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10 sources retrieved Β· Most recent: April 2026 Β· Index updated 14 days ago
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TNNT3
troponin T3, fast skeletal type
Chromosome 11 Β· 11p15.5
NCBI Gene: 7140Ensembl: ENSG00000130595.20HGNC: HGNC:11950UniProt: A0A286YFB1
46PubMed Papers
21Diseases
2Drugs
4Pathogenic Variants
CLINICAL
Clinical TrialsOMIM Disease Gene
DATA QUALITY
βœ“ Experimental GO Evidenceβœ“ Swiss-Prot Reviewed
positive regulation of calcium-dependent ATPase activitytroponin complextroponin C bindingtroponin I bindingdistal arthrogryposisSheldon-hall syndromecongenital myopathyamyotrophic lateral sclerosis
✦AI Summary

TNNT3 encodes fast skeletal muscle troponin T, the tropomyosin-binding subunit of the troponin complex that regulates calcium-dependent contraction of fast-twitch skeletal muscle fibers 1. TNNT3 is a single-copy gene located on chromosome 11.5 containing 19 exons with developmentally regulated alternative splicing 2. The protein functions as a central regulator of actin thin filament dynamics, conferring calcium-sensitivity to striated muscle actomyosin ATPase activity and enabling contraction through tropomyosin binding and troponin complex assembly 1. Pathogenic variants in TNNT3 cause distinct neuromuscular phenotypes depending on inheritance pattern. Dominant missense mutations cause Sheldon-Hall syndrome, a congenital contracture disorder affecting distal joints 3, and have been implicated in familial dilated cardiomyopathy through impaired troponin-tropomyosin binding 4. Recessive TNNT3 variants, including splice-affecting intronic mutations, associate with congenital myopathy presenting with hypotonia, proximal weakness, and myofibrillar disorganization with nemaline bodies 5. Alternative splicing of TNNT3 is dynamically regulated by metabolic factors; saturated fatty acids and ceramides modulate TNNT3 isoform expression through protein phosphatase 2A activation 6. These findings establish TNNT3 as critical for skeletal muscle development, contraction, and cardiac function, with disease relevance spanning congenital myopathies and cardiomyopathies.

Sources cited
1
TNNT3 encodes fast skeletal muscle troponin T isoform; troponin T is central to calcium regulation of thin filament function and muscle contraction
PMID: 26774798
2
TNNT3 is a single-copy gene on chromosome 11p15.5 with 19 exons and developmentally regulated alternative splicing
PMID: 18629027
3
TNNT3 mutations cause Sheldon-Hall syndrome, a rare congenital contracture disorder affecting distal joints, found in ~50% of cases
PMID: 19309503
4
TNNT3 missense variants can cause familial dilated cardiomyopathy by impairing troponin T-tropomyosin binding and muscle contraction
PMID: 40437600
5
Recessive TNNT3 splice variants cause congenital myopathy with hypotonia, weakness, and nemaline bodies; multi-omics approach diagnosed novel intronic variant
PMID: 40554860
6
Saturated fatty acids and ceramides modulate TNNT3 alternative splicing through protein phosphatase 2A activation
PMID: 30564278
Disease Associationsβ“˜21
distal arthrogryposisOpen Targets
0.65Moderate
Sheldon-hall syndromeOpen Targets
0.52Moderate
congenital myopathyOpen Targets
0.40Moderate
amyotrophic lateral sclerosisOpen Targets
0.37Weak
digitotalar dysmorphismOpen Targets
0.37Weak
congenital myopathy with coresOpen Targets
0.37Weak
genetic disorderOpen Targets
0.34Weak
hypertensionOpen Targets
0.29Weak
nemaline myopathyOpen Targets
0.27Weak
breast carcinomaOpen Targets
0.27Weak
KeloidOpen Targets
0.19Weak
arthrogryposis multiplex congenitaOpen Targets
0.19Weak
distal arthrogryposis type 2B1Open Targets
0.19Weak
urinary bladder cancerOpen Targets
0.17Weak
luminal B breast carcinomaOpen Targets
0.17Weak
estrogen-receptor positive breast cancerOpen Targets
0.15Weak
atrial fibrillationOpen Targets
0.12Weak
hypertensive heart diseaseOpen Targets
0.12Weak
musculoskeletal system diseaseOpen Targets
0.10Weak
breast cancerOpen Targets
0.10Suggestive
Arthrogryposis, distal, 2B2UniProt
Pathogenic Variants4
NM_006757.4(TNNT3):c.188G>A (p.Arg63His)Pathogenic
Arthrogryposis, distal, type 2B2|not provided|Sheldon-Hall syndrome
β˜…β˜…β˜†β˜†2025β†’ Residue 63
NM_006757.4(TNNT3):c.187C>T (p.Arg63Cys)Pathogenic
not provided|Arthrogryposis, distal, type 2B2|Sheldon-Hall syndrome
β˜…β˜…β˜†β˜†2024β†’ Residue 63
NM_006757.4(TNNT3):c.723-2A>GPathogenic
Arthrogryposis, distal, type 2B2
β˜…β˜…β˜†β˜†2024
NM_006757.4(TNNT3):c.187C>A (p.Arg63Ser)Likely pathogenic
Arthrogryposis, distal, type 2B2
β˜…β˜†β˜†β˜†2021β†’ Residue 63
View on ClinVar β†—
Drug Targets2
RELDESEMTIVPhase III
Fast skeletal troponin complex activator
amyotrophic lateral sclerosis
TIRASEMTIVPhase III
Fast skeletal troponin complex activator
amyotrophic lateral sclerosis
Related Genes
FRG2Protein interaction99%ACTN2Protein interaction89%ACTN3Protein interaction89%ATP2A1Protein interaction89%MYBPC2Protein interaction89%MYH4Protein interaction89%
Tissue Expression6 tissues
Heart
100%
Lung
10%
Brain
1%
Bone Marrow
1%
Liver
1%
Ovary
1%
Gene Interaction Network
Click a node to explore
TNNT3FRG2ACTN2ACTN3ATP2A1MYBPC2MYH4
PROTEIN STRUCTURE
Preparing viewer…
AlphaFoldAI-predicted Β· UniProt P45378
View on AlphaFold β†—
Constraintβ“˜
LOEUFβ“˜
0.87LoF Tolerant
pLIβ“˜
0.00Tolerant
Observed/Expected LoF0.66 [0.50–0.87]
RankingsWhere TNNT3 stands among ~20K protein-coding genes
  • #9,397of 20,598
    Most Researched46
  • #3,801of 5,498
    Most Pathogenic Variants4
  • #7,614of 17,882
    Most Constrained (LOEUF)0.87
Genes detectedTNNT3
Sources retrieved10 papers
Response timeβ€”
πŸ“„ Sources
10β–Ό
1
A 20-year Clinical and Genetic Neuromuscular Cohort Analysis in Lebanon: An International Effort.
PMID: 34602496
J Neuromuscul Dis Β· 2022
1.00
2
TNNT1, TNNT2, and TNNT3: Isoform genes, regulation, and structure-function relationships.
PMID: 26774798
Gene Β· 2016
0.90
3
Sheldon-Hall syndrome.
PMID: 19309503
Orphanet J Rare Dis Β· 2009
0.80
4
Structure and sequence of the human fast skeletal troponin T (TNNT3) gene: insight into the evolution of the gene and the origin of the developmentally regulated isoforms.
PMID: 18629027
Comp Funct Genomics Β· 2003
0.70
5
Assignment of the human fast skeletal troponin T gene (TNNT3) to chromosome 11p15.5: evidence for the presence of 11pter in a monochromosome 9 somatic cell hybrid in NIGMS mapping panel 2.
PMID: 8838323
Genomics Β· 1996
0.60