The way to understand Dillard's statement in Pilgrim at Tinker Creek is to fix it in its context, which is all metaphorical and jumping from one figure of speech to another with very few solid pieces to sink one's teeth into, metaphorically speaking. Dillard is discussing the existence of the...
The way to understand Dillard's statement in Pilgrim at Tinker Creek is to fix it in its context, which is all metaphorical and jumping from one figure of speech to another with very few solid pieces to sink one's teeth into, metaphorically speaking. Dillard is discussing the existence of the universe and the place of creatures in that universe. To this end she is contemplating fish in Tinker Creek and collecting mountains of generalized facts. She states that she is overwhelmed by the effort to see through the veil darkly, metaphorically speaking, into things so vast and indecipherable; she evens leaves the contemplation of birthrates and populations (both tied inexorably to climate change) to those who dare to contemplate it, as she dares not.
This brings us to the quote in question. Here Dillard is stating that the primary question, the most essential question, "the one crucial one" about the creation of the universe is also one that is too big for her to contemplate. She describes this question as a "blank one"--using a school allusion--as a tough question left blank on a big exam--no answer. She also describes the question of the creation of the universe as the question of the creation of "the existence of something" that is a "sign" to "nothing" while at the same time being an "affront to nothing." This employs figures of speech and gives literary personification to nothingness, to the void that was before matter trumped antimatter and became something ("trumped" in the terms of a bridge game allusion).
To summarize, Dillard is saying that the primary question, which is the question of how the universe was created, is one so big and so overwhelming--far more so than birthrates and world population--especially since the creation of the universe created a something that replaced and metaphorically affronted (i.e., insulted the dignity of) a personified nothingness while giving it some unidentified "sign," it is so big that she must leave it blank, unaddressed, uncontemplated, unpursued, unanswered.
This quote from Pilgrim at Tinker Creek might be considered oblique (i.e., indirect, not straightforward) or perhaps obtuse (i.e., blunt, not sharply delivered) but it cannot be considered ambiguous. Ambiguous is that which is equivocal, open to several modes of understanding. Ambiguous is very different from unclear. This quote, indeed the whole passage, may be unclear to readers who aren't able to sort through all the metaphor and creative punctuation; but it is not equivocal and open to many different meanings; it is not ambiguous.