Overall considerations: Paper is well written and presented with clear data. The paper is relevant to the journal and the field especially in light of the recent approval of Crysvita the anti-FGF23 Ab for the treatment XLH.

Major point:
- In studies evaluating mutation is a patient population, it is the gold standard to have a cohort of healthy volunteers sequenced in order to determine whether a variant is truly a mutation rather than a polymorphism present in the general population. This aspect is not addressed in this paper.
- In the discussion, the recently approved drug Crysvita the anti-FGF23 antibody is mentioned. It would be valuable to briefly put it into context in how this drug works by regulating Phosphate for completeness and better flow.
Minor points:
- In the abstract the full name of PHEX is not phosphate-regulating endopeptidase homolog but rather what is used in the introduction phosphate-regulating gene with homologies to endopeptidases on the X chromosome
- In the inro page 4 line 47 the word phex should be uppercase PHEX as we are talking about a human protein. Please correct this throughout the paper in all the sections.
- In methods - cell culture section page 6 line 41 it the country should be USA not American
- In the discussion, page 12 line 39 when mentioned burosumab specify that it is an antibody against FGF23 and also mention the drug name as it is now approved as Crysvita.
- Figure 1 it would be valuable to have in the legend the corresponding patient number in order for readers to evaluate the data with the other parameters described in the paper.
- In supplemental table S2, for the mutations that have already been described it would be valuable to reference the papers that have described these mutations as it would be helpful for the reader to study ethnicity or other aspect of this mutations across studies.

The reviewer thanks the authors for addressing the major and minor points of the paper.

A couple of minor points:

• On page 22 when referring to gnomAD please add a reference and give the website address.
• On page 25 should say "...(trade name Crysvita) was approved..."
• The concluding sentence should be re-written as it would only be applicable to mutations that have trafficking defects and the authors do not specify what the strategy would be. It would be beneficial to give an example.