TNNI3K

Summary

TNNI3K (TNNI3 interacting kinase, HGNC:19661) is a protein-coding gene on chromosome 1p31.1, encoding Serine/threonine-protein kinase TNNI3K (Q59H18). May play a role in cardiac physiology.

This gene encodes a protein that belongs to the MAP kinase kinase kinase (MAPKKK) family of protein kinases. The protein contains ankyrin repeat, protein kinase and serine-rich domains and is thought to play a role in cardiac physiology.

Source: NCBI Gene 51086 — RefSeq curated summary.

At a glance

• Gene–disease (curated): atrial conduction disease (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 41
• Clinical variants (ClinVar): 95 total — 1 likely-pathogenic
• Phenotypes (HPO): 14
• Druggable target: yes — 20 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_015978

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19661
Approved symbol	TNNI3K
Name	TNNI3 interacting kinase
Location	1p31.1
Locus type	gene with protein product
Status	Approved
Aliases	CARK
Ensembl gene	ENSG00000116783
Ensembl biotype	protein_coding
OMIM	613932
Entrez	51086

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 7 protein_coding, 2 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000326637, ENST00000370889, ENST00000465473, ENST00000497284, ENST00000525480, ENST00000526236, ENST00000530184, ENST00000534020, ENST00000897211, ENST00000945683, ENST00000945684

RefSeq mRNA: 1 — MANE Select: NM_015978 NM_015978

CCDS: CCDS664

Canonical transcript exons

ENST00000326637 — 25 exons

Exon	Start	End
ENSE00001288918	74235387	74235491
ENSE00001340768	74543906	74544428
ENSE00003478094	74250672	74250769
ENSE00003485635	74436474	74436526
ENSE00003507811	74353266	74353360
ENSE00003514839	74370288	74370392
ENSE00003542908	74492097	74492266
ENSE00003567112	74353980	74354129
ENSE00003568058	74367908	74367964
ENSE00003577888	74369207	74369264
ENSE00003588373	74369022	74369114
ENSE00003594563	74342842	74342986
ENSE00003595306	74436080	74436132
ENSE00003599078	74367256	74367342
ENSE00003600193	74439490	74439622
ENSE00003605275	74271598	74271708
ENSE00003608262	74463441	74463550
ENSE00003617273	74249459	74249544
ENSE00003623776	74540234	74540313
ENSE00003635714	74336011	74336149
ENSE00003637162	74331450	74331548
ENSE00003670073	74489189	74489248
ENSE00003676470	74343075	74343179
ENSE00003694644	74369391	74369585
ENSE00003710824	74236102	74236210

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 95.22.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.3616 / max 358.5586, expressed in 15 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
3510	0.3386	15
3509	0.0142	4
3508	0.0087	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	95.22	gold quality
heart left ventricle	UBERON:0002084	94.62	gold quality
right atrium auricular region	UBERON:0006631	92.23	gold quality
heart	UBERON:0000948	90.99	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	88.84	gold quality
cerebellar hemisphere	UBERON:0002245	88.07	gold quality
cerebellar cortex	UBERON:0002129	87.98	gold quality
cerebellum	UBERON:0002037	87.69	gold quality
right hemisphere of cerebellum	UBERON:0014890	87.51	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	87.32	gold quality
quadriceps femoris	UBERON:0001377	86.38	gold quality
primary visual cortex	UBERON:0002436	83.22	gold quality
Brodmann (1909) area 9	UBERON:0013540	83.21	gold quality
right frontal lobe	UBERON:0002810	81.54	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	81.54	gold quality
superior frontal gyrus	UBERON:0002661	80.85	gold quality
sural nerve	UBERON:0015488	79.64	gold quality
frontal cortex	UBERON:0001870	79.24	gold quality
cerebral cortex	UBERON:0000956	78.66	gold quality
prefrontal cortex	UBERON:0000451	77.78	gold quality
brain	UBERON:0000955	77.77	gold quality
anterior cingulate cortex	UBERON:0009835	77.63	gold quality
corpus callosum	UBERON:0002336	77.49	gold quality
calcaneal tendon	UBERON:0003701	76.51	gold quality
nucleus accumbens	UBERON:0001882	76.10	gold quality
hypothalamus	UBERON:0001898	75.19	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	75.03	gold quality
spinal cord	UBERON:0002240	74.99	gold quality
putamen	UBERON:0001874	74.89	gold quality
tibial nerve	UBERON:0001323	74.82	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.40

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MEF2C

miRNA regulators (miRDB)

29 targeting TNNI3K, 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-4803	99.98	71.99	3117
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-944	99.82	70.85	3042
HSA-MIR-448	99.79	72.37	2103
HSA-MIR-3680-3P	99.75	72.51	3095
HSA-MIR-1296-3P	99.72	64.04	636
HSA-MIR-3618	99.69	68.57	1012
HSA-MIR-802	99.61	67.70	1254
HSA-MIR-5582-5P	99.27	71.42	1879
HSA-MIR-4263	99.18	69.25	2236
HSA-MIR-491-5P	99.13	65.98	1468
HSA-MIR-7854-3P	99.08	66.26	1117
HSA-MIR-4801	98.96	69.42	2096
HSA-MIR-138-2-3P	98.91	68.33	1643
HSA-MIR-34B-3P	98.70	67.40	1171
HSA-MIR-4731-3P	98.56	68.60	1860
HSA-MIR-548AO-5P	98.55	69.57	1362
HSA-MIR-548AX	98.55	69.58	1362
HSA-MIR-92A-1-5P	98.28	64.51	631
HSA-MIR-4423-3P	97.98	69.66	912
HSA-MIR-6782-3P	97.60	67.75	931
HSA-MIR-596	97.48	63.13	469
HSA-MIR-6509-5P	97.39	68.27	969
HSA-MIR-4690-3P	97.02	64.72	981
HSA-MIR-5685	97.02	64.34	1004
HSA-MIR-4727-3P	96.75	64.97	415
HSA-MIR-4704-5P	96.13	68.67	608
HSA-MIR-4693-3P	95.23	65.92	735

Literature-anchored findings (GeneRIF, showing 21)

• cloning of TNNI3K which interacts specifically with cardiac troponin I; data suggest that TNNI3K is a cardiac-specific kinase and plays important roles in the cardiac system (PMID:12721663)
• TNNI3K exhibits dual-specific kinase activity and forms dimers or oligomers that may be necessary for its activation (PMID:17660584)
• coexpression of AOP-1 inhibited TNNI3K kinase activity (PMID:18205602)
• TNNI3K promotes cardiomyogenesis, enhances cardiac performance, and protects the myocardium from ischemic injury by suppressing p38/JNK-mediated apoptosis. (PMID:18552163)
• [review] TNNI3K is a novel cardiac troponin I-interacting kinase gene that may be involved in the development of cardiac hypertrophy. (PMID:19925440)
• The finding of a de novo mutation in TNNI3 (R204H) enabled a genetic diagnosis and counselling. We suggest that the previously reported overlap of functional and morphologic phenotypes in sarcomeric genes may also be a feature of TNNI3 mutations. (PMID:20569525)
• Results suggest that TNNI3K overexpression induces cardiomyocytes hypertrophy and accelerates hypertrophy in hypertrophic cardiomyocytes. (PMID:21314842)
• TNNI3K mediates cell signaling to modulate cardiac response to stress. (PMID:23085512)
• using novel genetic animal models and newly developed small-molecule TNNI3K inhibitors, we demonstrated that TNNI3K-mediated IR injury occurs through impaired mitochondrial function and is in part dependent on p38 MAPK. (PMID:24899531)
• we demonstrate that mutation of TNNI3K, encoding a heart-specific kinase known to modulate murine cardiac conduction and myocardial function, underlies a familial syndrome of electrical and myopathic heart disease in humans. (PMID:24925317)
• A heterozygous p.Thr539Ala mutation in TNNI3K, a cardiac-specific kinase, is the likely cause for a novel familial cardiac conduction disease (FCCD) (PMID:25791106)
• TNNI3K overexpression promoted mouse embryonic stem cells differentiating into beating cardiomyocytes and induced up-regulating expression of cTnT by PKCepsilon signal pathway (PMID:28135716)
• results suggest that ACE2, TNNI3K and CALM3 polymorphisms are associated with increased risk of hypertrophic cardiomyopathies and dilated cardiomyopathies and may act as disease modifiers of these diseases. (PMID:28744816)
• A splice site mutation of TNNI3 Interacting Kinase (TNNI3K) was identified and co-segregated with the dilated cardiomyopathy (DCM) and cardiac conduction disease (CCD) affected family members. (PMID:29355681)
• Results showed that TNNI3K was highly in cholangiocarcinoma (CCA) patients. Furthermore, TNNI3K-knockdown decreased the growth of CCA cell lines. (PMID:30334579)
• we show that several common human TNNI3K kinase domain variants substantially compromise kinase activity, suggesting that TNNI3K may influence human heart regenerative capacity and potentially also other aspects of human heart disease. (PMID:31589606)
• New Insights into 4-Anilinoquinazolines as Inhibitors of Cardiac Troponin I-Interacting Kinase (TNNi3K). (PMID:32272798)
• Identification of a nonsense mutation in TNNI3K associated with cardiac conduction disease. (PMID:32529721)
• A SPRY1 domain cardiac ryanodine receptor variant associated with short-coupled torsade de pointes. (PMID:33664309)
• A Novel Missense Mutation in TNNI3K Causes Recessively Inherited Cardiac Conduction Disease in a Consanguineous Pakistani Family. (PMID:34440456)
• Reduced kinase function in two ultra-rare TNNI3K variants in families with congenital junctional ectopic tachycardia. (PMID:38424693)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	tnni3k	ENSDARG00000086933
mus_musculus	Tnni3k	ENSMUSG00000040086
rattus_norvegicus	Tnni3k	ENSRNOG00000028225
caenorhabditis_elegans		WBGENE00016030

Paralogs (23): MAP3K9 (ENSG00000006432), TESK2 (ENSG00000070759), MAP3K13 (ENSG00000073803), ARAF (ENSG00000078061), MAP3K20 (ENSG00000091436), RIPK2 (ENSG00000104312), LIMK1 (ENSG00000106683), TESK1 (ENSG00000107140), RIPK3 (ENSG00000129465), MAP3K10 (ENSG00000130758), RAF1 (ENSG00000132155), RIPK1 (ENSG00000137275), MAP3K12 (ENSG00000139625), KSR1 (ENSG00000141068), MAP3K21 (ENSG00000143674), BRAF (ENSG00000157764), ILK (ENSG00000166333), MLKL (ENSG00000168404), KSR2 (ENSG00000171435), MOS (ENSG00000172680), MAP3K11 (ENSG00000173327), LIMK2 (ENSG00000182541), LRRK2 (ENSG00000188906)

Protein

Protein identifiers

Serine/threonine-protein kinase TNNI3K — Q59H18 (reviewed: Q59H18)

Alternative names: Cardiac ankyrin repeat kinase, Cardiac troponin I-interacting kinase, TNNI3-interacting kinase

All UniProt accessions (4): Q59H18, H0YCE9, H0YDG1, H0YE48

UniProt curated annotations — full annotation on UniProt →

Function. May play a role in cardiac physiology.

Subunit / interactions. Interacts with TNNI3, ACTC1, ACTA1, MYBPC3, AIP, FABP3 and HADHB.

Subcellular location. Nucleus. Cytoplasm.

Tissue specificity. Highly expressed in both adult and fetal heart.

Post-translational modifications. Autophosphorylated.

Disease relevance. Cardiac conduction disease with or without dilated cardiomyopathy (CCDD) [MIM:616117] A cardiac disorder characterized by atrial tachyarrhythmia and conduction system disease. Some patients have dilated cardiomyopathy. CCDD inheritance is autosomal dominant. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. Based on a naturally occurring readthrough transcript which produces a FPGT-TNNI3K fusion protein. Based on a naturally occurring readthrough transcript which produces a FPGT-TNNI3K fusion protein. Based on a naturally occurring readthrough transcript which produces a FPGT-TNNI3K fusion protein.

Similarity. Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. MAP kinase kinase kinase subfamily.

Isoforms (4)

UniProt ID	Names	Canonical?
Q59H18-2	2	yes
Q59H18-1	1
Q59H18-3	3
Q59H18-4	4

RefSeq proteins (1): NP_057062* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR001245	Ser-Thr/Tyr_kinase_cat_dom	Domain
IPR002110	Ankyrin_rpt	Repeat
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR036770	Ankyrin_rpt-contain_sf	Homologous_superfamily

Pfam: PF07714, PF12796

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 (77 total): sequence variant 21, helix 16, repeat 10, strand 9, splice variant 5, sequence conflict 4, mutagenesis site 3, binding site 2, chain 1, domain 1, region of interest 1, coiled-coil region 1, compositionally biased region 1, active site 1, turn 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
4YFI	X-RAY DIFFRACTION	2.7
7MGJ	X-RAY DIFFRACTION	2.95
6B5J	X-RAY DIFFRACTION	2.97
4YFF	X-RAY DIFFRACTION	3.07
7MGK	X-RAY DIFFRACTION	3.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q59H18-F1	80.07	0.53

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 (1): 588 (proton acceptor)

Ligand- & substrate-binding residues (2): 469–477; 490

Mutagenesis-validated functional residues (3):

Position	Phenotype
490	loss of autophosphorylation activity.
512	increased autophosphorylation.
556–590	loss of autophosphorylation.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 106 (showing top): GOBP_BUNDLE_OF_HIS_CELL_TO_PURKINJE_MYOCYTE_COMMUNICATION, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_PEPTIDYL_SERINE_MODIFICATION, MEF2_02, GOBP_REGULATION_OF_STRIATED_MUSCLE_CONTRACTION, GOBP_REGULATION_OF_MUSCLE_CONTRACTION, GOBP_MUSCLE_CONTRACTION, GOBP_CELL_COMMUNICATION_INVOLVED_IN_CARDIAC_CONDUCTION, GOBP_REGULATION_OF_HEART_RATE, OCT1_07, TGACATY_UNKNOWN, GOBP_REGULATION_OF_SYSTEM_PROCESS, GOBP_HEART_PROCESS, GOBP_MUSCLE_SYSTEM_PROCESS, GOBP_REGULATION_OF_CARDIAC_MUSCLE_CONTRACTION

GO Biological Process (6): regulation of heart rate (GO:0002027), protein phosphorylation (GO:0006468), peptidyl-serine autophosphorylation (GO:0036289), regulation of cardiac muscle contraction (GO:0055117), bundle of His cell to Purkinje myocyte communication (GO:0086069), regulation of cardiac conduction (GO:1903779)

GO Molecular Function (9): protein kinase activity (GO:0004672), protein serine/threonine kinase activity (GO:0004674), ATP binding (GO:0005524), metal ion binding (GO:0046872), 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 (2): nucleus (GO:0005634), cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of heart contraction	3
protein kinase activity	2
regulation of biological quality	1
phosphorylation	1
protein modification process	1
peptidyl-serine phosphorylation	1
protein autophosphorylation	1
regulation of striated muscle contraction	1
cardiac muscle contraction	1
cell communication involved in cardiac conduction	1
cardiac conduction	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
cation 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
intracellular anatomical structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1390 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TNNI3K	TNNI3	P19429	972
TNNI3K	SEC16B	Q96JE7	697
TNNI3K	GNPDA2	Q8TDQ7	660
TNNI3K	TMEM18	Q96B42	660
TNNI3K	LRRIQ3	A6PVS8	625
TNNI3K	QPCTL	Q9NXS2	608
TNNI3K	MTIF3	Q9H2K0	596
TNNI3K	TMEM160	Q9NX00	591
TNNI3K	FAIM2	Q9BWQ8	588
TNNI3K	POC5	Q8NA72	583
TNNI3K	GPRC5B	Q9NZH0	575
TNNI3K	NUDT3	O95989	574
TNNI3K	DNAJC27	Q9NZQ0	572
TNNI3K	FPGT	O14772	545
TNNI3K	ZNF608	Q9ULD9	541

IntAct

15 interactions, top by confidence:

A	B	Type	Score
TNNI3K	FBXO4	psi-mi:“MI:0915”(physical association)	0.560
TNNI3K	HIF1AN	psi-mi:“MI:0914”(association)	0.530
TNNI3K	TNNI3	psi-mi:“MI:0915”(physical association)	0.510
ACTC1	TNNI3K	psi-mi:“MI:0915”(physical association)	0.370
TNNI3K	ACTA1	psi-mi:“MI:0915”(physical association)	0.370
TNNI3K	MYBPC3	psi-mi:“MI:0915”(physical association)	0.370
TNNI3K	AIP	psi-mi:“MI:0915”(physical association)	0.370
FABP3	TNNI3K	psi-mi:“MI:0915”(physical association)	0.370
HADHB	TNNI3K	psi-mi:“MI:0915”(physical association)	0.370
TNNI3K	HSP90AA1	psi-mi:“MI:0914”(association)	0.350
PIM2	HSP90AA1	psi-mi:“MI:0914”(association)	0.350
FBXO4	TNNI3K	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (25): MYBPC3 (Two-hybrid), ACTC1 (Two-hybrid), ACTA1 (Two-hybrid), FABP3 (Two-hybrid), HADHB (Two-hybrid), TNNI3K (Affinity Capture-Western), AIP (Two-hybrid), FBXO4 (Two-hybrid), TNNI3K (Affinity Capture-MS), HIF1AN (Affinity Capture-MS), ASB3 (Affinity Capture-MS), TNNI3 (Two-hybrid), KLHL42 (Affinity Capture-MS), HSP90AA1 (Affinity Capture-MS), HSP90AB1 (Affinity Capture-MS)

ESM2 similar proteins: A0A3L7I2I8, A0FKG7, A2AGL3, A7MB89, B0LPN4, E9Q401, O60733, P30957, P42694, P49754, P97570, P97819, Q15413, Q29RM5, Q2KIX2, Q2T9K6, Q32PW3, Q3SX45, Q4V890, Q59H18, Q5F361, Q5GIG6, Q5KU39, Q5RF15, Q5U2S6, Q5ZKK2, Q66H07, Q66H63, Q6B858, Q6DFV5, Q6NYU2, Q7T3P8, Q7TQP6, Q8C0T1, Q8CEF1, Q8K0L0, Q8K114, Q8TC84, Q91W86, Q92736

Diamond homologs: A0A2R6XIK6, A2VDU3, A7J1T0, A7J1T2, A7MBB4, A8X775, D3ZG83, F4JTP5, G5EE56, O01700, O22558, O35346, O43283, O43318, O64768, P08630, P0C8E4, P0CD62, P18106, P18160, P18161, P29317, P32577, P34152, P41239, P41240, P41241, P42680, P42686, P42690, P51813, P80192, P97504, Q00944, Q02779, Q02977, Q03145, Q05397, Q05609, Q0VBZ0

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	68
Likely benign	18
Benign	4

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
3024572	GRCh37/hg19 1p31.1-22.3(chr1:73616197-87012961)x1	Likely pathogenic

SpliceAI

6974 predictions. Top by Δscore:

Variant	Effect	Δscore
1:74236199:G:GT	donor_gain	1.0000
1:74236200:A:T	donor_gain	1.0000
1:74236216:GTT:G	donor_gain	1.0000
1:74249453:TTTCA:T	acceptor_loss	1.0000
1:74249454:TTCA:T	acceptor_loss	1.0000
1:74249455:TCA:T	acceptor_loss	1.0000
1:74249455:TCAGC:T	acceptor_loss	1.0000
1:74249456:CAGCT:C	acceptor_loss	1.0000
1:74249457:A:AG	acceptor_gain	1.0000
1:74249457:A:C	acceptor_loss	1.0000
1:74249457:A:G	acceptor_loss	1.0000
1:74249458:G:GA	acceptor_gain	1.0000
1:74249458:GCTC:G	acceptor_gain	1.0000
1:74249458:GCTCT:G	acceptor_gain	1.0000
1:74249541:GGAG:G	donor_gain	1.0000
1:74249542:GAG:G	donor_gain	1.0000
1:74249542:GAGG:G	donor_gain	1.0000
1:74249545:G:GA	donor_loss	1.0000
1:74249545:GTGA:G	donor_loss	1.0000
1:74249546:T:G	donor_loss	1.0000
1:74249546:TGAG:T	donor_loss	1.0000
1:74249547:GAG:G	donor_loss	1.0000
1:74250670:A:G	acceptor_gain	1.0000
1:74261193:T:G	donor_gain	1.0000
1:74271592:TTACA:T	acceptor_loss	1.0000
1:74271593:TACA:T	acceptor_loss	1.0000
1:74271595:CA:C	acceptor_loss	1.0000
1:74271596:A:AG	acceptor_gain	1.0000
1:74271596:A:AT	acceptor_loss	1.0000
1:74271596:AG:A	acceptor_gain	1.0000

AlphaMissense

5504 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:74343153:C:A	N302K	1.000
1:74343153:C:G	N302K	1.000
1:74369262:A:C	K490N	1.000
1:74369262:A:T	K490N	1.000
1:74370383:A:T	D588V	1.000
1:74436124:A:T	D606V	1.000
1:74439499:T:A	W630R	1.000
1:74439499:T:C	W630R	1.000
1:74439501:G:C	W630C	1.000
1:74439501:G:T	W630C	1.000
1:74342853:G:C	D232H	0.999
1:74342960:T:A	N267K	0.999
1:74342960:T:G	N267K	0.999
1:74343079:T:C	C278R	0.999
1:74353270:T:C	C313R	0.999
1:74353272:T:G	C313W	0.999
1:74353992:C:A	A347D	0.999
1:74353994:T:C	C348R	0.999
1:74353995:G:A	C348Y	0.999
1:74353996:C:G	C348W	0.999
1:74354019:T:A	V356D	0.999
1:74354031:T:C	L360P	0.999
1:74354114:T:A	W388R	0.999
1:74354114:T:C	W388R	0.999
1:74354116:G:C	W388C	0.999
1:74354116:G:T	W388C	0.999
1:74354118:C:A	A389D	0.999
1:74367271:T:A	V398D	0.999
1:74367277:T:C	L400P	0.999
1:74367280:T:C	L401P	0.999

dbSNP variants (sampled 300 via entrez): RS1000001265 (1:74334881 T>C,G), RS1000007289 (1:74359113 A>C), RS1000007403 (1:74272523 C>T), RS1000009318 (1:74509097 A>G,T), RS1000023285 (1:74429021 G>T), RS1000027318 (1:74348998 T>A,C), RS1000044157 (1:74532088 C>A), RS1000045616 (1:74251806 C>G), RS1000053256 (1:74493493 A>G,T), RS1000055319 (1:74472470 T>C), RS1000057950 (1:74407409 T>C), RS1000063103 (1:74509482 T>G), RS1000070260 (1:74460499 TCTC>T), RS1000080768 (1:74348874 T>C,G), RS1000115313 (1:74308558 G>A,T)

Disease associations

OMIM: gene MIM:613932 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
atrial conduction disease	Strong	Autosomal dominant
cardiac conduction disease with or without dilated cardiomyopathy 1	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
dilated cardiomyopathy	Moderate	AD

Mondo (2): atrial conduction disease (MONDO:0014500), cardiac conduction disease with or without dilated cardiomyopathy 1 (MONDO:0700388)

Orphanet (1): Hereditary atrial tachyarrhythmia-infra-Hisian cardiac conduction disease (Orphanet:436242)

HPO phenotypes

14 total (14 of 14 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0001635	Congestive heart failure
HP:0001644	Dilated cardiomyopathy
HP:0001649	Tachycardia
HP:0001688	Sinus bradycardia
HP:0001692	Atrial arrhythmia
HP:0001695	Cardiac arrest
HP:0004749	Atrial flutter
HP:0004763	Paroxysmal supraventricular tachycardia
HP:0005110	Atrial fibrillation
HP:0005184	Prolonged QTc interval
HP:0006682	Premature ventricular contraction
HP:0011711	Left anterior fascicular block
HP:0011712	Complete right bundle branch block

GWAS associations

41 associations (top):

Study	Trait	p-value
GCST000830_31	Body mass index	8.000000e-14
GCST001876_11	Pubertal anthropometrics	6.000000e-06
GCST001953_24	Obesity	5.000000e-09
GCST001953_62	Obesity	1.000000e-08
GCST002021_8	Body mass index	3.000000e-11
GCST002541_29	Menarche (age at onset)	2.000000e-16
GCST003177_7	Childhood body mass index	2.000000e-10
GCST003993_27	Menarche (age at onset)	2.000000e-12
GCST004066_102	Hip circumference	3.000000e-07
GCST004066_61	Hip circumference	4.000000e-10
GCST004495_80	BMI (adjusted for smoking behaviour)	3.000000e-07
GCST004495_81	BMI (adjusted for smoking behaviour)	2.000000e-08
GCST004497_58	Body mass index (joint analysis main effects and smoking interaction)	7.000000e-09
GCST004497_59	Body mass index (joint analysis main effects and smoking interaction)	8.000000e-07
GCST004557_146	Body mass index	1.000000e-09
GCST004557_252	Body mass index	5.000000e-09
GCST004557_4	Body mass index	4.000000e-10
GCST004557_73	Body mass index	6.000000e-09
GCST004558_115	Body mass index (joint analysis main effects and physical activity interaction)	4.000000e-09
GCST004558_188	Body mass index (joint analysis main effects and physical activity interaction)	3.000000e-10
GCST004558_193	Body mass index (joint analysis main effects and physical activity interaction)	2.000000e-08
GCST004558_46	Body mass index (joint analysis main effects and physical activity interaction)	2.000000e-08
GCST004559_143	Body mass index in physically active individuals	6.000000e-08
GCST004559_175	Body mass index in physically active individuals	2.000000e-08
GCST004559_36	Body mass index in physically active individuals	9.000000e-09
GCST004559_63	Body mass index in physically active individuals	4.000000e-08
GCST004904_248	Body mass index	6.000000e-19
GCST005950_6	Body mass index x sex x age interaction (4df test)	1.000000e-15
GCST005951_197	Body mass index	4.000000e-13
GCST005953_11	Body mass index (age <50)	3.000000e-15

EFO canonical traits (12, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0001382	puberty
EFO:0004703	age at menarche
EFO:0004318	smoking behavior
EFO:0008002	physical activity measurement
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0007796	parental longevity
EFO:0005670	smoking initiation
EFO:0010130	health study participation
EFO:0009819	comparative body size at age 10, self-reported
EFO:0009749	age at first sexual intercourse measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5260 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

20 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 473,168 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1287853	FEDRATINIB	4	3,554
CHEMBL1336	SORAFENIB	4	86,060
CHEMBL24828	VANDETANIB	4	42,230
CHEMBL255863	NILOTINIB	4	38,627
CHEMBL288441	BOSUTINIB	4	12,255
CHEMBL5416410	DASATINIB	4	655
CHEMBL553	ERLOTINIB	4	108,300
CHEMBL601719	CRIZOTINIB	4	14,403
CHEMBL941	IMATINIB	4	111,611
CHEMBL31965	CANERTINIB	3	8,083
CHEMBL428690	ALVOCIDIB	3	27,781
CHEMBL572881	MOTESANIB	3	4,642
CHEMBL603469	LESTAURTINIB	3
CHEMBL1230609	FORETINIB	2	3,096
CHEMBL230011	TG100-115	2	1,504
CHEMBL384304	RG-547	2	93
CHEMBL475251	R-406	2	762
CHEMBL558752	RAF-265	2	2,721
CHEMBL607707	PELITINIB	2	6,340
CHEMBL574738	AST-487	1	451

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — HH498 subfamily

Most potent curated ligand interactions (2 total), top 2:

Ligand	Action	Affinity	Parameter
GSK329	Inhibition	8.0	pIC50
sorafenib	Binding	6.55	pKd

Binding affinities (BindingDB)

14 measured of 14 human assays (14 total across all organisms); most potent 14 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
Staurosporine	KD	1.7 nM
4-[4-(4-fluorophenyl)-2-(4-methanesulfinylphenyl)-1H-imidazol-5-yl]pyridine	KD	12 nM
BMS-354825	KD	27 nM
N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine	KD	150 nM
AMG 706	KD	300 nM
4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)phenoxy]-N-methylpyridine-2-carboxamide	KD	370 nM
4-[(4-methylpiperazin-1-yl)methyl]-N-[4-methyl-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]phenyl]benzamide	KD	1000 nM
ERLOTINIB HYDROCHLORIDE	KD	1200 nM
1-[4-[(4-ethyl-1-piperazinyl)methyl]-3-(trifluoromethyl)phenyl]-3-[4-[[6-(methylamino)-4-pyrimidinyl]oxy]phenyl]urea	KD	1400 nM
CI-1033	KD	1700 nM
1-Acyl-1H-[1,2,4]triazole-3,5-diamine Analogue 3b	KD	3100 nM
(E)-N-[4-(3-chloro-4-fluoro-anilino)-3-cyano-7-ethoxy-6-quinolyl]-4-(dimethylamino)but-2-enamide	KD	3500 nM
1-methyl-5-[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyridin-4-yl]oxy-N-[4-(trifluoromethyl)phenyl]benzimidazol-2-amine	KD	4500 nM
2-(2-chlorophenyl)-5,7-dihydroxy-8-[(3S)-3-hydroxy-1-methyl-4-piperidinyl]-1-benzopyran-4-one	KD	5300 nM

ChEMBL bioactivities

313 potent at pChembl≥5 of 318 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.27	Ki	0.54	nM	CHEMBL4869303
9.15	IC50	0.7	nM	CHEMBL3613198
8.80	IC50	1.6	nM	CHEMBL3613197
8.20	IC50	6.3	nM	CHEMBL3613305
8.10	IC50	7.9	nM	CHEMBL3613199
8.10	IC50	8	nM	CHEMBL4094739
8.10	IC50	7.9	nM	CHEMBL4868757
8.00	IC50	10	nM	CHEMBL3613309
8.00	IC50	10	nM	CHEMBL3814834
8.00	IC50	10	nM	CHEMBL3911058
8.00	IC50	10	nM	CHEMBL3984331
8.00	IC50	10	nM	CHEMBL4875220
8.00	IC50	10	nM	CHEMBL4867760
8.00	IC50	10	nM	CHEMBL4869303
7.96	Kd	11	nM	DASATINIB
7.89	IC50	13	nM	CHEMBL3613185
7.89	IC50	13	nM	CHEMBL3613186
7.89	IC50	13	nM	CHEMBL3613187
7.89	IC50	13	nM	CHEMBL3613189
7.89	IC50	13	nM	CHEMBL3613199
7.89	IC50	13	nM	CHEMBL3613307
7.89	IC50	13	nM	CHEMBL3814998
7.89	IC50	13	nM	CHEMBL3813957
7.89	IC50	13	nM	CHEMBL3813948
7.89	IC50	13	nM	CHEMBL3952704
7.89	IC50	13	nM	CHEMBL4074231
7.80	IC50	16	nM	CHEMBL3613309
7.80	IC50	16	nM	CHEMBL3613307
7.80	IC50	16	nM	CHEMBL3814010
7.80	IC50	16	nM	CHEMBL3920011
7.80	IC50	16	nM	CHEMBL3913963
7.80	IC50	16	nM	CHEMBL4102182
7.80	IC50	16	nM	CHEMBL4869054
7.80	IC50	16	nM	CHEMBL4849349
7.70	IC50	20	nM	CHEMBL3613190
7.70	IC50	20	nM	CHEMBL3613193
7.70	IC50	20	nM	CHEMBL3909313
7.70	IC50	20	nM	CHEMBL4066586
7.70	IC50	20	nM	CHEMBL4061645
7.70	IC50	20	nM	CHEMBL4845883
7.70	IC50	20	nM	CHEMBL4857556
7.70	IC50	20	nM	CHEMBL4865373
7.70	IC50	20	nM	CHEMBL4863580
7.64	IC50	23	nM	CHEMBL4856992
7.60	IC50	25	nM	CHEMBL3613184
7.60	IC50	25	nM	CHEMBL3815093
7.60	IC50	25	nM	CHEMBL3815116
7.60	IC50	25	nM	CHEMBL3814635
7.60	IC50	25	nM	CHEMBL3814442
7.60	IC50	25	nM	CHEMBL3814871

PubChem BioAssay actives

648 with measured affinity, of 1012 total; 50 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
1-[3,5-dichloro-4-[6-(methylamino)pyrimidin-4-yl]oxyphenyl]-3-[3-(trifluoromethyl)phenyl]urea	1782138: Binding affinity to full length human His-MBP-TNNI3K assessed as off-rate constant in presence of rhodamine green labeled GW805818X by fluorescence competitive binding assay	ki	0.0005	uM
3-[(5-bromo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-4-(dimethylamino)-N-methylbenzenesulfonamide	1245740: Inhibition of human myc-tagged TNNI3K autophosphorylation overexpressed in HEKMSRII cells preincubated for 30 mins followed by pervanadate solution addition measured after 20 mins by DELFIA	ic50	0.0007	uM
4-(dimethylamino)-N-methyl-3-[(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]benzenesulfonamide	1245740: Inhibition of human myc-tagged TNNI3K autophosphorylation overexpressed in HEKMSRII cells preincubated for 30 mins followed by pervanadate solution addition measured after 20 mins by DELFIA	ic50	0.0016	uM
3-[(5-bromo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-N-methyl-4-morpholin-4-ylbenzenesulfonamide	1245740: Inhibition of human myc-tagged TNNI3K autophosphorylation overexpressed in HEKMSRII cells preincubated for 30 mins followed by pervanadate solution addition measured after 20 mins by DELFIA	ic50	0.0063	uM
1-[3,5-dimethyl-4-[6-(methylamino)pyrimidin-4-yl]oxyphenyl]-3-[3-(trifluoromethyl)phenyl]urea	1782128: Inhibition of human myc-TNNI3K expressed in HEK-MSR2 cells assessed as reduction in TNNI3K autophosphorylation preincubated for 30 mins followed by pervanadate addition and measured after 20 mins by DELFIA	ic50	0.0079	uM
N-methyl-3-[(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-4-morpholin-4-ylbenzenesulfonamide	1245740: Inhibition of human myc-tagged TNNI3K autophosphorylation overexpressed in HEKMSRII cells preincubated for 30 mins followed by pervanadate solution addition measured after 20 mins by DELFIA	ic50	0.0079	uM
3-[[6-[(5-chloro-2-pyridinyl)amino]pyrimidin-4-yl]amino]-4-ethylsulfonyl-N-methylbenzenesulfonamide	1469700: Inhibition of human Myc-tagged TNNI3K autophosphorylation expressed in HEKMSR2 cells after 30 mins by DELFIA	ic50	0.0080	uM
1-[4-[6-[3-(pyrrolidin-1-ylmethyl)anilino]pyrimidin-4-yl]oxyphenyl]-3-[3-(trifluoromethyl)phenyl]urea	1782127: Inhibition of TNNI3K (unknown origin)	ic50	0.0100	uM
2-[3-[[6-[4-[[3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]pyrimidin-4-yl]amino]phenyl]acetic acid	1782127: Inhibition of TNNI3K (unknown origin)	ic50	0.0100	uM
4-(dimethylamino)-3-[[7-(3-methoxypropoxy)quinazolin-4-yl]amino]-N-methylbenzenesulfonamide	1306020: Displacement of 5-({[2-({[3-({4-[(5-hydroxy-2-methylphenyl)amino]-2-pyrimidinyl}amino)phenyl]carbonyl}amino)-ethyl]amino}carbonyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid from full length human TNNI3K expressed in baculovirus system incubated for 60 mins by fluorescence polarization assay	ic50	0.0100	uM
4-(dimethylamino)-N-methyl-3-[[7-(3-morpholin-4-ylpropoxy)quinazolin-4-yl]amino]benzenesulfonamide	1306020: Displacement of 5-({[2-({[3-({4-[(5-hydroxy-2-methylphenyl)amino]-2-pyrimidinyl}amino)phenyl]carbonyl}amino)-ethyl]amino}carbonyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid from full length human TNNI3K expressed in baculovirus system incubated for 60 mins by fluorescence polarization assay	ic50	0.0100	uM
3-[(5,7-dimethoxyquinazolin-4-yl)amino]-4-(dimethylamino)-N-methylbenzenesulfonamide	1306020: Displacement of 5-({[2-({[3-({4-[(5-hydroxy-2-methylphenyl)amino]-2-pyrimidinyl}amino)phenyl]carbonyl}amino)-ethyl]amino}carbonyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid from full length human TNNI3K expressed in baculovirus system incubated for 60 mins by fluorescence polarization assay	ic50	0.0100	uM
3-[(5,7-dimethoxyquinazolin-4-yl)amino]-N-methyl-4-(2,2,2-trifluoroethoxy)benzenesulfonamide	1306020: Displacement of 5-({[2-({[3-({4-[(5-hydroxy-2-methylphenyl)amino]-2-pyrimidinyl}amino)phenyl]carbonyl}amino)-ethyl]amino}carbonyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid from full length human TNNI3K expressed in baculovirus system incubated for 60 mins by fluorescence polarization assay	ic50	0.0100	uM
N-methyl-4-(2,2,2-trifluoroethoxy)-3-[(5,6,7-trimethoxyquinazolin-4-yl)amino]benzenesulfonamide	1306020: Displacement of 5-({[2-({[3-({4-[(5-hydroxy-2-methylphenyl)amino]-2-pyrimidinyl}amino)phenyl]carbonyl}amino)-ethyl]amino}carbonyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid from full length human TNNI3K expressed in baculovirus system incubated for 60 mins by fluorescence polarization assay	ic50	0.0100	uM
3-[[4-(4-chloroanilino)-1,3,5-triazin-2-yl]amino]-4-(dimethylamino)-N-methylbenzenesulfonamide	1322627: Displacement of 5-({[2-({[3-({4-[(5-hydroxy-2-methylphenyl)amino]-2-pyrimidinyl}amino)phenyl]carbonyl}amino)-ethyl]amino}carbonyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid from His6-MBP-TEV-full length human TNNI3K expressed in Baculovirus expression system after 60 mins by fluorescence polarization assay	ic50	0.0100	uM
4-(3,3-difluoropiperidin-1-yl)-N-methyl-3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)benzenesulfonamide	1322627: Displacement of 5-({[2-({[3-({4-[(5-hydroxy-2-methylphenyl)amino]-2-pyrimidinyl}amino)phenyl]carbonyl}amino)-ethyl]amino}carbonyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid from His6-MBP-TEV-full length human TNNI3K expressed in Baculovirus expression system after 60 mins by fluorescence polarization assay	ic50	0.0100	uM
N-methyl-4-[methyl(2,2,2-trifluoroethyl)amino]-3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)benzenesulfonamide	1322627: Displacement of 5-({[2-({[3-({4-[(5-hydroxy-2-methylphenyl)amino]-2-pyrimidinyl}amino)phenyl]carbonyl}amino)-ethyl]amino}carbonyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid from His6-MBP-TEV-full length human TNNI3K expressed in Baculovirus expression system after 60 mins by fluorescence polarization assay	ic50	0.0100	uM
N-methyl-4-morpholin-4-yl-3-[[6-[3-(trifluoromethyl)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]benzenesulfonamide	1245740: Inhibition of human myc-tagged TNNI3K autophosphorylation overexpressed in HEKMSRII cells preincubated for 30 mins followed by pervanadate solution addition measured after 20 mins by DELFIA	ic50	0.0100	uM
4-(dimethylamino)-3-[[5-(furan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]-N-methylbenzenesulfonamide	1322627: Displacement of 5-({[2-({[3-({4-[(5-hydroxy-2-methylphenyl)amino]-2-pyrimidinyl}amino)phenyl]carbonyl}amino)-ethyl]amino}carbonyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid from His6-MBP-TEV-full length human TNNI3K expressed in Baculovirus expression system after 60 mins by fluorescence polarization assay	ic50	0.0100	uM
3-[(5-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-N-methyl-4-morpholin-4-ylbenzenesulfonamide	1306020: Displacement of 5-({[2-({[3-({4-[(5-hydroxy-2-methylphenyl)amino]-2-pyrimidinyl}amino)phenyl]carbonyl}amino)-ethyl]amino}carbonyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid from full length human TNNI3K expressed in baculovirus system incubated for 60 mins by fluorescence polarization assay	ic50	0.0100	uM
N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-yl]amino]-1,3-thiazole-5-carboxamide;hydrate	435200: Binding constant for full-length TNNI3K	kd	0.0110	uM
3-[(7-ethoxy-6-methoxyquinazolin-4-yl)amino]-N-methyl-4-(2,2,2-trifluoroethoxy)benzenesulfonamide	1306020: Displacement of 5-({[2-({[3-({4-[(5-hydroxy-2-methylphenyl)amino]-2-pyrimidinyl}amino)phenyl]carbonyl}amino)-ethyl]amino}carbonyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid from full length human TNNI3K expressed in baculovirus system incubated for 60 mins by fluorescence polarization assay	ic50	0.0130	uM
N-methyl-3-[[7-(3-morpholin-4-ylpropoxy)quinazolin-4-yl]amino]-4-(2,2,2-trifluoroethoxy)benzenesulfonamide	1306020: Displacement of 5-({[2-({[3-({4-[(5-hydroxy-2-methylphenyl)amino]-2-pyrimidinyl}amino)phenyl]carbonyl}amino)-ethyl]amino}carbonyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid from full length human TNNI3K expressed in baculovirus system incubated for 60 mins by fluorescence polarization assay	ic50	0.0130	uM
N-methyl-4-piperidin-1-yl-3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)benzenesulfonamide	1322627: Displacement of 5-({[2-({[3-({4-[(5-hydroxy-2-methylphenyl)amino]-2-pyrimidinyl}amino)phenyl]carbonyl}amino)-ethyl]amino}carbonyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid from His6-MBP-TEV-full length human TNNI3K expressed in Baculovirus expression system after 60 mins by fluorescence polarization assay	ic50	0.0130	uM
4-(dimethylamino)-N-methyl-3-[[6-[3-(trifluoromethyl)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]benzenesulfonamide	1245733: Displacement of 5-({[2-({[3-({4-[(5-hydroxy-2-methylphenyl)amino]-2-pyrimidinyl}amino)phenyl]carbonyl}amino)-ethyl]amino}carbonyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid from His6-MBP-TEV-full length human TNNI3K expressed in Baculovirus expression system after 60 mins by fluorescence polarization assay	ic50	0.0130	uM
N-methyl-3-[[6-(3-methylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]benzenesulfonamide	1245733: Displacement of 5-({[2-({[3-({4-[(5-hydroxy-2-methylphenyl)amino]-2-pyrimidinyl}amino)phenyl]carbonyl}amino)-ethyl]amino}carbonyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid from His6-MBP-TEV-full length human TNNI3K expressed in Baculovirus expression system after 60 mins by fluorescence polarization assay	ic50	0.0130	uM
3-[[6-[(5-chloro-2-pyridinyl)amino]pyrimidin-4-yl]amino]-N-methyl-4-methylsulfonylbenzenesulfonamide	1469699: Inhibition of 5-({[2-({[3-({4-[(5-hydroxy-2-methylphenyl)amino]-2-pyrimidinyl}amino)phenyl]carbonyl}amino)-ethyl]amino}carbonyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid binding to human full length His/MBP-fused TNNI3K expressed in baculovirus expression system after 60 mins by fluorescence polarization assay	ic50	0.0130	uM
N-methyl-3-[[6-(4-methylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]benzenesulfonamide	1245733: Displacement of 5-({[2-({[3-({4-[(5-hydroxy-2-methylphenyl)amino]-2-pyrimidinyl}amino)phenyl]carbonyl}amino)-ethyl]amino}carbonyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid from His6-MBP-TEV-full length human TNNI3K expressed in Baculovirus expression system after 60 mins by fluorescence polarization assay	ic50	0.0130	uM
N-methyl-3-[[6-(2-methylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]benzenesulfonamide	1245733: Displacement of 5-({[2-({[3-({4-[(5-hydroxy-2-methylphenyl)amino]-2-pyrimidinyl}amino)phenyl]carbonyl}amino)-ethyl]amino}carbonyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid from His6-MBP-TEV-full length human TNNI3K expressed in Baculovirus expression system after 60 mins by fluorescence polarization assay	ic50	0.0130	uM
3-[[6-(4-hydroxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]-N-methylbenzenesulfonamide	1245733: Displacement of 5-({[2-({[3-({4-[(5-hydroxy-2-methylphenyl)amino]-2-pyrimidinyl}amino)phenyl]carbonyl}amino)-ethyl]amino}carbonyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid from His6-MBP-TEV-full length human TNNI3K expressed in Baculovirus expression system after 60 mins by fluorescence polarization assay	ic50	0.0130	uM
4-(dimethylamino)-N-methyl-3-[(5-methylpyrrolo[3,2-d]pyrimidin-4-yl)amino]benzenesulfonamide	1306020: Displacement of 5-({[2-({[3-({4-[(5-hydroxy-2-methylphenyl)amino]-2-pyrimidinyl}amino)phenyl]carbonyl}amino)-ethyl]amino}carbonyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid from full length human TNNI3K expressed in baculovirus system incubated for 60 mins by fluorescence polarization assay	ic50	0.0160	uM
1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl]-3-[3-(trifluoromethyl)phenyl]urea	1782127: Inhibition of TNNI3K (unknown origin)	ic50	0.0160	uM
4-(dimethylamino)-N-methyl-3-(7H-purin-6-ylamino)benzenesulfonamide	1322627: Displacement of 5-({[2-({[3-({4-[(5-hydroxy-2-methylphenyl)amino]-2-pyrimidinyl}amino)phenyl]carbonyl}amino)-ethyl]amino}carbonyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid from His6-MBP-TEV-full length human TNNI3K expressed in Baculovirus expression system after 60 mins by fluorescence polarization assay	ic50	0.0160	uM
1-[4-(6-aminopyrimidin-4-yl)oxyphenyl]-3-[3-(trifluoromethyl)phenyl]urea	1782128: Inhibition of human myc-TNNI3K expressed in HEK-MSR2 cells assessed as reduction in TNNI3K autophosphorylation preincubated for 30 mins followed by pervanadate addition and measured after 20 mins by DELFIA	ic50	0.0160	uM
N-methyl-3-[[6-[[5-(trifluoromethyl)-2-pyridinyl]amino]pyrimidin-4-yl]amino]benzenesulfonamide	1469699: Inhibition of 5-({[2-({[3-({4-[(5-hydroxy-2-methylphenyl)amino]-2-pyrimidinyl}amino)phenyl]carbonyl}amino)-ethyl]amino}carbonyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid binding to human full length His/MBP-fused TNNI3K expressed in baculovirus expression system after 60 mins by fluorescence polarization assay	ic50	0.0160	uM
N-methyl-3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-4-(2,2,2-trifluoroethoxy)benzenesulfonamide	1322627: Displacement of 5-({[2-({[3-({4-[(5-hydroxy-2-methylphenyl)amino]-2-pyrimidinyl}amino)phenyl]carbonyl}amino)-ethyl]amino}carbonyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid from His6-MBP-TEV-full length human TNNI3K expressed in Baculovirus expression system after 60 mins by fluorescence polarization assay	ic50	0.0160	uM
N-[6-[4-[[3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]pyrimidin-4-yl]acetamide	1782127: Inhibition of TNNI3K (unknown origin)	ic50	0.0200	uM
1-[2,3-difluoro-4-[6-(methylamino)pyrimidin-4-yl]oxyphenyl]-3-[3-(trifluoromethyl)phenyl]urea	1782127: Inhibition of TNNI3K (unknown origin)	ic50	0.0200	uM
1-[3,5-difluoro-4-[6-(methylamino)pyrimidin-4-yl]oxyphenyl]-3-[3-(trifluoromethyl)phenyl]urea	1782127: Inhibition of TNNI3K (unknown origin)	ic50	0.0200	uM
N-methyl-3-[[4-(3-methylanilino)-1,3,5-triazin-2-yl]amino]benzenesulfonamide	1469699: Inhibition of 5-({[2-({[3-({4-[(5-hydroxy-2-methylphenyl)amino]-2-pyrimidinyl}amino)phenyl]carbonyl}amino)-ethyl]amino}carbonyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid binding to human full length His/MBP-fused TNNI3K expressed in baculovirus expression system after 60 mins by fluorescence polarization assay	ic50	0.0200	uM
4-chloro-N-methyl-3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)benzenesulfonamide	1245733: Displacement of 5-({[2-({[3-({4-[(5-hydroxy-2-methylphenyl)amino]-2-pyrimidinyl}amino)phenyl]carbonyl}amino)-ethyl]amino}carbonyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid from His6-MBP-TEV-full length human TNNI3K expressed in Baculovirus expression system after 60 mins by fluorescence polarization assay	ic50	0.0200	uM
1-[4-[6-(methylamino)pyrimidin-4-yl]oxyphenyl]-3-[3-(trifluoromethyl)phenyl]urea	1782128: Inhibition of human myc-TNNI3K expressed in HEK-MSR2 cells assessed as reduction in TNNI3K autophosphorylation preincubated for 30 mins followed by pervanadate addition and measured after 20 mins by DELFIA	ic50	0.0200	uM
3-[[6-[(5-chloro-2-pyridinyl)amino]pyrimidin-4-yl]amino]-N-methylbenzenesulfonamide	1469699: Inhibition of 5-({[2-({[3-({4-[(5-hydroxy-2-methylphenyl)amino]-2-pyrimidinyl}amino)phenyl]carbonyl}amino)-ethyl]amino}carbonyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid binding to human full length His/MBP-fused TNNI3K expressed in baculovirus expression system after 60 mins by fluorescence polarization assay	ic50	0.0200	uM
N-methyl-3-[(6-pyridin-4-yl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]benzenesulfonamide	1245733: Displacement of 5-({[2-({[3-({4-[(5-hydroxy-2-methylphenyl)amino]-2-pyrimidinyl}amino)phenyl]carbonyl}amino)-ethyl]amino}carbonyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid from His6-MBP-TEV-full length human TNNI3K expressed in Baculovirus expression system after 60 mins by fluorescence polarization assay	ic50	0.0200	uM
4-(2,5-dimethylpyrrolidin-1-yl)-N-methyl-3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)benzenesulfonamide	1322627: Displacement of 5-({[2-({[3-({4-[(5-hydroxy-2-methylphenyl)amino]-2-pyrimidinyl}amino)phenyl]carbonyl}amino)-ethyl]amino}carbonyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid from His6-MBP-TEV-full length human TNNI3K expressed in Baculovirus expression system after 60 mins by fluorescence polarization assay	ic50	0.0200	uM
1-[4-(6,7-dimethoxyquinazolin-4-yl)oxyphenyl]-3-[3-(trifluoromethyl)phenyl]urea	1782127: Inhibition of TNNI3K (unknown origin)	ic50	0.0230	uM
4-(dimethylamino)-N-methyl-3-(5H-pyrrolo[3,2-d]pyrimidin-4-ylamino)benzenesulfonamide	1306020: Displacement of 5-({[2-({[3-({4-[(5-hydroxy-2-methylphenyl)amino]-2-pyrimidinyl}amino)phenyl]carbonyl}amino)-ethyl]amino}carbonyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid from full length human TNNI3K expressed in baculovirus system incubated for 60 mins by fluorescence polarization assay	ic50	0.0250	uM
1-[4-[6-(ethylamino)pyrimidin-4-yl]oxyphenyl]-3-[3-(trifluoromethyl)phenyl]urea	1782127: Inhibition of TNNI3K (unknown origin)	ic50	0.0250	uM
1-[4-[6-(methylamino)pyrimidin-4-yl]oxynaphthalen-1-yl]-3-[3-(trifluoromethyl)phenyl]urea	1782127: Inhibition of TNNI3K (unknown origin)	ic50	0.0250	uM
1-[3-fluoro-4-[6-(methylamino)pyrimidin-4-yl]oxyphenyl]-3-[3-(trifluoromethyl)phenyl]urea	1782127: Inhibition of TNNI3K (unknown origin)	ic50	0.0250	uM

CTD chemical–gene interactions

14 total (human), top 14 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression	2
methylmercuric chloride	decreases expression	1
thallium sulfate	increases expression	1
sodium arsenite	affects methylation	1
CGP 52608	affects binding, increases reaction	1
Benzo(a)pyrene	affects methylation	1
Doxorubicin	decreases expression	1
Folic Acid	decreases expression	1
Silicon Dioxide	decreases expression	1
Zinc	increases expression	1
Cyclosporine	decreases expression	1
Aflatoxin B1	decreases methylation	1
Sodium Selenite	decreases expression	1
Coal Ash	increases expression	1

ChEMBL screening assays

92 unique, capped per target: 92 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1059384	Binding	Inhibition of TNNI3K assessed as enzyme activity at 1 uM relative to untreated control	Selective inhibitors of the mutant B-Raf pathway: discovery of a potent and orally bioavailable aminoisoquinoline. — J Med Chem

Clinical trials (associated diseases)

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