**Core Concept**
Systemic mastocytosis is a rare disorder characterized by the abnormal accumulation of mast cells in various organs, including the skin, bone marrow, and internal organs. The disease is often associated with mutations in genes involved in the regulation of mast cell proliferation and survival.

**Why the Correct Answer is Right**
The most common gene mutation associated with systemic mastocytosis is the KIT D816V mutation. This mutation occurs in the KIT gene, which encodes a receptor tyrosine kinase involved in mast cell signaling. The KIT D816V mutation leads to the constitutive activation of the KIT receptor, resulting in uncontrolled mast cell proliferation and survival. This mutation is present in the majority of systemic mastocytosis cases and is often used as a diagnostic marker.

**Why Each Wrong Option is Incorrect**
* **Option A:** The c-KIT gene is the correct gene involved in systemic mastocytosis, but the specific mutation is not mentioned.
* **Option B:** The JAK2 V617F mutation is associated with myeloproliferative neoplasms, such as polycythemia vera, but not systemic mastocytosis.
* **Option D:** The NPM1 mutation is associated with acute myeloid leukemia, but not systemic mastocytosis.

**Clinical Pearl / High-Yield Fact**
The KIT D816V mutation is a key diagnostic marker for systemic mastocytosis and can be detected in mast cells from affected organs or in peripheral blood. A high degree of suspicion for systemic mastocytosis should be maintained in patients with unexplained anaphylaxis or mast cell-related symptoms.

**Correct Answer: C. KIT D816V**