Allele-specific ASO — coverage explorer

Adjust the assumptions below to see how much of a gene's global patient population can be reached by allele-specific ASOs. Coverage is haplotype-level (the paper metric): a patient counts ½ per haplotype that carries a targetable variant allele. Gene  · 
ASO filterswhich ASOs qualify for each candidate allele · biallelic + footprint isolation + frequency (0.05–0.95) + transcriptome off-target applied upstream
Selectivity threshold (ΔΔG ≥)
kcal/mol. 4 is the paper's allele-selectivity threshold (the default). At ΔΔG ≥ 4, fewer than 1% of off-target transcripts stay within 5-fold potency of the target (Watt et al. 2020).
Screening & selectionthe development programme: screen ASOs under attrition, then advance the best K winners to the clinic
Per-ASO success rate (q)
1/500 · full pipeline 1/20 · bench hit 1/5
Probability a single synthesised ASO clears. An allele is reached if ≥1 of its ASOs clears.
ASO screening budget
How many ASOs you evaluate (simulate pass/fail against, at rate q). Spread across the highest-coverage alleles, fully testing each before the next; an allele is won once one of its ASOs passes, and the K highest-coverage winners are advanced to the clinic.
Min valid ASOs per allele
An allele is only pursued if it has at least this many qualifying ASOs.
Final portfolio (K alleles)
From the alleles whose ASOs pass screening, keep the (up to) K that jointly maximise coverage, re-optimised on whatever cleared, not a fixed ranking.
Costsper-site: create & test the two allelic constructs · per-ASO: synthesise & screen one oligo
Cost per site
Fixed cost per distinct genomic site screened: both allelic constructs are created and tested for selectivity. The two alleles of a SNP share their constructs, so a site is charged once (see the site count on the "Alleles screened" card).
Cost per ASO
Cost to synthesise and screen one ASO. Multiplied by the ASOs screened.
– expected coverage
ASOs screened
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Alleles screened
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Expected portfolio (≤K)
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Ceiling (best K)
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Total cost
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Coverage distribution · 1,000 Monte-Carlo screens under attrition

Coverage vs ASO budget · expected coverage & 5–95% spread under attrition

Top-K portfolio alleles · the jointly-optimal K, if all screened alleles pass

rsIDpositionallele freqASOsP(pass)marg. cov
Reading q: the bench in-vitro hit-rate (≈1/20 — find a potent, selective ASO among those synthesised) and the full preclinical-to-clinic pass rate (≈1/500) are different stages and swing the answer widely. Ceiling is coverage if every pursued lead yields a working ASO (no attrition). Targetability is heterozygosity for the variant allele; coverage concentrates in a few common, high-LD alleles. Built from ; selectivity + transcriptome off-target + isolation filters already applied.