# IndoVarPriority

- **Event:** [Built with Claude: Life Sciences](https://cerebralvalley.ai/e/built-with-claude-life-sciences)
- **When:** Jul 7 at 12:00 PM – Jul 14 at 12:00 AM (EDT)
- **Where:** Online
- **Team:** [Nirmala Kadali](https://cerebralvalley.ai/u/29-2004)
- **GitHub:** https://github.com/Nirmala-k/IndoVarPriorityScore
- **Demo video:** https://1drv.ms/v/c/4cd4940fed94a88c/IQByN52ingZyTYIcVJCXgbDhATWj4V1AnQlqpdMlpQfO6Vc?e=PBL6vC
- **Gallery:** https://cerebralvalley.ai/e/built-with-claude-life-sciences/hackathon/gallery
- **Page:** https://cerebralvalley.ai/e/built-with-claude-life-sciences/hackathon/gallery/153

VPS - Variant Priority Score

Current genetic-testing tools (ClinVar, InterVar, Franklin) can only classify variants that already exist in reference databases - roughly 80% of which are European-ancestry. For the 2 billion people of South Asian descent, most clinically relevant variants are novel: never seen, never classified, never scored. A "negative" report is often not truly negative - it is uninformative.

We built VPS, a phenotype-driven, population-aware, inheritance-aware engine that scores exactly these novel and uncertain-significance variants. A clinician starts from a clinical question, not a gene list; VPS assembles the relevant gene panel, then scores every variant on five transparent axes , pathogenicity (blending the ESM-2 protein language model, the Evo2 DNA language model, and REVEL/AlphaMissense/CADD), inheritance-aware population frequency (Whiffin–Ware maximum credible allele frequency), domain criticality, regional pathogenic density, and AlphaFold structural confidence , into a single 0–100 priority with a plain-English rationale for each variant. Crucially, the frequency axis is inheritance-specific: the same allele can score consistent with a recessive disease yet be far too common for a dominant one, so every panel is split by inheritance model.

Applied to IndiGenomes (1,029 open-source Indian whole genomes, CSIR-IGIB), we scored 3,594 novel variants , absent from every global database , across 6 inheritance panels and 52 genes spanning Wilson disease, sudden cardiac death (recessive and dominant), primary immunodeficiency/HLH, treatable neurometabolic disease, and hereditary breast/ovarian cancer, at 100% coverage across all variant classes (missense, truncating, in-frame indel, and non-coding). As blinded validation, known ClinVar Pathogenic/Likely-Pathogenic variants scored measurably higher than known Benign variants (Wilson: 64.3 vs 57.9) without ClinVar labels ever being used as scoring input — the separation comes purely from independent evidence.

This matters because every one of these 3,594 variants sits in a gene where a missed variant can mean a preventable death , a homozygous cardiac variant in a child, a treatable neurometabolic disorder with a closing therapeutic window, a hereditary-cancer variant invisible to a European-calibrated panel. VPS is a framework for ethnicity-aware variant interpretation: same data, same patient, a different  and defensible answer, because it scores what other tools call negative.

(Research-triage tool it ranks which variants warrant functional follow-up, not a clinical diagnostic.)

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