Septerna, Inc.

FOR THE 2026 ANNUAL MEETING OF STOCKHOLDERS

TO BE HELD ON JUNE 26, 2026

This proxy statement contains information about the 2026 Annual Meeting of Stockholders (the “Annual Meeting”) of Septerna, Inc., which will be held on June 26, 2026, at 2:00 p.m. Pacific Time. In order to leverage technology to enhance stockholder access to the Annual Meeting by enabling stockholder attendance and participation from any location, the Annual Meeting will be held virtually via live webcast. The board of directors of Septerna, Inc. (the “board of directors” or “board”) is using this proxy statement to solicit proxies for use at the Annual Meeting. In this proxy statement, the terms “Septerna,” the “Company,” “we,” “us,” “our,” and similar designations refer to Septerna, Inc. The mailing address of our principal executive office is Septerna, Inc., 250 East Grand Avenue, South San Francisco, CA 94080.

In order to attend the Annual Meeting virtually, you will be required to enter the 16-digit control number provided in the Notice of Internet Availability of Proxy Materials (the “Notice”) or the proxy card atwww.ProxyVote.com. Beneficial owners of shares held in “street name” should follow the instructions provided in the voting instructions form by the broker, bank or other nominee that holds their shares on how to attend and vote at the Annual Meeting. Please see the “General Information” section of the proxy statement for more details regarding the logistics of the virtual Annual Meeting, including the ability of stockholders to submit questions during the Annual Meeting, and technical details and support related to accessing the virtual platform. You will not be able to attend the Annual Meeting in person.

All properly submitted proxies will be voted in accordance with the instructions contained in those proxies. If no instructions are specified, the proxies will be voted in accordance with the recommendation of our board of directors with respect to each of the matters set forth in the accompanying Notice of Meeting. You may revoke your proxy at any time before it is exercised at the Annual Meeting by giving our Corporate Secretary written notice to that effect.

We made this proxy statement and our Annual Report to Stockholders for the fiscal year ended December 31, 2025 (the “2025 Annual Report”), available to stockholders on or about April 30, 2026.

We are an “emerging growth company” under applicable federal securities laws and therefore permitted to conform with certain reduced public company reporting requirements. As an emerging growth company, we provide in this proxy statement the scaled disclosure permitted under the Jumpstart Our Business Startups Act of 2012, including the compensation disclosures required of a “smaller reporting company,” as that term is defined in Rule 12b-2 promulgated under the Securities Exchange Act of 1934, as amended (the “Exchange Act”). In addition, as an emerging growth company, we are not required to conduct votes seeking approval, on an advisory basis, of the compensation of our named executive officers or the frequency with which such votes must be conducted, and we are not required to provide pay versus performance disclosure under Item 402(v) of Regulation S-K. We will remain an “emerging growth company” until the earliest of (i) the last day of the fiscal year following the fifth anniversary of our initial public offering (“IPO”) in October 2024; (ii) the last day of the fiscal year in which our total annual gross revenue is equal to or more than $1.235 billion; (iii) the date on which we have issued more than $1 billion in nonconvertible debt during the previous three years; or (iv) the date on which we are deemed to be a large accelerated filer under the rules of the Securities and Exchange Commission (the “SEC”). Even after we are no longer an “emerging growth company,” we may remain a “smaller reporting company.”

Important Notice Regarding the Availability of Proxy Materials for the Annual Meeting of Stockholders to be Held on June 26, 2026:

This proxy statement and the 2025 Annual Report are available for

viewing, printing and downloading atwww.ProxyVote.com.

A copy of our Annual Report on Form 10-K for the fiscal year ended December 31, 2025, as filed with the

SEC, except for exhibits, will be furnished without charge to any stockholder upon written request to

Septerna, Inc., 250 East Grand Avenue, South San Francisco, CA 94080, Attention: Corporate

Secretary. This proxy statement, and our Annual Report on Form 10-K for the fiscal year ended December 31, 2025, are also available on the SEC’s website atwww.sec.govand on the Investors page of our website atwww.Septerna.com.

PROXY STATEMENT

FOR THE 2026 ANNUAL MEETING OF STOCKHOLDERS