| . | Troponin subunit or subunit region . | Size of region (aa) . | Sites with pathogenic substitution . | Density of sites with pathogenic substitution (%) . | P vs. troponin . | P vs. TnI-TnT . | Sites without pathogenic substitution . | Sites without pathogenic and with VUS substitution . | Density of sites without pathogenic and with VUS substitution (%) . | P vs. TnI-TnT . |
|---|---|---|---|---|---|---|---|---|---|---|
| Troponin | ||||||||||
| All | TnI, TnT, TnC | 659 | 52 | 7.9 | 607 | 44 | 7.2 | |||
| All except TnC | TnI,TnT | 498 | 51 | 10.2 | 447 | 41 | 9.2 | |||
| Unseen by cryo-EM | (see legend) | 190 | 11 | 5.8 | 0.0064 | 179 | 12 | 6.7 | NS | |
| TnI | ||||||||||
| All | 1–210 | 210 | 26 | 12.4 | NS | 184 | 19 | 10.3 | NS | |
| N 2/3 | 1–136 | 136 | 3 | 2.2 | 0.0001 | 133 | 9 | 6.8 | NS | |
| C 1/3 | 137–210 | 74 | 23 | 31.1 | <0.0001 | 51 | 10 | 19.6 | NS | |
| TnT | ||||||||||
| All | 1–288 | 288 | 25 | 8.7 | NS | 263 | 22 | 8.4 | NS | |
| Cryo-EM tail helix | 87–150 | 64 | 10 | 15.6 | NS | 54 | 6 | 11.1 | NS | |
| TnC | ||||||||||
| All | 1–161 | 161 | 1 | 0.6 | <0.0001 | 160 | 3 | 1.9 | ||
| N-lobe | 1–85 | 85 | 0 | 0 | 0.0010 | 85 | 0 | 0 | ||
| C-lobe | 86–161 | 76 | 1 | 1 | 0.012 | 75 | 3 | 4.0 | ||
| . | Troponin subunit or subunit region . | Size of region (aa) . | Sites with pathogenic substitution . | Density of sites with pathogenic substitution (%) . | P vs. troponin . | P vs. TnI-TnT . | Sites without pathogenic substitution . | Sites without pathogenic and with VUS substitution . | Density of sites without pathogenic and with VUS substitution (%) . | P vs. TnI-TnT . |
|---|---|---|---|---|---|---|---|---|---|---|
| Troponin | ||||||||||
| All | TnI, TnT, TnC | 659 | 52 | 7.9 | 607 | 44 | 7.2 | |||
| All except TnC | TnI,TnT | 498 | 51 | 10.2 | 447 | 41 | 9.2 | |||
| Unseen by cryo-EM | (see legend) | 190 | 11 | 5.8 | 0.0064 | 179 | 12 | 6.7 | NS | |
| TnI | ||||||||||
| All | 1–210 | 210 | 26 | 12.4 | NS | 184 | 19 | 10.3 | NS | |
| N 2/3 | 1–136 | 136 | 3 | 2.2 | 0.0001 | 133 | 9 | 6.8 | NS | |
| C 1/3 | 137–210 | 74 | 23 | 31.1 | <0.0001 | 51 | 10 | 19.6 | NS | |
| TnT | ||||||||||
| All | 1–288 | 288 | 25 | 8.7 | NS | 263 | 22 | 8.4 | NS | |
| Cryo-EM tail helix | 87–150 | 64 | 10 | 15.6 | NS | 54 | 6 | 11.1 | NS | |
| TnC | ||||||||||
| All | 1–161 | 161 | 1 | 0.6 | <0.0001 | 160 | 3 | 1.9 | ||
| N-lobe | 1–85 | 85 | 0 | 0 | 0.0010 | 85 | 0 | 0 | ||
| C-lobe | 86–161 | 76 | 1 | 1 | 0.012 | 75 | 3 | 4.0 | ||
The left two columns delineate troponin regions analyzed. The middle columns concern pathogenic sites, defined in publications as amino acid residues with at least one confirmed pathogenic or likely pathogenic substitution (Walsh et al., 2017; Ho et al., 2018; Alfares et al., 2015). The right four columns concern troponin residues with no pathogenic missense mutations and at least one missense VUS (VUS substitution site) observed in cardiomyopathy subjects. P values for the observed densities were calculated as described in Materials and methods. NS indicates P > 0.05. Areas unseen by cryo-EM are TnI 1–40 and TnT residues 1–86, 151–198, and 273–288.