OneLetterLottery
Also: CodonCall, translation as a call-and-card game: why some cards finish sooner.
It is tempting to think that changing one letter in a protein’s recipe always breaks it. Usually it doesn’t: most single amino-acid changes change little or nothing, a few change everything — and the same spot can go either way. Draw a real variant, call its effect before the reveal, and learn to calibrate. Everything runs locally; nothing about you is collected.
This is the tool — a free calibration game. Watch for the two β6 draws of beta-globin: the same position, two different letters. Make your call on each before its reveal. Every variant + effect is listed in full below (works without JavaScript). A native version, when it ships, adds offline use; it never gates the web.
Loading the game… If it does not start, the full variant guide below still works.
Before you call it: guessing alone would be right about 1 time in 3.
Most first predictions in science miss. Checking is the point.
How to play. Press Start. A real amino-acid change appears — call its effect No / little, Mild, or Drastic (buttons or keys 1, 2, 3). The documented effect is revealed and your call is scored. Press Enter or Next to continue. There is no way to lose.
Why one letter can matter so much
In haemoglobin β, the swap at β6 (UniProt residue 7) from glutamate to valine puts an oily side chain on the protein's surface. In low oxygen, that patch binds a pocket on a neighbouring haemoglobin, and the molecules stack into long fibres that bend red blood cells into the sickle shape. The same spot changed to lysine (HbC) does not form those fibres, which is why the position alone does not set the outcome: the new letter matters as much.
Why not every letter is drastic
A protein’s sequence is a recipe, but proteins are robust: many positions tolerate a swap with little change, and only certain letters at certain spots matter a lot. Reading “one letter changed” as “it’s broken” is a common misreading. This game trains calibration — and the clearest lesson is the two beta-globin draws at position β6: the same spot, a different letter, and the reveal shows how far apart their effects are. These seven are famous variants, and famous ones are often drastic: across all human proteins, AlphaMissense predicts more than half of the possible single-letter changes to be benign (about 57%; see TolerancePaint).
The variants
Answer key — open it after you play
| Protein | Change | Effect | What it does |
|---|---|---|---|
| Beta-globin HBB · P68871 | β6 Glu → Val | Drastic | Sickle-cell disease (both copies) — the hemoglobin sticks into fibres. |
| Beta-globin HBB · P68871 | β6 Glu → Lys | Mild | Hemoglobin C — same spot, different letter: usually mild or symptom-free. |
| CFTR CFTR · P13569 | Phe508 deleted (ΔF508) | Drastic | The most common cystic-fibrosis change; the protein misfolds. |
| Glucose-6-phosphate dehydrogenase G6PD · P11413 | Asn126 → Asp (A+) | No / little | A common variant with near-normal activity — most carriers never notice. |
| Aldehyde dehydrogenase 2 ALDH2 · P05091 | Glu504 → Lys (ALDH2*2) | Mild | The alcohol-flush letter — much lower activity; a real but conditional effect. |
| Melanocortin-1 receptor MC1R · Q01726 | Arg151 → Cys | Mild | A red-hair / fair-skin letter: the receptor signals less, which changes pigment. Not a disease itself, but a known risk factor for skin cancer, including melanoma. |
| p53 TP53 · P04637 | Arg175 → His | Drastic | A cancer hotspot — cripples p53’s DNA-binding core. |
Methods & about
This is a teaching game, honest about being a simplification. Real variant effects depend on which copies you carry, background, and environment; the buckets here (no/little · mild · drastic) are lay summaries of well-documented cases, each verified before publishing. Structures are the real AlphaFold predictions fetched in your browser (shown for context; the exact residue is not highlighted, to avoid numbering confusion). The game keeps no score history, uses no accounts, and sends nothing anywhere. It is not a variant-effect predictor or a diagnostic.
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