TPM2

Summary

TPM2 (tropomyosin 2, HGNC:12011) is a protein-coding gene on chromosome 9p13.3, encoding Tropomyosin beta chain (P07951). Binds to actin filaments in muscle and non-muscle cells.

This gene encodes beta-tropomyosin, a member of the actin filament binding protein family, and mainly expressed in slow, type 1 muscle fibers. Mutations in this gene can alter the expression of other sarcomeric tropomyosin proteins, and cause cap disease, nemaline myopathy and distal arthrogryposis syndromes. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 7169 — RefSeq curated summary.

At a glance

• Gene–disease (curated): TPM2-related myopathy (Definitive, ClinGen) — +9 more curated relationships
• GWAS associations: 3
• Clinical variants (ClinVar): 381 total — 14 pathogenic, 25 likely-pathogenic
• Phenotypes (HPO): 189
• Dosage sensitivity (ClinGen): haploinsufficiency little evidence, triplosensitivity no evidence
• MANE Select transcript: NM_003289

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12011
Approved symbol	TPM2
Name	tropomyosin 2
Location	9p13.3
Locus type	gene with protein product
Status	Approved
Aliases	DA1, NEM4
Ensembl gene	ENSG00000198467
Ensembl biotype	protein_coding
OMIM	190990
Entrez	7169

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 15 protein_coding, 3 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000329305, ENST00000378292, ENST00000471212, ENST00000486018, ENST00000604975, ENST00000607559, ENST00000643485, ENST00000644325, ENST00000645482, ENST00000647435, ENST00000951577, ENST00000951578, ENST00000951579, ENST00000951580, ENST00000951581, ENST00000951582, ENST00000951583, ENST00000951584, ENST00000951585

RefSeq mRNA: 4 — MANE Select: NM_003289 NM_001301226, NM_001301227, NM_003289, NM_213674

CCDS: CCDS6586, CCDS6587, CCDS78394, CCDS87651

Canonical transcript exons

ENST00000645482 — 9 exons

Exon	Start	End
ENSE00001401789	35684246	35684315
ENSE00001412957	35684488	35684550
ENSE00001735286	35684732	35684807
ENSE00003482810	35685269	35685339
ENSE00003557967	35685647	35685780
ENSE00003609632	35689146	35689271
ENSE00003639281	35685434	35685551
ENSE00003820846	35682932	35683241
ENSE00003903831	35689704	35689925

Expression profiles

Bgee: expression breadth ubiquitous, 283 present calls, max score 99.98.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 336.7965 / max 15628.9990, expressed in 1384 samples.

FANTOM5 promoters (17 alternative TSS)

Promoter ID	TPM avg	Samples expressed
100628	326.9068	1354
100622	2.3440	705
100619	2.1102	670
100623	0.7153	327
100609	0.6106	178
100618	0.5924	195
100611	0.5905	226
100621	0.5212	197
100615	0.5099	238
100617	0.3557	114

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
saphenous vein	UBERON:0007318	99.98	gold quality
popliteal artery	UBERON:0002250	99.97	gold quality
blood vessel layer	UBERON:0004797	99.97	gold quality
tibial artery	UBERON:0007610	99.97	gold quality
aorta	UBERON:0000947	99.96	gold quality
hindlimb stylopod muscle	UBERON:0004252	99.96	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	99.96	gold quality
mucosa of stomach	UBERON:0001199	99.95	gold quality
ascending aorta	UBERON:0001496	99.95	gold quality
thoracic aorta	UBERON:0001515	99.95	gold quality
right coronary artery	UBERON:0001625	99.95	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	99.94	gold quality
lower esophagus	UBERON:0013473	99.94	gold quality
lower esophagus muscularis layer	UBERON:0035833	99.94	gold quality
seminal vesicle	UBERON:0000998	99.93	gold quality
biceps brachii	UBERON:0001507	99.93	gold quality
descending thoracic aorta	UBERON:0002345	99.93	gold quality
coronary artery	UBERON:0001621	99.92	gold quality
left coronary artery	UBERON:0001626	99.92	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	99.92	gold quality
gluteal muscle	UBERON:0002000	99.91	gold quality
diaphragm	UBERON:0001103	99.89	gold quality
triceps brachii	UBERON:0001509	99.89	gold quality
vastus lateralis	UBERON:0001379	99.88	gold quality
tendon of biceps brachii	UBERON:0008188	99.87	gold quality
muscle layer of sigmoid colon	UBERON:0035805	99.87	gold quality
myometrium	UBERON:0001296	99.86	gold quality
body of uterus	UBERON:0009853	99.86	gold quality
body of tongue	UBERON:0011876	99.86	gold quality
urethra	UBERON:0000057	99.85	gold quality

Single-cell (SCXA)

Detected in 54 experiment(s), a significant marker in 52.

Experiment	Marker?	Max mean expression
E-CURD-126	yes	9659.03
E-MTAB-10885	yes	7799.23
E-MTAB-8410	yes	7713.94
E-HCAD-36	yes	7447.86
E-MTAB-10287	yes	6608.93
E-HCAD-1	yes	5852.14
E-GEOD-134144	yes	5826.56
E-GEOD-124263	yes	5790.45
E-GEOD-124472	yes	5510.83
E-MTAB-9841	yes	5157.82
E-MTAB-8322	yes	4769.07
E-MTAB-8381	yes	4338.01
E-HCAD-11	yes	4243.04
E-CURD-46	yes	4202.43
E-HCAD-15	yes	3767.95

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): BARX1, MYC, MYOG, SP1, SRF

miRNA regulators (miRDB)

24 targeting TPM2, 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-6758-5P	100.00	66.21	1470
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-6745	99.74	65.33	1321
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-363-5P	99.46	64.51	1015
HSA-MIR-4786-3P	99.36	68.35	1390
HSA-MIR-7974	99.24	65.48	1137
HSA-MIR-4477A	98.83	69.75	2952
HSA-MIR-6792-5P	98.39	68.16	1330
HSA-MIR-3179	98.22	65.90	1445
HSA-MIR-4483	98.09	64.12	1642
HSA-MIR-4253	97.48	65.11	692
HSA-MIR-6862-5P	97.48	64.84	713
HSA-MIR-4786-5P	97.45	67.89	924
HSA-MIR-5000-5P	97.40	66.11	1055
HSA-MIR-541-3P	96.07	66.11	1271
HSA-MIR-654-5P	96.07	66.18	1280

Functional genomics

ClinGen dosage: haploinsufficiency 1 (little evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• beta-tropomyosin exon 6B splicing requires hnRNP A1 and ASF/SF2 and SC35 (PMID:15208309)
• We describe two patients, a woman and her daughter, with muscle weakness and distal arthrogryposis (DA) type 2B, caused by a heterozygous missense mutation, R133W. (PMID:17339586)
• R133W beta-Tm mutation induces alterations in myosin-actin kinetics causing a reduced number of myosin molecules in the strong actin-binding state, resulting in overall muscle weakness in the absence of muscle wasting. (PMID:17430991)
• results indicate that mutations in TPM2 may cause nemaline myopathy as well as cap disease with a dominant mode of inheritance; these disorders may thus be phenotypic variants of the same genetic defect (PMID:17846275)
• Tropomyosin 2 plays a role in growth and metastasis of hepatic tumors. (PMID:18246790)
• beta-TM gene mutations can alter the expression of other sarcomeric TM isoforms (PMID:18422639)
• Mutations in TPM2 seem to be a frequent cause of cap disease. (PMID:19047562)
• Skeletal muscle contractile gene (TNNT3, MYH3, TPM2) mutations not found in vertical talus or clubfoot. (PMID:19142688)
• This first report of the clinical expression of the complete absence of TPM2 in human indicated that TPM2 expression at the early period of prenatal life plays a major role for normal fetal movements. (PMID:19155175)
• The destabilizing effect of the disease-causing arginine91glycine mutation spreads along the coiled-coil, reflecting the high extent of cooperativity within this part of the beta-tropomyosin molecule. [review] (PMID:19214762)
• Our patient has an identical TPM2 mutation to the first genetically diagnosed cap disease patient, a denovo heterozygous three base pair deletion that removes glutamic acid 139 from the centre of beta-tropomyosin. (PMID:19345583)
• While demonstrating suppressed levels of Tm1 in the prostate cancer cell lines LNCaP, PC3, and DU-145 compared to normal prostate epithelial cell primary isolates, a novel splice variant of the TPM2 gene was identified. (PMID:20336778)
• This protein has been found differentially expressed in the anterior cingulate cortex from patients with schizophrenia (PMID:20381070)
• in cells expressing R133W beta-tropomyosin mutation, during activation, switching of positive to neutral charge at position 133 partially hinders calcium- and myosin-induced tropomyosin movement over the thin filament blocking actin conformation change (PMID:20457903)
• actin binding was weak in three of five mutants suggesting that abnormal binding between actin and aberrant Tm is the pathogenetic mechanism causing muscle weakness in patients with nemaline and cap myopathy. (PMID:22084935)
• Molecular genetic investigations revealed pathogenic mutations in MYH3, TPM2, and TNNI2 in one sporadic and 19 familial cases of distal arthrogryposis. (PMID:22519952)
• distal arthrogryposis syndromes associated with TPM2 mutations include the less severe forms[review] (PMID:22749895)
• The TPM2-null mutations decreased cooperative thin filament activation in combination with reductions in the myosin cross-bridge number and force production (PMID:22798622)
• Novel de novo missense mutations in TPM2 were found to be associated with marked fibre size disproportion in two patients with congenital fibre type disproportion. (PMID:22832343)
• This study demonistrated that most patients with TPM2 mutations show a predominant involvement of masticatory and distal leg muscles with the other regions relatively spared. (PMID:22980765)
• expanding the spectrum of TPM2 myopathies to very mild patients who could still be pathologically recognized by the presence of cap structures (PMID:23015096)
• Elevated TPM1 and TPM2 expression is associated with epithelial-mesenchymal transition of lens epithelial cells. (PMID:23205574)
• p.K7del is a common hetreozygous recurrent TPM2 mutation associated with nemaline myopathy. (PMID:23378224)
• A novel beta-tropomyosin mutation is described that is associated with two clinical-histopathological phenotypes not previously associated with it. (PMID:23413262)
• We showed that TPM2, CLU, and COL4A6 mRNA levels are downregulated in prostate cancer. (PMID:23621580)
• The p.R133W mutation in TPM2 is associated with Sheldon-Hall syndrome. (PMID:23678273)
• The E117K mutation in tropomyosin beta chain that causes nemaline myopathy shifts the tropomyosin strands to the closed position and suppresses their conformational rearrangements on the thin filament. (PMID:23689010)
• In addition to CLIC1 and TPM1, which were the proteins initially discovered in a xenograft mouse model, CLIC4, TPM2, TPM3, and TPM4 were present in ovarian cancer patient sera at significantly elevated levels compared with controls. (PMID:23792823)
• Histopathological phenotype association of muscle fibers expressing Beta-tropomyosin mutational variants that occur in human myopathies. (PMID:24039757)
• in a cohort of 94 patients with congenital myopathy, 2 related female patients and 2 sporadic male patients were found to carry mutations in TPM2 and TPM3 genes respectively; clinical presentation and muscle morphological findings differed in the patients (PMID:24507666)
• effect of the skeletal myopathy-causing E117K mutation in human beta-tropomyosin on actomyosin structure during the ATPase cycle (PMID:24657080)
• Patients with TPM2 mutations tended to present with milder symptoms than those with TPM3 mutations, DA being present only in the TPM2 group. (PMID:24692096)
• Changes for CRMP2, TCP1epsilon, TPM2 and 14-3-3gamma were confirmed in experimental tumors and in a series of 28 human SI-NETs. (PMID:25224486)
• Myo1c significantly increases the frequency of kinesin-1-driven microtubule-based runs that begin at actin/microtubule intersections. The actin-binding protein tropomyosin 2 abolishes Myo1c-specific effects on both run initiation and run termination. (PMID:25660542)
• tropomyosin 2.1 acts as a suppressor of growth on soft matrices by supporting proper rigidity sensing (PMID:26619148)
• Despite its reduced affinity for actin in co-sedimentation assay, the Q147P mutant incorporates into the muscle fiber ..Q147P tropomyosin (TPM2)binds to actin in ghost muscle fiber. (PMID:26708479)
• Promoter variants in HOXA9, TPM1, and TPM2, alter promoter expression suggesting that they have a functional role in clubfoot. (PMID:27020427)
• The increased expression of TPM1lambda and the decreased expression of TPM1delta RNA and TPM2beta may lead to decreased stress fiber formation and malignant transformation in human breast epithelial cells. (PMID:27108600)
• TPM2 appears to be commonly silenced by aberrant DNA methylation in colon cancer. TPM2 loss is associated with RhoA activation and tumor proliferation. (PMID:27333992)
• Stress fibre formation and up-regulation of alpha-smooth muscle actin (alphaSMA) induced by TGFbeta2 could be reversed by Tpm1/2 knock-down by siRNA. (PMID:27976512)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
mus_musculus	Tpm2	ENSMUSG00000028464
rattus_norvegicus	Tpm2	ENSRNOG00000016731
drosophila_melanogaster	Tm1	FBGN0003721
drosophila_melanogaster	Tm2	FBGN0004117
caenorhabditis_elegans	lev-11	WBGENE00002978

Paralogs (3): TPM1 (ENSG00000140416), TPM3 (ENSG00000143549), TPM4 (ENSG00000167460)

Protein

Protein identifiers

Tropomyosin beta chain — P07951 (reviewed: P07951)

Alternative names: Beta-tropomyosin, Tropomyosin-2

All UniProt accessions (6): P07951, A0A2R8Y6A3, A7XZE4, Q5TCU3, U3KQK2, V9HW25

UniProt curated annotations — full annotation on UniProt →

Function. Binds to actin filaments in muscle and non-muscle cells. Plays a central role, in association with the troponin complex, in the calcium dependent regulation of vertebrate striated muscle contraction. Smooth muscle contraction is regulated by interaction with caldesmon. In non-muscle cells is implicated in stabilizing cytoskeleton actin filaments. The non-muscle isoform may have a role in agonist-mediated receptor internalization.

Subunit / interactions. Homodimer. Heterodimer of an alpha (TPM1, TPM3 or TPM4) and a beta (TPM2) chain.

Subcellular location. Cytoplasm. Cytoskeleton.

Tissue specificity. Present in primary breast cancer tissue, absent from normal breast tissue.

Post-translational modifications. Phosphorylated on Ser-61 by PIK3CG. Phosphorylation on Ser-61 is required for ADRB2 internalization.

Disease relevance. Congenital myopathy 23 (CMYO23) [MIM:609285] An autosomal dominant muscular disorder characterized clinically by hypotonia and muscle weakness, and a static or slowly progressive clinical course. Disease onset ranges from birth to childhood. Histologic examination of muscle fibers shows various anomalies including fiber type disproportion, an irregular myofibrillar network, abnormal thread-like or rod-shaped structures, and cap-like structures which are well demarcated and peripherally located under the sarcolemma with abnormal accumulation of sarcomeric proteins. The disease is caused by variants affecting the gene represented in this entry. Arthrogryposis, distal, 1A (DA1A) [MIM:108120] A form of distal arthrogryposis, a disease characterized by congenital joint contractures that mainly involve two or more distal parts of the limbs, in the absence of a primary neurological or muscle disease. Distal arthrogryposis type 1 is characterized largely by camptodactyly and clubfoot. Hypoplasia and/or absence of some interphalangeal creases is common. The shoulders and hips are less frequently affected. The disease is caused by variants affecting the gene represented in this entry. Arthrogryposis, distal, 2B4 (DA2B4) [MIM:108120] A form of distal arthrogryposis, a disease characterized by congenital joint contractures that mainly involve two or more distal parts of the limbs, in the absence of a primary neurological or muscle disease. Distal arthrogryposis type 2 is characterized by contractures of the hands and feet, and a distinctive face characterized by prominent nasolabial folds, small mouth and downslanting palpebral fissures. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The molecule is in a coiled coil structure that is formed by 2 polypeptide chains. The sequence exhibits a prominent seven-residues periodicity.

Similarity. Belongs to the tropomyosin family.

Isoforms (3)

UniProt ID	Names	Canonical?
P07951-1	1, Skeletal muscle	yes
P07951-2	2, non-muscle, Fibroblast TM36, Epithelial TMe1
P07951-3	3, non-muscle

RefSeq proteins (4): NP_001288155, NP_001288156, NP_003280, NP_998839 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000533	Tropomyosin	Family

Pfam: PF00261

UniProt features (49 total): sequence variant 25, modified residue 14, splice variant 3, region of interest 2, compositionally biased region 2, chain 1, coiled-coil region 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P07951-F1	91.51	0.73

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 (14): 87, 108, 158, 206, 215, 252, 261, 271, 282, 283, 1, 53, 61, 79

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-390522	Striated Muscle Contraction
R-HSA-445355	Smooth Muscle Contraction

MSigDB gene sets: 643 (showing top): MODULE_52, BERTUCCI_MEDULLARY_VS_DUCTAL_BREAST_CANCER_DN, KAAB_FAILED_HEART_ATRIUM_DN, NKX25_02, GCANCTGNY_MYOD_Q6, DACOSTA_UV_RESPONSE_VIA_ERCC3_UP, MCBRYAN_PUBERTAL_TGFB1_TARGETS_UP, TGACCTY_ERR1_Q2, MEF2_02, RIZKI_TUMOR_INVASIVENESS_3D_DN, TOMLINS_PROSTATE_CANCER_DN, CAGCTG_AP4_Q5, HUMMERICH_SKIN_CANCER_PROGRESSION_DN, CEBPB_01, COUP_01

GO Biological Process (3): muscle contraction (GO:0006936), actin filament organization (GO:0007015), regulation of ATP-dependent activity (GO:0043462)

GO Molecular Function (7): actin binding (GO:0003779), structural constituent of muscle (GO:0008307), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), protein heterodimerization activity (GO:0046982), actin filament binding (GO:0051015), protein binding (GO:0005515)

GO Cellular Component (6): cytosol (GO:0005829), muscle thin filament tropomyosin (GO:0005862), actin filament (GO:0005884), actin cytoskeleton (GO:0015629), cytoplasm (GO:0005737), cytoskeleton (GO:0005856)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Muscle contraction	2

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein dimerization activity	2
cellular anatomical structure	2
muscle system process	1
actin cytoskeleton organization	1
supramolecular fiber organization	1
regulation of molecular function	1
ATP-dependent activity	1
cytoskeletal protein binding	1
structural molecule activity	1
protein binding	1
identical protein binding	1
actin binding	1
protein-containing complex binding	1
binding	1
cytoplasm	1
striated muscle thin filament	1
protein-containing complex	1
actin cytoskeleton	1
polymeric cytoskeletal fiber	1
cytoskeleton	1
intracellular anatomical structure	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

78 interactions, top by confidence:

A	B	Type	Score
PRKAG2	PRKAB2	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
FAM9C	NDC80	psi-mi:“MI:0914”(association)	0.670
TPM4	TPM3	psi-mi:“MI:0914”(association)	0.670
TPM2	TPM1	psi-mi:“MI:0915”(physical association)	0.560
HSPB8	VWA8	psi-mi:“MI:0914”(association)	0.530
KXD1	HIP1	psi-mi:“MI:0914”(association)	0.530
CFTR	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
CALR	TPM2	psi-mi:“MI:0915”(physical association)	0.400
Zwint	NDC80	psi-mi:“MI:0915”(physical association)	0.400
Poc1b		psi-mi:“MI:0915”(physical association)	0.400
Pafah1b1	EDIL3	psi-mi:“MI:0915”(physical association)	0.400
Ccdc15		psi-mi:“MI:0915”(physical association)	0.400
	TPM2	psi-mi:“MI:0915”(physical association)	0.400
TPM2	SKIL	psi-mi:“MI:0915”(physical association)	0.370
ANLN	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
MYO18A	PLEKHG3	psi-mi:“MI:0914”(association)	0.350

BioGRID (279): TPM2 (Affinity Capture-MS), TPM2 (Affinity Capture-MS), TPM2 (Affinity Capture-MS), TPM2 (Affinity Capture-MS), TPM2 (Affinity Capture-MS), TPM2 (Affinity Capture-MS), TPM2 (Affinity Capture-MS), TPM2 (Affinity Capture-MS), TPM2 (Affinity Capture-MS), TPM2 (Reconstituted Complex), ACTN1 (Co-fractionation), ACTN4 (Co-fractionation), CKMT1B (Co-fractionation), CKMT1A (Co-fractionation), PSMD5 (Co-fractionation)

ESM2 similar proteins: A1XQV4, A2V735, C5J049, O18416, O96764, O97192, P02561, P04268, P04692, P06753, P07951, P09491, P09493, P09495, P0DSM6, P0DSM7, P13104, P13105, P15846, P19352, P21107, P31816, P42637, P42639, P58771, P58772, P58773, P58774, P58775, P58776, P67936, P67937, P84335, Q01173, Q07068, Q1HPQ0, Q1HPU0, Q22866, Q23758, Q23939

Diamond homologs: A1XQV4, P02561, P04268, P04692, P06753, P07951, P09493, P13104, P13105, P19352, P21107, P42639, P58771, P58772, P58773, P58774, P58775, P58776, P67936, P67937, P84335, Q01173, Q07068, Q5KR47, Q5KR48, Q5KR49, Q9NDS0, O97162, P15846, Q22866, Q25632, Q8IT89, Q8WR63, Q95VA8, Q9NAS5

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
PIK3CG	“up-regulates activity”	TPM2	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 83 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
Signaling by ALK fusions and activated point mutants	6	17.7×	6e-04
Translocation of SLC2A4 (GLUT4) to the plasma membrane	5	15.1×	4e-03
PIP3 activates AKT signaling	6	7.9×	4e-03
Diseases of signal transduction by growth factor receptors and second messengers	7	7.8×	4e-03
Vesicle-mediated transport	8	5.5×	4e-03

GO biological processes:

GO term	Partners	Fold	FDR
actin filament organization	6	10.0×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	14
Likely pathogenic	25
Uncertain significance	133
Likely benign	138
Benign	23

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
12460	NM_003289.4(TPM2):c.271C>G (p.Arg91Gly)	Pathogenic
12463	NM_003289.4(TPM2):c.397C>T (p.Arg133Trp)	Pathogenic
12464	NM_003289.4(TPM2):c.121G>A (p.Glu41Lys)	Pathogenic
12465	NM_003289.4(TPM2):c.412GAG[1] (p.Glu139del)	Pathogenic
12467	NM_003289.4(TPM2):c.606C>G (p.Asn202Lys)	Pathogenic
140486	NM_003289.4(TPM2):c.14AGA[2] (p.Lys7del)	Pathogenic
140493	NM_003289.4(TPM2):c.628C>T (p.Gln210Ter)	Pathogenic
1686270	NM_003289.4(TPM2):c.394_396dup (p.Asn132dup)	Pathogenic
451987	NM_003289.4(TPM2):c.320del (p.Ala107fs)	Pathogenic
452383	NM_003289.4(TPM2):c.210del (p.Lys70fs)	Pathogenic
631479	NM_003289.4(TPM2):c.308A>G (p.Gln103Arg)	Pathogenic
631480	NM_003289.4(TPM2):c.374+2T>C	Pathogenic
632042	NM_003289.4(TPM2):c.663T>A (p.Tyr221Ter)	Pathogenic
816832	NM_003289.4(TPM2):c.620_631dup (p.Gln210_Ala211insValGluAlaGln)	Pathogenic
1067848	NM_003289.4(TPM2):c.364G>A (p.Glu122Lys)	Likely pathogenic
12466	NM_003289.4(TPM2):c.142AAG[1] (p.Lys49del)	Likely pathogenic
1299603	NM_213674.1(TPM2):c.773-2A>C	Likely pathogenic
1468701	NM_003289.4(TPM2):c.493-2A>G	Likely pathogenic
167743	NM_003289.4(TPM2):c.279G>T (p.Gln93His)	Likely pathogenic
2017054	NM_003289.4(TPM2):c.479G>T (p.Arg160Leu)	Likely pathogenic
2434213	NM_003289.4(TPM2):c.492+2T>C	Likely pathogenic
2634361	NM_003289.4(TPM2):c.836dup (p.Asn279fs)	Likely pathogenic
2663287	NM_003289.4(TPM2):c.289G>A (p.Glu97Lys)	Likely pathogenic
3233245	NM_003289.4(TPM2):c.5A>G (p.Asp2Gly)	Likely pathogenic
3340416	NM_003289.4(TPM2):c.541G>A (p.Glu181Lys)	Likely pathogenic
3367960	NM_003289.4(TPM2):c.559G>A (p.Glu187Lys)	Likely pathogenic
3667651	NM_003289.4(TPM2):c.640-1G>A	Likely pathogenic
372795	NM_003289.4(TPM2):c.279G>C (p.Gln93His)	Likely pathogenic
3776330	NM_003289.4(TPM2):c.433G>A (p.Glu145Lys)	Likely pathogenic
423115	NM_003289.4(TPM2):c.240+4_240+5del	Likely pathogenic

SpliceAI

1127 predictions. Top by Δscore:

Variant	Effect	Δscore
9:35684225:A:AC	donor_gain	1.0000
9:35684226:C:CC	donor_gain	1.0000
9:35684311:TCAGC:T	acceptor_gain	1.0000
9:35684312:CAGC:C	acceptor_gain	1.0000
9:35684312:CAGCC:C	acceptor_gain	1.0000
9:35684313:AGC:A	acceptor_gain	1.0000
9:35684314:GC:G	acceptor_gain	1.0000
9:35684314:GCC:G	acceptor_loss	1.0000
9:35684315:CC:C	acceptor_gain	1.0000
9:35684316:C:CC	acceptor_gain	1.0000
9:35684317:T:G	acceptor_loss	1.0000
9:35684322:G:C	acceptor_gain	1.0000
9:35684322:G:GC	acceptor_gain	1.0000
9:35684329:C:CT	acceptor_gain	1.0000
9:35684330:A:T	acceptor_gain	1.0000
9:35684482:TCTCA:T	donor_loss	1.0000
9:35684483:CTCAC:C	donor_loss	1.0000
9:35684484:TCAC:T	donor_loss	1.0000
9:35684485:CACCT:C	donor_loss	1.0000
9:35684487:C:CA	donor_loss	1.0000
9:35684489:T:TA	donor_gain	1.0000
9:35684548:ATA:A	acceptor_gain	1.0000
9:35684549:TA:T	acceptor_gain	1.0000
9:35684550:ACTT:A	acceptor_loss	1.0000
9:35684551:C:A	acceptor_loss	1.0000
9:35684551:C:CC	acceptor_gain	1.0000
9:35684552:T:C	acceptor_gain	1.0000
9:35684552:T:G	acceptor_loss	1.0000
9:35684552:T:TC	acceptor_gain	1.0000
9:35684554:T:C	acceptor_gain	1.0000

AlphaMissense

1884 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:35685326:A:G	L169P	1.000
9:35685463:C:G	A155P	1.000
9:35685475:C:G	A151P	1.000
9:35685483:A:G	L148P	1.000
9:35685675:C:G	A116P	1.000
9:35685696:C:G	A109P	1.000
9:35685704:A:G	L106P	1.000
9:35685725:A:G	L99P	1.000
9:35685740:A:G	L94P	1.000
9:35685752:C:G	R90P	1.000
9:35684251:A:G	L256P	0.999
9:35684294:C:G	A242P	0.999
9:35684303:C:G	A239P	0.999
9:35684315:C:G	A235P	0.999
9:35684740:C:G	A211P	0.999
9:35684746:C:G	A209P	0.999
9:35684751:A:G	L207P	0.999
9:35684781:A:G	L197P	0.999
9:35685285:C:G	A183P	0.999
9:35685305:A:G	L176P	0.999
9:35685336:C:G	A166P	0.999
9:35685447:C:G	R160P	0.999
9:35685454:A:G	S158P	0.999
9:35685462:G:T	A155D	0.999
9:35685526:C:G	A134P	0.999
9:35685528:C:G	R133P	0.999
9:35685551:T:A	R125S	0.999
9:35685551:T:G	R125S	0.999
9:35685663:C:G	A120P	0.999
9:35685683:A:G	L113P	0.999

dbSNP variants (sampled 300 via entrez): RS1000685666 (9:35686649 A>T), RS1001211829 (9:35691392 C>G), RS1001224051 (9:35686373 C>G), RS1001315026 (9:35690942 T>A), RS1001494830 (9:35684872 G>A,T), RS1001835124 (9:35685059 A>C), RS1002180028 (9:35689921 G>A), RS1002622899 (9:35690129 C>T), RS1002887918 (9:35688245 C>G,T), RS1003150989 (9:35690008 C>G,T), RS1003217306 (9:35688732 T>A,C), RS1003244236 (9:35683725 A>G), RS1003595789 (9:35688296 G>A), RS1003702202 (9:35682575 C>G), RS1003763543 (9:35683707 A>T)

Disease associations

OMIM: gene MIM:190990 | disease phenotypes: MIM:108120, MIM:609285, MIM:256030, MIM:601680

GenCC curated gene-disease

Disease	Classification	Inheritance
arthrogryposis, distal, type 1A	Strong	Autosomal dominant
congenital myopathy 23	Strong	Autosomal dominant
congenital myopathy	Moderate	Autosomal recessive
digitotalar dysmorphism	Supportive	Autosomal dominant
Sheldon-hall syndrome	Supportive	Autosomal dominant
typical nemaline myopathy	Supportive	Autosomal dominant
childhood-onset nemaline myopathy	Supportive	Autosomal dominant
cap myopathy	Supportive	Autosomal dominant
congenital fiber-type disproportion myopathy	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
TPM2-related myopathy	Definitive	AD

Mondo (14): arthrogryposis, distal, type 1A (MONDO:0007157), congenital myopathy 23 (MONDO:0012240), arthrogryposis (MONDO:0008779), arthrogryposis, distal, type 2B4 (MONDO:0800200), congenital fiber-type disproportion myopathy (MONDO:0009711), nemaline myopathy (MONDO:0018958), distal arthrogryposis type 2B1 (MONDO:0020820), TPM2-related myopathy (MONDO:0100196), congenital myopathy (MONDO:0019952), digitotalar dysmorphism (MONDO:0015240), Sheldon-hall syndrome (MONDO:0011128), typical nemaline myopathy (MONDO:0015737), childhood-onset nemaline myopathy (MONDO:0015738), cap myopathy (MONDO:0015753)

Orphanet (4): Distal arthrogryposis type 1 (Orphanet:1146), Congenital fiber-type disproportion myopathy (Orphanet:2020), Nemaline myopathy (Orphanet:607), Sheldon-Hall syndrome (Orphanet:1147)

HPO phenotypes

189 total (30 of 189 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000028	Cryptorchidism
HP:0000160	Narrow mouth
HP:0000211	Trismus
HP:0000218	High palate
HP:0000275	Narrow face
HP:0000276	Long face
HP:0000278	Retrognathia
HP:0000316	Hypertelorism
HP:0000347	Micrognathia
HP:0000369	Low-set ears
HP:0000407	Sensorineural hearing impairment
HP:0000411	Protruding ear
HP:0000431	Wide nasal bridge
HP:0000465	Webbed neck
HP:0000467	Neck muscle weakness
HP:0000470	Short neck
HP:0000508	Ptosis
HP:0000602	Ophthalmoplegia
HP:0000678	Dental crowding
HP:0000709	Psychosis
HP:0000767	Pectus excavatum
HP:0000768	Pectus carinatum
HP:0000774	Narrow chest
HP:0000954	Single transverse palmar crease
HP:0001032	Absent distal interphalangeal creases
HP:0001181	Adducted thumb
HP:0001188	Hand clenching
HP:0001193	Ulnar deviation of the hand or of fingers of the hand
HP:0001249	Intellectual disability

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST90002387_336	Immature fraction of reticulocytes	3.000000e-12
GCST90002402_58	Platelet count	5.000000e-19
GCST90002407_111	White blood cell count	2.000000e-17

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004309	platelet count

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D001176	Arthrogryposis	C05.550.150; C05.651.102; C05.660.077; C16.131.621.077
D017696	Myopathies, Nemaline	C05.651.575.290; C10.668.491.550.290
C579969	Cap Myopathy (supp.)
C565097	Digitotalar Dysmorphism (supp.)
C538351	Nemaline myopathy 4 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, increases expression	4
Cadmium Chloride	decreases expression, increases expression, increases methylation	4
Tretinoin	decreases expression, increases expression	3
perfluorooctanoic acid	decreases expression	2
entinostat	decreases expression, affects cotreatment	2
Decitabine	affects expression, decreases expression, decreases reaction	2
Benzo(a)pyrene	decreases methylation, increases expression	2
Doxorubicin	affects expression, increases expression	2
Smoke	decreases expression, decreases reaction, increases expression	2
Valproic Acid	decreases expression, increases methylation, affects cotreatment, increases expression	2
Aflatoxin B1	increases methylation, increases expression	2
Particulate Matter	affects expression, decreases expression, increases abundance	2
aristolochic acid I	increases expression	1
bisphenol F	increases expression	1
methylmercuric chloride	decreases expression, increases expression	1
beta-lapachone	decreases expression	1
trimellitic anhydride	decreases expression	1
sodium arsenite	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
chloropicrin	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	increases expression	1
jinfukang	decreases expression, affects cotreatment	1
Temozolomide	increases expression	1
Sunitinib	decreases expression	1
Zoledronic Acid	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1

Cellosaurus cell lines

2 cell lines: 2 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_D6PQ	INNDSUi004-A	Induced pluripotent stem cell	Female
CVCL_XI74	SDQLCHi004-A	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01028833	PHASE2	COMPLETED	Effects of Power Mobility on Young Children With Severe Motor Impairments
NCT02035501	PHASE2	UNKNOWN	Treatment of TNNT1-Myopathy With L-Tyrosine.
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
NCT01144741	Not specified	TERMINATED	Survey Study and Records Review of Treatment Outcomes in Freeman-Sheldon Syndrome
NCT05393375	Not specified	COMPLETED	Arthrogryposis Multiplex Congenita in Pediatric Age: Correlation Between MUScular MRI and Functional Evaluation
NCT05673265	Not specified	UNKNOWN	Pediatric and Adult Registry for Patients With ARThrogryposis
NCT06130592	Not specified	UNKNOWN	Technical Feasibility Study of Ultrasound Muscle Imaging in Antenatal Ultrasound
NCT07360574	Not specified	NOT_YET_RECRUITING	Piezo2-related Arthrogryposis & physiopathOLOgy 3
NCT05419245	Not specified	UNKNOWN	Survey Study and Records Review of Treatment Outcomes in Freeman-Sheldon Syndrome
NCT00272883	Not specified	RECRUITING	Molecular and Genetic Studies of Congenital Myopathies
NCT01306994	Not specified	WITHDRAWN	Study of Resting and Exercising Body Functioning in Freeman-Sheldon Syndrome and Related Conditions
NCT01307475	Not specified	TERMINATED	Study of Quality of Life in Freeman-Sheldon Syndrome and Related Conditions
NCT02218593	Not specified	COMPLETED	WREX Outcome Study
NCT04789746	Not specified	UNKNOWN	Ready, Set, Go! A Physical Fitness Intervention for Children With Mobility Challenges
NCT04798378	Not specified	ACTIVE_NOT_RECRUITING	NuroSleeve Powered Brace & Stimulation System to Restore Arm Function
NCT06192134	Not specified	NOT_YET_RECRUITING	Continuous Passive Motion Device for Children With Arthrogryposis
NCT07429188	Not specified	RECRUITING	Impact Study on Users of Upper Limb Assistive Devices
NCT03728803	Not specified	COMPLETED	Inspiratory Muscle Training in Nemaline Myopathy
NCT06157268	Not specified	RECRUITING	The Natural History and Muscle Fatigability of Patients With Congenital Myopathies.
NCT06670378	Not specified	ACTIVE_NOT_RECRUITING	Natural History Study for Patients With Nemaline Myopathy in the UK
NCT06774703	Not specified	NOT_YET_RECRUITING	Nemaline Myopathy Clinical Research Network (NM-CTRN)
NCT07201636	Not specified	NOT_YET_RECRUITING	Natural History Study for Patients With Nemaline Myopathy in Belgium
NCT07478172	Not specified	RECRUITING	Effects of Whole-body Electrical Muscle Stimulation Exercise on Adults With Neuromuscular Disease
NCT07488806	Not specified	RECRUITING	Natural History Study for Patients With Nemaline Myopathy in Spain