Visceral myopathy 1

Summary

Visceral myopathy 1 (MONDO:0020754) is a disease caused by ACTG2 (GenCC Strong), with 6 cohort genes. The dominant Reactome pathway is Smooth Muscle Contraction (5 cohort genes).

At a glance

• Causal gene: ACTG2 (GenCC Strong)
• Cohort genes: 6
• ClinVar variants: 52

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	visceral myopathy 1
Mondo ID	MONDO:0020754
OMIM	155310
UMLS	C5542197
MedGen	1785391
GARD	0027875
Is cancer (heuristic)	no

Also known as: visceral myopathy · visceral myopathy 1 · VSCM

Data availability: 52 ClinVar variants · 2 GenCC gene-disease records · 2 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › familial visceral myopathy › visceral myopathy 1

Related subtypes (1): visceral myopathy 2

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

52 retrieved; paginated sample, class counts are floors:

19 pathogenic, 12 uncertain significance, 8 likely pathogenic, 7 pathogenic/likely pathogenic, 4 benign, 2 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
132797	NM_001615.4(ACTG2):c.442C>A (p.Arg148Ser)	ACTG2	Pathogenic	criteria provided, single submitter
132798	NM_001615.4(ACTG2):c.533G>T (p.Arg178Leu)	ACTG2	Pathogenic	criteria provided, multiple submitters, no conflicts
132799	NM_001615.4(ACTG2):c.118C>T (p.Arg40Cys)	ACTG2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
132800	NM_001615.4(ACTG2):c.532C>T (p.Arg178Cys)	ACTG2	Pathogenic	criteria provided, multiple submitters, no conflicts
132801	NM_001615.4(ACTG2):c.533G>A (p.Arg178His)	ACTG2	Pathogenic	criteria provided, multiple submitters, no conflicts
132802	NM_001615.4(ACTG2):c.119G>A (p.Arg40His)	ACTG2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
132803	NM_001615.4(ACTG2):c.769C>T (p.Arg257Cys)	ACTG2	Pathogenic	criteria provided, multiple submitters, no conflicts
132805	NM_001615.4(ACTG2):c.400T>A (p.Tyr134Asn)	ACTG2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
156554	NM_001615.4(ACTG2):c.806_807delinsAA (p.Gly269Glu)	ACTG2	Pathogenic	no assertion criteria provided
1804921	NM_001615.4(ACTG2):c.632G>T (p.Arg211Leu)	ACTG2	Pathogenic	criteria provided, single submitter
180620	NM_001615.4(ACTG2):c.443G>T (p.Arg148Leu)	ACTG2	Pathogenic/Likely pathogenic	no assertion criteria provided
208792	NM_001615.4(ACTG2):c.770G>A (p.Arg257His)	ACTG2	Pathogenic	criteria provided, multiple submitters, no conflicts
218309	NM_001615.4(ACTG2):c.134T>C (p.Met45Thr)	ACTG2	Pathogenic	criteria provided, single submitter
218310	NM_001615.4(ACTG2):c.187C>G (p.Arg63Gly)	ACTG2	Pathogenic	criteria provided, multiple submitters, no conflicts
218311	NM_001615.4(ACTG2):c.255+210C>A	ACTG2	Pathogenic	criteria provided, single submitter
218312	NM_001615.4(ACTG2):c.593G>A (p.Gly198Asp)	ACTG2	Pathogenic	criteria provided, multiple submitters, no conflicts
3024243	NM_001615.4(ACTG2):c.532C>A (p.Arg178Ser)	ACTG2	Pathogenic	criteria provided, single submitter
369682	NM_001615.4(ACTG2):c.613G>A (p.Ala205Thr)	ACTG2	Pathogenic	criteria provided, multiple submitters, no conflicts
495145	NM_001615.4(ACTG2):c.632G>A (p.Arg211Gln)	ACTG2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
694268	NM_001615.4(ACTG2):c.116C>T (p.Pro39Leu)	ACTG2	Pathogenic	criteria provided, single submitter
694269	NM_001615.4(ACTG2):c.188G>A (p.Arg63Gln)	ACTG2	Pathogenic	criteria provided, single submitter
973102	NM_001615.4(ACTG2):c.588G>C (p.Glu196Asp)	ACTG2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
264986	NM_012134.3(LMOD1):c.1108C>T (p.Arg370Ter)	LMOD1	Pathogenic	no assertion criteria provided
156401	NM_002474.3(MYH11):c.3598A>T (p.Lys1200Ter)	MYH11	Pathogenic/Likely pathogenic	no assertion criteria provided
264987	NM_053025.4(MYLK):c.3838_3844dup (p.Glu1282fs)	MYLK	Pathogenic	no assertion criteria provided
427851	NM_053025.4(MYLK):c.3985+5G>T	MYLK	Pathogenic	criteria provided, single submitter
1177291	NM_001615.4(ACTG2):c.442C>T (p.Arg148Cys)	ACTG2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1339551	NM_001615.4(ACTG2):c.590G>C (p.Arg197Thr)	ACTG2	Likely pathogenic	criteria provided, single submitter
3062129	NM_001615.4(ACTG2):c.28G>A (p.Val10Met)	ACTG2	Likely pathogenic	criteria provided, single submitter
3895473	NM_001615.4(ACTG2):c.209A>G (p.Tyr70Cys)	ACTG2	Likely pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 10 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
ACTG2	Strong	Autosomal dominant	visceral myopathy 1	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ACTG2	Orphanet:104077	Myopathic intestinal pseudoobstruction
ACTG2	Orphanet:2241	Megacystis-microcolon-intestinal hypoperistalsis syndrome
ACTG2	Orphanet:2604	Familial visceral myopathy
LMOD1	Orphanet:2241	Megacystis-microcolon-intestinal hypoperistalsis syndrome
MYH11	Orphanet:2241	Megacystis-microcolon-intestinal hypoperistalsis syndrome
MYH11	Orphanet:229	Familial aortic dissection
MYH11	Orphanet:91387	Familial thoracic aortic aneurysm and aortic dissection
MYH11	Orphanet:98829	Acute myeloid leukemia with abnormal bone marrow eosinophils inv(16)(p13q22) or t(16;16)(p13;q22)
MYLK	Orphanet:2241	Megacystis-microcolon-intestinal hypoperistalsis syndrome
MYLK	Orphanet:91387	Familial thoracic aortic aneurysm and aortic dissection

Cohort genes → proteins

6 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ACTG2	HGNC:145	ENSG00000163017	P63267	Actin, gamma-enteric smooth muscle	gencc,clinvar
MYL9	HGNC:15754	ENSG00000101335	P24844	Myosin regulatory light polypeptide 9	clinvar
DLGAP4-AS1	HGNC:51223	ENSG00000232907		DLGAP4 antisense RNA 1	clinvar
LMOD1	HGNC:6647	ENSG00000163431	P29536	Leiomodin-1	clinvar
MYH11	HGNC:7569	ENSG00000133392	P35749	Myosin-11	clinvar
MYLK	HGNC:7590	ENSG00000065534	Q15746	Myosin light chain kinase, smooth muscle	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ACTG2	Actin, gamma-enteric smooth muscle	Actins are highly conserved proteins that are involved in various types of cell motility and are ubiquitously expressed in all eukaryotic cells.
MYL9	Myosin regulatory light polypeptide 9	Myosin regulatory subunit that plays an important role in regulation of both smooth muscle and nonmuscle cell contractile activity via its phosphorylation.
LMOD1	Leiomodin-1	Required for proper contractility of visceral smooth muscle cells.
MYH11	Myosin-11	Muscle contraction.
MYLK	Myosin light chain kinase, smooth muscle	Calcium/calmodulin-dependent myosin light chain kinase implicated in smooth muscle contraction via phosphorylation of myosin light chains (MLC).

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 4 · Druggable fraction: 0.17

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Kinase	1	4.6×	0.451
Scaffold/PPI	1	2.9×	0.451
Other/Unknown	4	1.2×	0.458

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ACTG2	Other/Unknown	no		Actin, Actin_CS, Actin/actin-like_CS
MYL9	Other/Unknown	no		EF_hand_dom, EF-hand-dom_pair, EF_Hand_1_Ca_BS
DLGAP4-AS1	Other/Unknown	no
LMOD1	Other/Unknown	no		WH2_dom, TMOD, LRR_dom_sf
MYH11	Scaffold/PPI	no		IQ_motif_EF-hand-BS, Myosin_head_motor_dom-like, Myosin_tail
MYLK	Kinase	yes	2.7.11.18	Prot_kinase_dom, Ig_sub2, Ig_sub

Expression context

Cohort genes with no expression data: 0.

5 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	6
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right coronary artery	3
cauda epididymis	2
saphenous vein	2
seminal vesicle	2
popliteal artery	2
tibial artery	2
left testis	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1
lower esophagus	1
lower esophagus muscularis layer	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ACTG2	241	broad	marker	seminal vesicle, cauda epididymis, saphenous vein
MYL9	263	ubiquitous	marker	popliteal artery, tibial artery, right coronary artery
DLGAP4-AS1	161	broad	yes	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, left testis
LMOD1	245	broad	marker	right coronary artery, popliteal artery, tibial artery
MYH11	143	broad	marker	right coronary artery, lower esophagus, lower esophagus muscularis layer
MYLK	289	ubiquitous	marker	cauda epididymis, saphenous vein, seminal vesicle

Protein interactions among cohort

Intra-cohort edges: 6.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MYH11	3,818
MYL9	3,272
MYLK	2,763
LMOD1	968
ACTG2	133
DLGAP4-AS1	0

Intra-cohort edges

A	B	Sources
LMOD1	MYH11	string_interaction
LMOD1	MYL9	string_interaction
LMOD1	MYLK	string_interaction
MYH11	MYL9	string_interaction
MYH11	MYLK	string_interaction
MYL9	MYLK	string_interaction

Structural data

PDB: 4 · AlphaFold-only: 1 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MYLK	Q15746	8
ACTG2	P63267	4
LMOD1	P29536	3
MYH11	P35749	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MYL9	P24844	84.10

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 29. Enrichment computed across 6 evidence-associated genes (5 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Smooth Muscle Contraction	5	265.6×	2e-11	ACTG2, MYL9, LMOD1, MYH11, MYLK
Muscle contraction	5	77.2×	5e-09	ACTG2, MYL9, LMOD1, MYH11, MYLK
RHO GTPases activate PAKs	3	326.3×	5e-07	MYL9, MYH11, MYLK
Sema4D in semaphorin signaling	2	268.7×	1e-04	MYL9, MYH11
RHO GTPases activate CIT	2	240.4×	1e-04	MYL9, MYH11
RHO GTPases Activate ROCKs	2	240.4×	1e-04	MYL9, MYH11
Sema4D induced cell migration and growth-cone collapse	2	228.4×	1e-04	MYL9, MYH11
RHO GTPase Effectors	3	40.8×	1e-04	MYL9, MYH11, MYLK
Semaphorin interactions	2	157.5×	2e-04	MYL9, MYH11
EPHA-mediated growth cone collapse	2	152.3×	2e-04	MYL9, MYH11
RHO GTPases activate PKNs	2	126.9×	3e-04	MYL9, MYH11
Signaling by Rho GTPases	3	20.5×	6e-04	MYL9, MYH11, MYLK
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	3	20.1×	6e-04	MYL9, MYH11, MYLK
EPH-Ephrin signaling	2	66.2×	7e-04	MYL9, MYH11
Regulation of CDH1 Function	1	190.3×	0.009	ACTG2
Axon guidance	2	18.1×	0.009	MYL9, MYH11
Nervous system development	2	17.2×	0.009	MYL9, MYH11
Signal Transduction	3	6.1×	0.013	MYL9, MYH11, MYLK
Developmental Lineage of Mammary Gland Myoepithelial Cells	1	108.8×	0.014	MYH11
Formation of the dystrophin-glycoprotein complex (DGC)	1	61.7×	0.023	ACTG2
Activation of STAT3 by cadherin engagement	1	32.6×	0.042	ACTG2
Non-integrin membrane-ECM interactions	1	30.9×	0.042	ACTG2
Transcriptional regulation by RUNX1	1	29.3×	0.042	MYL9
RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function	1	24.0×	0.048	MYL9
Developmental Biology	2	5.8×	0.048	MYL9, MYH11
Extracellular matrix organization	1	12.6×	0.086	ACTG2
RNA Polymerase II Transcription	1	4.5×	0.218	MYL9
Gene expression (Transcription)	1	3.6×	0.260	MYL9
Generic Transcription Pathway	1	3.0×	0.290	MYL9

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
myofibril assembly	2	449.4×	2e-04	MYL9, LMOD1
smooth muscle contraction	2	321.0×	2e-04	MYH11, MYLK
tonic smooth muscle contraction	1	3370.4×	0.003	MYLK
skeletal muscle myosin thick filament assembly	1	1123.5×	0.006	MYH11
aorta smooth muscle tissue morphogenesis	1	842.6×	0.006	MYLK
mesenchyme migration	1	674.1×	0.006	ACTG2
cellular response to acetaldehyde	1	674.1×	0.006	ACTG2
pointed-end actin filament capping	1	481.5×	0.007	LMOD1
actin nucleation	1	374.5×	0.008	LMOD1
regulation of muscle contraction	1	337.0×	0.008	MYL9
bleb assembly	1	306.4×	0.008	MYLK
elastic fiber assembly	1	306.4×	0.008	MYH11
cellular hypotonic response	1	280.9×	0.008	MYLK
cellular response to interleukin-6	1	198.3×	0.010	ACTG2
regulation of synaptic vesicle endocytosis	1	177.4×	0.011	MYLK
stress fiber assembly	1	153.2×	0.011	MYL9
cardiac muscle cell development	1	124.8×	0.013	MYH11
positive regulation of calcium ion transport	1	116.2×	0.013	MYLK
actomyosin structure organization	1	112.3×	0.013	MYH11
positive regulation of wound healing	1	105.3×	0.013	MYLK
platelet aggregation	1	67.4×	0.019	MYL9
positive regulation of actin filament polymerization	1	66.1×	0.019	LMOD1
muscle contraction	1	41.6×	0.029	LMOD1
response to ethanol	1	29.3×	0.039	ACTG2
actin filament organization	1	23.7×	0.046	LMOD1
protein phosphorylation	1	13.6×	0.077	MYLK
positive regulation of cell migration	1	12.3×	0.081	MYLK
positive regulation of gene expression	1	7.8×	0.123	ACTG2

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 5

Druggability breadth: 1 of 6 evidence-associated genes (17%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
MYLK	PONATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MYLK	28	4
ACTG2	0	0
MYL9	0	0
DLGAP4-AS1	0	0
LMOD1	0	0
MYH11	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PONATINIB	4	MYLK
AFATINIB	4	MYLK
FEDRATINIB	4	MYLK
RUXOLITINIB	4	MYLK
NIFEDIPINE	4	MYLK
BOSUTINIB	4	MYLK
GILTERITINIB	4	MYLK
TOVORAFENIB	4	MYLK
NINTEDANIB	4	MYLK
SUNITINIB	4	MYLK
DASATINIB	4	MYLK
QUIZARTINIB	4	MYLK
MIDOSTAURIN	4	MYLK
FASUDIL	3	MYLK
DOVITINIB	3	MYLK
LESTAURTINIB	3	MYLK
RUBOXISTAURIN	3	MYLK
VX-702	2	MYLK
SU-014813	2	MYLK
REBASTINIB	2	MYLK
TANZISERTIB	2	MYLK
CEP-32496	2	MYLK
BAFETINIB	2	MYLK
PEXMETINIB	2	MYLK
R-406	2	MYLK
BI-2536	2	MYLK
KW-2449	1	MYLK
IMD-0354	1	MYLK

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
MYLK	303	Binding:303

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MYLK	2.7.11.18	myosin-light-chain kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
MYLK	303

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

28 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
PONATINIB	4	MYLK
AFATINIB	4	MYLK
FEDRATINIB	4	MYLK
RUXOLITINIB	4	MYLK
NIFEDIPINE	4	MYLK
BOSUTINIB	4	MYLK
GILTERITINIB	4	MYLK
TOVORAFENIB	4	MYLK
NINTEDANIB	4	MYLK
SUNITINIB	4	MYLK
DASATINIB	4	MYLK
QUIZARTINIB	4	MYLK
MIDOSTAURIN	4	MYLK
FASUDIL	3	MYLK
DOVITINIB	3	MYLK
LESTAURTINIB	3	MYLK
RUBOXISTAURIN	3	MYLK
VX-702	2	MYLK
SU-014813	2	MYLK
REBASTINIB	2	MYLK
TANZISERTIB	2	MYLK
CEP-32496	2	MYLK
BAFETINIB	2	MYLK
PEXMETINIB	2	MYLK
R-406	2	MYLK
BI-2536	2	MYLK
KW-2449	1	MYLK
IMD-0354	1	MYLK

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	MYLK
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	5	ACTG2, MYL9, DLGAP4-AS1, LMOD1, MYH11

Undrugged target profiles

5 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
MYL9	0	MYLK
ACTG2	0	—
DLGAP4-AS1	0	—
LMOD1	0	—
MYH11	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.