Table 1.

APP, PSEN1 and PSEN2 variants of unknown significance evaluated by the pathogenicity algorithm.

Variant	≥5 alleles in EVS/ExAC	Conserved between PSEN1 and PSEN2	Known pathogenic mutations	Predicted to damage proteina	Increase Aβ42/40 or Aβ42b	Predicted pathogenicityc
APP A201V	Yes	N/A	No	Benign	No	Not pathogenic
APP A235V	Yes	N/A	No	Benign	No	Not pathogenic
APP D243N	Yes	N/A	No	Benign	No	Not pathogenic
APP E246K	No	N/A	No	Possibly damaging	No	Risk factor
APP E296K	No	N/A	No	Probably damaging	N/A	Probable pathogenic; Risk factor
APP P299L	No	N/A	No	Probably damaging	N/A	Probable pathogenic; Risk factor
APP V340M	No	N/A	No	Probably damaging	No	Not pathogenic
APP R468H	No	N/A	No	Probably damaging	No	Not pathogenic
APP A479S	Yes	N/A	No	Benign	No	Not pathogenic
APP K496Q	No	N/A	No	Probably damaging	No	Not pathogenic
APP A500T	No	N/A	No	Probably damaging	No	Not pathogenic
APP K510N	No	N/A	No	Probably damaging	No	Not pathogenic
APP Y538H	No	N/A	No	Possibly damaging	No	Not pathogenic; Possibly protective
APP V562I	No	N/A	No	Benign	No	Not pathogenic
APP E599K	Yes	N/A	No	Probably damaging	No	Not pathogenic
APP T600M	Yes	N/A	No	Probably damaging	No	Not pathogenic
APP S614G	Yes	N/A	No	Benign	Yes	Risk factor
APP P620A	No	N/A	No	Possibly damaging	Yes	Probable pathogenic
APP P620L	No	N/A	No	Probably damaging	Yes	Probable pathogenic
APP E665D	No	N/A	No	Benign	No	Not pathogenic
APP A673T	Yes	N/A	Yes	Benign	No	Not pathogenic; Possibly protective
APP H677R	No	N/A	No	Possibly damaging	N/A	Probable pathogenic; Risk factor
APP G708G	Yes	N/A	No	N/A	Yes	Risk factor
APP G709S	Yes	N/A	No	Probably damaging	N/A	Not pathogenic; Risk factor
APP A713T	Yes	N/A	No	Probably damaging	Yes	Risk factor
APP A713V	Yes	N/A	No	Probably damaging	No	Not pathogenic; Possibly protective
APP H733P	No	N/A	No	Probably damaging	Yes	Probable pathogenic
APP IVS17 83–88delAAGTAT	No	N/A	No	N/A	N/A	Unknown
APP c *18C > T	No	N/A	No	N/A	N/A	Unknown
APP c *372 A > G	No	N/A	No	N/A	N/A	Unknown
PSEN1 N32N	No	No	No	N/A	N/A	Not pathogenic
PSEN1 R35Q	Yes	No	No	Benign	No	Not pathogenic
PSEN1 D40del	Yes	Yes	No	N/A	Yes	Risk factor
PSEN1 E69D	No	No	No	Benign	Yes	Probable pathogenic
PSEN1 M84V	No	Yes	Yes	Probably damaging	Yes	Probable pathogenic
PSEN1 T99A	No	Yes	No	Probably damaging	Yes	Probable pathogenic
PSEN1 R108Q	No	No	No	Benign	Yes	Probable pathogenic
PSEN1 QR127G	No	Yes	No	N/A	Yes	Probable pathogenic
PSEN1 H131R	No	No	No	Benign	Yes	Probable pathogenic
PSEN1 M146V	No	Yes	Yes	Probably damaging	Yes	Probable pathogenic
PSEN1 H163P	No	Yes	Yes	Probably damaging	N/A	Probable pathogenic; Risk factor
PSEN1 I168T	No	No	No	Benign	No	Not pathogenic
PSEN1 F175S	No	Yes	No	Probably damaging	No	Not pathogenic
PSEN1 F176L	No	No	No	Benign	No	Not pathogenic
PSEN1 V191A	No	Yes	No	Possibly damaging	No	Not pathogenic; Possibly protective
PSEN1 L219R	No	Yes	Yes	Probably damaging	N/A	Probable pathogenic; Risk factor
PSEN1 E318G	Yes	Yes	No	Benign	No	Not pathogenic
PSEN1 D333G	Yes	No	No	Possibly damaging	N/A	Not pathogenic
PSEN1 R352C	Yes	No	No	Possibly damaging	No	Not pathogenic
PSEN1 InsR352	No	No	No	N/A	N/A	Unknown
PSEN1 T354I	No	No	No	Probably damaging	N/A	Probable pathogenic; Risk factor
PSEN1 R358Q	No	Yes	No	Probably damaging	Yes	Probable pathogenic
PSEN1 S365Y	No	No	No	Possibly damaging	N/A	Probable pathogenic; Risk factor
PSEN1 G378fs	No	Yes	Yes	N/A	Yes	Probable pathogenic
PSEN1 A396T	No	No	Yes	Probably damaging	Yes	Probable pathogenic
PSEN1 I439V	No	Yes	Yes	Benign	Yes	Probable pathogenic
PSEN2 T18M	Yes	No	No	Probably damaging	N/A	Probable pathogenic; Risk factor
PSEN2 R29H	No	No	No	Probably damaging	N/A	Probable pathogenic; Risk factor
PSEN2 G34S	Yes	No	No	Benign	No	Not pathogenic
PSEN2 R62C	Yes	Yes	No	Possibly damaging	No	Not pathogenic
PSEN2 R62H	Yes	Yes	No	Benign	No	Not pathogenic
PSEN2 P69A	Yes	Yes	No	Benign	No	Not pathogenic
PSEN2 R71W	Yes	Yes	No	Benign	No	Not pathogenic
PSEN2 K82R	No	Yes	No	Probably damaging	No	Risk factor
PSEN2 A85V	No	Yes	No	Probably damaging	No	Risk factor
PSEN2 V101M	No	Yes	No	Probably damaging	N/A	Not pathogenic; Risk factor
PSEN2 P123L	No	Yes	No	Probably damaging	Yes	Probable pathogenic
PSEN2 E126fs	No	Yes	Yes	N/A	No	Risk factor
PSEN2 S130L	Yes	No	No	Possibly damaging	N/A	Not pathogenic; Risk factor
PSEN2 V139M	Yes	No	No	Possibly damaging	No	Not pathogenic
PSEN2 L143H	No	No	No	Probably damaging	N/A	Not pathogenic
PSEN2 R163H	No	No	No	Probably damaging	No	Not Pathogenic
PSEN2 H162N	Yes	No	No	Probably damaging	N/A	Not pathogenic; Risk factor
PSEN2 M174V	No	No	No	Benign	No	Not pathogenic
PSEN2 V214L	Yes	Yes	No	Probably damaging	N/A	Not pathogenic; Risk factor
PSEN2 I235F	No	Yes	No	Probably damaging	Yes	Probable pathogenic
PSEN2 A237V	Yes	Yes	No	Probably damaging	N/A	Not pathogenic; Risk factor
PSEN2 L238F	No	Yes	No	Probably damaging	Yes	Probable pathogenic
PSEN2 A252T	Yes	Yes	No	Possibly damaging	No	Not pathogenic; Possibly protective
PSEN2 A258V	No	No	No	Benign	No	Not pathogenic
PSEN2 R284G	No	Yes	No	Probably damaging	Yes	Probable pathogenic
PSEN2 T301M	Yes	No	No	Possibly damaging	N/A	Not pathogenic; Risk factor
PSEN2 K306fs	No	No	No	N/A	N/A	Unknown
PSEN2 P334A	No	No	No	Benign	No	Not pathogenic
PSEN2 P334R	Yes	No	No	Benign	N/A	Not pathogenic
PSEN2 P348L	No	No	No	Benign	Yes	Probable pathogenic
PSEN2 A377V	Yes	Yes	No	Probably damaging	N/A	Not pathogenic
PSEN2 V393M	Yes	Yes	No	Probably damaging	No	Not pathogenic
PSEN2 T421M	No	Yes	No	Probably damaging	No	Not pathogenic
PSEN2 D439A	Yes	Yes	No	Probably damaging	Yes	Risk factor

^aBenign, assigned by PolyPhen to mean not damaging.

^bN/A, cell-based data not available (see Materials and Methods).

^cUnknown indicates there is not sufficient functional/bioinformatic evidence to assign pathogenicity. Two assignments are made when functional/bioinformatics data is not complete.