I use two SYN-2s in my Mark V. So those 8 channels, plus the three in the Mesa.
There can be a difference, based on how you have the channels set up. When you engage the Synergy module(s), the Mesa still "knows" what channel it is on. so it boils down to a few factors:
1) Each channel has its own power setting. So you need to make all three the same if you want the ability to play your Synergy preamp modules without worrying about what channel the Mark V was left on - even though you are bypassing the front end of the Mesa.
2) Not all of the knobs on the front of the Mark V are for the preamp. When you are playing a Synergy preamp, and thus bypassing the Mesa front end, the Presence knob is always in play. And since there are three Presence knobs, it matters which channel you are on if all three aren't set the same.
3) I'm fairly certain that Channel Three of the Mesa is a bit different than the other three channels due to the final Mode: Extreme. That channel has three modes: Mark IIC+, Mark IV, and Extreme. I'm fairly certain that the Mark IV and Extreme preamp is the exact same, with the difference being in the power amp feedback. No clue if its more or less feedback in Extreme, but it's different. So if you try to make the three power settings match for each channel, and you make the Presence knobs match for each channel, you will have a noticable volume change while using the Synergy preamps with the Mesa in Channel Three vs the other two channels if Channel Three happens to be set to Extreme.
The way I look at it, you can view these things as hindrances or pseudo features. If you don't want to hassle with it all, then make all three power toggles match, make all three Presence settings match (with your ears, not the physical knob positions!), and don't use Extreme on Channel Three. Or, if you want to use these for your advantage, you can use the differences between the channels as added tweaks to your Synergy channels. But to do so, you have to remember which channel the Mesa is in while selecting the Synergy module. If, for instance, you like more Presence on Channel One than Two, you can use that difference to add a Presence "boost" to your Synergy module by changing the Mesa channel in the background.
For me, I do the latter. I set all three channels to the same power level and I match the Presence knobs the best I can. It's a compromise, but it takes remembering out of the equation.