Human rare variants in each representative family member’s RGS domain are predicted to disrupt function due to structural changes or inability to bind/GAP Gα

Residues were selected based on our criteria (outlined in the text) of CADD >20, residues that overlap with conserved sites important for Gα interaction (determined by structural insights), and PTM alignment analysis. Each residue mutation (native, residue position, mutation) has a description as to why it is predicted to disrupt function (“LoF Rationale”), its associated combined annotation-dependent depletion score (“CADD”), associated genic intolerance score (“MTR”), number of reported PTMs, number of neighboring PTMs (where a PTM is found within seven amino acids before/after), and prevalence in the population (“Prevalence”). Note that if the human variants are reported in the noncanonical transcript, the analogous residue position for the canonical sequence is coded in gray.

Selected Human RGS Protein Rare Variants
RGS ProteinResidue MutationLoF RationaleCADDMTRPTMNeighboring PTMsPrevalence
RGS4L170(73)PProline in α helix231.01000.0043% (South Asian)
E214(117)KSalt bridge partner27.30.50000.0063% (Latino)
D227(130)G100% conserved, salt bridge partner29.60.90000.0065% (African)
R231(134)WHighly conserved, stabilizes switch III29.81.04000.0065% (African)
D260(163)NHighly conserved, salt bridge partner, very high CADD321.19000.0065% (African)
D260(163)GHighly conserved, salt bridge partner29.41.19000.0009% (European)
R263(166)CContact with α helical domain of Gαi128.41.07000.0116% (East Asian)
R263(166)HContact with α helical domain of Gαi124.51.07000.0032% (Global)
R264(167)CHighly conserved, salt bridge partner, very high CADD351.06000.0009% (European)
RGS9W299RLink to disease, participates in electrostatic interaction29.10.71010.0229% (European)
R364CStabilizes α5-α6 loop of RGS domain29.50.78000.0018% (European)
K400Q100% conserved, contact with α helical domain28.10.97000.0018% (European)
R406C100% conserved, salt bridge partner, very high CADD350.98010.0030% (Latino)
R406H100% conserved, salt bridge partner, very high CADD340.98010.0009% (European)
Y413CPhosphorylation27.20.94110.0032% (South Asian)
RGS10L46(38)PProline in α helix29.60.78020.0032% (South Asian)
V52(44)MPossible link to schizophrenia, hydrophobic core partner340.78011.9239% (East Asian)
D141(133)NHighly conserved, ionic stabilization, very high CADD350.90020.0183% (Other)
R145(137)CHighly conserved, ionic stabilization, very high CADD350.86020.0617% (East Asian)
K148(140)RUbiquitination250.81110.0009% (European)
RGS17E148G100% conserved, likely ionic interaction28.20.87000.0010% (European)
P166L100% conserved within and across family, high CADD28.30.73010.0009% (European)
R189T100% conserved, likely ionic interaction28.11.03000.0009% (European)