TMPO

Summary

TMPO (thymopoietin, HGNC:11875) is a protein-coding gene on chromosome 12q23.1, encoding Lamina-associated polypeptide 2, isoform alpha (P42166). May be involved in the structural organization of the nucleus and in the post-mitotic nuclear assembly.

Through alternative splicing, this gene encodes several distinct LEM domain containing protein isoforms. LEM domain proteins include inner nuclear membrane and intranuclear proteins, and are involved in a variety of cellular functions including gene expression, chromatin organization, and replication and cell cycle control. The encoded alpha isoform is broadly diffuse in the nucleus and contains a lamin binding domain, while the beta and gamma isoforms are localized to the nuclear membrane and contain an HDAC3 interaction domain. The distinct isoforms may compete with each other when acting to chaperone other proteins and regulate transcription.

Source: NCBI Gene 7112 — RefSeq curated summary.

At a glance

• Gene–disease (curated): familial isolated dilated cardiomyopathy (Supportive, GenCC) — +3 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 838 total
• Phenotypes (HPO): 13
• Druggable target: yes
• MANE Select transcript: NM_001032283

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11875
Approved symbol	TMPO
Name	thymopoietin
Location	12q23.1
Locus type	gene with protein product
Status	Approved
Aliases	TP, LAP2, LEMD4
Ensembl gene	ENSG00000120802
Ensembl biotype	protein_coding
OMIM	188380
Entrez	7112

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 8 protein_coding, 5 protein_coding_CDS_not_defined, 2 retained_intron

ENST00000261210, ENST00000266732, ENST00000343315, ENST00000393053, ENST00000546828, ENST00000547214, ENST00000548223, ENST00000548911, ENST00000549938, ENST00000551987, ENST00000552831, ENST00000556029, ENST00000556678, ENST00000715724, ENST00000852285

RefSeq mRNA: 4 — MANE Select: NM_001032283 NM_001032283, NM_001032284, NM_001307975, NM_003276

CCDS: CCDS31879, CCDS31880, CCDS76589, CCDS9064

Canonical transcript exons

ENST00000556029 — 9 exons

Exon	Start	End
ENSE00000922719	98537475	98537572
ENSE00000994627	98544230	98544349
ENSE00002447487	98547573	98550351
ENSE00003477182	98544951	98545061
ENSE00003510419	98546359	98546447
ENSE00003534864	98544442	98544537
ENSE00003573266	98531680	98531838
ENSE00003601997	98527886	98528012
ENSE00004027705	98515590	98516146

Expression profiles

Bgee: expression breadth ubiquitous, 287 present calls, max score 99.14.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 80.8931 / max 743.9307, expressed in 1826 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
127544	78.1473	1825
127545	1.4432	744
127546	0.6168	370
127547	0.5283	300
127543	0.1575	64

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	99.14	gold quality
ganglionic eminence	UBERON:0004023	99.01	gold quality
embryo	UBERON:0000922	97.50	gold quality
calcaneal tendon	UBERON:0003701	97.29	gold quality
monocyte	CL:0000576	97.26	gold quality
mononuclear cell	CL:0000842	96.85	gold quality
trabecular bone tissue	UBERON:0002483	96.76	gold quality
leukocyte	CL:0000738	96.61	gold quality
tonsil	UBERON:0002372	95.69	gold quality
adrenal tissue	UBERON:0018303	95.42	gold quality
lymph node	UBERON:0000029	95.29	gold quality
rectum	UBERON:0001052	95.19	gold quality
colonic epithelium	UBERON:0000397	95.13	gold quality
oocyte	CL:0000023	95.07	gold quality
bone marrow	UBERON:0002371	95.04	gold quality
bone element	UBERON:0001474	94.58	gold quality
mucosa of sigmoid colon	UBERON:0004993	94.53	gold quality
endometrium	UBERON:0001295	94.47	gold quality
sperm	CL:0000019	94.40	gold quality
epithelium of nasopharynx	UBERON:0001951	94.31	gold quality
cortical plate	UBERON:0005343	94.23	gold quality
colonic mucosa	UBERON:0000317	94.11	gold quality
ovary	UBERON:0000992	94.04	gold quality
bone marrow cell	CL:0002092	93.92	gold quality
left ovary	UBERON:0002119	93.83	gold quality
secondary oocyte	CL:0000655	93.74	gold quality
pylorus	UBERON:0001166	93.73	gold quality
caecum	UBERON:0001153	93.56	gold quality
jejunal mucosa	UBERON:0000399	93.55	gold quality
superficial temporal artery	UBERON:0001614	93.48	gold quality

Single-cell (SCXA)

Detected in 12 experiment(s), a significant marker in 10.

Experiment	Marker?	Max mean expression
E-GEOD-110499	yes	529.68
E-MTAB-10290	yes	348.07
E-CURD-112	yes	43.60
E-CURD-122	yes	24.99
E-HCAD-5	yes	18.65
E-HCAD-1	yes	17.99
E-GEOD-125970	yes	16.75
E-MTAB-6678	yes	9.91
E-ANND-3	yes	7.91
E-CURD-88	yes	7.03
E-GEOD-81383	no	472.68
E-MTAB-7606	no	400.28

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F4, EGR1, HIC1, SP1, WT1

miRNA regulators (miRDB)

88 targeting TMPO, 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-4795-3P	100.00	74.62	4024
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-12136	99.98	72.81	5713
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-7152-3P	99.97	67.47	849
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-3143	99.93	71.96	3104

Literature-anchored findings (GeneRIF, showing 21)

• data suggest that hypophosphorylated Rb is anchored in the nucleus by the interaction of pocket C with LAP2alpha-lamin A/C complexes (PMID:12475961)
• Results indicate that in vitro, the interaction between HA95 and LAP2beta is influenced by a PKA-mediated phosphorylation of HA95 rather than by CDK1- or PKC-mediated phosphorylation of LAP2beta (PMID:12950172)
• LAP2alpha and BAF transiently localize to telomeres and specific regions on chromatin during nuclear assembly (PMID:15546916)
• A predicted Arg690Cys substitution within the LAP2 gene is implicated in the pathogenesis of genetic forms of dilated cardiomyopathy. (PMID:16247757)
• The effects of LAP2alpha on cell cycle progression and differentiation may be highly relevant for the cell- and tissue-specific phenotypes observed in laminopathic diseases. (PMID:16606692)
• In agreement with its regulation by E2F, LAP2alpha over expression in primary tumors was found to be correlated with tumor proliferation rate (PMID:16760672)
• LAP2alpha forms higher order structures containing multiple LAP2alpha molecules in vivo and that complex formation is mediated by the C terminus. (PMID:17213199)
• Results suggest that LAP2alpha and lamin A/C are involved in controlling retinoblastoma protein localization and phosphorylation, and a lack or mislocalization of either protein leads to cell cycle arrest in fibroblasts. (PMID:17227891)
• Lamina associated protein 2Beta (LAP2beta) is expressed in acute hematopoietic malignant cells, but not in chronic hematopoietic malignant cells. (PMID:17364180)
• Co-expression of LAP2beta and LAP2zeta results in inhibition of LAP2beta-induced gene silencing while overexpression of LAP2zeta alone leads to a small increase in transcriptional activity of various transcription factors. (PMID:18403046)
• this study provides evidence for elevated LAP2alpha expression in cervical cancer and suggests that E2F and p53 activities associate with the positive and negative regulation of LAP2alpha expression, respectively (PMID:21990273)
• Data indicate that cells lacking either high mobility group protein N5 (HMGN5) and lamina-associated polypeptide 2alpha (LAP2alpha) showed that loss of either protein affects the genome-wide distribution of the remaining partner. (PMID:23673662)
• Results highlight the interactions at the nuclear envelope where mutations in the EMD and TMPO gene in combination with mutations in SUN1 have an impact on several components of the network. (PMID:24375709)
• Results suggest that TMPObeta and -gamma isoforms could provide a potential reliable diagnostic marker for breast cancer. (PMID:25837847)
• The findings unveil a unique mechanism where the nuclear periphery proteins lamin-A/C, LAP2alpha and BAF1 are assembled into a protein complex during mitosis in order to regulate assembly and positioning of the mitotic spindle. (PMID:26092935)
• The authors find that LAP2alpha (lamina-associated polypeptide-alpha) interacts with lamin A, while its interaction with progerin is significantly reduced. (PMID:26312502)
• LAP2alpha can regulate extracellular matrix components independently of lamins A/C, which may help explain the proliferation-promoting function of LAP2alpha in cells expressing progerin. (PMID:26443848)
• Study found TMPO is significantly upregulated in glioblastoma tissues.TMPO knockdown promoted cell apoptosis by upregulation of the cleavage of caspase-3 and PARP protein levels. (PMID:27756319)
• TMPO-AS1 contributes to lung carcinogenesis, which may be partially through upregulation TMPO. (PMID:31230752)
• LncRNA TMPO-AS1 Aggravates the Development of Hepatocellular Carcinoma via miR-429/GOT1 Axis. (PMID:32988599)
• LncRNA TMPO-AS1 promotes esophageal squamous cell carcinoma progression by forming biomolecular condensates with FUS and p300 to regulate TMPO transcription. (PMID:35760875)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	tmpoa	ENSDARG00000007315
danio_rerio	tmpob	ENSDARG00000022978
danio_rerio	lemd1	ENSDARG00000040161
mus_musculus	Tmpo	ENSMUSG00000019961
rattus_norvegicus	Slc25a3	ENSRNOG00000008797
caenorhabditis_elegans	emr-1	WBGENE00001309

Paralogs (1): LEMD1 (ENSG00000186007)

Protein

Protein identifiers

Lamina-associated polypeptide 2, isoform alpha — P42166 (reviewed: P42166, P42167)

Alternative names: Thymopoietin isoform alpha, Thymopoietin-related peptide isoform alpha

All UniProt accessions (4): G5E972, H0YJH7, P42166, P42167

UniProt curated annotations — full annotation on UniProt →

Function. May be involved in the structural organization of the nucleus and in the post-mitotic nuclear assembly. Plays an important role, together with LMNA, in the nuclear anchorage of RB1. TP and TP5 may play a role in T-cell development and function. TP5 is an immunomodulating pentapeptide.

Subunit / interactions. Interacts with LMNA, BANF1 and RB1 and with chromosomes. Associates directly or indirectly with lamins at specific cell-cycle stages. Interacts with CMTM6.

Subcellular location. Nucleus. Chromosome.

Tissue specificity. Expressed in many tissues. Most abundant in adult thymus and fetal liver.

Post-translational modifications. Phosphorylated in a mitose-specific manner.

Domain organisation. The N-terminal part contains two structurally independent, non-interacting domains: LEM-like (also called LAP2-N or LEM-D) and LEM (also called LAP2-C or LEM-B). LEM-like binds DNA while LEM interacts with BANF1. The C-terminal domain forms a four-stranded coiled coil.

Similarity. Belongs to the LEM family.

Isoforms (4)

UniProt ID	Names	Canonical?
P42166-1	Alpha	yes
P42167-1	Beta
P42167-2	Gamma
P42167-3	Zeta

RefSeq proteins (4): NP_001027454, NP_001027455, NP_001294904, NP_003267 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003887	LEM_dom	Domain
IPR011015	LEM/LEM-like_dom_sf	Homologous_superfamily
IPR013146	LEM-like_dom	Domain
IPR021623	LAP2alpha_C	Domain
IPR051656	LEM_domain	Family

Pfam: PF03020, PF08198, PF11560

UniProt features (122 total): modified residue 58, compositionally biased region 11, region of interest 11, sequence variant 9, strand 6, helix 5, peptide 4, domain 4, turn 3, splice variant 3, chain 2, initiator methionine 1, coiled-coil region 1, short sequence motif 1, transmembrane region 1, topological domain 1, cross-link 1

Structure

Experimental structures (PDB)

14 structures.

PDB	Method	Resolution (Å)
8FNG	ELECTRON MICROSCOPY	2.2
8FNP	ELECTRON MICROSCOPY	2.2
8FNJ	ELECTRON MICROSCOPY	2.4
8FNO	ELECTRON MICROSCOPY	2.46
8FNH	ELECTRON MICROSCOPY	2.5
8FNN	ELECTRON MICROSCOPY	2.7
8FN7	ELECTRON MICROSCOPY	2.8
8FNL	ELECTRON MICROSCOPY	2.8
8FNM	ELECTRON MICROSCOPY	2.8
8FNQ	ELECTRON MICROSCOPY	2.8
8FND	ELECTRON MICROSCOPY	3
1GJJ	SOLUTION NMR
1H9E	SOLUTION NMR
1H9F	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P42166-F1	60.49	0.19
AF-P42167-F1	60.70	0.20

Functional residue map

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

P42166 (canonical)

Post-translational modifications (22): 57, 59, 66, 67, 74, 79, 86, 88, 154, 156, 159, 160, 164, 166, 168, 272, 312, 351, 354, 370 …

P42167

Post-translational modifications (37): 57, 59, 66, 67, 74, 79, 86, 88, 154, 156, 159, 160, 164, 166, 168, 177, 180, 184, 190, 207 …

Function

Pathways and Gene Ontology

Reactome pathways

17 pathways

ID	Pathway
R-HSA-8980692	RHOA GTPase cycle
R-HSA-9013106	RHOC GTPase cycle
R-HSA-9013148	CDC42 GTPase cycle
R-HSA-9013149	RAC1 GTPase cycle
R-HSA-9013404	RAC2 GTPase cycle
R-HSA-9013405	RHOD GTPase cycle
R-HSA-9013408	RHOG GTPase cycle
R-HSA-9013409	RHOJ GTPase cycle
R-HSA-9013423	RAC3 GTPase cycle
R-HSA-9035034	RHOF GTPase cycle
R-HSA-2980766	Nuclear Envelope Breakdown
R-HSA-2995383	Initiation of Nuclear Envelope (NE) Reformation
R-HSA-4419969	Depolymerization of the Nuclear Lamina
R-HSA-162582	Signal Transduction
R-HSA-194315	Signaling by Rho GTPases
R-HSA-9012999	RHO GTPase cycle
R-HSA-9716542	Signaling by Rho GTPases, Miro GTPases and RHOBTB3

MSigDB gene sets: 406 (showing top): E2F_Q4, SHEPARD_BMYB_MORPHOLINO_UP, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, MULLIGHAN_NPM1_SIGNATURE_3_UP, HORIUCHI_WTAP_TARGETS_DN, WANG_CLIM2_TARGETS_UP, GNF2_CENPF, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, E2F4DP1_01, PAL_PRMT5_TARGETS_UP, CHIARETTI_T_ALL_REFRACTORY_TO_THERAPY, TTTGTAG_MIR520D, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GRAESSMANN_RESPONSE_TO_MC_AND_SERUM_DEPRIVATION_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN

GO Biological Process (0):

GO Molecular Function (4): DNA binding (GO:0003677), lamin binding (GO:0005521), cadherin binding (GO:0045296), protein binding (GO:0005515)

GO Cellular Component (8): chromatin (GO:0000785), nucleus (GO:0005634), nuclear envelope (GO:0005635), nuclear inner membrane (GO:0005637), cytoplasm (GO:0005737), membrane (GO:0016020), nuclear membrane (GO:0031965), chromosome (GO:0005694)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
RHO GTPase cycle	10
Mitotic Prophase	1
Nuclear Envelope (NE) Reassembly	1
Nuclear Envelope Breakdown	1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1
Signaling by Rho GTPases	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
nucleus	2
nucleic acid binding	1
protein binding	1
cell adhesion molecule binding	1
binding	1
chromosome	1
intracellular membrane-bounded organelle	1
endomembrane system	1
organelle envelope	1
organelle inner membrane	1
nuclear membrane	1
intracellular anatomical structure	1
nuclear envelope	1
organelle membrane	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

154 interactions, top by confidence:

A	B	Type	Score
MED29	MED19	psi-mi:“MI:0914”(association)	0.890
XRCC5	PARP1	psi-mi:“MI:0915”(physical association)	0.880
MED9	MED19	psi-mi:“MI:0914”(association)	0.790
MED19	MED19	psi-mi:“MI:0914”(association)	0.730
MED26	MED19	psi-mi:“MI:0914”(association)	0.730
NCBP2	KPNA3	psi-mi:“MI:0914”(association)	0.640
GYPA	TCAF2	psi-mi:“MI:0914”(association)	0.640
TMPO	LMNA	psi-mi:“MI:0407”(direct interaction)	0.630
RPN1	APBB1	psi-mi:“MI:0914”(association)	0.530
LRRK2	DFFA	psi-mi:“MI:0914”(association)	0.530
TMPO	NEK7	psi-mi:“MI:0915”(physical association)	0.500
LMNA	TMPO	psi-mi:“MI:0407”(direct interaction)	0.440
H3C1	SMCHD1	psi-mi:“MI:2364”(proximity)	0.410
TMPO	BANF1	psi-mi:“MI:0915”(physical association)	0.400
LEMD3	TMPO	psi-mi:“MI:0915”(physical association)	0.400
SDC1	ILVBL	psi-mi:“MI:0915”(physical association)	0.400
TMPO	FXR1	psi-mi:“MI:0915”(physical association)	0.370
Mad2l2	CHD1	psi-mi:“MI:0914”(association)	0.350
Cbx1		psi-mi:“MI:0914”(association)	0.350
USP7	STIL	psi-mi:“MI:0914”(association)	0.350
JUN		psi-mi:“MI:0914”(association)	0.350
JUN	TPM3	psi-mi:“MI:0914”(association)	0.350
		psi-mi:“MI:0914”(association)	0.350
	ESYT2	psi-mi:“MI:0914”(association)	0.350
E5	ESYT2	psi-mi:“MI:0914”(association)	0.350
	HAX1	psi-mi:“MI:0914”(association)	0.350

BioGRID (973): TMPO (Affinity Capture-MS), TMPO (Affinity Capture-MS), TMPO (Affinity Capture-MS), TMPO (Affinity Capture-MS), TMPO (Reconstituted Complex), TMPO (Affinity Capture-MS), TMPO (Affinity Capture-MS), TMPO (Affinity Capture-RNA), TMPO (Affinity Capture-MS), LARS (Co-fractionation), TMPO (Co-fractionation), TMPO (Co-fractionation), TMPO (Affinity Capture-RNA), TMPO (Proximity Label-MS), TMPO (Proximity Label-MS)

ESM2 similar proteins: D0RLZ2, O11457, O50917, P02896, P02897, P02898, P04478, P06013, P06014, P06015, P06016, P07208, P0CV03, P0CV07, P10593, P20946, P20947, P20948, P20949, P20950, P21840, P21875, P26326, P26327, P26328, P26329, P26330, P26331, P26332, P26333, P26334, P32777, P32779, P42166, P56165, P70897, P70899, P70901, P70902, P70903

Diamond homologs: O01971, P42166, P42167, Q14C37, Q61029, Q61033, Q62733, Q68G75, Q9XTB5, P01249, P01250, P01251, Q9WU40, Q9Y2U8, O13845, Q14498, Q5RC80, Q6DVA0, Q8NC56, Q8VH51, Q7JRE4

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 173 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
PD-L1(CD274) glycosylation and translocation to plasma membrane	5	20.0×	5e-04
Regulation of CDH1 posttranslational processing and trafficking to plasma membrane	7	18.1×	2e-05
Maturation of spike protein	6	12.3×	9e-04
Maturation of DENV proteins	7	11.4×	4e-04
Signaling by BRAF and RAF1 fusions	7	9.2×	1e-03
RSV-host interactions	6	7.2×	9e-03
Adipogenesis	6	7.2×	9e-03
Processing of Capped Intron-Containing Pre-mRNA	10	6.3×	5e-04

GO biological processes:

GO term	Partners	Fold	FDR
obsolete protein N-linked glycosylation via asparagine	5	22.2×	1e-03
positive regulation of transcription elongation by RNA polymerase II	6	11.9×	3e-03
positive regulation of miRNA transcription	6	11.5×	3e-03
positive regulation of transcription initiation by RNA polymerase II	6	10.7×	3e-03
protein N-linked glycosylation	6	10.4×	3e-03
mRNA transport	6	10.4×	3e-03
negative regulation of translation	7	9.0×	3e-03
fat cell differentiation	7	8.3×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	504
Likely benign	236
Benign	39

Top pathogenic / likely-pathogenic (0)

SpliceAI

677 predictions. Top by Δscore:

Variant	Effect	Δscore
12:98516143:CAGGG:C	donor_loss	1.0000
12:98516144:AGGG:A	donor_loss	1.0000
12:98516145:GG:G	donor_gain	1.0000
12:98516146:GG:G	donor_gain	1.0000
12:98516147:GTAAG:G	donor_loss	1.0000
12:98527880:TTACA:T	acceptor_loss	1.0000
12:98527882:ACAG:A	acceptor_loss	1.0000
12:98527883:CAG:C	acceptor_loss	1.0000
12:98527884:A:AC	acceptor_loss	1.0000
12:98527884:A:AG	acceptor_gain	1.0000
12:98527885:G:GC	acceptor_gain	1.0000
12:98527885:GA:G	acceptor_gain	1.0000
12:98527885:GAA:G	acceptor_gain	1.0000
12:98527885:GAAA:G	acceptor_gain	1.0000
12:98528009:GTGG:G	donor_gain	1.0000
12:98528010:TGG:T	donor_gain	1.0000
12:98528011:GG:G	donor_gain	1.0000
12:98528011:GGG:G	donor_gain	1.0000
12:98528011:GGGT:G	donor_loss	1.0000
12:98528012:GG:G	donor_gain	1.0000
12:98528013:G:GG	donor_gain	1.0000
12:98528013:GT:G	donor_loss	1.0000
12:98531677:CAG:C	acceptor_loss	1.0000
12:98531678:A:AG	acceptor_gain	1.0000
12:98531678:AG:A	acceptor_gain	1.0000
12:98531679:G:GA	acceptor_loss	1.0000
12:98531679:G:GG	acceptor_gain	1.0000
12:98531679:GG:G	acceptor_gain	1.0000
12:98531800:G:GT	donor_gain	1.0000
12:98531834:AGAAG:A	donor_loss	1.0000

AlphaMissense

2941 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:98515914:T:C	L16S	1.000
12:98515926:T:C	L20S	0.999
12:98515969:A:C	K34N	0.999
12:98515969:A:T	K34N	0.999
12:98515980:T:A	V38D	0.999
12:98515988:T:G	Y41D	0.999
12:98515992:T:C	L42P	0.999
12:98527965:T:C	L120P	0.999
12:98527977:T:A	L124H	0.999
12:98527977:T:C	L124P	0.999
12:98531690:G:C	R139S	0.999
12:98531690:G:T	R139S	0.999
12:98531710:T:C	L146P	0.999
12:98515877:T:C	F4L	0.998
12:98515879:C:A	F4L	0.998
12:98515879:C:G	F4L	0.998
12:98515914:T:G	L16W	0.998
12:98515926:T:G	L20W	0.998
12:98515968:A:T	K34I	0.998
12:98515986:T:C	L40P	0.998
12:98516060:T:C	F65L	0.998
12:98516062:C:A	F65L	0.998
12:98516062:C:G	F65L	0.998
12:98528001:G:A	G132D	0.998
12:98515967:A:G	K34E	0.997
12:98516001:T:C	L45P	0.997
12:98527897:A:C	K97N	0.997
12:98527897:A:T	K97N	0.997
12:98528007:T:A	I134N	0.997
12:98531689:G:C	R139T	0.997

dbSNP variants (sampled 300 via entrez): RS1000019644 (12:98513842 T>G), RS1000061533 (12:98529347 G>A), RS1000194270 (12:98525305 C>T), RS1000209772 (12:98540463 C>G,T), RS1000261339 (12:98544750 T>A,C), RS1000311744 (12:98547302 T>C), RS1000411925 (12:98523471 T>A), RS1000544748 (12:98545787 C>T), RS1000555492 (12:98539214 T>C), RS1000571513 (12:98527385 T>G), RS1000597026 (12:98547087 T>A), RS1000700347 (12:98521886 T>G), RS1000841141 (12:98535002 A>G), RS1001003264 (12:98549552 A>C,G), RS1001129724 (12:98513738 A>C)

Disease associations

OMIM: gene MIM:188380 | disease phenotypes: MIM:610168, MIM:607487, MIM:192600, MIM:617468, MIM:208150

GenCC curated gene-disease

Disease	Classification	Inheritance
familial isolated dilated cardiomyopathy	Supportive	Autosomal dominant
hypertrophic cardiomyopathy	Limited	Autosomal dominant
dilated cardiomyopathy	Refuted Evidence	Autosomal dominant

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
hypertrophic cardiomyopathy	Limited	AD
obsolete familial isolated dilated cardiomyopathy	Refuted	AD

Mondo (12): Loeys-Dietz syndrome 2 (MONDO:0012427), dilated cardiomyopathy (MONDO:0005021), hypertrophic cardiomyopathy 25 (MONDO:0011843), hypertrophic cardiomyopathy (MONDO:0005045), familial hypertrophic cardiomyopathy (MONDO:0024573), arrhythmogenic right ventricular cardiomyopathy (MONDO:0016587), amyloidosis (MONDO:0019065), long QT syndrome (MONDO:0002442), cardiomyopathy (MONDO:0004994), arthrogryposis multiplex congenita (MONDO:0015168), fetal akinesia deformation sequence 1 (MONDO:0100101), (MONDO:0015470)

Orphanet (12): Marfan syndrome type 2 (Orphanet:284973), Marfan syndrome (Orphanet:558), Familial isolated dilated cardiomyopathy (Orphanet:154), Dilated cardiomyopathy (Orphanet:217604), Rare hypertrophic cardiomyopathy (Orphanet:217569), Rare familial disorder with hypertrophic cardiomyopathy (Orphanet:99739), Inherited arrhythmogenic cardiomyopathy (Orphanet:247), Amyloidosis (Orphanet:69), Rare cardiomyopathy (Orphanet:167848), Arthrogryposis multiplex congenita (Orphanet:1037), Fetal akinesia deformation sequence (Orphanet:994), NON RARE IN EUROPE: Familial isolated hypertrophic cardiomyopathy (Orphanet:155)

HPO phenotypes

13 total (15 of 13 shown, HPO-id order):

HPO	Term
HP:0000407	Sensorineural hearing impairment
HP:0000969	Edema
HP:0001635	Congestive heart failure
HP:0001644	Dilated cardiomyopathy
HP:0001727	Thromboembolic stroke
HP:0002875	Exertional dyspnea
HP:0003198	Myopathy
HP:0003457	EMG abnormality
HP:0011675	Arrhythmia
HP:0012378	Fatigue
HP:0012764	Orthopnea
HP:0025169	Left ventricular systolic dysfunction
HP:0100578	Lipoatrophy
HP:0001639	Hypertrophic cardiomyopathy
HP:0011034	Amyloid deposition

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST009391_1610	Metabolite levels	8.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0010377	phosphatidylcholine 34:3 measurement

MeSH disease descriptors (9)

Descriptor	Name	Tree numbers
D000686	Amyloidosis	C18.452.845.500
D019571	Arrhythmogenic Right Ventricular Dysplasia	C14.240.400.145; C14.280.238.028; C14.280.400.145; C16.131.240.400.145
D009202	Cardiomyopathies	C14.280.238
D002311	Cardiomyopathy, Dilated	C14.280.195.160; C14.280.238.070; C16.320.488.750
D002312	Cardiomyopathy, Hypertrophic	C14.280.238.100; C14.280.484.048.750.070.160
D024741	Cardiomyopathy, Hypertrophic, Familial	C14.280.238.100.500; C14.280.484.048.750.070.160.500; C16.320.160
D008133	Long QT Syndrome	C14.280.067.565; C14.280.123.625; C16.131.240.400.715; C23.550.073.547
C537783	Aortic aneurysm, familial thoracic 3 (supp.)
C564388	Cardiomyopathy, Dilated, 1N (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5725102 (SINGLE PROTEIN)

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

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.47	Kd	3348	nM	CHEMBL3752910
5.47	ED50	3348	nM	CHEMBL3752910
5.18	Kd	6613	nM	CHEMBL5653589
5.18	ED50	6613	nM	CHEMBL5653589

PubChem BioAssay actives

2 with measured affinity, of 10 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149619: Binding affinity to human TMPO (P42166) incubated for 45 mins by Kinobead based pull down assay	kd	3.3484	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149619: Binding affinity to human TMPO (P42166) incubated for 45 mins by Kinobead based pull down assay	kd	6.6128	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, decreases methylation, increases expression, affects expression	5
bisphenol A	affects expression, decreases expression, increases expression	4
sodium arsenite	increases expression, affects methylation, decreases expression	4
Benzo(a)pyrene	decreases expression	4
Estradiol	decreases phosphorylation, increases expression	4
trichostatin A	affects cotreatment, decreases expression, affects expression	3
Resveratrol	affects cotreatment, increases expression, decreases phosphorylation	3
Cyclosporine	decreases expression	3
Cadmium Chloride	decreases expression	3
cobaltous chloride	decreases expression	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, affects cotreatment, increases expression	2
Arsenic Trioxide	decreases expression, increases expression	2
Acetaminophen	decreases expression	2
Doxorubicin	decreases expression, affects response to substance	2
Phenylmercuric Acetate	decreases expression, affects cotreatment	2
Tobacco Smoke Pollution	decreases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
tert-Butylhydroperoxide	decreases expression	2
aristolochic acid I	decreases expression	1
afuresertib	decreases expression	1
FR900359	affects phosphorylation	1
TAK-243	increases sumoylation	1
triphenyl phosphate	affects expression	1
propionaldehyde	decreases expression	1
deoxynivalenol	increases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, decreases expression	1
beta-lapachone	decreases expression	1
arsenite	affects expression	1
methylparaben	decreases expression	1
mono-(2-ethylhexyl)phthalate	decreases expression	1

ChEMBL screening assays

7 unique, capped per target: 7 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652661	Binding	Binding affinity to human TMPO (P42166) incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00374465	PHASE4	UNKNOWN	Therapy With Verapamil or Carvedilol in Chronic Heart Failure
NCT01293903	PHASE4	COMPLETED	Study of Qiliqiangxin Capsule to Treat Dilated Cardiomyopathy
NCT01557140	PHASE4	COMPLETED	A Randomized Trial of Carvedilol in Chronic Chagas Cardiomyopathy
NCT01917149	PHASE4	COMPLETED	Supramaximal Titrated Inhibition of RAAS in Dilated Cardiomyopathy
NCT02115581	PHASE4	COMPLETED	Coenzyme Q10 Supplementation in Children With Idiopathic Dilated Cardiomyopathy
NCT06236022	PHASE4	RECRUITING	The Effects of Sirolimus in Patients With Dilated Cardiomyopathy Infected With Kaposi Sarcoma-associated Virus
NCT00879060	PHASE4	COMPLETED	Clinical and Therapeutic Implications of Fibrosis in Hypertrophic Cardiomyopathy
NCT01721967	PHASE4	COMPLETED	Ranolazine for the Treatment of Chest Pain in HCM Patients
NCT02948998	PHASE4	UNKNOWN	Evaluating the Effect of Spironolactone on Hypertrophic Cardiomyopathy
NCT03249272	PHASE4	TERMINATED	Microvascular Dysfunction in Nonischemic Cardiomyopathy: Insights From CMR Assessment of Coronary Flow Reserve
NCT04133532	PHASE4	COMPLETED	Effect of Metoprolol in Post Alcohol Septal Ablation Patients With Hypertrophic Cardiomyopathy
NCT06401343	PHASE4	RECRUITING	Use of SGLT2i in noHCM With HFpEF
NCT07103655	PHASE4	NOT_YET_RECRUITING	The Therapeutic Value of Mavacamten in Hypertrophic Cardiomyopathy With Mid-to-Apical Left Ventricular Obstruction
NCT07600177	PHASE4	RECRUITING	Mavacamten to Aficamten Transition in Patients With Obstructive Hypertrophic Cardiomyopathy
NCT00333827	PHASE3	COMPLETED	Cell Therapy In Dilated Cardiomyopathy
NCT00505154	PHASE3	COMPLETED	Effect of Rosuvastatin on Left Ventricular Remodeling
NCT01223703	PHASE3	COMPLETED	PUFAs and Left Ventricular Function in Heart Failure
NCT01583114	PHASE3	TERMINATED	PREclinical Mutation CARriers From Families With DIlated Cardiomyopathy and ACE Inhibitors
NCT01914081	PHASE3	UNKNOWN	Resveratrol: A Potential Anti- Remodeling Agent in Heart Failure, From Bench to Bedside
NCT02989181	PHASE3	UNKNOWN	Continues Positive Airway Pressure Treatment for Patients With Dilated Cardiomyopathy and Obstructive Sleep Apnea
NCT03439514	PHASE3	TERMINATED	A Study of ARRY-371797 (PF-07265803) in Patients With Symptomatic Dilated Cardiomyopathy Due to a Lamin A/C Gene Mutation
NCT05237323	PHASE3	COMPLETED	Micophenolate Mofetil Versus Azathioprine in Myocarditis
NCT05849766	PHASE3	COMPLETED	Effect of Dapagliflozin on Cardiac Structure, Function and Secondary Mitral Regurgitation in Patients with Left Ventricle Dysfunction
NCT06250257	PHASE3	RECRUITING	Bromocriptine in Dilated Cardiomyopathy Among Women of Reproductive Age
NCT00317967	PHASE3	COMPLETED	Study to Determine if Atorvastatin Reduces Size and Stiffness of Muscle in the Left Ventricle of the Heart
NCT00698074	PHASE3	UNKNOWN	Diastolic Ventricular Interaction and the Effects of Biventricular Pacing in Hypertrophic Cardiomyopathy
NCT00821353	PHASE3	COMPLETED	Antiarrhythmic Therapy Versus Catheter Ablation for Atrial Fibrillation in Hypertrophic Cardiomyopathy
NCT02431221	PHASE3	WITHDRAWN	Efficacy, Safety, and Tolerability of Perhexiline in Subjects With Hypertrophic Cardiomyopathy and Heart Failure
NCT03470545	PHASE3	COMPLETED	Clinical Study to Evaluate Mavacamten (MYK-461) in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy
NCT05174416	PHASE3	COMPLETED	A Study to Evaluate the Efficacy and Safety of Mavacamten in Chinese Adults With Symptomatic Obstructive HCM
NCT05182658	PHASE3	ACTIVE_NOT_RECRUITING	Empagliflozin in Hypertrophic Cardiomyopathy
NCT05186818	PHASE3	COMPLETED	Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic oHCM
NCT05767346	PHASE3	COMPLETED	Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Metoprolol Succinate in Adults With Symptomatic oHCM
NCT06116968	PHASE3	COMPLETED	An Open-Label Study of Aficamten for Chinese Patients With Symptomatic oHCM
NCT06873828	PHASE3	NOT_YET_RECRUITING	Evaluation of the Efficacy and Safety of Wearable ECG (AT-Patch) in Patients With Hypertrophic Cardiomyopathy Requiring 48-Hour Holter MonitoringEvaluation of the Efficacy and Safety of Wearable ECG (AT-Patch) in Patients With Hypertrophic Cardiomyopathy Requiring 48-Hour Holter Monitoring
NCT07021976	PHASE3	RECRUITING	A Phase III Trial of HRS-1893 in Patients With Obstructive Hypertrophic Cardiomyopathy
NCT07023341	PHASE3	ACTIVE_NOT_RECRUITING	A Study to Learn More About How Well Aficamten Works in Japanese Participants With Symptomatic Obstructive Hypertrophic Cardiomyopathy
NCT07202897	PHASE3	NOT_YET_RECRUITING	LA-HCM Study : Rivaroxaban for Antithrombotic Prevention in Hypertrophic Cardiomyopathy Patients With Abnormal Left Atrial Strain.
NCT00629018	PHASE2	COMPLETED	Safety and Efficacy Study of Stem Cell Transplantation to Treat Dilated Cardiomyopathy
NCT00629096	PHASE2	COMPLETED	Intracoronary Infusion of Autologous Bone Marrow Cells for Treatment of Idiopathic Dilated Cardiomyopathy