Fears surrounding President Donald Trump drove U.S. markets sharply lower Wednesday, but longtime bull Jeremy Siegel certainly isn't concerned.

That's because the market rally has been based on the Republican agenda, not the Trump agenda, he said. In fact, he believes Wall Street would prefer a President Michael Pence rather than Trump.

"If Donald Trump resigned tomorrow I think the Dow would go up 1,000 points," the Wharton School finance professor said in an interview Wednesday with "Closing Bell."

Speculation about Trump's impeachment or resignation heated up after news that fired FBI Director James Comey left a memo detailing a conversation in which Trump allegedly asked him to stop his investigation of former national security advisor Michael Flynn.

That sent equities tumbling. The Dow Jones industrial average closed about 370 lower on Wednesday, while the dropped 1.8 percent. The Nasdaq shed 2.6 percent.

Siegel sees the sell-off as a buying opportunity and thinks tax reform will still get done no matter what happens with Trump.

"The Republicans have a lock. Nothing can change that for two years," Siegel argued.

And he believes Trump will sign whatever tax or regulatory reform the GOP presents.

"Trump will more likely, if he stays in power, be really controlled by Congress."

— CNBC's Fred Imbert contributed to this report.