If the filing person has previously filed a statement on Schedule 13G to report the acquisition which is the subject of this Schedule 13D, and is filing this schedule because of Rule 13d-1(e), Rule 13d-1(f) or Rule 13d-1(g), check the following box  ¨.

NOTE: Schedules filed in paper format shall include a signed original and five copies of the Schedule, including all exhibits. See Rule 13d-7 for other parties to whom copies are to be sent.

The information required on the remainder of this cover page shall not be deemed to be “filed” for purpose of Section 18 of the Securities Exchange Act of 1934 (“Act”) or otherwise subject to the liabilities of that section of the Act but shall be subject to all other provisions of the Act (however, see the Notes).

(1)    Based on 377,249,186 shares of Class A Common Stock, par value $0.0001 per share, of Sema4 Holdings Corp., a Delaware corporation (the “Issuer”), outstanding as of April 30, 2022, as set forth in the Issuer’s Registration Statement on Form S-1 (File No. 333-264626) filed with the SEC on May 2, 2022.

This Schedule 13D is filed with respect to the Class A common stock, par value $0.0001 per share (“Sema4 Common Stock”), of Sema4 Holdings Corp., a Delaware corporation (“Sema4” or the “Issuer”). The principal executive offices of the Issuer are located at 333 Ludlow Street, North Tower, 8th Floor, Stamford, Connecticut 06902.

(a), (f)    This Schedule 13D is filed by OPKO Health, Inc., a Delaware corporation (the “Company”, “OPKO” or the “Reporting Person”). Set forth on Schedule I to this Schedule 13D are the name, business address and present principal occupation or employment and citizenship of each executive officer and director of the Company.

On September 7, 2018, the Securities and Exchange Commission (the “SEC”) filed a civil complaint in the Southern District of New York (the “Complaint”), against a number of individuals and entities, including OPKO and its CEO and Chairman, Dr. Phillip Frost and Frost Gamma Investments Trust (“FGIT”), an entity of which Dr. Frost is trustee. In December 2018, OPKO, Dr. Frost and FGIT entered into settlements with the SEC, which, upon approval by the court in January 2019, resolved the claims against OPKO, Dr. Frost and FGIT. Under the terms of the settlement between the SEC, Dr. Frost and FGIT, and without admitting or denying any of the allegations in the Complaint, Dr. Frost agreed to injunctions from violations of Sections 5(a) and (c) and 17(a)(2) of the Securities Act of 1933, as amended (the “Securities Act”), claims which may be satisfied by strict liability and negligence, respectively, and Section 13(d) of the Securities Exchange Act of 1934, as amended (the “Exchange Act”), also a strict liability claim; to pay a civil monetary penalty, disgorgement and pre-judgment interest, which have been paid; and to be prohibited, with certain exceptions, from trading in penny stocks. Pursuant to the settlement between OPKO and the SEC, and without admitting or denying any of the allegations of the Complaint, OPKO agreed to be enjoined from future violations of Section 13(d) of the Exchange Act, a claim that requires no showing of scienter, and to pay a civil monetary penalty, which has been paid.

On January 14, 2022, the Company entered into an Agreement and Plan of Merger and Reorganization (the “Merger Agreement”) with Sema4, its two wholly owned subsidiaries, Orion Merger Sub I, Inc., a Delaware corporation, and Orion Merger Sub II, LLC, a Delaware limited liability company, GeneDx Inc., a New Jersey corporation and an indirect wholly owned subsidiary of the Company (“GeneDx”), and GeneDx Holding 2, Inc., a Delaware corporation and wholly owned subsidiary of the Company.

On April 29, 2022, the transactions contemplated by the Merger Agreement closed (the “Closing”), with GeneDx (now a Delaware limited liability company) surviving the mergers contemplated thereby as a wholly owned indirect subsidiary of Sema4.

At Closing, Sema4 paid to the Company aggregate consideration of $150.0 million in cash (before deduction of transaction expenses and other customary purchase price adjustments), together with 80.0 million shares of Sema4 Common Stock (the “Closing Shares”). Additionally, Sema4 has agreed to pay the Company up to an additional $150.0 million, which may be paid in Sema4 Common Stock, cash or a combination thereof in Sema4’s discretion,

subject to GeneDx achieving certain revenue targets for the fiscal years ending December 31, 2022 and 2023 (the “Milestone Consideration”). If the Milestone Consideration in respect of the year ending December 31, 2022 becomes payable in full, then the Milestone Consideration conditionally payable in respect of the year ending December 31, 2023 is subject to acceleration in the event of a change in control of Sema4.

All Common Shares beneficially owned by the Company are held solely for investment purposes. The Company has no present plan or proposal that relates to, or could result in, any of the events referred to in paragraphs (a) through (j), inclusive, of Item 4 of Schedule 13D. Pursuant to the terms of the Merger Agreement, the Company designated one of its current independent directors, Richard C. Pfenniger, Jr., as a director designee to serve on Sema4’s board of directors (the “Sema4 Board”). At a special meeting of Sema4’s stockholders held on April 27, 2022, Mr. Pfenniger was elected to serve as a director on the Sema4 Board for a term expiring at Sema4’s 2024 annual meeting of stockholders.

(1)    Based on 377,249,186 shares of Sema4 Common Stock outstanding as of April 30, 2022, as set forth in the Issuer’s Registration Statement on Form S-1 (File No. 333-264626) filed with the SEC on May 2, 2022.

In connection with the transactions contemplated by the Merger Agreement, on January 14, 2022, the Company entered into a Shareholder Agreement (the “Shareholder Agreement”) with Sema4, pursuant to which the Company

has agreed to, among other things, be subject to a lock-up period with respect to its shares of Sema4 Common Stock (the “Lock-Up Shares”), which include the Closing Shares, together with any shares issued in respect of the Milestone Consideration (the “Milestone Shares”). The lock-up period extends from the Closing until (a) in the case of the Closing Shares, April 29, 2023, (b) if and to the extent earned, in the case of the Milestone Shares for the first payment in respect of the Milestone Consideration, the date that is one (1) year from the date of issuance for such stock and (c) if and to the extent earned, in the case of the Milestone Shares for the second payment in respect of the Milestone Consideration, the date that is six (6) months from the date of issuance for such stock (as applicable, the “Lock-Up Period”). During this Lock-Up Period, the Company may not transfer any Lock-Up Shares or engage in any short sales or other hedging or derivative transactions, subject to certain limited exceptions. Following such Lock-Up Period, the Company has agreed to dispose of its Lock-Up Shares in a marketed sale process under certain circumstances for so long as it continues to hold at least 5% of the outstanding shares of Sema4 Common Stock.

Exhibit 1.    Agreement and Plan of Merger and Reorganization, dated as of January 14, 2022, by and among the Company, Sema4, Orion Merger Sub I, Inc., Orion Merger Sub II, LLC, GeneDx Inc. and GeneDx Holding 2, Inc. (incorporated by reference to Exhibit 2.1 to the Company’s Current Report on Form 8-K filed with the SEC on January 18, 2022).

Exhibit 2.    Shareholder Agreement, dated as of January 14, 2022, by and among the Company and Sema4 Holdings Corp (incorporated by reference to Exhibit 10.1 to the Company’s Current Report on Form 8-K filed with the SEC on January 18, 2022).