Myopathy, proximal, and ophthalmoplegia

Summary

Myopathy, proximal, and ophthalmoplegia (MONDO:0011577) is a disease caused by MYH2 (GenCC Strong), with 5 cohort genes.

At a glance

• Causal gene: MYH2 (GenCC Strong)
• Cohort genes: 5
• ClinVar variants: 1,476

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	myopathy, proximal, and ophthalmoplegia
Mondo ID	MONDO:0011577
MeSH	C565311
OMIM	605637
DOID	DOID:0080719
UMLS	C1854106
MedGen	381340
GARD	0024809
Is cancer (heuristic)	no

Also known as: inclusion body myopathy 3, autosomal dominant · myopathy with congenital joint contractures, ophthalmoplegia, and rimmed vacuoles · myopathy, proximal, and ophthalmoplegia · MYPOP

Data availability: 1,476 ClinVar variants · 6 GenCC gene-disease records.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › muscle tissue disorder › skeletal muscle disorder › myopathy › myositis disease › inclusion body myositis › myopathy, proximal, and ophthalmoplegia

Related subtypes (1): GNE myopathy

Subtypes (2): childhood-onset autosomal recessive myopathy with external ophthalmoplegia, hereditary inclusion body myopathy-joint contractures-ophthalmoplegia syndrome

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

600 retrieved; paginated sample, class counts are floors:

312 uncertain significance, 222 likely benign, 29 pathogenic, 13 conflicting classifications of pathogenicity, 11 likely pathogenic, 6 benign/likely benign, 4 pathogenic/likely pathogenic, 3 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1029470	NM_017534.6(MYH2):c.4537+1G>A	LOC126862500	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068578	NM_017534.6(MYH2):c.4511del (p.Leu1504fs)	LOC126862500	Pathogenic	criteria provided, single submitter
2021065	NM_017534.6(MYH2):c.4756del (p.Asp1586fs)	LOC126862500	Pathogenic	criteria provided, single submitter
2028163	NM_017534.6(MYH2):c.4371+1del	LOC126862500	Pathogenic	criteria provided, single submitter
2169656	NM_017534.6(MYH2):c.4510del (p.Thr1503_Leu1504insTer)	LOC126862500	Pathogenic	criteria provided, single submitter
1453317	NM_017534.6(MYH2):c.625G>T (p.Glu209Ter)	LOC126862501	Pathogenic	criteria provided, single submitter
183666	NM_017534.6(MYH2):c.706G>A (p.Ala236Thr)	LOC126862501	Pathogenic	no assertion criteria provided
1391790	NM_017534.6(MYH2):c.3757A>T (p.Lys1253Ter)	MYH2	Pathogenic	criteria provided, single submitter
1399827	NM_017534.6(MYH2):c.2365del (p.Gln789fs)	MYH2	Pathogenic	criteria provided, single submitter
14137	NM_017534.6(MYH2):c.2116G>A (p.Glu706Lys)	MYH2	Pathogenic	no assertion criteria provided
1453954	NC_000017.11:g.10535371_10535372insGGAGGGAGGAGCCAAGATGGCCGAATAGGAACAGCTCCGGTCTACAGCTCCCAGCGTGAGCGACGCAGAAGACGGTGATTTCTGCATTTCCATCTGAGGTACCGGGTTCANNNNNNNNNNAAAAAAAAAAAAAAAAAAAAAAATTCTCCTGTAA	MYH2	Pathogenic	criteria provided, single submitter
1459021	NC_000017.10:g.(?10424597)(10451237_?)del	MYH2	Pathogenic	criteria provided, single submitter
183660	NM_017534.6(MYH2):c.5609T>C (p.Leu1870Pro)	MYH2	Pathogenic	no assertion criteria provided
183662	NM_017534.6(MYH2):c.2347C>T (p.Arg783Ter)	MYH2	Pathogenic	criteria provided, single submitter
183664	NM_017534.6(MYH2):c.2405T>A (p.Leu802Ter)	MYH2	Pathogenic	criteria provided, single submitter
2172073	NM_017534.6(MYH2):c.2418del (p.Glu806fs)	MYH2	Pathogenic	criteria provided, single submitter
2420285	NM_017534.6(MYH2):c.5554C>T (p.Arg1852Ter)	MYH2	Pathogenic	criteria provided, single submitter
1072835	NM_017534.6(MYH2):c.2461C>T (p.Gln821Ter)	MYHAS	Pathogenic	criteria provided, single submitter
1199204	NM_017534.6(MYH2):c.1925del (p.Gly642fs)	MYHAS	Pathogenic	criteria provided, single submitter
1301892	NM_017534.6(MYH2):c.5630T>C (p.Leu1877Pro)	MYHAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1323305	NM_017534.6(MYH2):c.3019G>T (p.Glu1007Ter)	MYHAS	Pathogenic	criteria provided, multiple submitters, no conflicts
1374776	NM_017534.6(MYH2):c.4810C>T (p.Gln1604Ter)	MYHAS	Pathogenic	criteria provided, single submitter
1397674	NM_017534.6(MYH2):c.3205del (p.Gln1069fs)	MYHAS	Pathogenic	criteria provided, single submitter
1424105	NM_017534.6(MYH2):c.4842del (p.Asn1615fs)	MYHAS	Pathogenic	criteria provided, single submitter
1451903	NM_017534.6(MYH2):c.52C>T (p.Arg18Ter)	MYHAS	Pathogenic	criteria provided, multiple submitters, no conflicts
1457319	NM_017534.6(MYH2):c.2173A>T (p.Lys725Ter)	MYHAS	Pathogenic	criteria provided, single submitter
1477208	NM_017534.6(MYH2):c.2305-1G>A	MYHAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1708074	NM_017534.6(MYH2):c.3291_3315del (p.Gln1097fs)	MYHAS	Pathogenic	criteria provided, single submitter
1803154	NM_017534.6(MYH2):c.2176C>T (p.Gln726Ter)	MYHAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
183661	NM_017534.6(MYH2):c.904+1G>A	MYHAS	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 3 · 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
MYH2	Strong	Semidominant	myopathy, proximal, and ophthalmoplegia	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MYH2	Orphanet:363677	Childhood-onset autosomal recessive myopathy with external ophthalmoplegia
MYH2	Orphanet:79091	Hereditary inclusion body myopathy-joint contractures-ophthalmoplegia syndrome
SCO1	Orphanet:1561	Fatal infantile cytochrome C oxidase deficiency

Cohort genes → proteins

5 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MYH2	HGNC:7572	ENSG00000125414	Q9UKX2	Myosin-2	gencc,clinvar
SCO1	HGNC:10603	ENSG00000133028	O75880	Cytochrome c oxidase assembly factor SCO1	clinvar
GAS7	HGNC:4169	ENSG00000007237	O60861	Growth arrest-specific protein 7	clinvar
MYHAS	HGNC:50609	ENSG00000272975		myosin heavy chain gene cluster antisense RNA	clinvar
HORMAD2-AS1	HGNC:50729	ENSG00000227117		HORMAD2 and MTMR3 antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MYH2	Myosin-2	Myosins are actin-based motor molecules with ATPase activity essential for muscle contraction.
SCO1	Cytochrome c oxidase assembly factor SCO1	Copper metallochaperone essential for the maturation of cytochrome c oxidase subunit II (MT-CO2/COX2).
GAS7	Growth arrest-specific protein 7	May play a role in promoting maturation and morphological differentiation of cerebellar neurons.

Protein-family classification

Druggable: 0 · Difficult: 2 · Unknown: 3 · Druggable fraction: 0.0

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
Scaffold/PPI	2	6.9×	0.059
Other/Unknown	3	1.1×	0.608

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MYH2	Scaffold/PPI	no		IQ_motif_EF-hand-BS, Myosin_head_motor_dom-like, Myosin_tail
SCO1	Other/Unknown	no		SCO1/SenC, Synth_of_cyt-c-oxidase_Sco1/2, Thioredoxin-like_sf
GAS7	Scaffold/PPI	no		FCH_dom, WW_dom, SH3_domain
MYHAS	Other/Unknown	no
HORMAD2-AS1	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

3 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
biceps brachii	1
skeletal muscle tissue of biceps brachii	1
skeletal muscle tissue of rectus abdominis	1
left ventricle myocardium	1
mucosa of transverse colon	1
primordial germ cell in gonad	1
Brodmann (1909) area 10	1
cerebellar vermis	1
parietal lobe	1
hindlimb stylopod muscle	1
muscle of leg	1
skeletal muscle tissue	1
liver	1
male germ line stem cell (sensu Vertebrata) in testis	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MYH2	163	tissue_specific	marker	skeletal muscle tissue of rectus abdominis, biceps brachii, skeletal muscle tissue of biceps brachii
SCO1	243	ubiquitous	marker	left ventricle myocardium, primordial germ cell in gonad, mucosa of transverse colon
GAS7	288	ubiquitous	marker	cerebellar vermis, parietal lobe, Brodmann (1909) area 10
MYHAS	65	tissue_specific	yes	skeletal muscle tissue, hindlimb stylopod muscle, muscle of leg
HORMAD2-AS1	118	tissue_specific	yes	right lobe of liver, liver, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GAS7	3,192
SCO1	2,050
MYH2	2,008
MYHAS	0
HORMAD2-AS1	0

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 2

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SCO1	O75880	10
GAS7	O60861	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MYH2	Q9UKX2	73.51

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 15. Enrichment computed across 5 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Parasite infection	1	173.0×	0.023	MYH2
Leishmania phagocytosis	1	173.0×	0.023	MYH2
Fcgamma receptor (FCGR) dependent phagocytosis	1	139.3×	0.023	MYH2
Complex IV assembly	1	114.2×	0.023	SCO1
FCGR3A-mediated phagocytosis	1	93.6×	0.023	MYH2
Regulation of actin dynamics for phagocytic cup formation	1	92.1×	0.023	MYH2
Leishmania infection	1	81.6×	0.023	MYH2
Parasitic Infection Pathways	1	81.6×	0.023	MYH2
Respiratory electron transport	1	47.6×	0.034	SCO1
Aerobic respiration and respiratory electron transport	1	44.3×	0.034	SCO1
Innate Immune System	1	12.8×	0.099	MYH2
Infectious disease	1	12.4×	0.099	MYH2
Disease	1	6.5×	0.159	MYH2
Immune System	1	6.5×	0.159	MYH2
Metabolism	1	5.8×	0.165	SCO1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
muscle filament sliding	1	351.1×	0.007	MYH2
intracellular copper ion homeostasis	1	312.1×	0.007	SCO1
clathrin coat assembly	1	295.6×	0.007	GAS7
mitochondrial respiratory chain complex IV assembly	1	208.1×	0.007	SCO1
clathrin-dependent endocytosis	1	193.7×	0.007	GAS7
neuron projection morphogenesis	1	92.1×	0.013	GAS7
muscle contraction	1	69.3×	0.014	MYH2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 5

Druggability breadth: 1 of 5 evidence-associated genes (20%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MYH2	0	0
SCO1	0	0
GAS7	0	0
MYHAS	0	0
HORMAD2-AS1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
MYH2	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
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	MYH2, SCO1, GAS7, MYHAS, HORMAD2-AS1

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)
MYH2	1	—
SCO1	0	—
GAS7	0	—
MYHAS	0	—
HORMAD2-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.