DNA, genes, and proteins
Your body runs on instructions stored in DNA. DNA is written with just four chemical "letters" (A, C, G, and T), arranged in a long sequence. A gene is one section of that sequence — a single instruction, usually a recipe for making one protein. Proteins do the actual work in your cells: they build structures, carry signals, and run the chemistry of life. The whole set of your DNA is your genome, and it is packaged into 46 chromosomes — 23 inherited from each parent.
What a variant is
A variant is a spelling change in the DNA — a place where your sequence differs from the common reference. Most variants are completely harmless; we all carry millions of them, and they are part of normal human difference. A few variants change a protein enough to affect health. The older word for a variant was "mutation," but "variant" is now preferred because it does not assume the change is harmful.
Variants come in different shapes:
- A missense variant swaps one protein building block for another.
- A nonsense variant inserts a premature "stop," cutting the protein short.
- A frameshift (from an insertion or deletion) shifts the reading frame, garbling everything after it.
- A deletion or duplication removes or repeats a stretch of DNA — sometimes a whole gene or more.
How variants are named (HGVS)
Labs describe variants in a standard shorthand so any lab anywhere means exactly the same change. This is the HGVS notation. For example, a coding-sequence change might be written c.1045_1046del (letters 1045–1046 of the coding sequence are deleted), and its effect on the protein as p.Gln349fs (a frameshift starting at protein position 349). You do not need to read the code fluently — but recognizing the parts (c. for the coding DNA, p. for the protein, del / dup / > for the kind of change) helps you follow a genetic report.
Pathogenic, VUS, benign — what the labels mean
When a lab reviews a variant, it sorts it into one of five tiers, following criteria from the American College of Medical Genetics (ACMG):
- Pathogenic — strong evidence this variant causes disease.
- Likely pathogenic — good but not conclusive evidence it causes disease.
- Variant of uncertain significance (VUS) — not enough evidence yet to say either way. A VUS is genuinely a question mark, not a hidden "yes." Many VUS are later reclassified as benign as more data arrives.
- Likely benign — good evidence it is harmless.
- Benign — strong evidence it is harmless.
These labels can change over time as labs gather more cases. That is normal, not a mistake — it is the science catching up.
How a condition is inherited
- X-linked — the gene sits on the X chromosome. Because of how the X chromosome works, X-linked conditions often affect boys and girls differently (more on this in the CASK module).
- Inherited vs. de novo — a variant can be passed down from a parent (inherited), or it can be brand new in the child and present in neither parent (de novo). De novo variants are common in rare neurodevelopmental conditions.
- Mosaicism — sometimes a variant is present in only *some* of a person's cells, not all of them. This is called mosaicism, and it can affect how a condition shows up and whether it can be passed on.
> This is general education, not medical advice. A clinical-genetics team — a geneticist and a genetic counselor — is who interprets what a specific variant means for a specific person.