Activating mutations in Gα proteins are frequent in uveal melanoma, the most common eye cancer arising from the uveal tract. A small proportion of uveal melanomas have a D630Y mutation in phospholipase C β4 (PLCβ4), an effector of Gα. Here, we found that the D630Y mutation in PLCβ4 results in a high level of constitutive PLCβ4 activity. Mutations at the corresponding position in other PLC isoforms also resulted in constitutive activity, revealing an unrecognized mechanism underlying PLC activation. In cultured human uveal melanoma cell lines, inhibition of PLC suppressed proliferation in Gα-dependent cells. Furthermore, we found that PLCβ4(D630Y) mediated proliferation in cutaneous melanocytes and the growth of melanomas in mice. These results are consistent with PLCβ4(D630Y) driving oncogenic signaling downstream of Gα.