General Structure Information
| PDB ID | 4mle |
| HGNC Gene Label(s) | GCK |
| Structure Name | human glucokinase in complex with novel amino thiazole activator |
| Resolution | 2.6Å |
| Reference | AUTH R.J.HINKLIN,S.A.BOYD,M.J.CHICARELLI,K.R.CONDROSKI,AUTH 2 W.E.DEWOLF,P.A.LEE,W.LEE,A.SINGH,L.THOMAS,W.C.VOEGTLI,AUTH 3 L.WILLIAMS,T.D.AICHERTITL IDENTIFICATION OF A NEW CLASS OF GLUCOKINASE ACTIVATORSTITL 2 THROUGH STRUCTURE-BASED DESIGN.REF J.MED.CHEM. V. 56 7669 2013REFN ISSN 0022-2623PMID 24015910DOI 10.1021/JM401116K |
Variant Set Distributions
ExAC Variants
| Number Of Residues | 446 |
| Number Of SNVs | 72 |
| Number Of Permutations | 13725 |
| Optimal Distance Threshold | 16.0 |
| K Statistic | 0.126 |
| p-value | 0.049 |
ClinVar
| Number Of Residues | 446 |
| Number Of SNVs | 77 |
| Number Of Permutations | 14723 |
| Optimal Distance Threshold | 17.0 |
| K Statistic | 0.241 |
| p-value | 0.0 |
COSMIC
| Number Of Residues | 446 |
| Number Of SNVs | 9 |
| Number Of Permutations | 2614 |
| Optimal Distance Threshold | 17.0 |
| K Statistic | 0.056 |
| p-value | 0.708 |
Ripley’s K Analysis Plots
ExACClinVarCOSMIC
Variant Set Comparisons
ClinVar vs. ExAC
| Number Of ExAC SNVs | 72 |
| Number Of ClinVar SNVs | 73 |
| Optimal Distance Threshold | 16.0 |
| K Statistic | 0.079 |
| p-value | 0.001 |
Cosmic vs. ExAC
| Number Of ExAC SNVs | 72 |
| Number Of COSMIC SNVs | 8 |
| Optimal Distance Threshold | 22.0 |
| K Statistic | 0.122 |
| p-value | 0.453 |
Pathogenic Proximity Analysis
ClinVar PathProx Analysis
COSMIC PathProx Analysis
Mapped Variants
[+] ExAC Missense Variants
| Position | Variant | AA Change | PDB Chain Position | Structure Coordinates |
|---|---|---|---|---|
| 7:44193055 | Q>R | A:18 | (23.45, -32.07, 71.31) | |
| 7:44193002 | COSM3881222 COSM3881224 COSM3881223 CM940823 |
R>W | A:36 | (30.87, -12.31, 52.15) |
| 7:44192980 | R>H | A:43 | (29.60, -4.87, 46.99) | |
| 7:44192966 | E>K | A:48 | (30.02, -0.19, 40.50) | |
| 7:44192933 | rs193922287 | P>S | A:59 | (30.75, 8.72, 53.17) |
| 7:44192929 | T>I | A:60 | (31.99, 10.69, 57.38) | |
| 7:44192920 | COSM3638928 COSM3638930 COSM3638929 |
R>H | A:63 | (38.58, 15.05, 54.73) |
| 7:44192921 | COSM368973 COSM368974 |
R>C | A:63 | (38.58, 15.05, 54.73) |
| 7:44191949 | E>G | A:95 | (52.42, 19.20, 72.85) | |
| 7:44191944 | G>R | A:97 | (46.60, 18.74, 70.21) | |
| 7:44191932 | V>M | A:101 | (36.40, 18.27, 78.96) | |
| 7:44191893 | A>T | A:114 | (8.43, 10.54, 70.94) | |
| 7:44191890 | M>V | A:115 | (9.74, 6.67, 69.91) | |
| 7:44191884 | G>S | A:117 | (5.35, 9.89, 66.12) | |
| 7:44191875 | E>K | A:120 | (8.56, 16.85, 63.30) | |
| 7:44190668 | D>N | A:124 | (9.92, 19.29, 69.27) | |
| 7:44190653 | rs377106269 COSM3950537 COSM3950539 COSM3950538 |
C>R | A:129 | (15.87, 18.70, 76.57) |
| 7:44190644 | D>N | A:132 | (15.93, 21.80, 80.96) | |
| 7:44190623 | rs368137186 | M>L | A:139 | (24.58, 28.97, 79.04) |
| 7:44190605 | rs150779253 | P>S | A:145 | (29.23, 25.63, 68.72) |
| 7:44190598 | rs193922296 | G>D | A:147 | (27.27, 18.62, 68.21) |
| 7:44190578 | V>L | A:154 | (23.76, 9.10, 57.57) | |
| 7:44189629 | rs34389297 rs370966942 |
A>V | A:173 | (9.90, 8.17, 63.75) |
| 7:44189587 | D>V | A:187 | (13.23, 22.62, 61.32) | |
| 7:44189585 | A>T | A:188 | (13.12, 22.71, 66.23) | |
| 7:44189582 | I>V | A:189 | (16.19, 25.20, 67.28) | |
| 7:44189572 | R>K | A:192 | (11.20, 25.84, 71.45) | |
| 7:44189570 | rs376050856 COSM3638909 COSM3638911 COSM3638910 CM012121 |
G>R | A:193 | (13.62, 30.84, 70.04) |
| 7:44189433 | rs193922311 CM064009 CM076210 |
M>T | A:202 | (25.86, 14.81, 61.66) |
| 7:44189415 | A>V | A:208 | (33.32, 10.03, 67.92) | |
| 7:44189407 | I>V | A:211 | (38.03, 11.64, 66.85) | |
| 7:44189392 | COSM3638903 COSM3638905 COSM3638904 CM020442 |
E>K | A:216 | (45.80, 9.49, 74.13) |
| 7:44189389 | rs147065275 | D>N | A:217 | (46.78, 6.80, 69.92) |
| 7:44189362 | rs148311934 | V>M | A:226 | (29.89, -3.12, 71.26) |
| 7:44187429 | rs80356655 | T>M | A:228 | (22.19, -1.53, 71.82) |
| 7:44187396 | Q>R | A:239 | (42.12, 6.40, 46.37) | |
| 7:44187370 | E>K | A:248 | (45.05, 13.34, 47.43) | |
| 7:44187363 | rs370375148 CM097117 |
R>H | A:250 | (43.66, 8.40, 55.42) |
| 7:44187355 | V>I | A:253 | (34.14, 5.10, 56.29) | |
| 7:44187346 | E>K | A:256 | (26.42, 1.14, 59.16) | |
| 7:44187339 | G>D | A:258 | (25.02, -4.50, 60.67) | |
| 7:44187331 | rs104894008 | G>R | A:261 | (23.54, -10.11, 55.69) |
| 7:44187328 | D>N | A:262 | (20.92, -7.57, 55.20) | |
| 7:44187288 | R>H | A:275 | (15.87, -17.71, 61.07) | |
| 7:44187289 | rs556436603 CM015282 |
R>C | A:275 | (15.87, -17.71, 61.07) |
| 7:44187276 | rs143484733 | E>G | A:279 | (10.52, -13.54, 62.29) |
| 7:44187267 | A>V | A:282 | (11.29, -3.32, 64.02) | |
| 7:44187259 | G>R | A:285 | (15.76, -8.03, 57.45) | |
| 7:44187249 | L>R | A:288 | (20.79, -9.73, 60.25) | |
| 7:44186152 | V>G | A:310 | (11.52, -25.45, 78.56) | |
| 7:44186129 | rs193922340 CM030447 |
G>W | A:318 | (8.84, -27.29, 81.71) |
| 7:44186117 | COSM746814 COSM746815 |
E>K | A:322 | (3.60, -15.54, 82.72) |
| 7:44186113 | Q>R | A:323 | (8.02, -13.00, 83.72) | |
| 7:44186101 | R>H | A:327 | (8.42, -10.97, 72.60) | |
| 7:44186093 | F>V | A:330 | (17.05, -12.65, 79.80) | |
| 7:44186086 | T>M | A:332 | (21.67, -7.94, 77.93) | |
| 7:44185324 | T>R | A:342 | (31.34, -16.52, 91.93) | |
| 7:44185241 | A>S | A:370 | (23.40, -20.11, 77.44) | |
| 7:44185231 | rs574763474 CM096926 |
S>T | A:373 | (26.89, -19.77, 74.07) |
| 7:44185209 | H>Q | A:380 | (34.22, -15.57, 68.45) | |
| 7:44185208 | M>L | A:381 | (30.58, -13.11, 64.23) | |
| 7:44185202 | S>A | A:383 | (36.14, -10.86, 65.62) | |
| 7:44185189 | rs193921338 CM032922 |
A>V | A:387 | (39.53, -8.34, 61.02) |
| 7:44185160 | rs370464857 CM096946 |
R>C | A:397 | (50.26, 0.56, 56.86) |
| 7:44185154 | COSM1568962 COSM1568963 CM051930 |
E>K | A:399 | (54.33, -0.97, 57.77) |
| 7:44185149 | D>E | A:400 | (57.04, -5.35, 58.64) | |
| 7:44185150 | D>G | A:400 | (57.04, -5.35, 58.64) | |
| 7:44185148 | V>I | A:401 | (54.16, -4.77, 62.23) | |
| 7:44185109 | rs193922272 CM096799 CM930308 |
K>E | A:414 | (32.86, -0.99, 78.52) |
| 7:44184851 | rs552762648 COSM1089919 COSM1089920 |
R>C | A:428 | (44.99, -9.82, 69.33) |
| 7:44184847 | rs146683328 | R>K | A:429 | (42.64, -16.23, 67.02) |
| 7:44184842 | rs188718376 | T>A | A:431 | (45.09, -9.97, 63.00) |
| 7:44184827 | I>V | A:436 | (45.51, -4.62, 67.53) | |
| 7:44184809 | E>K | A:442 | (36.17, 8.42, 79.27) | |
| 7:44184769 | V>E | A:455 | (37.48, 21.43, 62.56) |
[+] ClinVar Missense Variants
| Position | Variant | AA Change | PDB Chain Position | Structure Coordinates |
|---|---|---|---|---|
| 7:44193051 | rs193922308 | I>M | A:19 | (20.89, -27.47, 71.97) |
| 7:44193034 | rs193922325 | L>R | A:25 | (31.58, -20.30, 65.15) |
| 7:44193001 | rs193922261 | R>P | A:36 | (30.87, -12.31, 52.15) |
| 7:44192990 | rs794727236 | E>K | A:40 | (30.06, -6.91, 51.04) |
| 7:44192977 | rs193922279 | G>D | A:44 | (30.23, -0.00, 48.97) |
| 7:44192962 | rs193922286 | T>N | A:49 | (27.93, -1.91, 44.07) |
| 7:44192933 | rs193922287 | P>S | A:59 | (30.75, 8.72, 53.17) |
| 7:44192019 | rs193922289 | G>R | A:72 | (36.11, 26.02, 73.20) |
| 7:44191980 | rs193922290 | R>W | A:85 | (24.07, 12.05, 76.39) |
| 7:44191911 | rs193922292 | Y>D | A:108 | (17.23, 14.88, 79.12) |
| 7:44190668 | rs759072800 | D>N | A:124 | (9.92, 19.29, 69.27) |
| 7:44190647 | rs104894010 | S>P | A:131 | (15.96, 24.08, 77.03) |
| 7:44190598 | rs193922296 | G>D | A:147 | (27.27, 18.62, 68.21) |
| 7:44190589 | rs193922297 | F>Y | A:150 | (21.93, 10.59, 64.32) |
| 7:44190581 | rs193922300 | P>S | A:153 | (22.02, 5.05, 59.14) |
| 7:44190575 | rs193922301 | R>G | A:155 | (23.48, 8.56, 51.81) |
| 7:44189638 | rs193922303 | G>V | A:170 | (13.87, 0.79, 67.50) |
| 7:44189620 | rs193922304 | A>G | A:176 | (12.62, 10.68, 59.08) |
| 7:44189615 | rs193922305 | G>R | A:178 | (15.23, 11.09, 53.75) |
| 7:44189605 | rs193922306 | V>A | A:181 | (19.15, 15.03, 60.63) |
| 7:44189603 | rs587780345 | V>M | A:182 | (20.88, 18.94, 60.60) |
| 7:44189584 | rs193922307 | A>V | A:188 | (13.12, 22.71, 66.23) |
| 7:44189451 | rs193922309 | E>G | A:196 | (20.08, 31.25, 68.41) |
| 7:44189433 | rs193922311 | M>T | A:202 | (25.86, 14.81, 61.66) |
| 7:44189434 | rs193922310 | M>V | A:202 | (25.86, 14.81, 61.66) |
| 7:44189423 | rs193922312 | D>E | A:205 | (28.65, 6.25, 67.53) |
| 7:44189422 | rs587780346 | T>P | A:206 | (31.70, 5.02, 65.32) |
| 7:44189408 | rs193922313 | M>I | A:210 | (38.04, 7.54, 65.88) |
| 7:44189409 | rs80356654 | M>K | A:210 | (38.04, 7.54, 65.88) |
| 7:44189397 | rs104894015 | Y>C | A:214 | (44.39, 11.55, 66.83) |
| 7:44189379 | rs193922316 | C>Y | A:220 | (43.21, 5.88, 66.34) |
| 7:44189380 | rs193922315 | C>R | A:220 | (43.21, 5.88, 66.34) |
| 7:44189377 | rs193922317 | E>K | A:221 | (43.23, 5.06, 61.66) |
| 7:44189361 | rs193922319 | V>A | A:226 | (29.89, -3.12, 71.26) |
| 7:44189362 | rs148311934 | V>M | A:226 | (29.89, -3.12, 71.26) |
| 7:44187429 | rs80356655 | T>M | A:228 | (22.19, -1.53, 71.82) |
| 7:44187418 | rs193922322 | A>T | A:232 | (32.40, 0.47, 62.44) |
| 7:44187408 | rs193922323 | M>T | A:235 | (40.46, 6.48, 58.23) |
| 7:44187406 | rs587780347 | E>K | A:236 | (39.76, 4.30, 53.16) |
| 7:44187360 | rs193922326 | M>T | A:251 | (37.18, 10.17, 54.25) |
| 7:44187354 | rs193921400 | V>G | A:253 | (34.14, 5.10, 56.29) |
| 7:44187352 | rs193922327 | N>H | A:254 | (29.85, 4.50, 58.61) |
| 7:44187344 | rs193922328 | E>D | A:256 | (26.42, 1.14, 59.16) |
| 7:44187333 | rs193922330 | F>S | A:260 | (27.43, -8.70, 56.99) |
| 7:44187331 | rs104894008 | G>R | A:261 | (23.54, -10.11, 55.69) |
| 7:44187325 | rs193922331 | S>P | A:263 | (22.28, -9.92, 51.06) |
| 7:44187322 | rs193929373 | G>S | A:264 | (22.87, -13.60, 52.65) |
| 7:44187300 | rs193922332 | L>P | A:271 | (20.59, -20.29, 64.56) |
| 7:44187279 | rs193922333 | D>V | A:278 | (14.43, -10.85, 62.17) |
| 7:44186186 | rs104894009 | G>R | A:299 | (18.77, -11.61, 75.56) |
| 7:44186174 | rs193922336 | R>W | A:303 | (13.07, -15.15, 75.71) |
| 7:44186164 | rs193922337 | L>P | A:306 | (16.36, -20.51, 78.07) |
| 7:44186137 | rs193922338 | L>H | A:315 | (15.19, -25.65, 81.99) |
| 7:44186134 | rs193922339 | F>Y | A:316 | (13.18, -23.82, 84.36) |
| 7:44186129 | rs193922340 | G>W | A:318 | (8.84, -27.29, 81.71) |
| 7:44186110 | rs193922341 | L>P | A:324 | (10.78, -16.83, 80.41) |
| 7:44186066 | rs397514580 | E>K | A:339 | (28.61, -14.61, 81.98) |
| 7:44186063 | rs193922255 | S>G | A:340 | (29.50, -12.62, 87.01) |
| 7:44185307 | rs193922260 | I>F | A:348 | (22.26, -17.22, 88.35) |
| 7:44185237 | rs587780343 | C>F | A:371 | (24.73, -16.94, 78.34) |
| 7:44185225 | rs193922263 | S>F | A:375 | (28.39, -14.13, 74.45) |
| 7:44185219 | rs193922264 | R>H | A:377 | (26.89, -16.36, 68.15) |
| 7:44185216 | rs193929374 | A>V | A:378 | (29.21, -12.35, 69.57) |
| 7:44185217 | rs104894016 | A>T | A:378 | (29.21, -12.35, 69.57) |
| 7:44185213 | rs193922265 | A>E | A:379 | (32.66, -12.18, 70.29) |
| 7:44185207 | rs193922266 | M>R | A:381 | (30.58, -13.11, 64.23) |
| 7:44185196 | rs193922267 | G>R | A:385 | (35.06, -7.64, 61.36) |
| 7:44185192 | rs193922268 | L>P | A:386 | (37.85, -5.62, 63.79) |
| 7:44185189 | rs193921338 | A>V | A:387 | (39.53, -8.34, 61.02) |
| 7:44185180 | rs193921340 | I>N | A:390 | (42.33, -4.40, 60.74) |
| 7:44185174 | rs193922269 | R>L | A:392 | (40.27, -2.92, 53.05) |
| 7:44185159 | rs193929375 | R>L | A:397 | (50.26, 0.56, 56.86) |
| 7:44185142 | rs193922271 | R>G | A:403 | (52.68, -0.40, 65.83) |
| 7:44185109 | rs193922272 | K>E | A:414 | (32.86, -0.99, 78.52) |
| 7:44184865 | rs193922273 | F>Y | A:423 | (36.86, -8.91, 70.33) |
| 7:44184844 | rs193922277 | L>P | A:430 | (41.60, -13.38, 62.55) |
| 7:44184826 | rs193922278 | I>N | A:436 | (45.51, -4.62, 67.53) |
| 7:44184794 | rs193922281 | R>G | A:447 | (35.88, 14.10, 74.35) |
| 7:44184788 | rs193922282 | A>T | A:449 | (31.56, 16.19, 68.47) |
| 7:44184775 | rs193922283 | S>L | A:453 | (32.57, 20.78, 65.60) |
| 7:44184770 | rs104894012 | V>M | A:455 | (37.48, 21.43, 62.56) |
| 7:44184766 | rs104894014 | A>V | A:456 | (33.90, 22.87, 61.15) |
[+] COSMIC Missense Variants
| Position | Variant | AA Change | PDB Chain Position | Structure Coordinates |
|---|---|---|---|---|
| 7:44193002 | COSM3881223 | R>W | A:36 | (30.87, -12.31, 52.15) |
| 7:44192921 | COSM4362482 | R>C | A:63 | (38.58, 15.05, 54.73) |
| 7:44192914 | COSM1698623 | T>I | A:65 | (44.75, 16.82, 57.17) |
| 7:44190599 | COSM3262619 | G>C | A:147 | (27.27, 18.62, 68.21) |
| 7:44190569 | COSM232394 | E>K | A:157 | (25.88, 16.85, 50.88) |
| 7:44190560 | COSM1253129 | D>N | A:160 | (26.78, 20.22, 57.81) |
| 7:44189640 | COSM3262616 | K>N | A:169 | (19.09, 0.65, 67.46) |
| 7:44189575 | COSM188925 | R>Q | A:191 | (9.49, 23.96, 65.92) |
| 7:44189392 | COSM3638905 | E>K | A:216 | (45.80, 9.49, 74.13) |
| 7:44186153 | COSM3663211 | V>M | A:310 | (11.52, -25.45, 78.56) |