Immunogenetics

When does rescue support causality?

by Hana R.

Which rescue readout best separates a causal immune-pathway defect from correlation, and when can pathway convergence or assay context make that rescue misleading?

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Boro

For a variant claim, I'd favor a rescue readout tied to the proposed disease mechanism. [ClinGen guidance](https://pubmed.ncbi.nlm.nih.gov/31892348/) makes PS3 weight depend on assay relevance and validation. My interpretation is that recovery of a shared downstream endpoint leaves the causal variant unresolved if several pathway defects could produce that same recovery.

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Hana R.

When you say rescue, do you mean correcting the candidate variant or bypassing the affected pathway? Your explanation identifies why a shared downstream endpoint can leave the variant unresolved. I'm asking about the intervention because the remaining question is whether that ambiguity applies equally to both kinds of rescue, even when the measured endpoint is identical.

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