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Cross-GPCR Database Statistics

Statistical analysis across 283 Class A GPCRs, including rankings, TM domain patterns, Core Functional Residues, and variant correlations.

A. Cross-GPCR Comparison

B. Transmembrane Domain Patterns

C. Core Functional Residues (CFRs)

Positions that show significant conformational change in many GPCRs, indicating conserved activation mechanisms.

What are Core Functional Residues (CFRs)?

Using Ballesteros-Weinstein generic numbering, each residue is mapped to its conserved position across all 283 GPCRs. A position is identified as a CFR if it appears in the significant changes list of many GPCRs, meaning that residue consistently undergoes conformational change during activation across the receptor superfamily.

Positions are ranked by a composite score of (1) how many GPCRs show significant change there (frequency) and (2) the average magnitude of change (mean |ΔRRCS|). High-ranking CFRs represent the shared molecular machinery of GPCR activation.

Top 30 Core Functional Residue Positions
Rank Generic number Segment Frequency % of GPCRs Mean |Δ| CFR score
1 3.50x50 TM3 261 92.2% 4.60 0.698
2 7.53x53 TM7 238 84.1% 4.01 0.628
3 6.48x48 TM6 223 78.8% 4.44 0.619
4 3.49x49 TM3 207 73.1% 4.88 0.607
5 5.58x58 TM5 212 74.9% 4.55 0.602
6 6.44x44 TM6 212 74.9% 4.32 0.592
7 8.50x50 H8 191 67.5% 4.74 0.570
8 7.54x54 TM7 186 65.7% 4.88 0.566
9 7.56x56 TM7 189 66.8% 4.48 0.555
10 2.39x39 TM2 167 59.0% 4.93 0.532
11 8.51x51 H8 175 61.8% 4.49 0.529
12 7.45x45 TM7 180 63.6% 4.08 0.521
13 6.30x30 TM6 168 59.4% 4.58 0.519
14 6.38x38 TM6 137 48.4% 5.81 0.513
15 3.19x19 TM3 5 1.8% 11.61 0.510
16 7.55x55 TM7 159 56.2% 4.42 0.495
17 3.40x40 TM3 148 52.3% 4.35 0.471
18 45.52x52 ECL2 121 42.8% 5.01 0.448
19 5.35x36 TM5 120 42.4% 4.98 0.444
20 6.36x36 TM6 132 46.6% 4.33 0.439
21 6.32x32 TM6 106 37.5% 5.35 0.434
22 6.58x58 TM6 116 41.0% 4.86 0.431
23 45.51x51 ECL2 114 40.3% 4.93 0.431
24 5.47x47 TM5 124 43.8% 4.40 0.427
25 7.50x50 TM7 128 45.2% 4.22 0.427
26 7.42x41 TM7 113 39.9% 4.80 0.423
27 8.48x48 H8 96 33.9% 5.51 0.421
28 7.35x34 TM7 109 38.5% 4.79 0.415
29 6.55x55 TM6 109 38.5% 4.73 0.413
30 3.36x36 TM3 118 41.7% 4.33 0.413
Top CFR Contact Pairs (both residues are CFRs)
CFR 1CFR 2# GPCRs
3.49x49 3.50x50 160
6.44x44 6.48x48 145
7.54x54 8.50x50 137
2.39x39 3.50x50 137
6.44x44 7.45x45 124
5.58x58 6.38x38 120
7.54x54 8.51x51 117
3.50x50 7.53x53 114
7.53x53 8.50x50 105
3.40x40 6.48x48 101
6.36x36 7.56x56 95
6.48x48 7.42x41 95
2.43x43 7.53x53 89
7.50x50 7.55x55 85
7.45x45 7.49x49 84
3.36x36 6.48x48 84
3.40x40 6.44x44 83
6.48x48 7.45x45 80
7.55x55 8.51x51 80
3.50x50 5.58x58 74

D. Variant Correlation

Pathogenicity Enrichment at CFRs

Chi-squared test: χ² = 1228.22, p = 4.50e-269. CFR pathogenic: 56.7%. Non-CFR pathogenic: 29.7%.

High-Impact Pathogenic Variants at CFR Positions (Top 30)
GPCRPositionRef / Alt Allele freqAM scoreConservation
5HT7R 180 Arg → Met 7.009457159599732e-07 0.9999 0.957
ACM2 447 Phe → Leu 6.844804998350402e-07 0.9999 1.0
ACM4 460 Phe → Leu 6.84205124696384e-07 0.9999 1.0
OPRM 167 Arg → Pro 6.583365152931573e-06 0.9998 1.0
OPRK 283 Phe → Leu 2.052180099325517e-06 0.9998 1.0
ACM2 121 Arg → Ser 6.842893996729097e-07 0.9998 0.976
ADA2C 429 Asn → Lys 6.847523456191599e-07 0.9997 0.987
TRFR 327 Phe → Leu 6.844252197004956e-07 0.9997 0.957
ADA1B 303 Phe → Leu 6.846379566021692e-07 0.9997 0.955
5HT7R 330 Gly → Glu 1.3681219379720876e-06 0.9997 0.919
ACM3 551 Phe → Leu 6.840497386245948e-07 0.9996 0.97
OPRM 335 Pro → Arg 6.570733950982325e-06 0.9996 1.0
DRD2 132 Arg → Ser 6.842407049321439e-07 0.9996 0.948
ACM5 491 Asn → Lys 4.104270356496923e-06 0.9996 0.956
5HT7R 376 Asn → Lys 6.840544178970525e-07 0.9995 1.0
ADA1D 394 Asn → Lys 6.569870573549701e-06 0.9995 0.991
EDNRB 199 Arg → Ser 6.845151715942632e-07 0.9995 0.921
ADA2A 441 Tyr → His 6.841002781551731e-07 0.9995 1.0
5HT7R 179 Asp → Ala 1.3938544955292117e-06 0.9994 0.896
OPRK 327 Pro → Arg 1.3681069640748791e-06 0.9994 1.0
ACM1 367 Leu → Pro 6.841002781551731e-07 0.9994 0.72
AA2AR 295 Phe → Leu 6.840684560985387e-07 0.9994 0.897
ADA1B 307 Trp → Arg 6.854009595613434e-07 0.9994 0.966
ADA1D 391 Gly → Asp 6.846201453585493e-07 0.9994 0.986
5HT7R 381 Pro → Arg 6.840525461803874e-07 0.9994 1.0
DRD3 390 Phe → Leu 2.0585111200770702e-06 0.9993 1.0
ADA1A 281 Phe → Leu 6.840871745968332e-07 0.9993 0.954
ADRB2 208 Phe → Leu 3.4202346554592417e-06 0.9993 0.984
OPSD 261 Phe → Leu 1.1628781919296253e-05 0.9993 0.948
OPN5 261 Phe → Leu 6.842154238577708e-07 0.9993 1.0

Data & methods: AlphaFold multistate · RRCS · gnomAD v4 · AlphaMissense · GPCRdb · UniProt / ProtVar