Myopathy, centronuclear, 5

Summary

Myopathy, centronuclear, 5 (MONDO:0014418) is a disease caused by SPEG (GenCC Definitive), with 4 cohort genes.

At a glance

• Causal gene: SPEG (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 154

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	myopathy, centronuclear, 5
Mondo ID	MONDO:0014418
OMIM	615959
DOID	DOID:0111222
UMLS	C4014814
MedGen	863251
GARD	0016035
Is cancer (heuristic)	no

Also known as: autosomal recessive centronuclear myopathy caused by mutation in SPEG · CNM5 · myopathy, centronuclear, 5 · myopathy, centronuclear, type 5 · SPEG autosomal recessive centronuclear myopathy

Data availability: 154 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › muscle tissue disorder › skeletal muscle disorder › myopathy › congenital myopathy › centronuclear myopathy › autosomal recessive centronuclear myopathy › myopathy, centronuclear, 5

Related subtypes (1): myopathy, centronuclear, 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

154 retrieved; paginated sample, class counts are floors:

114 uncertain significance, 14 conflicting classifications of pathogenicity, 9 benign, 7 pathogenic, 6 likely pathogenic, 2 pathogenic/likely pathogenic, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
144077	NM_005876.5(SPEG):c.6697C>T (p.Gln2233Ter)	ASIC4-AS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1451459	NM_005876.5(SPEG):c.8839C>T (p.Arg2947Ter)	ASIC4-AS1	Pathogenic	criteria provided, multiple submitters, no conflicts
2412683	NM_005876.5(SPEG):c.8872C>T (p.Arg2958Ter)	ASIC4-AS1	Pathogenic	criteria provided, single submitter
3251499	NM_005876.5(SPEG):c.6618dup (p.Ala2207fs)	ASIC4-AS1	Pathogenic	criteria provided, single submitter
813888	NM_005876.5(SPEG):c.8965_8989dup (p.Val2997fs)	ASIC4-AS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
144078	NM_005876.5(SPEG):c.4276C>T (p.Arg1426Ter)	SPEG	Pathogenic	no assertion criteria provided
144079	NM_005876.5(SPEG):c.3709_3715+29del	SPEG	Pathogenic	criteria provided, single submitter
144080	NM_005876.5(SPEG):c.2915_2916delinsA (p.Ala972fs)	SPEG	Pathogenic	no assertion criteria provided
3366614	NM_005876.5(SPEG):c.4360_4375del (p.Val1454fs)	SPEG	Pathogenic	criteria provided, single submitter
1686639	NM_005876.5(SPEG):c.6011del (p.Ser2004fs)	ASIC4-AS1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2690719	NM_005876.5(SPEG):c.7262_7280dup (p.Ala2428fs)	ASIC4-AS1	Likely pathogenic	criteria provided, single submitter
2692318	NM_005876.5(SPEG):c.7795G>T (p.Glu2599Ter)	ASIC4-AS1	Likely pathogenic	criteria provided, single submitter
3237517	NM_005876.5(SPEG):c.9004G>T (p.Glu3002Ter)	ASIC4-AS1	Likely pathogenic	criteria provided, single submitter
3780657	NM_005876.5(SPEG):c.5428C>T (p.Arg1810Ter)	SPEG	Likely pathogenic	criteria provided, single submitter
813889	NM_005876.5(SPEG):c.2183del (p.Leu728fs)	SPEG	Likely pathogenic	criteria provided, single submitter
1541332	NM_005876.5(SPEG):c.5724G>T (p.Met1908Ile)	ASIC4-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1590816	NM_005876.5(SPEG):c.9078C>T (p.His3026=)	ASIC4-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
374595	NM_005876.5(SPEG):c.7810C>T (p.Leu2604Phe)	ASIC4-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
424132	NM_005876.5(SPEG):c.8860G>A (p.Gly2954Ser)	ASIC4-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
638484	NM_005876.5(SPEG):c.7262C>T (p.Pro2421Leu)	ASIC4-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
713059	NM_005876.5(SPEG):c.7302G>A (p.Gly2434=)	ASIC4-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
721483	NM_005876.5(SPEG):c.8188G>A (p.Asp2730Asn)	ASIC4-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1472366	NM_005876.5(SPEG):c.4400G>A (p.Arg1467Gln)	SPEG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1536381	NM_005876.5(SPEG):c.4117C>G (p.Pro1373Ala)	SPEG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1537533	NM_005876.5(SPEG):c.1149C>T (p.Arg383=)	SPEG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2066188	NM_005876.5(SPEG):c.1148G>C (p.Arg383Pro)	SPEG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
721102	NM_005876.5(SPEG):c.206C>T (p.Thr69Met)	SPEG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
723823	NM_005876.5(SPEG):c.2572C>T (p.Arg858Cys)	SPEG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
770512	NM_005876.5(SPEG):c.3700C>T (p.Arg1234Trp)	SPEG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1028953	NM_005876.5(SPEG):c.5743A>C (p.Ser1915Arg)	ASIC4-AS1	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 13 · 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
SPEG	Definitive	Autosomal recessive	myopathy, centronuclear, 5	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SPEG	Orphanet:169186	Autosomal recessive centronuclear myopathy
CYP1B1	Orphanet:708	Peters anomaly
CYP1B1	Orphanet:98976	Congenital glaucoma
CYP1B1	Orphanet:98977	Juvenile glaucoma
NF1	Orphanet:139474	17q11.2 microduplication syndrome
NF1	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
NF1	Orphanet:293199	Pleomorphic rhabdomyosarcoma
NF1	Orphanet:363700	Neurofibromatosis type 1 due to NF1 mutation or intragenic deletion
NF1	Orphanet:638	Neurofibromatosis-Noonan syndrome
NF1	Orphanet:86834	Juvenile myelomonocytic leukemia
NF1	Orphanet:97685	17q11 microdeletion syndrome
NF1	Orphanet:99756	Alveolar rhabdomyosarcoma
NF1	Orphanet:99757	Embryonal rhabdomyosarcoma

Cohort genes → proteins

4 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SPEG	HGNC:16901	ENSG00000072195	Q15772	Striated muscle preferentially expressed protein kinase	gencc,clinvar
CYP1B1	HGNC:2597	ENSG00000138061	Q16678	Cytochrome P450 1B1	clinvar
ASIC4-AS1	HGNC:40960	ENSG00000227432		ASIC4 antisense RNA 1	clinvar
NF1	HGNC:7765	ENSG00000196712	P21359	Neurofibromin	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SPEG	Striated muscle preferentially expressed protein kinase	Isoform 3 may have a role in regulating the growth and differentiation of arterial smooth muscle cells.
CYP1B1	Cytochrome P450 1B1	A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids, steroid hormones and vitamins.
NF1	Neurofibromin	Stimulates the GTPase activity of Ras.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.25

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	6.9×	0.273
Other/Unknown	3	1.3×	0.404

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SPEG	Kinase	yes		Prot_kinase_dom, Ig_sub2, Ig_sub
CYP1B1	Other/Unknown	no		Cyt_P450, Cyt_P450_E_grp-I, Cyt_P450_CS
ASIC4-AS1	Other/Unknown	no
NF1	Other/Unknown	no		CRAL-TRIO_dom, RasGAP_dom, Rho_GTPase_activation_prot

Expression context

Cohort genes with no expression data: 0.

2 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
popliteal artery	1
right coronary artery	1
tibial artery	1
cartilage tissue	1
pericardium	1
synovial joint	1
islet of Langerhans	1
male germ line stem cell (sensu Vertebrata) in testis	1
pituitary gland	1
adrenal tissue	1
calcaneal tendon	1
colonic epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SPEG	249	ubiquitous	yes	popliteal artery, tibial artery, right coronary artery
CYP1B1	285	ubiquitous	marker	pericardium, cartilage tissue, synovial joint
ASIC4-AS1	115		yes	male germ line stem cell (sensu Vertebrata) in testis, islet of Langerhans, pituitary gland
NF1	283	ubiquitous	marker	colonic epithelium, calcaneal tendon, adrenal tissue

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NF1	5,540
CYP1B1	2,883
SPEG	1,107
ASIC4-AS1	0

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NF1	P21359	26
CYP1B1	Q16678	2
SPEG	Q15772	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. Enrichment computed across 4 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
Defective CYP1B1 causes Glaucoma	1	5710.0×	0.002	CYP1B1
RAS signaling downstream of NF1 loss-of-function variants	1	815.7×	0.005	NF1
Synthesis of epoxy (EET) and dihydroxyeicosatrienoic acids (DHET)	1	713.8×	0.005	CYP1B1
Synthesis of (16-20)-hydroxyeicosatetraenoic acids (HETE)	1	634.4×	0.005	CYP1B1
Endogenous sterols	1	196.9×	0.013	CYP1B1
Oncogenic MAPK signaling	1	124.1×	0.017	NF1
Regulation of RAS by GAPs	1	96.8×	0.019	NF1
MAPK1/MAPK3 signaling	1	65.6×	0.025	NF1
MAPK family signaling cascades	1	51.4×	0.028	NF1
RAF/MAP kinase cascade	1	30.5×	0.041	NF1
Diseases of signal transduction by growth factor receptors and second messengers	1	28.4×	0.041	NF1
Disease	1	6.5×	0.159	NF1
Signal Transduction	1	5.1×	0.187	NF1

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
positive regulation of mast cell apoptotic process	1	5617.3×	0.005	NF1
benzene-containing compound metabolic process	1	5617.3×	0.005	CYP1B1
regulation of glial cell differentiation	1	5617.3×	0.005	NF1
observational learning	1	5617.3×	0.005	NF1
trabecular meshwork development	1	2808.7×	0.005	CYP1B1
gamma-aminobutyric acid secretion, neurotransmission	1	2808.7×	0.005	NF1
Schwann cell proliferation	1	1872.4×	0.005	NF1
forebrain astrocyte development	1	1872.4×	0.005	NF1
Schwann cell migration	1	1872.4×	0.005	NF1
glutamate secretion, neurotransmission	1	1872.4×	0.005	NF1
negative regulation of mast cell proliferation	1	1872.4×	0.005	NF1
negative regulation of Schwann cell migration	1	1872.4×	0.005	NF1
vascular associated smooth muscle cell migration	1	1872.4×	0.005	NF1
mast cell apoptotic process	1	1404.3×	0.005	NF1
negative regulation of Rac protein signal transduction	1	1404.3×	0.005	NF1
obsolete membrane lipid catabolic process	1	1404.3×	0.005	CYP1B1
endothelial cell-cell adhesion	1	1404.3×	0.005	CYP1B1
myeloid leukocyte migration	1	1404.3×	0.005	NF1
collagen fibril organization	2	149.8×	0.005	CYP1B1, NF1
negative regulation of cell migration	2	74.4×	0.005	CYP1B1, NF1
angiogenesis	2	41.6×	0.005	CYP1B1, NF1
mast cell proliferation	1	1123.5×	0.005	NF1
positive regulation of apoptotic process	2	37.8×	0.005	CYP1B1, NF1
amygdala development	1	936.2×	0.005	NF1
regulation of blood vessel endothelial cell migration	1	936.2×	0.005	NF1
vascular associated smooth muscle cell proliferation	1	936.2×	0.005	NF1
steroid catabolic process	1	802.5×	0.005	CYP1B1
negative regulation of Schwann cell proliferation	1	802.5×	0.005	NF1
negative regulation of neurotransmitter secretion	1	802.5×	0.005	NF1
retinal blood vessel morphogenesis	1	802.5×	0.005	CYP1B1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 4 evidence-associated genes (25%) 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
CYP1B1	PAZOPANIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CYP1B1	22	4
SPEG	0	0
ASIC4-AS1	0	0
NF1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PAZOPANIB	4	CYP1B1
INDACATEROL	4	CYP1B1
ESTRADIOL	4	CYP1B1
CANNABIDIOL	4	CYP1B1
BERBERINE	4	CYP1B1
MELATONIN	4	CYP1B1
ERYTHROMYCIN	4	CYP1B1
CARVEDILOL	4	CYP1B1
RESVERATROL	3	CYP1B1
BERGAPTEN	3	CYP1B1
QUERCETIN	3	CYP1B1
CANNABINOL	3	CYP1B1
LUTEOLIN	2	CYP1B1
FORMONONETIN	2	CYP1B1
FLAVONE	2	CYP1B1
2-METHOXYESTRADIOL	2	CYP1B1
PINOCEMBRIN	2	CYP1B1
KHELLIN	2	CYP1B1
BAICALEIN	2	CYP1B1
PTEROSTILBENE	2	CYP1B1
KAEMPFEROL	1	CYP1B1
PLUMBAGIN	1	CYP1B1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
CYP1B1	408	ADMET:281, Binding:127

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
CYP1B1	408

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

22 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)
PAZOPANIB	4	CYP1B1
INDACATEROL	4	CYP1B1
ESTRADIOL	4	CYP1B1
CANNABIDIOL	4	CYP1B1
BERBERINE	4	CYP1B1
MELATONIN	4	CYP1B1
ERYTHROMYCIN	4	CYP1B1
CARVEDILOL	4	CYP1B1
RESVERATROL	3	CYP1B1
BERGAPTEN	3	CYP1B1
QUERCETIN	3	CYP1B1
CANNABINOL	3	CYP1B1
LUTEOLIN	2	CYP1B1
FORMONONETIN	2	CYP1B1
FLAVONE	2	CYP1B1
2-METHOXYESTRADIOL	2	CYP1B1
PINOCEMBRIN	2	CYP1B1
KHELLIN	2	CYP1B1
BAICALEIN	2	CYP1B1
PTEROSTILBENE	2	CYP1B1
KAEMPFEROL	1	CYP1B1
PLUMBAGIN	1	CYP1B1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CYP1B1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	SPEG
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	ASIC4-AS1, NF1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SPEG	0	—
ASIC4-AS1	0	—
NF1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.