Table 1.

Genetics and Functional Parameters of MT₂ Variants

Localizationa	Amino Acid Positionb	Mutationc	Functional Responsed			MAF%e	Increased T2D Riskf
			Ligand Binding	Gi Activation	ERK Activation
Extracellular N terminus	8	Ala → Ser	+	+	+	<0.1
	13	Ala → Val	+	+	+	<0.1
	21	Gly → Ser	+	+	+	<0.1
	22	Trp → Leu	+	No response	+	<0.1	*
	24	Gly → Glu	+	+	+	>1
	25	Ala → Thr	+	+	+	<0.1
	36	Pro → Ser	+	+	+	<0.1
TM1	42	Ala → Pro	No binding	No response	No response	<0.1	*
	52	Ala → Thr	+	No response	+	<0.1	*
	60	Leu → Arg	No binding	No response	No response	<0.1	*
i1
TM2	74	Ala → Thr	+	No response	+	<0.1	*
	95	Pro → Leu	No binding	No response	No response	<0.1	*
e1
TM3	109	Gly → Ala	+	+	+	<0.1
	120	Met → Val	+	+	+	<0.1
	120	Met → Ile	+	+	+	<0.1
	123	Ser → Arg	+	+	+	<0.1
	124	Val → Ile	+	+	+	<0.1
	138	Arg → Leu	+	No response	+	<0.1	*
	138	Arg → His	+	No response	+	<0.1	*
	138	Arg → Cys	+	No response	No response	0.1 < x < 1
i2	141	Tyr → Phe	+	+	+	<0.1
	146	Met → Val	+	+	+	<0.1
	154	Arg → His	+	+	+	<0.1
TM4	166	Leu → Ile	+	No response	+	<0.1	*
e2
TM5	201	Thr → Met	+	+	+	<0.1
	222	Arg → His	+	No response	+	<0.1	*
	223	Ile → Thr	+	+	+	<0.1
i3	231	Arg → His	+	+	+	0.1 < x < 1
	234	Ala → Thr	+	+	+	<0.1
	237	Glu → Lys	+	+	+	<0.1
	238	Ser → Gly	+	+	+	<0.1
TM6	243	Lys → Arg	+	+	+	>1
	246	Asp → Asn	+	+	+	<0.1
	250	Phe → Val	+	+	No response	<0.1
e3
TM7	308	Tyr → Ser	No binding	No response	No response	<0.1	*
Intracellular C terminus	316	Arg → His	+	+	+	<0.1
	330	Arg → Trp	+	No response	+	<0.1	*
	342	Ala → Val	+	+	+	<0.1
	353	Ile → Thr	+	No response	+	<0.1	*
	359	Ala → Glu	+	+	+	<0.1

^a Receptor domain localization of mutated amino acids (TM, transmembrane domain; e, extracellular loop; i, intracellular loop).

^b Position of mutated amino acid in the receptor protein sequence. Full “loss-of-function” mutants (no ligand binding) are indicated in bold letters.

^c Amino acid change (3-letter code) introduced by the mutation.

^d + Indicates functional characteristics comparable to the wild-type MT₂. Receptor surface expression was not affected by the mutation.

^e Minor allelic frequency of the mutation.

^f * Indicates increased T2D risk: only rare mutations (minor alleic frequency < 0.1%) leading to Gi activation deficiency are associated with increased T2D risk.