SPEG

Summary

SPEG (striated muscle enriched protein kinase, HGNC:16901) is a protein-coding gene on chromosome 2q35, encoding Striated muscle preferentially expressed protein kinase (Q15772). Isoform 3 may have a role in regulating the growth and differentiation of arterial smooth muscle cells.

This gene encodes a protein with similarity to members of the myosin light chain kinase family. This protein family is required for myocyte cytoskeletal development. Along with the desmin gene, expression of this gene may be controlled by the desmin locus control region. Mutations in this gene are associated with centronuclear myopathy 5.

Source: NCBI Gene 10290 — RefSeq curated summary.

At a glance

• Gene–disease (curated): myopathy, centronuclear, 5 (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 87
• Clinical variants (ClinVar): 1,296 total — 20 pathogenic, 5 likely-pathogenic
• Phenotypes (HPO): 47
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_005876

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16901
Approved symbol	SPEG
Name	striated muscle enriched protein kinase
Location	2q35
Locus type	gene with protein product
Status	Approved
Aliases	MGC12676, KIAA1297, SPEGalpha, SPEGbeta, BPEG, MYLK6
Ensembl gene	ENSG00000072195
Ensembl biotype	protein_coding
OMIM	615950
Entrez	10290

Gene structure

Transcript identifiers

Ensembl transcripts: 22 — 8 protein_coding, 7 protein_coding_CDS_not_defined, 4 nonsense_mediated_decay, 3 retained_intron

ENST00000312358, ENST00000396686, ENST00000396688, ENST00000396689, ENST00000396698, ENST00000403148, ENST00000409595, ENST00000420132, ENST00000431523, ENST00000435853, ENST00000451076, ENST00000452101, ENST00000462545, ENST00000463218, ENST00000464989, ENST00000475921, ENST00000485069, ENST00000485813, ENST00000491248, ENST00000496786, ENST00000497065, ENST00000498378

RefSeq mRNA: 2 — MANE Select: NM_005876 NM_001173476, NM_005876

CCDS: CCDS42824, CCDS54432

Canonical transcript exons

ENST00000312358 — 41 exons

Exon	Start	End
ENSE00001407226	219492594	219493629
ENSE00001914206	219434843	219435365
ENSE00003460191	219482784	219482852
ENSE00003461493	219471868	219471987
ENSE00003473755	219461882	219462057
ENSE00003483933	219468578	219468736
ENSE00003490048	219477689	219477785
ENSE00003491147	219479783	219479860
ENSE00003495516	219477277	219477445
ENSE00003506310	219489054	219489221
ENSE00003513518	219472227	219472331
ENSE00003524461	219464433	219464608
ENSE00003526931	219469156	219469379
ENSE00003533372	219479962	219480140
ENSE00003534344	219488498	219488665
ENSE00003550314	219477905	219478105
ENSE00003552014	219451625	219451807
ENSE00003572195	219468859	219469048
ENSE00003581092	219490733	219490956
ENSE00003583133	219451136	219451279
ENSE00003590573	219473504	219473627
ENSE00003600312	219472890	219473096
ENSE00003602805	219488778	219488900
ENSE00003621709	219473728	219473903
ENSE00003621949	219489336	219489939
ENSE00003632063	219483098	219485072
ENSE00003637638	219481638	219481680
ENSE00003639522	219490409	219490648
ENSE00003643349	219462298	219462386
ENSE00003646971	219467174	219467434
ENSE00003652700	219447974	219449271
ENSE00003659618	219485346	219485477
ENSE00003660647	219479144	219479201
ENSE00003665136	219480671	219480697
ENSE00003671556	219476870	219476982
ENSE00003672540	219444825	219445161
ENSE00003676199	219491794	219491869
ENSE00003676522	219481304	219481456
ENSE00003677713	219444653	219444742
ENSE00003689037	219488194	219488310
ENSE00003850870	219492111	219492260

Expression profiles

Bgee: expression breadth ubiquitous, 249 present calls, max score 99.27.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 13.4532 / max 201.0363, expressed in 1364 samples.

FANTOM5 promoters (19 alternative TSS)

Promoter ID	TPM avg	Samples expressed
25493	9.6296	1334
25506	0.9166	375
25508	0.5654	250
25490	0.5001	48
25495	0.2957	88
25507	0.2920	159
25511	0.2536	80
25491	0.2336	129
25492	0.2313	63
25512	0.1457	67

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
popliteal artery	UBERON:0002250	99.27	gold quality
tibial artery	UBERON:0007610	99.27	gold quality
right coronary artery	UBERON:0001625	99.20	gold quality
aorta	UBERON:0000947	99.13	gold quality
descending thoracic aorta	UBERON:0002345	99.10	gold quality
thoracic aorta	UBERON:0001515	99.09	gold quality
ascending aorta	UBERON:0001496	99.07	gold quality
mucosa of stomach	UBERON:0001199	98.86	gold quality
lower esophagus muscularis layer	UBERON:0035833	98.70	gold quality
lower esophagus	UBERON:0013473	98.67	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	98.54	gold quality
body of uterus	UBERON:0009853	98.53	gold quality
left uterine tube	UBERON:0001303	98.37	gold quality
muscle layer of sigmoid colon	UBERON:0035805	98.32	gold quality
left coronary artery	UBERON:0001626	98.28	gold quality
hindlimb stylopod muscle	UBERON:0004252	98.27	gold quality
coronary artery	UBERON:0001621	97.79	gold quality
gastrocnemius	UBERON:0001388	96.96	gold quality
muscle of leg	UBERON:0001383	95.97	gold quality
endocervix	UBERON:0000458	95.93	gold quality
right atrium auricular region	UBERON:0006631	95.69	gold quality
apex of heart	UBERON:0002098	95.68	gold quality
blood vessel layer	UBERON:0004797	95.57	gold quality
right hemisphere of cerebellum	UBERON:0014890	95.19	gold quality
ectocervix	UBERON:0012249	94.99	gold quality
cerebellar hemisphere	UBERON:0002245	94.83	gold quality
cerebellar cortex	UBERON:0002129	94.71	gold quality
cardiac atrium	UBERON:0002081	94.19	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	93.62	gold quality
heart left ventricle	UBERON:0002084	93.13	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	4.24

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): USF1, USF2

miRNA regulators (miRDB)

77 targeting SPEG, 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-5692A	100.00	74.40	6850
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-4500	99.99	72.72	2367
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-4267	99.96	66.53	2368
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-1-3P	99.93	72.35	1914
HSA-MIR-206	99.93	72.50	1893
HSA-MIR-613	99.91	71.50	1710
HSA-MIR-4493	99.90	66.48	977
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-629-3P	99.85	67.99	1875
HSA-MIR-202-3P	99.84	71.41	1290
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-4713-5P	99.78	67.80	1794
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-4517	99.76	69.19	1867
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6752-3P	99.72	66.71	1587
HSA-MIR-10393-3P	99.72	66.56	961

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 10)

• Genomic rearrangement on APEG1 in arteriosclerosis was studied. (PMID:15784173)
• the RGD motif might play a role not only in the adhesion of Aortic Preferentially Expressed Protein-1 and extracellular proteins but also in intracellular protein-protein interactions (PMID:16354304)
• SPEG is present in cardiac muscle, where it plays a critical role; therefore, individuals with SPEG mutations additionally present with dilated cardiomyopathy. (PMID:25087613)
• Clinicians should consider evaluating a centronuclear myopathies patient for SPEG mutations even in the absence of centronuclear myopathies features (PMID:30412272)
• Novel SPEG variant cause centronuclear myopathy in China. (PMID:31625632)
• Striated muscle-specific serine/threonine-protein kinase beta segregates with high versus low responsiveness to endurance exercise training. (PMID:31790338)
• Loss of SPEG Inhibitory Phosphorylation of Ryanodine Receptor Type-2 Promotes Atrial Fibrillation. (PMID:32683896)
• A Novel Recessive Mutation in SPEG Causes Early Onset Dilated Cardiomyopathy. (PMID:32925938)
• Homozygous SPEG Mutation Is Associated With Isolated Dilated Cardiomyopathy. (PMID:33794647)
• A Novel SPEG mutation causing congenital myopathy with fiber size disproportion and dilated cardiomyopathy with heart transplantation. (PMID:34742623)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
mus_musculus	Speg	ENSMUSG00000026207
rattus_norvegicus	Speg	ENSRNOG00000019850
drosophila_melanogaster	bt	FBGN0005666
drosophila_melanogaster	zormin	FBGN0052311
caenorhabditis_elegans		WBGENE00001000
caenorhabditis_elegans		WBGENE00006759

Paralogs (9): MYOT (ENSG00000120729), PALLD (ENSG00000129116), ALPK3 (ENSG00000136383), MYPN (ENSG00000138347), HMCN1 (ENSG00000143341), OBSCN (ENSG00000154358), IGFN1 (ENSG00000163395), CCDC141 (ENSG00000163492), SPEGNB (ENSG00000286095)

Protein

Protein identifiers

Striated muscle preferentially expressed protein kinase — Q15772 (reviewed: Q15772)

Alternative names: Aortic preferentially expressed protein 1

All UniProt accessions (8): Q15772, B9ZVR7, C9J8D8, C9JWU5, F8WCA7, G5E9J7, H0Y3W0, H7C3Y5

UniProt curated annotations — full annotation on UniProt →

Function. Isoform 3 may have a role in regulating the growth and differentiation of arterial smooth muscle cells.

Subunit / interactions. Interacts with MTM1. Isoform 3 is found as a monomer or homodimer.

Subcellular location. Nucleus.

Tissue specificity. Isoform 1 is preferentially expressed in striated muscle. Non-kinase form such as isoform 3 is predominantly expressed in the aorta. Isoform 3 appears to be expressed only in highly differentiated ASMC in normal vessel walls and down-regulated in dedifferentiated ASMC in vivo. In response to vascular injuries ASMC dedifferentiate and change from a quiescent and contractile phenotype to a proliferative and synthetic phenotype. This proliferation of vascular smooth muscle cells is one of the most prominent features of atherosclerosis.

Post-translational modifications. May be autophosphorylated.

Disease relevance. Myopathy, centronuclear, 5 (CNM5) [MIM:615959] A form of centronuclear myopathy, a congenital muscle disorder characterized by progressive muscular weakness and wasting involving mainly limb girdle, trunk, and neck muscles. It may also affect distal muscles. Weakness may be present during childhood or adolescence or may not become evident until the third decade of life. Ptosis is a frequent clinical feature. The most prominent histopathologic features include high frequency of centrally located nuclei in muscle fibers not secondary to regeneration, radial arrangement of sarcoplasmic strands around the central nuclei, and predominance and hypotrophy of type 1 fibers. CNM5 features include severe neonatal hypotonia with respiratory insufficiency, difficulty feeding, and delayed motor development. Some patients die in infancy, and some develop dilated cardiomyopathy. The disease is caused by variants affecting the gene represented in this entry.

Induction. Isoform 3 is quickly down-regulated in response to vascular injury, when ASMC cells change from a quiescent to a proliferative phenotype.

Miscellaneous. Expression is under the tight control of the locus control region (LCRs). Produced by alternative promoter usage. Produced by alternative splicing.

Similarity. Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q15772-5	4	yes
Q15772-3	2
Q15772-4	3, APEG1
Q15772-1	1, SPEG

RefSeq proteins (2): NP_001166947, NP_005867* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR003598	Ig_sub2	Domain
IPR003599	Ig_sub	Domain
IPR003961	FN3_dom	Domain
IPR007110	Ig-like_dom	Domain
IPR008271	Ser/Thr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR013098	Ig_I-set	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR036116	FN3_sf	Homologous_superfamily
IPR036179	Ig-like_dom_sf	Homologous_superfamily

Pfam: PF00069, PF07679, PF16650

Catalyzed reactions (Rhea), 2 shown:

• L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H(+) (RHEA:17989)
• L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H(+) (RHEA:46608)

UniProt features (128 total): modified residue 39, compositionally biased region 20, sequence variant 15, domain 13, region of interest 13, strand 8, splice variant 5, sequence conflict 4, binding site 4, helix 2, active site 2, disulfide bond 2, chain 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
1U2H	X-RAY DIFFRACTION	0.96

Predicted structure (AlphaFold)

No AlphaFold model available for Q15772 — AlphaFold DB does not currently provide models for proteins above ~3000 aa.

Functional residue map

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

Catalytic / active sites (2): 1719 (proton acceptor); 3085 (proton acceptor)

Ligand- & substrate-binding residues (4): 1607–1615; 1630; 2972–2980; 2995

Post-translational modifications (39): 139, 364, 371, 375, 378, 381, 419, 449, 453, 488, 506, 526, 549, 1128, 1172, 1988, 2014, 2015, 2037, 2055 …

Disulfide bonds (2): 989–1041, 2605–2657

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 265 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_DN, RNGTGGGC_UNKNOWN, BERTUCCI_MEDULLARY_VS_DUCTAL_BREAST_CANCER_DN, AAGTCCA_MIR422B_MIR422A, LFA1_Q6, GCANCTGNY_MYOD_Q6, AREB6_03, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GAUSSMANN_MLL_AF4_FUSION_TARGETS_C_UP, MODULE_329, GGGTGGRR_PAX4_03, CAGCTG_AP4_Q5, BONCI_TARGETS_OF_MIR15A_AND_MIR16_1, SMITH_TERT_TARGETS_DN, GOBP_MUSCLE_STRUCTURE_DEVELOPMENT

GO Biological Process (5): muscle organ development (GO:0007517), negative regulation of cell population proliferation (GO:0008285), muscle cell differentiation (GO:0042692), protein phosphorylation (GO:0006468), cell differentiation (GO:0030154)

GO Molecular Function (8): protein kinase activity (GO:0004672), protein serine/threonine kinase activity (GO:0004674), ATP binding (GO:0005524), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (1): nucleus (GO:0005634)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
muscle structure development	2
protein kinase activity	2
animal organ development	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
cell differentiation	1
phosphorylation	1
protein modification process	1
cellular developmental process	1
kinase activity	1
phosphotransferase activity, alcohol group as acceptor	1
catalytic activity, acting on a protein	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
transferase activity, transferring phosphorus-containing groups	1
catalytic activity	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1064 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SPEG	RYR2	Q92736	742
SPEG	JPH2	Q9BR39	719
SPEG	MTM1	Q13496	702
SPEG	ENGASE	Q8NFI3	473
SPEG	SDE2	Q6IQ49	471
SPEG	ESCO1	Q5FWF5	373
SPEG	ESCO2	Q56NI9	371
SPEG	CFAP141	Q5VU69	371
SPEG	MSRA	Q9UJ68	336
SPEG	BRD3	Q15059	329
SPEG	CHPF	Q8IZ52	326
SPEG	OR8D1	Q8WZ84	324
SPEG	OR10G9	Q8NGN4	323
SPEG	DNPEP	Q9ULA0	314
SPEG	C14orf93	Q9H972	311

IntAct

19 interactions, top by confidence:

A	B	Type	Score
VAPB	FAM83G	psi-mi:“MI:0914”(association)	0.730
VAPA	FAM83G	psi-mi:“MI:0914”(association)	0.640
SPEG	PRMT1	psi-mi:“MI:0915”(physical association)	0.560
PRMT1	SPEG	psi-mi:“MI:0915”(physical association)	0.560
YWHAB	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
YWHAQ	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
	PLK4	psi-mi:“MI:0914”(association)	0.350
	TBKBP1	psi-mi:“MI:0914”(association)	0.350
	AURKA	psi-mi:“MI:0914”(association)	0.350
MYC	PDZD2	psi-mi:“MI:0914”(association)	0.350
YWHAB	FOXO6	psi-mi:“MI:0914”(association)	0.350
YWHAG	FOXO6	psi-mi:“MI:0914”(association)	0.350
YWHAQ	FOXO6	psi-mi:“MI:0914”(association)	0.350
YWHAH	FOXO6	psi-mi:“MI:0914”(association)	0.350
YWHAZ	HECTD4	psi-mi:“MI:0914”(association)	0.350
CREB3L2	PLEKHG3	psi-mi:“MI:0914”(association)	0.350

BioGRID (24): SPEG (Two-hybrid), SPEG (Affinity Capture-MS), PICK1 (Two-hybrid), MEOX2 (Two-hybrid), PRMT1 (Two-hybrid), HSF2BP (Two-hybrid), SPEG (Affinity Capture-MS), SPEG (Affinity Capture-MS), SPEG (Affinity Capture-MS), SPEG (Affinity Capture-MS), SPEG (Affinity Capture-MS), SPEG (Affinity Capture-MS), SPEG (Affinity Capture-MS), SPEG (Affinity Capture-RNA), SPEG (Proximity Label-MS)

ESM2 similar proteins: A5PKL7, D3ZZN9, O15049, O43281, O94989, O95153, P56945, P60669, Q07912, Q13671, Q15772, Q16584, Q2M3G4, Q2M3V2, Q3LUD3, Q3LUD4, Q3UYR4, Q494U1, Q5BJT1, Q5FWH6, Q5SW24, Q5XJV6, Q61140, Q62407, Q63767, Q64355, Q66HA1, Q6PAJ3, Q6ZMQ8, Q6ZS72, Q6ZVH7, Q6ZW31, Q75VX8, Q7TNF8, Q80W87, Q80XI6, Q8BG26, Q8BLS7, Q8TER5, Q8VC98

Diamond homologs: A2ASS6, A2CG49, A4IFM7, A8C984, A8WXF6, E9PT87, F1M0Z1, G4SLH0, O02827, O08875, O43293, O44997, O54784, O60229, O62305, O70150, O75962, O88764, O94768, O94806, P07313, P08414, P10911, P13234, P18652, P18653, P18654, P20689, P22216, P25323, P29294, P51812, P53355, P97924, Q00168, Q0KHT7, Q0KL02, Q14012, Q15139, Q15418

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
SPEG	“down-regulates activity”	RYR2	phosphorylation
SPEG	“up-regulates activity”	JPH2	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 18 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
Activation of BAD and translocation to mitochondria	5	271.9×	2e-10
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	5	239.9×	3e-10
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	5	239.9×	3e-10
Activation of BH3-only proteins	5	177.3×	1e-09
RHO GTPases activate PKNs	5	113.3×	1e-08
Intrinsic Pathway for Apoptosis	5	104.6×	2e-08
SARS-CoV-1-host interactions	5	62.8×	2e-07
Apoptosis	5	60.0×	2e-07

GO biological processes:

GO term	Partners	Fold	FDR
intracellular protein localization	5	30.8×	4e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

1296 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	20
Likely pathogenic	5
Uncertain significance	606
Likely benign	558
Benign	50

Top pathogenic / likely-pathogenic (25)

Variant ID	HGVS	Classification
144078	NM_005876.5(SPEG):c.4276C>T (p.Arg1426Ter)	Pathogenic
144079	NM_005876.5(SPEG):c.3709_3715+29del	Pathogenic
144080	NM_005876.5(SPEG):c.2915_2916delinsA (p.Ala972fs)	Pathogenic
1453595	NM_005876.5(SPEG):c.2071C>T (p.Gln691Ter)	Pathogenic
1460236	NM_005876.5(SPEG):c.3712C>T (p.Gln1238Ter)	Pathogenic
2425430	NC_000002.11:g.(?220299700)(220357508_?)del	Pathogenic
2698618	NM_005876.5(SPEG):c.2878C>T (p.Arg960Ter)	Pathogenic
2765950	NM_005876.5(SPEG):c.5512C>T (p.Gln1838Ter)	Pathogenic
2768130	NM_005876.5(SPEG):c.1925_1926dup (p.Trp643fs)	Pathogenic
2771101	NM_005876.5(SPEG):c.4922_4943del (p.Ser1641fs)	Pathogenic
2808222	NM_005876.5(SPEG):c.3918del (p.Arg1307fs)	Pathogenic
2852715	NM_005876.5(SPEG):c.4350del (p.Ile1451fs)	Pathogenic
3366614	NM_005876.5(SPEG):c.4360_4375del (p.Val1454fs)	Pathogenic
3662180	NM_005876.5(SPEG):c.4321C>T (p.Gln1441Ter)	Pathogenic
3671877	NM_005876.5(SPEG):c.3918dup (p.Arg1307fs)	Pathogenic
3723424	NM_005876.5(SPEG):c.4645dup (p.Ala1549fs)	Pathogenic
4720412	NM_005876.5(SPEG):c.5407del (p.Arg1803fs)	Pathogenic
4720484	NM_005876.5(SPEG):c.1884_1903dup (p.Ala635fs)	Pathogenic
4720516	NM_005876.5(SPEG):c.1312C>T (p.Gln438Ter)	Pathogenic
4805226	NM_005876.5(SPEG):c.331C>T (p.Gln111Ter)	Pathogenic
2500467	NM_005876.5(SPEG):c.4399C>T (p.Arg1467Ter)	Likely pathogenic
2708736	NM_005876.5(SPEG):c.3484_3491+17del	Likely pathogenic
3233241	NM_005876.5(SPEG):c.1071_1074dup (p.Lys359fs)	Likely pathogenic
3780657	NM_005876.5(SPEG):c.5428C>T (p.Arg1810Ter)	Likely pathogenic
813889	NM_005876.5(SPEG):c.2183del (p.Leu728fs)	Likely pathogenic

SpliceAI

8313 predictions. Top by Δscore:

Variant	Effect	Δscore
2:219444008:T:A	acceptor_gain	1.0000
2:219444011:T:A	acceptor_gain	1.0000
2:219444739:ACGGG:A	donor_loss	1.0000
2:219444740:CGGGT:C	donor_loss	1.0000
2:219444741:GG:G	donor_gain	1.0000
2:219444742:GG:G	donor_gain	1.0000
2:219444742:GGT:G	donor_loss	1.0000
2:219444743:G:GC	donor_loss	1.0000
2:219444744:T:A	donor_loss	1.0000
2:219451278:AGG:A	donor_loss	1.0000
2:219451281:T:A	donor_loss	1.0000
2:219462053:TCAAG:T	donor_loss	1.0000
2:219462054:CAAGG:C	donor_loss	1.0000
2:219462055:AAGGT:A	donor_loss	1.0000
2:219462056:AGGTC:A	donor_loss	1.0000
2:219462058:G:A	donor_loss	1.0000
2:219462384:CTGGT:C	donor_loss	1.0000
2:219462385:TGG:T	donor_loss	1.0000
2:219462386:GGTG:G	donor_loss	1.0000
2:219462387:GTGA:G	donor_loss	1.0000
2:219462388:T:G	donor_loss	1.0000
2:219462389:GAG:G	donor_loss	1.0000
2:219464427:T:TA	acceptor_gain	1.0000
2:219464427:TGACA:T	acceptor_loss	1.0000
2:219464428:GACAG:G	acceptor_loss	1.0000
2:219464429:ACAG:A	acceptor_loss	1.0000
2:219464431:A:AG	acceptor_gain	1.0000
2:219464432:G:GT	acceptor_gain	1.0000
2:219464432:GGC:G	acceptor_gain	1.0000
2:219464432:GGCT:G	acceptor_gain	1.0000

AlphaMissense

20751 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:219435293:T:G	Y106D	0.999
2:219451630:T:A	W755R	0.999
2:219451630:T:C	W755R	0.999
2:219451741:T:G	Y792D	0.999
2:219467369:T:C	L1026P	0.999
2:219468683:T:C	F1083S	0.999
2:219468724:T:A	W1097R	0.999
2:219468724:T:C	W1097R	0.999
2:219469325:T:A	W1221R	0.999
2:219469325:T:C	W1221R	0.999
2:219471924:T:G	Y1258D	0.999
2:219472298:T:A	W1303R	0.999
2:219472298:T:C	W1303R	0.999
2:219476933:T:C	F1504S	0.999
2:219476974:T:A	W1518R	0.999
2:219476974:T:C	W1518R	0.999
2:219488843:T:A	W2698R	0.999
2:219488843:T:C	W2698R	0.999
2:219489141:T:C	F2746S	0.999
2:219451632:G:C	W755C	0.998
2:219451632:G:T	W755C	0.998
2:219451703:T:C	L779P	0.998
2:219462385:T:A	W902R	0.998
2:219462385:T:C	W902R	0.998
2:219464545:T:G	Y940D	0.998
2:219464564:A:T	N946I	0.998
2:219464565:T:A	N946K	0.998
2:219464565:T:G	N946K	0.998
2:219467252:T:C	F987S	0.998
2:219467293:T:A	W1001R	0.998

dbSNP variants (sampled 300 via entrez): RS1000006899 (2:219475825 C>A,T), RS1000191663 (2:219479579 C>G,T), RS1000202400 (2:219457176 A>C,G), RS1000245612 (2:219487310 A>G), RS1000249792 (2:219486262 C>T), RS1000260788 (2:219445696 G>A), RS1000271386 (2:219432946 T>G), RS1000274725 (2:219482361 TC>T), RS1000312782 (2:219445497 C>T), RS1000324534 (2:219439012 A>G), RS1000410908 (2:219491588 G>A), RS1000426254 (2:219451431 C>T), RS1000527240 (2:219478059 C>T), RS1000549661 (2:219436792 G>A), RS1000596502 (2:219444346 A>T)

Disease associations

OMIM: gene MIM:615950 | disease phenotypes: MIM:615959, MIM:601419, MIM:615325, MIM:117000, MIM:160150, MIM:614408

GenCC curated gene-disease

Disease	Classification	Inheritance
myopathy, centronuclear, 5	Definitive	Autosomal recessive
autosomal recessive centronuclear myopathy	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
myopathy, centronuclear, 5	Definitive	AR

Mondo (5): myopathy, centronuclear, 5 (MONDO:0014418), myofibrillar myopathy 1 (MONDO:0011076), congenital myopathy (MONDO:0019952), autosomal dominant centronuclear myopathy (MONDO:0008048), autosomal recessive centronuclear myopathy (MONDO:0015705)

Orphanet (5): Autosomal recessive centronuclear myopathy (Orphanet:169186), Autosomal recessive limb-girdle muscular dystrophy type 2R (Orphanet:363543), Desminopathy (Orphanet:98909), Congenital myopathy (Orphanet:97245), Autosomal dominant centronuclear myopathy (Orphanet:169189)

HPO phenotypes

47 total (30 of 47 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000160	Narrow mouth
HP:0000193	Bifid uvula
HP:0000218	High palate
HP:0000276	Long face
HP:0000278	Retrognathia
HP:0000347	Micrognathia
HP:0000411	Protruding ear
HP:0000597	Ophthalmoparesis
HP:0000602	Ophthalmoplegia
HP:0000750	Delayed speech and language development
HP:0001256	Mild intellectual disability
HP:0001260	Dysarthria
HP:0001270	Motor delay
HP:0001284	Areflexia
HP:0001290	Generalized hypotonia
HP:0001324	Muscle weakness
HP:0001349	Facial diplegia
HP:0001618	Dysphonia
HP:0001644	Dilated cardiomyopathy
HP:0001653	Mitral regurgitation
HP:0001654	Abnormal heart valve morphology
HP:0001712	Left ventricular hypertrophy
HP:0001761	Pes cavus
HP:0001762	Talipes equinovarus
HP:0001999	Abnormal facial shape
HP:0002093	Respiratory insufficiency
HP:0002515	Waddling gait
HP:0003273	Hip contracture
HP:0003307	Hyperlordosis

GWAS associations

87 associations (top):

Study	Trait	p-value
GCST003818_86	Resting heart rate	1.000000e-20
GCST005789_6	Resting heart rate	5.000000e-07
GCST008058_94	Estimated glomerular filtration rate	2.000000e-20
GCST008059_88	Estimated glomerular filtration rate	1.000000e-19
GCST010796_1000	Electrocardiogram morphology (amplitude at temporal datapoints)	5.000000e-20
GCST010796_1050	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-10
GCST010796_1051	Electrocardiogram morphology (amplitude at temporal datapoints)	4.000000e-13
GCST010796_1052	Electrocardiogram morphology (amplitude at temporal datapoints)	6.000000e-13
GCST010796_1053	Electrocardiogram morphology (amplitude at temporal datapoints)	5.000000e-10
GCST010796_1054	Electrocardiogram morphology (amplitude at temporal datapoints)	4.000000e-10
GCST010796_1055	Electrocardiogram morphology (amplitude at temporal datapoints)	4.000000e-09
GCST010796_1056	Electrocardiogram morphology (amplitude at temporal datapoints)	5.000000e-08
GCST010796_1057	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-09
GCST010796_1058	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-13
GCST010796_1059	Electrocardiogram morphology (amplitude at temporal datapoints)	4.000000e-14
GCST010796_1060	Electrocardiogram morphology (amplitude at temporal datapoints)	4.000000e-13
GCST010796_1061	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-14
GCST010796_1062	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-14
GCST010796_1063	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-13
GCST010796_1064	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-11
GCST010796_1065	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-12
GCST010796_1066	Electrocardiogram morphology (amplitude at temporal datapoints)	6.000000e-16
GCST010796_1067	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-17
GCST010796_1068	Electrocardiogram morphology (amplitude at temporal datapoints)	7.000000e-19
GCST010796_1069	Electrocardiogram morphology (amplitude at temporal datapoints)	5.000000e-19
GCST010796_1070	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-17
GCST010796_1071	Electrocardiogram morphology (amplitude at temporal datapoints)	5.000000e-17
GCST010796_1072	Electrocardiogram morphology (amplitude at temporal datapoints)	5.000000e-17
GCST010796_1073	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-16
GCST010796_1075	Electrocardiogram morphology (amplitude at temporal datapoints)	7.000000e-21

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004327	electrocardiography
EFO:0009749	age at first sexual intercourse measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — Trio family

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, increases expression	4
sodium arsenite	affects methylation, decreases expression	2
Cisplatin	decreases expression, increases expression	2
aristolochic acid I	increases expression	1
FR900359	increases phosphorylation	1
trimellitic anhydride	decreases expression	1
benzo(e)pyrene	increases methylation	1
coumarin	increases phosphorylation	1
4-aminophenylarsenoxide	affects binding, decreases reaction	1
2-palmitoylglycerol	increases expression	1
entinostat	increases expression	1
abrine	decreases expression	1
bisphenol S	affects cotreatment, decreases methylation	1
Resveratrol	affects cotreatment, decreases expression	1
Arsenic Trioxide	affects binding, decreases reaction	1
Fulvestrant	affects cotreatment, decreases methylation	1
Arsenic	affects methylation	1
Bleomycin	decreases expression	1
Carmustine	decreases expression	1
Doxorubicin	decreases expression	1
Haloperidol	increases expression	1
Hydrogen Peroxide	affects expression	1
Methapyrilene	increases methylation	1
Plant Extracts	decreases expression, affects cotreatment	1
Smoke	decreases expression	1
Tetrachlorodibenzodioxin	affects expression	1
Dronabinol	increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Vitamin E	increases expression	1
Aflatoxin B1	increases expression	1

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_TQ15	HAP1 SPEG (-) 1	Cancer cell line	Male
CVCL_TQ16	HAP1 SPEG (-) 2	Cancer cell line	Male
CVCL_TQ17	HAP1 SPEG (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02020187	Not specified	COMPLETED	Aerobic Training in Patients With Congenital Myopathies
NCT03018184	Not specified	COMPLETED	Contractile Cross Sectional Areas and Muscle Strength in Patients With Congenital Myopathies
NCT04733976	Not specified	COMPLETED	Bullying in Youth With Muscular Dystrophy and Congenital Myopathies
NCT05099107	Not specified	COMPLETED	Changes of Motor Function Tests in Congenital Myopathy Subjects Treated With Oral Salbutamol as Compared to no Treatment
NCT05199246	Not specified	COMPLETED	Assessment of Safety and Acute Effects of a Lower-limb Powered Dermoskeleton in Patients With Neuromuscular Disorders
NCT05200702	Not specified	COMPLETED	Assessment of Safety and Acute Effects of a Knee-hip Powered Soft Exoskeleton in Patients With Neuromuscular Disorders
NCT05692349	Not specified	UNKNOWN	Magnetic Resonance Imaging and Ultrasonography in Evaluation of Muscle Diseases
NCT06791369	Not specified	NOT_YET_RECRUITING	The Prevalence of RYR1-related Disease
NCT06833489	Not specified	RECRUITING	Transcriptomic Analysis to Put an End to Misdiagnosis in Patients With Rare Muscle Diseases
NCT07138963	Not specified	RECRUITING	Phenotype - Genotype Correlation in a Sample of Egyptian Patients With Congenital Myopathies and Congenital Muscular Dystrophies
NCT07415837	Not specified	RECRUITING	Evaluation of the Role of miR-1 in the Pathogenesis and as a Biomarker in Muscular Dystrophies and Congenital Myopathies
NCT07502989	Not specified	RECRUITING	Muscle Health Measurements Using Electrical Impedance Myography
NCT07580365	Not specified	NOT_YET_RECRUITING	VirtualPark_Pediatric