Safety and CTA identity

Only normal-tissue risk evidence can make a protein Unsafe. CTA admission also requires cancer expression, Reproductive evidence and adequate coverage.

One-page PDF · Actual thresholds

Current decision logic

Qualifying normal-tissue or applicable clinical safety exclusion -> Unsafe

Acceptable safety AND one qualifying cancer sample
AND a qualifying Reproductive route after concentration assessment
AND complete required coverage -> CTA

Otherwise: complete normal screen passes -> one named Other category
Remaining missing normal evidence or normal-screen holds -> Unassessed

Reproductive means reproductive, placental, extraembryonic, embryonic and fetal. Named branches retain anatomical and developmental precision. The current measured routes are full mapped HPA reproductive bulk RNA ≥5 nTPM, supported reproductive cell RNA ≥5 nTPM with ≥20 reads, reliable positive reproductive IHC, or supported Tyser/Petropoulos embryonic lineage mean ≥5 TPM (≥20 cells, ≥5 positive cells, ≥10% positive at ≥1 TPM). The current inputs do not cover every fetal stage.

Cancer requires one sample >0 TPM or HPA pTPM, or reviewed reliable tumor protein, without a normal-expression ratio. This establishes qualifying RNA, not necessarily translated protein, presentation or expression in a specified fraction of patients.

Required coverage includes the fixed GTEx v11 52-context bulk panel, every member locus, plus the existing normal bulk/cell/immune panels. Optional DICE/cornea absence does not block admission; observed counterevidence still counts. A missing measurement never becomes zero.

Safety remains an independent assessment

Vital/Protected above-ceiling RNA or qualifying protein evidence can establish Unsafe. Manageable excess blocks CTA without automatically establishing Unsafe. Negative IHC adjusts the RNA ceiling only with the required antibody and local-cell coverage. Missing or unrelated staining is not negative evidence. The exact numeric rules remain in the current policy table.

Reviewed TCR-T clinical experience can add one RNA ladder step, capped at the Enhanced-negative ceiling. It does not change the IHC grade or any cancer, Reproductive, coverage or diffuseness criterion. The exact epitope/HLA/product limitations and serious-event attribution remain attached to the protein-level credit. Clinical evidence and SAE review.

Profile concentration

The old rule requiring a Reproductive value above the highest normal measurement has been removed. A single normal outlier should not define whether a protein is diffuse. The score averages N / (N + R) over a fixed anatomy-weighted normal panel, including Disposable tissues. N is that tissue's RNA; R is the source's Reproductive reference. It is not a percentage of tissues.

The HPA v23 >10% boundary is active for completely measured adult/placental profiles with a positive RNA reference and a qualifying RNA or IHC association. RNA-only association still requires 5 nTPM. A zero RNA reference leaves concentration unassessed even when IHC qualifies. Disposable tissues count; Permissive thymus is excluded from both the comparator and the reference. The fixed panel is 38 contexts / 29 anatomy units. A failed route with no other qualifying Reproductive route and clear safety becomes Other:Diffuse. MTCP1 is one example (24.53%). Independent Unsafe assignments do not change.

A weak adult reference does not decide embryonic identity. Supported embryonic routes remain eligible with concentration explicitly unassessed until compatible developmental/adult data exist. Missing HPA comparisons remain unassessed; the GTEx core remains mandatory. Method and measured impacts.

MAGE-A4, NY-ESO-1, PRAME, CTAG2 and XAGE1A/B retain CTA classification and GTEx coverage. Removing the old maximum veto alone would admit TGIF2-RAB5IF and ATF7-NPFF; both lack the required GTEx core and remain unassigned for that explicit reason.

All entries called Proteins collapse identical selected reference sequences; originating loci remain listed. This is not a catalog of every alternative isoform or modified proteoform. Human measurements and thresholds do not transfer to dog or mouse through orthology.

Other reasons and independent attributes

Other reason	Proteins	Meaning
Nonreproductive	448	No qualifying reproductive / placental / embryonic-fetal presence
Reproductive	0	Reproductive presence qualifies; cancer presence does not
Diffuse	5	Both presence requirements pass; reproductive concentration fails

Normal abundance, tumor support and adult Disposable expression are separate attributes in cta_selection.profiles(). Disposable is an adult tissue designation; embryonic/fetal/placental measurements do not change it. The 2-unit descriptive floor is not a safety ceiling. Simple funnel and four example proteins.