Gene symbol RVIS %ile Gene Constraint %ile EvoTol ...

Supplementary Table 1. Pathogenicity analysis with respect to the de novo mutations identified in the Epi4K project (Allen et al. (2013) De novo mutations in epileptic encephalopathies. Nature, 501, 217–221). For each method, we report the genes within the 25th percentile and highlight a subset of 17 genes identified in the Epi4K study that are predicted to be pathogenic by all methods (RVIS, Gene Constraint Score and  EvoTol).

Gene  symbol ATP2B4 CHD4 DNM1 FLNA FLNC GABRA1 GABRB3 GNAO1 GRIN1 KCNQ2 MLL MLL4 MYH6 SCN1A SCN2A SCN8A WHSC1L1 ABCA2 ABCC1 ABCC5 ABCC8 ABCC9 ABCD1 ABCD3 ACACA ACLY ACTB ACTG1 ACVR2B ADAR ADARB1 ADCY3 ADCY6 ADCY9 AFG3L2 ALOX5 ALS2

RVIS  %ile 1.56 6.36 14.79 0.91 0.59 11.32 12.85 17.72 10.72 0.51 2.00 4.23 2.40 0.04 0.93 4.46 9.46 2.19 5.35 10.46 1.37 1.24 5.42 9.11 4.47 15.91 3.43 6.20 15.79 16.35 7.31 23.31 14.46 4.66 9.04 14.72 18.87

Gene  Constraint   EvoTol   %ile score  %ile 11.51 2.82 19.54 0.44 0.29 24.00 22.36 13.94 6.72 15.86 0.41 1.12 0.66 4.03 1.77 2.34 19.93 0.12 11.29 1.82 1.57 1.82 20.54 16.44 2.96 13.10 15.62 1.91 12.88 16.71 12.33 1.42 5.90 2.28 17.91 9.21 3.89

20.48 0.17 1.43 0.29 2.52 9.02 7.61 6.48 0.20 1.34 0.24 0.73 24.09 2.50 0.42 0.13 3.38 0.21 11.02 3.03 7.59 6.91 12.82 12.29 0.15 3.80 1.71 2.65 16.34 5.54 2.16 5.47 8.75 6.63 10.18 24.89 19.49

Epi4K YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO

AMPD2 ANAPC5 APP AQR AR ARHGEF1 ASH1L ATAD2 ATP13A1 ATP13A2 ATP13A3 ATP1A1 ATP1A2 ATP1A3 ATP2A1 ATP2A2 ATP2A3 ATP2B1 ATP2B2 ATP2B3 ATP4A ATP6V0A1 ATP8A1 ATP8A2 ATP9A ATRX BAIAP2L2 BANP BARHL2 BEGAIN BEND3 BRAF BTAF1 C10orf137 C20orf112 CACNA1C CACNA1D CACNA1E CACNA1G CACNA1I CACNB1 CASZ1 CD14 CHD1 CHD2 CHD3

2.79 13.56 0.16 9.04 1.70 22.64 1.99 5.89 10.09 1.16 12.61 3.89 9.03 15.59 2.29 6.18 0.20 9.32 4.75 3.10 6.39 2.20 10.04 24.56 20.73 0.85 18.41 22.40 17.21 15.11 10.95 4.97 13.36 12.66 19.11 0.03 0.57 7.05 0.06 1.97 12.68 0.59 7.67 5.21 10.98 0.96

3.79 19.80 8.80 8.14 17.31 2.07 2.22 9.75 5.34 6.10 8.95 8.37 4.43 3.37 4.27 3.04 3.74 7.94 1.89 2.68 8.99 15.20 16.68 6.89 2.80 9.75 24.19 11.77 19.31 18.06 7.54 17.75 2.47 13.15 7.66 1.57 0.32 0.71 1.11 11.55 19.73 1.06 14.40 12.05 2.37 0.97

2.80 8.70 10.36 4.12 19.92 22.81 1.64 16.66 3.39 24.55 22.48 0.61 1.04 0.26 10.02 2.09 23.43 1.48 0.77 6.61 4.38 9.15 11.85 13.61 1.09 2.47 19.97 10.14 17.65 7.16 4.78 4.81 4.96 17.00 11.62 0.18 2.01 0.83 0.76 0.38 11.47 6.47 24.96 7.26 1.15 0.64

NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO

CHD5 CHD7 CHD8 CHD9 CHRNB2 CHRNE CIC CLCN3 CLCN4 CLCN6 CLCN7 CLPTM1 CNNM4 CNTNAP1 COBRA1 COL11A2 COL1A1 COL1A2 COL2A1 COL4A1 COMP CPSF7 CPT1A CPT1C CREBBP CSDE1 CTBP1 CYLD DAAM1 DAXX DCAF15 DCTN1 DDR1 DDR2 DGKD DGKH DHCR24 DLG2 DLL1 DLL4 DMAP1 DNM1L DNM2 DNM3 DNMT1 DNMT3A

3.72 10.66 6.13 5.75 6.86 11.38 2.92 5.16 21.04 5.89 5.39 7.68 24.22 19.29 18.42 0.62 0.29 0.28 0.88 2.39 6.89 12.41 2.07 2.24 0.55 2.62 17.65 11.17 15.80 3.30 11.98 1.09 1.38 3.28 20.33 18.66 7.37 13.83 7.29 22.03 3.44 5.12 9.80 16.34 19.67 3.08

0.49 0.57 1.18 1.40 14.97 10.03 0.38 18.59 7.05 3.17 2.82 6.27 6.23 1.21 4.56 7.62 2.26 6.36 2.21 0.62 22.65 17.03 22.78 14.78 1.54 8.32 13.94 9.47 3.25 11.88 18.90 10.58 5.31 13.05 1.16 4.92 11.77 3.04 6.89 4.56 13.45 8.75 4.71 6.72 3.33 6.48

0.43 4.28 1.34 3.87 11.92 3.75 20.56 5.81 2.40 20.10 20.19 16.29 16.12 2.34 14.97 7.53 3.77 16.32 10.93 18.55 5.59 23.96 18.84 11.65 1.28 12.68 7.38 5.59 20.58 24.49 24.92 15.95 18.62 22.41 8.60 17.88 15.77 12.94 19.09 8.40 17.23 12.37 3.27 5.12 0.67 2.39

NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO

DNMT3B DPF2 DPYSL2 DPYSL5 DSP DTNA ECE1 EDC4 EGFR EHD4 EIF3D EIF4ENIF1 EP300 EP400 EPB41L1 EPC1 EPHB6 ERBB2 ERBB4 ESRRG EWSR1 EXOC1 EXOC7 EXT1 EXTL3 EZH1 EZH2 F2 F8 FBN1 FBXO18 FGFR1 FGFR3 FGR FIP1L1 FLNB FMNL3 FOXO3 FOXP2 FOXP4 FRMD4A FTSJD2 FURIN FYN FZD1 FZD7

0.53 23.25 16.67 10.73 6.16 11.30 2.02 8.02 10.12 22.53 15.62 1.14 1.33 0.57 3.49 18.47 24.60 14.25 17.31 3.95 4.18 1.73 0.71 9.69 6.59 20.46 12.83 8.93 0.40 0.35 2.04 0.71 1.35 17.25 23.07 0.04 15.46 7.21 9.17 6.75 7.41 14.02 23.60 14.50 22.00 17.88

2.54 24.00 13.45 22.51 1.32 21.65 15.32 4.00 1.44 13.58 19.31 8.90 0.26 0.22 14.15 17.40 4.00 18.28 1.79 19.31 12.88 16.53 9.61 6.43 2.24 24.19 20.54 14.57 13.77 0.64 1.68 4.58 1.64 10.30 18.44 3.94 8.10 22.36 11.68 9.27 3.17 7.11 12.57 20.54 9.90 23.43

15.79 7.71 6.30 7.26 24.80 22.01 24.00 3.14 19.76 17.05 5.51 22.71 7.23 2.02 13.17 13.22 19.28 6.19 24.45 11.85 9.98 22.33 17.63 20.81 17.35 3.21 2.61 18.90 15.06 1.88 14.23 6.33 23.86 14.19 13.16 16.07 5.19 2.36 12.41 22.06 8.50 6.57 6.50 13.67 3.00 1.45

NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO

GABBR2 GABRB2 GABRD GANAB GAPVD1 GATA3 GGNBP2 GLG1 GNA12 GNAT1 GNAZ GPS1 GRIA1 GRIA2 GRIA4 GRIK2 GRIK3 GRIK5 GRM3 GRM4 GRM5 GRM7 GUCY1A2 GUCY2D GUSB HCN1 HECA HELZ HK1 HK2 HNF1B HNRNPUL1 HPN HSD11B2 HTRA3 IGF1R ING1 INO80 INPPL1 INSR INSRR INTS3 INTS4 INTS5 INTS6 IRF2

23.20 23.27 17.05 1.71 7.00 8.48 11.54 1.26 13.03 14.16 22.64 11.85 21.01 9.94 8.36 8.81 23.38 23.85 12.26 6.29 0.68 3.36 12.95 4.98 2.80 14.96 19.82 5.04 2.28 6.05 3.95 12.31 8.73 9.79 15.03 19.36 21.67 4.63 4.36 2.44 9.71 13.60 18.70 6.83 19.00 19.01

5.08 14.97 21.65 16.02 10.95 16.36 9.47 2.65 23.04 17.75 11.06 10.43 5.79 12.88 7.05 6.48 2.68 6.52 5.08 0.96 5.26 2.94 7.66 4.51 11.88 13.33 15.62 5.71 5.64 9.38 20.26 14.08 23.25 23.25 11.77 2.49 21.56 6.93 2.84 1.49 1.28 5.03 18.78 8.95 10.73 17.75

1.93 17.73 9.10 11.54 12.13 5.92 19.66 3.88 17.86 7.73 4.82 22.26 3.75 9.39 7.99 13.68 11.32 3.60 3.37 18.05 5.72 6.13 14.39 19.89 11.80 5.49 6.29 4.56 1.63 22.30 12.96 1.97 19.64 24.66 23.37 9.50 19.97 5.26 17.61 2.79 14.86 2.05 17.48 11.90 17.98 11.78

NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO

IRF4 ISYNA1 ITGB1 ITPR1 ITPR2 ITPR3 JAG1 JAG2 JAK3 JARID2 KCNA1 KCNA4 KCNA6 KCNB2 KCNC1 KCNC2 KCND2 KCND3 KCNH1 KCNH2 KCNH3 KCNH4 KCNH5 KCNJ2 KCNJ4 KCNMA1 KCNN3 KCNQ4 KCNQ5 KDM5A KDM5B KDM5C KIAA0430 KIAA0664 KIAA0907 KIAA1468 KIAA1598 KIF26B KIF5A KIF5B KIT LGI1 LIN54 LIN9 LMNA LMX1B

11.45 5.00 0.92 2.13 5.50 1.67 4.26 1.09 12.25 8.77 11.97 18.89 23.97 20.63 10.81 1.94 13.72 4.65 4.21 0.02 5.70 5.18 2.25 3.96 15.60 1.62 11.62 4.04 1.04 10.18 7.25 14.91 2.55 21.47 22.43 24.94 20.41 20.89 24.84 18.24 3.44 19.11 3.89 14.04 0.07 17.79

17.91 17.31 5.94 0.40 2.78 0.17 1.49 4.99 8.56 2.42 19.54 20.54 21.20 6.83 15.62 11.68 16.44 12.24 7.15 3.81 10.56 2.66 3.81 18.44 10.30 2.65 19.54 15.76 14.08 13.79 2.48 3.50 3.45 1.33 18.44 5.08 24.00 18.26 4.88 9.55 15.36 14.40 20.54 22.36 9.96 11.06

15.09 6.85 22.53 0.27 1.59 1.83 19.41 7.55 7.44 8.24 4.67 23.28 1.25 14.25 1.06 8.11 6.35 1.25 9.38 3.45 3.23 12.54 3.52 20.36 1.65 0.84 3.15 2.98 5.22 15.72 9.64 1.03 11.29 1.85 17.39 4.74 15.47 15.36 2.82 16.70 19.81 21.81 20.61 21.96 5.80 10.50

NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO

LRP1 LRP1B LRP4 LRP5 LRP6 LTBP2 LTBP3 MATK MBD1 MCRS1 MEPCE MFSD2A MGA MGAT3 MLL2 MLL3 MLLT1 MNT MON1A MOV10 MTM1 MTMR4 MYH11 MYH3 MYH7 MYH9 MYO10 MYO15A MYO18A MYO1F MYO5A MYO9B NALCN NCDN NF1 NF2 NFRKB NIPBL NKRF NLRP3 NOL4 NOTCH1 NOTCH2 NOTCH3 NPR2 NR0B1

0.81 0.42 1.72 1.24 3.07 3.40 5.20 17.03 1.08 6.76 10.47 8.22 1.56 8.95 13.34 0.21 15.14 12.23 5.36 2.31 14.81 4.83 0.40 3.87 2.21 8.18 7.54 1.00 4.14 8.75 9.51 4.53 4.09 12.36 6.59 1.52 1.47 0.75 20.53 0.13 13.72 4.56 3.77 2.34 17.76 11.20

0.02 1.23 4.69 0.24 2.57 3.29 9.61 19.80 13.58 23.25 10.30 22.36 17.48 18.72 0.06 0.91 17.31 13.45 18.72 2.65 21.20 19.93 0.47 3.23 0.28 1.75 2.97 5.35 2.90 2.12 4.15 10.93 2.98 8.75 0.47 10.65 0.76 1.01 20.26 9.38 15.76 0.33 2.15 5.04 7.71 22.09

0.04 20.70 5.92 6.90 19.45 19.08 2.55 8.66 12.23 19.53 6.12 16.77 16.17 5.46 0.31 14.17 8.65 24.86 13.49 15.84 20.00 13.83 17.55 7.89 0.39 1.08 19.64 9.21 5.54 21.03 3.54 6.93 0.63 1.95 0.63 11.46 14.27 1.99 20.13 12.72 7.59 1.40 4.93 6.01 2.15 13.38

NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO

NR2C2 NR4A2 NRP1 NRP2 NSD1 NTRK2 ODZ1 ODZ3 OLFM1 PANK4 PAPL PAPOLA PARP8 PAX7 PC PCIF1 PCSK7 PDS5A PDS5B PFKFB2 PFKFB3 PFKM PHF12 PHKA1 PIK3R1 PLEKHH3 POU2F2 POU4F2 PPARD PPP2R5B PRICKLE2 PRKAG2 PRMT5 PRPF3 PSMC3 PSMC4 PTCHD1 PTPN9 PTPRA QRICH1 QTRT1 RAF1 RALGAPA1 RALGAPB RARA RARB

11.44 22.85 4.74 0.77 0.51 10.13 1.30 6.04 20.80 16.16 10.80 14.44 1.29 1.86 0.63 9.52 19.77 18.84 16.27 9.02 7.10 10.91 3.85 0.99 21.01 14.45 17.66 16.95 0.79 13.26 16.13 1.65 17.05 20.88 15.83 19.48 13.12 24.87 9.63 7.88 16.05 21.76 3.49 4.45 8.40 14.24

10.37 17.03 22.75 7.28 3.24 22.65 2.62 0.36 17.75 8.95 23.51 17.03 9.96 6.78 2.39 11.28 13.67 15.20 3.64 15.76 4.19 23.57 6.52 12.46 13.45 9.17 20.26 18.06 18.44 20.26 6.78 10.73 19.54 19.31 23.04 19.31 8.32 19.54 7.15 23.25 21.41 16.44 5.71 9.32 23.25 22.09

13.99 5.06 13.06 22.83 5.43 15.54 15.54 3.83 7.04 21.32 24.63 20.62 18.82 16.62 3.59 13.72 13.53 1.11 2.75 22.53 18.99 23.86 24.70 23.34 17.22 13.41 17.54 22.12 12.26 20.84 9.77 22.54 7.39 6.55 14.45 6.36 17.33 22.55 15.74 3.69 14.33 13.75 5.91 9.58 5.44 12.51

NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO

RASAL2 RB1 RBM14 RBPJ RCC1 RERE RET RNF10 RNF220 RNF8 RNGTT RORA RPS2 RSBN1 RXRA RXRG RYR1 RYR2 RYR3 SAMHD1 SAP130 SBF1 SBNO1 SCN3A SCN4A SCN5A SCO2 SCP2 SEC61A1 SERPINH1 SETBP1 SETD1A SETD5 SETDB1 SF3B1 SF3B2 SH3BP5L SHPRH SLC12A2 SLC12A5 SLC12A6 SLC20A1 SLC20A2 SLC22A12 SLC25A25 SLC2A1

22.11 5.72 14.74 12.01 11.13 20.13 1.78 7.44 11.05 14.10 20.43 0.61 20.04 12.15 19.04 23.54 0.03 3.75 1.58 7.01 2.42 7.36 17.17 0.65 1.49 0.00 1.69 5.18 24.57 9.13 13.12 3.86 5.92 2.11 16.78 9.21 16.47 16.40 5.55 4.98 1.08 9.22 7.72 6.08 22.05 21.27

1.53 15.12 14.57 21.20 19.54 0.78 3.00 18.14 16.44 20.26 19.54 9.09 19.31 11.18 15.12 11.06 0.01 0.05 0.06 14.02 2.94 0.17 12.01 0.97 13.68 1.99 17.31 12.24 20.26 17.91 6.61 0.56 12.60 3.81 6.43 7.11 13.94 7.58 4.88 4.45 6.51 22.36 13.67 6.23 24.46 7.66

17.89 22.32 5.34 11.60 24.40 3.84 12.84 18.43 20.88 20.34 17.91 18.30 7.47 5.41 10.04 12.66 1.29 0.12 20.44 14.60 11.73 15.15 8.02 1.20 7.15 3.66 5.11 24.61 4.57 11.05 9.96 5.68 18.54 4.66 0.34 6.50 23.77 14.84 19.77 2.73 3.79 14.56 11.62 18.14 19.14 11.43

NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO

SLC45A1 SLC4A5 SLC5A2 SLC5A3 SLC7A1 SLIT1 SLTM SMARCA2 SMARCA4 SMARCA5 SNED1 SNW1 SOS1 SOX10 SOX5 SOX6 SOX9 SRCAP SRRT SSBP3 STAT3 STAT5A STAT5B STAT6 STT3A STT3B SULF1 SUPT16H SUPT5H SUPT6H SYK SYMPK TADA3 TBX3 THBS1 THBS2 THOC1 THRA THRB TNIK TNPO3 TP63 TP73 TPCN1 TPP2 TRAF6

20.45 9.84 4.87 14.96 16.82 18.22 19.53 6.95 1.11 17.29 12.35 19.18 17.22 23.78 11.09 2.10 17.63 0.86 6.83 6.88 5.94 19.13 17.79 2.06 15.98 11.60 0.74 15.44 7.00 7.48 6.97 13.44 11.88 5.93 12.36 12.64 18.76 3.41 1.29 22.11 15.22 0.39 3.27 6.42 11.37 18.92

1.67 3.31 10.89 15.86 5.60 1.70 7.77 1.82 0.60 8.75 4.36 22.09 8.54 23.04 9.09 6.72 14.40 0.15 3.05 16.36 22.36 16.53 10.30 15.27 16.36 13.33 22.75 17.31 4.10 1.07 13.45 3.69 14.40 14.08 2.39 23.05 24.19 19.31 23.04 3.97 5.94 9.96 2.44 7.20 6.27 20.26

22.56 18.13 10.38 21.25 8.55 2.24 7.34 0.38 0.09 2.95 16.92 6.94 19.52 7.03 6.39 10.89 2.48 3.35 4.30 24.18 1.60 3.72 5.33 16.44 4.53 6.64 17.89 1.52 0.54 2.11 6.40 1.57 21.16 21.24 21.67 24.62 18.42 3.29 12.61 3.46 9.99 5.87 21.54 10.56 7.02 17.79

NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO

TRIM3 TRIM71 TRPC3 TRPC6 TSC1 UBTF UCKL1 UPF1 VANGL2 VASH1 VAV2 VIM VPS52 WDR11 WDR33 WHSC1 WIZ XKR4 XKR6 XPNPEP1 XRCC6 YME1L1 ZAP70 ZC3H14 ZMYND8 ZNFX1

21.30 21.14 10.84 10.46 1.30 13.96 5.59 13.36 16.42 19.70 19.76 8.85 10.50 5.07 6.23 0.89 15.92 22.42 23.12 7.86 16.56 6.01 4.62 1.18 2.58 2.75

5.76 6.43 5.41 5.08 7.83 6.17 4.19 3.39 7.94 22.09 2.55 11.68 21.56 9.75 12.05 4.48 12.46 11.68 11.68 14.02 15.62 11.88 6.17 16.63 3.98 24.22

2.70 2.03 8.44 20.73 5.55 2.24 16.41 0.30 16.58 19.90 23.76 12.66 9.83 16.33 4.48 14.14 4.14 5.90 3.95 17.34 10.20 24.87 5.46 21.55 10.74 16.16

NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO