The HAWAII-2RG is a major upgrade of our prior 2048 x 2048 CMOS readout for astronomy (HAWAII-2) to support the requirements of the Next Generation Space Telescope and enable breakthrough capability for ground-based astronomy. By migrating to 0.25μm CMOS, for the first time guide mode readout is simultaneously supported in combination with various programmable science modes on a frame-by-frame basis. Consequently, the readout simultaneously supports programmable guide mode window and full-field science using the rest of the 4.2 million pixels at read noise <5 e-. Also for the first time with any imaging sensor, low and high background astronomy is supported using from 1 to 32 low-noise outputs via low-speed and high-speed signal paths. The latter supports throughput rate of up 320 MHz for real time imaging at >60 Hz. As with the HAWAII-2, the readout can be mated to our infrared and visible detector arrays including low dark current MBE HgCdTe at cutoff wavelengths from 1.5μm to 14μm, 2.5μm PACE HgCdTe, and silicon p-i-n detectors with superior quantum efficiency to backside-illuminated CCDs.