002250	99.76	gold quality
tibial artery	UBERON:0007610	99.76	gold quality
prostate gland	UBERON:0002367	99.75	gold quality
myometrium	UBERON:0001296	99.74	gold quality
urethra	UBERON:0000057	99.73	gold quality
body of uterus	UBERON:0009853	99.72	gold quality
left uterine tube	UBERON:0001303	99.67	gold quality
blood vessel layer	UBERON:0004797	99.62	gold quality
vermiform appendix	UBERON:0001154	99.60	gold quality
right coronary artery	UBERON:0001625	99.57	gold quality
adult organism	UBERON:0007023	99.54	gold quality
urinary bladder	UBERON:0001255	99.53	gold quality
lower esophagus mucosa	UBERON:0035834	99.53	gold quality
aorta	UBERON:0000947	99.52	gold quality
vena cava	UBERON:0004087	99.51	gold quality
caecum	UBERON:0001153	99.48	gold quality
fundus of stomach	UBERON:0001160	99.46	gold quality
left coronary artery	UBERON:0001626	99.45	gold quality
gall bladder	UBERON:0002110	99.45	gold quality
coronary artery	UBERON:0001621	99.37	gold quality
nipple	UBERON:0002030	99.32	gold quality
descending thoracic aorta	UBERON:0002345	99.27	gold quality

Single-cell (SCXA)

Detected in 14 experiment(s), a significant marker in 14.

Experiment	Marker?	Max mean expression
E-MTAB-9906	yes	11366.78
E-MTAB-10287	yes	5911.12
E-HCAD-24	yes	5578.39
E-CURD-126	yes	4465.60
E-CURD-7	yes	3638.15
E-ENAD-21	yes	2819.31
E-HCAD-11	yes	2526.80
E-MTAB-8221	yes	2420.43
E-MTAB-10662	yes	1459.03
E-ANND-5	yes	840.79
E-HCAD-1	yes	38.86
E-MTAB-8410	yes	29.89
E-CURD-46	yes	9.61
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR, ARID4B, ASCL1, CEBPB, GATA6, GTF3A, HMGA2, KLF4, MEF2A, MYB, MYC, MYOCD, NKX2-5, NKX3-1, NR0B2, NR1H4, PGR, POU5F1, PPARD, PPARG, RARA, SMAD2, SMAD3, SMAD7, SP1, SRF, STAT3, TGIF1, ZEB1

Literature-anchored findings (GeneRIF, showing 32)

• SMGA gene activity in prostate epithelia is due, in part, to the androgen-dependent expression of Nkx 3.1 (PMID:12450213)
• RNA polymerase II accumulates in the promoter-proximal region of the dihydrofolate reductase and gamma-actin genes. (PMID:12612070)
• It was suggested that peritubular alphaSMA-positive myofibroblastic cells, in collaboration with interstitial macrophages, contribute to the progression of interstitial fibrosis in diabetic nephropathy. (PMID:17009076)
• TNF-alpha suppresses TGF-beta1-induced myofibroblast (fibroproliferative) phenotypic genes, for example, alpha-SMA, collagen type 1A, and fibronectin at the mRNA level. (PMID:17554369)
• The insertion-deletion polymorphism in intron 1 of the gamma 2 actin gene is unlikely to play any significant role in obstetric cholestasis or preeclampsia in patients from eastern Finland. (PMID:17934296)
• MYOCD can discriminate among several juxtaposed CArG elements, presumably through its novel partnership with NKX3.1, to optimally transactivate the human ACTG2 promoter (PMID:19797053)
• NOX4 and ROS have a role in myofibroblast differentiation and collagen and alpha-actin production of TGF- beta1-induced nasal polyp-derived fibroblasts. (PMID:22722757)
• The R148S variant in ACTG2 as a cause of autosomal dominant familial visceral myopathy in one family. (PMID:22960657)
• Two novel mutations in the ACTG2 gene, p.R178L and p.R178C, have been identified in two unrelated children with congenital distended bladder, microcolon, and intestinal hypoperistalsis (MMIHS). (PMID:24337657)
• ACTG2 encodes g2 enteric actin and is the first gene to be clearly associated with Megacystis-microcolon-intestinal hypoperistalsis syndrome, suggesting an important role for contractile proteins in enteric smooth muscle disease. (PMID:24676022)
• Phenotypic spectrum of ACTG2 missense variants involved severe pathology in multiple smooth muscle-dependent organs including the biliary tract and the uterus in the family with visceral myopathy. (PMID:25782675)
• Mutations within ACTG2 are associated with fetal megacystis in microcolon intestinal hypoperistalsis syndrome. (PMID:25998219)
• gammaSMA expression in hepatocellular carcinoma is strongly correlated with the EMT process, HCC aggressiveness and the identification of cancer stem cells (PMID:26110787)
• A heterozygous missense variant in ACTG2 was identified that impaired actin polymerization in sporadic Megacystis microcolon intestinal hypoperistalsis syndrome. (PMID:26647307)
• Missense variants in ACTG2 were identified in the patients with either megacystis-microcolon-intestinal hypoperistalsis syndrome or intestinal pseudo-obstruction. (PMID:26813947)
• R257 variant in the ACTG2 appear to be more frequent in populations of Asian ancestry; mutation of this locus could cause alterations of the intestinal and bladder smooth muscle filaments. (PMID:27007401)
• ACTG2 is expressed in a fraction of small intestinal neuroendocrine tumors, can inhibit cell growth in vitro, and is positively regulated by miR-145. (PMID:27107594)
• ACTG2 boosts the metastatic potential of hepatocellular carcinoma in a Notch1-dependent manner. (PMID:28385530)
• Whole exome and Sanger sequencing revealed a pathogenic variant in the ACTG2 gene in 4 out of 28 probands with chronic intestinal pseudo-obstruction and megacystis. Moreover, a mutational hotspot in the ACTG2 gene was recognized. Genetic heterogeneity is evident. (PMID:28422808)
• fetus with intestinal pseudo-obstruction heterozygous for p.R63G pathogenic variant (NM_001615.3 c.187C>G; rs864309491) in exon 3 (PMID:29072330)
• mutations represent a significant underlying cause of primary chronic intestinal pseudo-obstruction with visceral myopathy and associated phenotypes in Australasian patients. (PMID:29781137)
• Studied Actin G2 gene variants in patients with Hirschsprung disease as a possible molecular basis for abnormal smooth muscle function. (PMID:30885557)
• Recurrent arginine substitutions in the ACTG2 gene are the primary driver of disease burden and severity in visceral myopathy. (PMID:31769566)
• Variants in the Enteric Smooth Muscle Actin gamma-2 Cause Pediatric Intestinal Pseudo-obstruction in Chinese Patients. (PMID:32810037)
• Pseudo-obstruction-inducing ACTG2R257C alters actin organization and function. (PMID:32814715)
• Novel ACTG2 variants disclose allelic heterogeneity and bi-allelic inheritance in pediatric chronic intestinal pseudo-obstruction. (PMID:33294969)
• Expanding the genotypic spectrum of ACTG2-related visceral myopathy. (PMID:33883208)
• LINC01278 Sponges miR-500b-5p to Regulate the Expression of ACTG2 to Control Phenotypic Switching in Human Vascular Smooth Muscle Cells During Aortic Dissection. (PMID:33910387)
• Intestinal Pathology in Patients With Pathogenic ACTG2-Variant Visceral Myopathy: 16 Patients From 12 Families and Review of the Literature. (PMID:35695198)
• Variant in ACTG2 Causing Megacystis Microcolon Hypoperistalsis Syndrome and Severe Familial Postpartum Bleeding. (PMID:36509086)
• Analysis of the Regulatory Effect of ACTG2 on Biological Behavior of Bladder Cancer Cells Based on Database Screening. (PMID:37213144)
• Molecular mechanisms linking missense ACTG2 mutations to visceral myopathy. (PMID:38820162)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Actg2	ENSMUSG00000059430
rattus_norvegicus	Actg2	ENSRNOG00000029401

Paralogs (26): ACTR6 (ENSG00000075089), ACTB (ENSG00000075624), ACTL6B (ENSG00000077080), ACTR5 (ENSG00000101442), ACTR3C (ENSG00000106526), ACTA2 (ENSG00000107796), ACTR8 (ENSG00000113812), ACTR1B (ENSG00000115073), ACTR3 (ENSG00000115091), ACTL8 (ENSG00000117148), ACTRT1 (ENSG00000123165), ACTR10 (ENSG00000131966), ACTR3B (ENSG00000133627), ACTL6A (ENSG00000136518), ACTR2 (ENSG00000138071), ACTR1A (ENSG00000138107), ACTA1 (ENSG00000143632), ACTL7B (ENSG00000148156), ACTC1 (ENSG00000159251), ACTBL2 (ENSG00000169067), ACTRT2 (ENSG00000169717), ACTL9 (ENSG00000181786), ACTG1 (ENSG00000184009), ACTRT3 (ENSG00000184378), ACTL7A (ENSG00000187003), ACTL10 (ENSG00000288649)

Protein

Protein identifiers

Actin, gamma-enteric smooth muscle — P63267 (reviewed: P63267)

Alternative names: Alpha-actin-3, Gamma-2-actin, Smooth muscle gamma-actin

All UniProt accessions (5): B8ZZJ2, C9JFL5, P63267, F8WB63, F8WCH0

UniProt curated annotations — full annotation on UniProt →

Function. Actins are highly conserved proteins that are involved in various types of cell motility and are ubiquitously expressed in all eukaryotic cells.

Subunit / interactions. Polymerization of globular actin (G-actin) leads to a structural filament (F-actin) in the form of a two-stranded helix. Each actin can bind to 4 others.

Subcellular location. Cytoplasm. Cytoskeleton.

Tissue specificity. In the intestine, abundantly expressed in smooth muscle cells of muscularis mucosa and muscularis propria. Also detected in intestinal vascular smooth muscle cells.

Post-translational modifications. Oxidation of Met-45 and Met-48 by MICALs (MICAL1, MICAL2 or MICAL3) to form methionine sulfoxide promotes actin filament depolymerization. MICAL1 and MICAL2 produce the (R)-S-oxide form. The (R)-S-oxide form is reverted by MSRB1 and MSRB2, which promotes actin repolymerization. N-terminal cleavage of acetylated cysteine of intermediate muscle actin by ACTMAP. Monomethylation at Lys-85 (K84me1) regulates actin-myosin interaction and actomyosin-dependent processes. Demethylation by ALKBH4 is required for maintaining actomyosin dynamics supporting normal cleavage furrow ingression during cytokinesis and cell migration. Methylated at His-74 by SETD3. (Microbial infection) Monomeric actin is cross-linked by V.cholerae toxins RtxA and VgrG1 in case of infection: bacterial toxins mediate the cross-link between Lys-51 of one monomer and Glu-271 of another actin monomer, resulting in formation of highly toxic actin oligomers that cause cell rounding. The toxin can be highly efficient at very low concentrations by acting on formin homology family proteins: toxic actin oligomers bind with high affinity to formins and adversely affect both nucleation and elongation abilities of formins, causing their potent inhibition in both profilin-dependent and independent manners.

Disease relevance. Visceral myopathy 1 (VSCM1) [MIM:155310] An autosomal dominant form of myopathic pseudo-obstruction characterized by impaired function of enteric smooth muscle cells, resulting in abnormal intestinal motility, severe abdominal pain, malnutrition, and even death. The disease shows inter- and intrafamilial variability. Most severely affected patients exhibit prenatal bladder enlargement, intestinal malrotation, neonatal functional gastrointestinal obstruction, and dependence on total parenteral nutrition and urinary catheterization. The disease is caused by variants affecting the gene represented in this entry. Megacystis-microcolon-intestinal hypoperistalsis syndrome 5 (MMIHS5) [MIM:619431] A form of megacystis-microcolon-intestinal hypoperistalsis syndrome, a congenital visceral myopathy primarily affecting females, and characterized by loss of smooth muscle contraction in the bladder and intestine. Affected individuals present at birth with functional obstruction of intestine, microcolon, dilation of bladder, and secondary hydronephrosis. The majority of cases have a fatal outcome due to malnutrition and sepsis, followed by multiorgan failure. MMIHS5 is an autosomal dominant form with significant inter- and intrafamilial variability. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. In vertebrates 3 main groups of actin isoforms, alpha, beta and gamma have been identified. The alpha actins are found in muscle tissues and are a major constituent of the contractile apparatus. The beta and gamma actins coexist in most cell types as components of the cytoskeleton and as mediators of internal cell motility.

Similarity. Belongs to the actin family.

Isoforms (2)

UniProt ID	Names	Canonical?
P63267-1	1	yes
P63267-2	2

RefSeq proteins (2): NP_001186822, NP_001606* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004000	Actin	Family
IPR004001	Actin_CS	Conserved_site
IPR020902	Actin/actin-like_CS	Conserved_site
IPR043129	ATPase_NBD	Homologous_superfamily

Pfam: PF00022

Catalyzed reactions (Rhea), 1 shown:

• ATP + H2O = ADP + phosphate + H(+) (RHEA:13065)

UniProt features (78 total): helix 23, sequence variant 21, strand 17, modified residue 5, chain 2, mutagenesis site 2, sequence conflict 2, turn 2, cross-link 2, initiator methionine 1, splice variant 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
8V2O	ELECTRON MICROSCOPY	2.45
8V30	ELECTRON MICROSCOPY	2.54
6JAT	X-RAY DIFFRACTION	2.71
8V2Z	ELECTRON MICROSCOPY	2.72

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P63267-F1	95.46	0.93

Functional residue map

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

Post-translational modifications (7): 2, 3, 45, 48, 74, 51, 271

Mutagenesis-validated functional residues (2):

Position	Phenotype
72	abolished methylation by setd3.
72	slightly decreased methylation by setd3.

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-445355	Smooth Muscle Contraction
R-HSA-9764561	Regulation of CDH1 Function
R-HSA-9913351	Formation of the dystrophin-glycoprotein complex (DGC)
R-HSA-9958825	Activation of STAT3 by cadherin engagement
R-HSA-1474244	Extracellular matrix organization
R-HSA-3000171	Non-integrin membrane-ECM interactions
R-HSA-397014	Muscle contraction

MSigDB gene sets: 336 (showing top): GOBP_RESPONSE_TO_ETHANOL, WWTAAGGC_UNKNOWN, BERTUCCI_MEDULLARY_VS_DUCTAL_BREAST_CANCER_DN, GOBP_RESPONSE_TO_PEPTIDE, MCBRYAN_PUBERTAL_TGFB1_TARGETS_UP, DARWICHE_SKIN_TUMOR_PROMOTER_UP, DARWICHE_PAPILLOMA_RISK_LOW_DN, DARWICHE_PAPILLOMA_RISK_HIGH_DN, DARWICHE_SQUAMOUS_CELL_CARCINOMA_DN, MODULE_329, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, CAGCTG_AP4_Q5, SRF_Q5_01, REACTOME_ADHERENS_JUNCTIONS_INTERACTIONS, SRF_01

GO Biological Process (5): positive regulation of gene expression (GO:0010628), response to ethanol (GO:0045471), cellular response to interleukin-6 (GO:0071354), mesenchyme migration (GO:0090131), cellular response to acetaldehyde (GO:1905641)

GO Molecular Function (3): ATP binding (GO:0005524), hydrolase activity (GO:0016787), nucleotide binding (GO:0000166)

GO Cellular Component (12): obsolete extracellular space (GO:0005615), cytoplasm (GO:0005737), cytosol (GO:0005829), actin cytoskeleton (GO:0015629), lamellipodium (GO:0030027), filopodium (GO:0030175), myosin filament (GO:0032982), cell body (GO:0044297), extracellular exosome (GO:0070062), cell periphery (GO:0071944), blood microparticle (GO:0072562), cytoskeleton (GO:0005856)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Muscle contraction	1
Regulation of CDH1 Expression and Function	1
Non-integrin membrane-ECM interactions	1
Adherens junctions interactions	1
Extracellular matrix organization	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
response to alcohol	1
response to interleukin-6	1
cellular response to cytokine stimulus	1
mesenchyme morphogenesis	1
tissue migration	1
cellular response to aldehyde	1
response to acetaldehyde	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
catalytic activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
intracellular anatomical structure	1
cytoplasm	1
cytoskeleton	1
cell leading edge	1
plasma membrane bounded cell projection	1
actin-based cell projection	1
myosin complex	1
supramolecular fiber	1
extracellular vesicle	1
extracellular region	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

32 interactions, top by confidence:

A	B	Type	Score
GRB2	EGFR	psi-mi:“MI:0914”(association)	0.980
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
FLVCR1	TNFRSF10B	psi-mi:“MI:0914”(association)	0.530
ACTG2		psi-mi:“MI:0915”(physical association)	0.370
ACTG2	MLH1	psi-mi:“MI:0915”(physical association)	0.370
OCRL	MYO1C	psi-mi:“MI:0914”(association)	0.350
ARRB2		psi-mi:“MI:0914”(association)	0.350
NEK4	E2F8	psi-mi:“MI:0914”(association)	0.350
NEK4	QSOX1	psi-mi:“MI:0914”(association)	0.350
P		psi-mi:“MI:0914”(association)	0.350
CHCHD4	HAX1	psi-mi:“MI:0914”(association)	0.350
FAF2	ERLIN2	psi-mi:“MI:0914”(association)	0.350
FOXRED2	CASK	psi-mi:“MI:0914”(association)	0.350
CSAG2	CAMK2D	psi-mi:“MI:0914”(association)	0.350
GRB2	MYO1C	psi-mi:“MI:0914”(association)	0.350
ANK2	IGKV2-40	psi-mi:“MI:0914”(association)	0.350
IGSF8	SCAMP3	psi-mi:“MI:0914”(association)	0.350
SLC10A7	NUP155	psi-mi:“MI:0914”(association)	0.350
SLC16A2	TNFRSF10B	psi-mi:“MI:0914”(association)	0.350
SLC17A9	PIPSL	psi-mi:“MI:0914”(association)	0.350
SLC22A3	XPO1	psi-mi:“MI:0914”(association)	0.350
SLC37A3	PLXNB2	psi-mi:“MI:0914”(association)	0.350
TMEM165	ACTG2	psi-mi:“MI:0914”(association)	0.350
ICP34.5	TUBB	psi-mi:“MI:0914”(association)	0.350
UL36	MYO9A	psi-mi:“MI:0914”(association)	0.350
NS1	PIK3R2	psi-mi:“MI:0914”(association)	0.350
US11		psi-mi:“MI:0914”(association)	0.350
VP24	POTEF	psi-mi:“MI:0914”(association)	0.350

BioGRID (101): ACTG2 (Affinity Capture-MS), ACTG2 (Affinity Capture-MS), NEB (Reconstituted Complex), ACTG2 (Affinity Capture-MS), ACTG2 (Affinity Capture-MS), ACTG2 (Affinity Capture-MS), ACTG2 (Affinity Capture-MS), ACTG2 (Affinity Capture-MS), ACTG2 (Affinity Capture-Western), ACTG2 (Reconstituted Complex), ACTG2 (Affinity Capture-MS), ACTG2 (Affinity Capture-MS), ACTG2 (Affinity Capture-MS), ACTG2 (Affinity Capture-MS), ACTG2 (Affinity Capture-MS)

ESM2 similar proteins: O15998, O17503, P04751, P04752, P08023, P10995, P12717, P18499, P20399, P26198, P27130, P41113, P49055, P53460, P53466, P53474, P53475, P53479, P53480, P53482, P62736, P62737, P62738, P62739, P62740, P63267, P63268, P63269, P63270, P68032, P68033, P68034, P68035, P68133, P68134, P68135, P68136, P68137, P68138, P68139

Diamond homologs: A2WKK5, A2XLF2, A2XNS1, A2ZP58, A3C6D7, D0LWX4, O16808, O18499, O65314, O65315, O65316, O81221, P02576, P04751, P07828, P07830, P07836, P07837, P08023, P0C539, P0C540, P0C542, P0CJ46, P0CJ47, P10981, P12716, P12717, P17126, P17304, P18601, P23343, P24902, P30162, P30164, P30165, P30167, P30168, P30169, P30171, P30172

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
NKX3-1	“up-regulates quantity by expression”	ACTG2	“transcriptional regulation”
MYOCD	“up-regulates quantity by expression”	ACTG2	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 45 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
Clathrin-mediated endocytosis	5	17.0×	4e-03
RAF/MAP kinase cascade	5	12.2×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	21
Likely pathogenic	18
Uncertain significance	51
Likely benign	5
Benign	9

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
132797	NM_001615.4(ACTG2):c.442C>A (p.Arg148Ser)	Pathogenic
132798	NM_001615.4(ACTG2):c.533G>T (p.Arg178Leu)	Pathogenic
132800	NM_001615.4(ACTG2):c.532C>T (p.Arg178Cys)	Pathogenic
132801	NM_001615.4(ACTG2):c.533G>A (p.Arg178His)	Pathogenic
132803	NM_001615.4(ACTG2):c.769C>T (p.Arg257Cys)	Pathogenic
156554	NM_001615.4(ACTG2):c.806_807delinsAA (p.Gly269Glu)	Pathogenic
1804921	NM_001615.4(ACTG2):c.632G>T (p.Arg211Leu)	Pathogenic
208792	NM_001615.4(ACTG2):c.770G>A (p.Arg257His)	Pathogenic
217521	NM_001615.4(ACTG2):c.113G>A (p.Arg38His)	Pathogenic
218309	NM_001615.4(ACTG2):c.134T>C (p.Met45Thr)	Pathogenic
218310	NM_001615.4(ACTG2):c.187C>G (p.Arg63Gly)	Pathogenic
218311	NM_001615.4(ACTG2):c.255+210C>A	Pathogenic
218312	NM_001615.4(ACTG2):c.593G>A (p.Gly198Asp)	Pathogenic
3024243	NM_001615.4(ACTG2):c.532C>A (p.Arg178Ser)	Pathogenic
3247577	NC_000002.11:g.(?74143691)(74166169_?)del	Pathogenic
3247578	NC_000002.11:g.(?74143691)(74177879_?)del	Pathogenic
3362785	NM_001615.4(ACTG2):c.413A>G (p.Gln138Arg)	Pathogenic
369682	NM_001615.4(ACTG2):c.613G>A (p.Ala205Thr)	Pathogenic
3903193	NM_001615.4(ACTG2):c.577A>T (p.Ile193Phe)	Pathogenic
694268	NM_001615.4(ACTG2):c.116C>T (p.Pro39Leu)	Pathogenic
694269	NM_001615.4(ACTG2):c.188G>A (p.Arg63Gln)	Pathogenic
1047916	NM_001615.4(ACTG2):c.968C>T (p.Pro323Leu)	Likely pathogenic
1177291	NM_001615.4(ACTG2):c.442C>T (p.Arg148Cys)	Likely pathogenic
1339551	NM_001615.4(ACTG2):c.590G>C (p.Arg197Thr)	Likely pathogenic
1526399	NM_001615.4(ACTG2):c.439G>C (p.Gly147Arg)	Likely pathogenic
1703035	NM_001615.4(ACTG2):c.116C>G (p.Pro39Arg)	Likely pathogenic
1709289	NM_001615.4(ACTG2):c.188G>T (p.Arg63Leu)	Likely pathogenic
1803217	NM_001615.4(ACTG2):c.593G>T (p.Gly198Val)	Likely pathogenic
3062129	NM_001615.4(ACTG2):c.28G>A (p.Val10Met)	Likely pathogenic
3062659	GRCh37/hg19 2p13.3-12(chr2:71076472-76368354)x1	Likely pathogenic

SpliceAI

1106 predictions. Top by Δscore:

Variant	Effect	Δscore
2:73901266:A:AG	acceptor_gain	1.0000
2:73901267:A:G	acceptor_gain	1.0000
2:73908672:GATCT:G	acceptor_gain	1.0000
2:73909049:TTTAA:T	acceptor_loss	1.0000
2:73909050:TTAA:T	acceptor_loss	1.0000
2:73909051:TAA:T	acceptor_loss	1.0000
2:73909052:A:AG	acceptor_gain	1.0000
2:73909052:AAG:A	acceptor_loss	1.0000
2:73909053:A:G	acceptor_gain	1.0000
2:73909053:A:T	acceptor_loss	1.0000
2:73909054:G:GA	acceptor_gain	1.0000
2:73909054:GATC:G	acceptor_gain	1.0000
2:73909135:GACAG:G	donor_gain	1.0000
2:73909136:ACAGG:A	donor_loss	1.0000
2:73909137:CAGG:C	donor_loss	1.0000
2:73909139:GGT:G	donor_loss	1.0000
2:73909140:G:GA	donor_loss	1.0000
2:73909140:G:GG	donor_gain	1.0000
2:73909141:T:A	donor_loss	1.0000
2:73913482:CAGGC:C	acceptor_loss	1.0000
2:73913483:A:AG	acceptor_gain	1.0000
2:73913483:AG:A	acceptor_gain	1.0000
2:73913483:AGG:A	acceptor_loss	1.0000
2:73913484:G:GA	acceptor_gain	1.0000
2:73913484:GG:G	acceptor_gain	1.0000
2:73913484:GGC:G	acceptor_gain	1.0000
2:73913484:GGCA:G	acceptor_gain	1.0000
2:73913484:GGCAT:G	acceptor_gain	1.0000
2:73913644:CAGG:C	donor_loss	1.0000
2:73913647:GT:G	donor_loss	1.0000

AlphaMissense

2485 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:73901345:G:C	D12H	1.000
2:73901346:A:T	D12V	1.000
2:73901351:G:C	G14R	1.000
2:73901351:G:T	G14C	1.000
2:73901352:G:A	G14D	1.000
2:73901352:G:T	G14V	1.000
2:73901368:G:C	K19N	1.000
2:73901368:G:T	K19N	1.000
2:73901372:G:C	G21R	1.000
2:73901373:G:A	G21D	1.000
2:73901373:G:T	G21V	1.000
2:73901393:C:A	P28T	1.000
2:73901393:C:T	P28S	1.000
2:73901394:C:A	P28H	1.000
2:73901394:C:G	P28R	1.000
2:73901420:G:C	G37R	1.000
2:73901421:G:A	G37D	1.000
2:73901421:G:T	G37V	1.000
2:73902399:G:A	G56R	1.000
2:73902399:G:C	G56R	1.000
2:73902399:G:T	G56W	1.000
2:73902400:G:A	G56E	1.000
2:73902400:G:T	G56V	1.000
2:73902409:C:A	A59D	1.000
2:73902423:G:A	G64R	1.000
2:73902423:G:C	G64R	1.000
2:73902423:G:T	G64W	1.000
2:73902424:G:A	G64E	1.000
2:73902430:T:A	L66Q	1.000
2:73902430:T:C	L66P	1.000

dbSNP variants (sampled 300 via entrez): RS1000199093 (2:73908499 A>C,G), RS1000372949 (2:73901865 G>T), RS1000399666 (2:73893089 G>A,C), RS1000425403 (2:73902086 A>C), RS1000433198 (2:73910599 A>G), RS1000561527 (2:73891514 G>A,T), RS1000600943 (2:73894646 G>A), RS1000717654 (2:73908225 C>G), RS1000755587 (2:73899388 G>A), RS1000780432 (2:73891729 G>A), RS1000808836 (2:73896678 G>A), RS1000822879 (2:73898374 A>C,T), RS1000833124 (2:73916832 C>T), RS1001112058 (2:73913361 G>A), RS1001321013 (2:73906772 T>A,C,G)

Disease associations

OMIM: gene MIM:102545 | disease phenotypes: MIM:155310, MIM:619431, MIM:609629, MIM:249210

GenCC curated gene-disease

Disease	Classification	Inheritance
visceral myopathy 1	Strong	Autosomal dominant
familial visceral myopathy	Strong	Autosomal dominant
megacystis-microcolon-intestinal hypoperistalsis syndrome	Supportive	Autosomal dominant

Mondo (10): visceral myopathy 1 (MONDO:0020754), chronic intestinal pseudoobstruction (MONDO:0017574), intestinal obstruction (MONDO:0004565), megacystis-microcolon-intestinal hypoperistalsis syndrome 5 (MONDO:0030329), constipation disorder (MONDO:0002203), visceral neuropathy, familial, 3, autosomal dominant (MONDO:0012317), intestinal pseudo-obstruction (MONDO:0002803), megacystis-microcolon-intestinal hypoperistalsis syndrome (MONDO:0025986), (MONDO:0007960), familial visceral myopathy (MONDO:0016829)

Orphanet (3): Familial visceral myopathy (Orphanet:2604), Chronic intestinal pseudoobstruction syndrome (Orphanet:2978), Megacystis-microcolon-intestinal hypoperistalsis syndrome (Orphanet:2241)

HPO phenotypes

54 total (30 of 54 shown, HPO-id order):

HPO	Term
HP:0000003	Multicystic kidney dysplasia
HP:0000006	Autosomal dominant inheritance
HP:0000016	Urinary retention
HP:0000021	Megacystis
HP:0000028	Cryptorchidism
HP:0000072	Hydroureter
HP:0000076	Vesicoureteral reflux
HP:0000126	Hydronephrosis
HP:0000175	Cleft palate
HP:0000252	Microcephaly
HP:0000311	Round face
HP:0000337	Broad forehead
HP:0000347	Micrognathia
HP:0000358	Posteriorly rotated ears
HP:0000426	Prominent nasal bridge
HP:0000463	Anteverted nares
HP:0000774	Narrow chest
HP:0000843	Hyperparathyroidism
HP:0001166	Arachnodactyly
HP:0001387	Joint stiffness
HP:0001399	Hepatic failure
HP:0001409	Portal hypertension
HP:0001522	Death in infancy
HP:0001537	Umbilical hernia
HP:0001539	Omphalocele
HP:0001561	Polyhydramnios
HP:0001562	Oligohydramnios
HP:0001733	Pancreatitis
HP:0001798	Anonychia
HP:0002013	Vomiting

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST010605_2	Parent of origin effect on receptive language ability (paternal)	5.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0005686	receptive language perception
EFO:0005939	parental genotype effect measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D003248	Constipation	C23.888.821.150
D007415	Intestinal Obstruction	C06.405.469.531
D007418	Intestinal Pseudo-Obstruction	C06.405.469.531.492.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression	4
Cadmium	increases expression, decreases expression, increases abundance	2
Calcitriol	increases expression, affects cotreatment	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tretinoin	affects cotreatment, increases expression	2
methylmercuric chloride	decreases expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
bisphenol A	decreases expression	1
methylselenic acid	increases expression	1
2,5,2’,5’-tetrachlorobiphenyl	decreases expression	1
trimellitic anhydride	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	affects cotreatment, increases expression	1
butyraldehyde	increases expression	1
zinc chromate	increases abundance, decreases expression	1
cadmium acetate	decreases expression	1
nickel sulfate	increases expression	1
triadimefon	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	increases expression, affects cotreatment, decreases expression, affects response to substance	1
mercuric bromide	affects cotreatment, increases expression	1
chromium hexavalent ion	increases abundance, decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	increases expression	1
quinocetone	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
3-hydroxy-4-prenyl-5-methoxystilbene-2-carboxylic acid	increases expression	1
Dasatinib	increases expression	1
Temozolomide	increases expression	1
Zoledronic Acid	decreases expression	1

Cellosaurus cell lines

2 cell lines: 1 induced pluripotent stem cell, 1 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_C6SS	CHOPi012-A	Induced pluripotent stem cell	Female
CVCL_C9EC	CHOPe003-A	Embryonic stem cell	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01507220	PHASE4	TERMINATED	A Health Economic Trial in Adult Patients Undergoing Open Colectomy MA402S23B301
NCT01507233	PHASE4	TERMINATED	A Health Economic Trial in Adult Patients Undergoing Open Colectomy MA402S23B302
NCT01507246	PHASE4	COMPLETED	Adult Patients Undergoing Open Colectomy MA402S23B303
NCT02058290	PHASE4	TERMINATED	A Health Economic Trial in Adult Patients Undergoing Laparoscopic Colectomy
NCT02812186	PHASE4	COMPLETED	Deep Versus Moderate Neuromuscular Blockade During Laparoscopic Surgery
NCT03334578	PHASE4	WITHDRAWN	The Use of Gastrografin to Help Alleviate Bowel Obstruction in Gastroschisis Patients.
NCT06089551	PHASE4	UNKNOWN	Early vs Postponed Parenteral Nutrition After Emergency Abdominal Surgery
NCT00149877	PHASE4	COMPLETED	Efficacy, Safety and Tolerability of Tegaserod in Patients With Chronic Constipation
NCT00153114	PHASE4	COMPLETED	PolyethyleneGlycol3350 Laxative vs Placebo in Constipated Children
NCT00153127	PHASE4	COMPLETED	Comparison of PolyethyleneGlycol and Placebo for Relief of Constipation From Constipating Medications
NCT00153140	PHASE4	COMPLETED	Polyethyleneglycol3350 vs Tegaserod in Treatment of Patients With Chronic Constipation
NCT00153153	PHASE4	COMPLETED	Extended Use of Polyethyleneglycol3350 Laxative in Constipated Patients
NCT00157638	PHASE4	COMPLETED	Integrating Family Medicine and Pharmacy to Advance Primary Care Therapeutics
NCT00164125	PHASE4	COMPLETED	An Open Label Study of Chronic Polyethyleneglycol3350 Use in Constipated Patients
NCT00171522	PHASE4	COMPLETED	Preference of Tegaserod vs. PEG 3350 in Patients With Constipation
NCT00256984	PHASE4	COMPLETED	Study of Stapled Transanal Rectal Resection (STARR) Surgery in Refractory Constipation Associated With Obstructive Defecation Syndrome (ODS)
NCT00276354	PHASE4	COMPLETED	Study of Long-term Use of Forlax® in Elderly Patients With Chronic Constipation
NCT00286520	PHASE4	COMPLETED	Treatment of Fecal Incontinence and Constipation in Patients With Spinal Cord Injury
NCT00319670	PHASE4	COMPLETED	A Pilot Study of a New MiraLax® Dose Formulation For Use in Constipated Children
NCT00348634	PHASE4	TERMINATED	Effect of Tegaserod on Orocecal Transit in Elderly Chronic Constipation Patients
NCT00452335	PHASE4	COMPLETED	Safety and Efficacy of Lubiprostone in Pediatric Patients With Constipation
NCT00521872	PHASE4	COMPLETED	Stapled Trans Anal Rectal Resection (STARR) for Outlet Obstruction: Functional and Morphological Outcome
NCT00583609	PHASE4	COMPLETED	A Pilot Study of a New PEG3350 Dose Formulation For Use in Constipated Children
NCT00603681	PHASE4	COMPLETED	Comparison of PEG Solutions With and Without Electrolytes in the Treatment of Constipation
NCT00712543	PHASE4	COMPLETED	A Preference Study Comparing Kristalose® and Liquid Lactulose
NCT00763399	PHASE4	COMPLETED	Effect of Probiotics on Intestinal Bacterial Population and Immune Modulation
NCT00770432	PHASE4	COMPLETED	Study Comparing PEG 3350 Laxative to Placebo in the Treatment of Occasional Constipation (Study CL2007-12)(P08216)
NCT00799201	PHASE4	TERMINATED	Enteral Naloxone Versus a Traditional Bowel Regimen for the Prevention of Opioid Induced Constipation in Trauma Patients
NCT00844831	PHASE4	COMPLETED	Effects of Lubiprostone on Small Bowel and Colonic Bacteria: A Correlation Study With Segmental and Whole Gut Transit
NCT00949377	PHASE4	WITHDRAWN	Can Methylnaltrexone Safely Treat Opioid Related Constipation in the Emergency Department?
NCT01003249	PHASE4	TERMINATED	Dysfunctional Voiding and Lower Urinary Tract Symptoms With Baclofen
NCT01096290	PHASE4	TERMINATED	Comparison of Lubiprostone and Placebo for the Relief of Constipation From Constipating Medications
NCT01114997	PHASE4	TERMINATED	Effect of Lidocaine and Esmolol to Improve the Quality of Recovery
NCT01170039	PHASE4	COMPLETED	The Effectiveness of Lubiprostone in Constipated Diabetics
NCT01180725	PHASE4	COMPLETED	Investigation of Dried Plums in the Treatment of Adults With Constipation
NCT01189409	PHASE4	TERMINATED	Polyethylene Glycol (PEG) Versus Sennosides Study in Opioid-Induced Constipation in Cancer Patients
NCT01230840	PHASE4	COMPLETED	Effect of Wheat Dextrin on Calcium and Magnesium Absorption
NCT01236534	PHASE4	COMPLETED	Lubiprostone in Patients With Multiple Sclerosis Associated Constipation
NCT01267370	PHASE4	COMPLETED	Soy Polysaccharide Fiber for the Treatment of Chronic Constipation in Children: a Randomized, Double-blind Trial
NCT01333787	PHASE4	COMPLETED	Dietary Fiber Mixture in Constipated Pediatric Patients