We Reformed types know very well that “inability does not negate responsibility.” The very opening words of WCF 1.1 are in this vein: “the light of nature, and the works of creation and providence do so far manifest the goodness, wisdom, and power of God, as to leave men unexcusable,” and of course, at the core of Paul’s arguments in Rom 1-2 is that man knows the moral law by natural revelation, and stands in condemnation for violating it. Paul’s justification for “God’s wrath is revealed from heaven” is not “that’s just the way it is”, but “what can be known about God is plain to them, because God has shown it to them. … ever since the creation of the world, in the things that have been made. So they are without excuse.”
Paul’s argument, however, does not apply to the 4th commandment (note Paul does not accuse natural man of Sabbath-breaking here or anywhere else), because it is not a part of natural revelation. The pile of sins for which natural man will be judged is big enough without including violations of special revelation. As Mike Horton describes (in The Law of Perfect Freedom),
The Sabbath is unique among the Ten Commandments. It is not, I would maintain, stamped on the human conscience because of creation; rather it is an ordinance, like circumcision, for the redeemed community of Israel pointing forward to Christ. Whereas pagans know that setting up idols in the place of God is wrong, but do it anyway, it is difficult to find a universal principle of Sabbath. … one would be hard-pressed to simply take a native in the South Pacific and ask him or her to come up with anything equivalent to the Jewish Sabbath. That is because it is the only commandment of the 10 that is not given to all people by way of creation, but is a special gift for the people of God, pointing them in a unique way to their coming Messiah.
Calvin also highlights the uniqueness of the 4th commandment. From his commentary on Ezekiel 20:12 (this commentary is actually a transcription of lectures, which were cut off by Calvin’s death three lectures later):
To worship one God, to abominate idols, to use God’s name reverently, these things are, as I have said, the simple duties of piety in themselves: so the honor which sons pay to their parents is a duty pleasing to God in itself, like chastity, abstinence, and such like. But Sabbaths do not please God simply and by themselves. We ought, therefore, to look for another purpose, if we wish to understand the reason of this precept.
Most importantly, there is biblical evidence that the 4th commandment is distinct from its neighbors. Note in these passages how the Sabbath is set apart from statutes, rules, laws, and commandments:
Ezek 20:11–: I gave them my statutes and made known to them my rules, by which, if a person does them, he shall live. Moreover, I gave them my Sabbaths, as a sign between me and them, that they might know that I am the Lord who sanctifies them. But the house of Israel rebelled against me in the wilderness. They did not walk in my statutes but rejected my rules, by which, if a person does them, he shall live; and my Sabbaths they greatly profaned.
Neh 9:13-14: You came down on Mount Sinai and spoke with them from heaven and gave them right rules and true laws, good statutes and commandments, and you made known to them your holy Sabbath and commanded them commandments and statutes and a law by Moses your servant.
Think I’m stretching it? Even Westminster agrees! Without following through with the implications, LC 121 cites Neh 9:14 as proof that “there is less light of nature for” the 4th commandment.
My point? Because the contents of the 4th commandment are not included in natural revelation, WCF 21.7 is incorrect in asserting that the Sabbath commandment is a “positive, moral, and perpetual commandment binding all men in all ages.”