Exhibit 32.1

CERTIFICATIONS OF PRINCIPAL EXECUTIVE OFFICER AND PRINCIPAL FINANCIAL OFFICER PURSUANT TO 18 U.S.C. SECTION 1350, AS ADOPTED PURSUANT TO

SECTION 906 OF THE SARBANES-OXLEY ACT OF 2002

In connection with the Quarterly Report of Septerna, Inc. (the “Company”) on Form 10-Q for the period ended September 30, 2024 as filed with the Securities and Exchange Commission on the date hereof (the “Report”), the undersigned officers of the Company hereby certify, pursuant to 18 U.S.C. § 1350, as adopted pursuant to § 906 of the Sarbanes-Oxley Act of 2002, that:

(1)The Report fully complies with the requirements of section 13(a) or 15(d) of the Securities Exchange Act of 1934, as amended; and

(2)The information contained in the Report fairly presents, in all material respects, the financial condition and result of operations of the Company.

Date: November 20, 2024	By:	/s/ Jeffrey Finer, M.D., Ph.D.
		Jeffrey Finer, M.D., Ph.D.
		President and Chief Executive Officer (Principal Executive Officer)

Date: November 20, 2024	By:	/s/ Ran Xiao, M.B.A., CFA
		Ran Xiao, M.B.A., CFA
		Interim Chief Financial Officer, Vice President of Finance and Business Operations (Principal Financial Officer and Principal Accounting Officer)