**Core Concept**
A missense mutation involves a single nucleotide change that results in the substitution of one amino acid for another in the protein sequence. In sickle-cell anemia, a point mutation in the HBB gene changes glutamic acid to valine at position 6 of the β-globin chain, altering hemoglobin’s structure and function.

**Why the Correct Answer is Right**
The mutation replaces glutamic acid (Glu) with valine (Val) at position 6 of the β-globin chain due to a single nucleotide substitution (A → T) in the DNA. This change is a **missense mutation** because only one amino acid is substituted, not a deletion, insertion, or frameshift. The altered hemoglobin (HbS) polymerizes under low oxygen conditions, causing red blood cells to sickle, demonstrating the functional consequence of this single amino acid change.

**Why Each Wrong Option is Incorrect**
Option A: Deletion involves the loss of one or more nucleotides, leading to a shorter protein or frameshift. This is not the case here, where only one amino acid is substituted.
Option B: Frameshift mutations occur due to insertions or deletions not divisible by three, altering the reading frame and producing a completely different, often nonfunctional protein. This mutation does not disrupt the reading frame.
Option C: Insertion adds nucleotides, shifting the reading frame. No nucleotides are added here—only a substitution occurs.

**Clinical Pearl / High-Yield Fact**
Missense mutations are common in genetic disorders like sickle-cell anemia and cystic fibrosis. Remember: **"Missense = one amino acid changed"** — a key differentiator from deletions, insertions, or frameshifts.

✓ Correct Answer: D. Missense