This gets to a key point. Polar Bears NEED an APOB to function more effectively than it does for brown bears. So yes, the APOB (in a perverse sense) loses a lower level of function to get an a higher level of function. In what backwards sense is this “damaging”?
I’d point out too that these predictors are just predictors, and they are commonly used in cancer where, by convention, even gain of function mutations are called “damaging.” For this reason, they assume that a FUNCTIONAL mutation = DAMAGING mutation. This, however, is not correct in this case. The purportedly “damaging” mutations could very well be the gain of function mutations. Seee, for example, the score outputs for HDivPred and HVarPred:
Prediction outcome can be one of probably damaging, possibly damaging, or benign. “
Notice, it cannot be “improved function.” The reason why is that the program assumes that change of function mutations are damaging, and this is likely the case in cancer (in that they cause cancer). It is not true, however, in the case we are applying it.