Table 3.

Overall impact prediction of Kabuki variants derived from the assessment at each layer. Impact assignment of the variants at each layer are tentatively given by referring to the control values. These data illustrate the multiple pathways these variants may be affecting KDM6A function

Variant	Sequence	Structure	pK Shift	Dynamics	Substrate and Zn interaction	Active site interactions	Overall impact prediction
H1146A	Damaging	Benign	Damaging	Damaging	Damaging	Damaging	Damaging control
E1148A	Damaging	Damaging	Damaging	Damaging	Damaging	Damaging	Damaging control
H1060L	Benign	Benign	Benign	Benign	Benign	Benign	Benign control
S912N	Benign	Benign	Benign	Benign	Benign	Benign	Benign control
T1323A	Benign	Benign	Benign	Benign	Benign	Benign	Benign control
N910S	Benign	Damaging	Benign	Damaging	Benign	VUS	Damaging
D980V	Damaging	VUS	VUS	Damaging	Benign	Damaging	Damaging
S1025G	Damaging	VUS	Benign	Damaging	Damaging	VUS	Damaging
C1153R	Damaging	Damaging	Damaging	Damaging	Damaging	Damaging	Damaging
C1153Y	Damaging	Damaging	Damaging	Damaging	Damaging	VUS	Damaging
P1195L	VUS	Damaging	Damaging	Damaging	Damaging	VUS	Damaging
L1200F	Damaging	Damaging	Damaging	Damaging	Benign	Benign	Damaging
Q1212R	Damaging	Damaging	Damaging	Damaging	Damaging	VUS	Damaging
Q1248R	Damaging	Damaging	Damaging	Damaging	Damaging	VUS	Damaging
R1255W	Damaging	Damaging	Damaging	Damaging	Damaging	Damaging	Damaging
R1351Q	Benign	Damaging	Damaging	Damaging	Damaging	VUS	Damaging