## AGR3
- **UniProt:** Q8TD06 · **batch:** proteostasis-batch-2026-06-03 · **review status:** COMPLETE
- **PN placement:** `ER proteostasis|Folding enzyme|Protein disulfide isomerases` ; **PN-node mapping:** group `mapped` ok_for_propagation GO:0003756 protein disulfide isomerase activity (goa_status=new_to_goa); class/branch `no_mapping`.
- **Consistency:** Major, well-supported divergence. PN places AGR3 in the PDI folding-enzyme group and projects GO:0003756 PDI activity as new-to-GOA. Deep research (falcon, citing Nguyen 2018 crystal structure) and the review both reject canonical PDI activity: AGR3 lacks the CXXC catalytic motif (has DCYQS, only one cysteine; Cys71 solvent-exposed, reduced state), so classical thiol-disulfide exchange is unlikely. The review's core_function explicitly says "current evidence does not justify a canonical protein disulfide isomerase activity annotation." Review YAML, notes, and deep research are internally consistent; they jointly contradict the PN projection (intentionally).
- **PN story / NEW pressure:** PN asserts a PDI MF not in GOA. GO:0003756 is real/non-obsolete, but the gene-level evidence over-reaches for AGR3. Instead the review proposes two NEW process annotations from the mouse-knockout/airway physiology: GO:0003351 epithelial cilium movement involved in extracellular fluid movement and GO:0019722 calcium-mediated signaling (ISS from PMID:25751668). Verdict on PN PDI: **over-reaches** (family-fold inference, not catalytically supported). Verdict on review NEW cilium/Ca terms: defensible ADD (already in review).
- **Mapping strategy:** This gene should NOT propagate the node's GO:0003756 mapping. The PDI group mapping is correct for catalytically active members but AGR3 is a divergent, likely-inactive member — a clear case for gene-level gating against the group projection (analogous to AIP vs PPIase group).
- **Evidence alignment:** PN dossier has no reference titles. Review/notes anchor on Nguyen 2018 (structure, DCYQS), Bonser/PMID:25751668 (Agr3-KO ciliary beat frequency, mucociliary clearance), PMID:12592373 (dystroglycan/C4.4a), PMID:18086916 (ER retrieval). PMID:25751668 is abstract-only (full_text_unavailable) — ISS NEW terms appropriately conservative.
- **Verdict:** PN PDI projection (GO:0003756) over-reaches for AGR3; correctly overruled — best-supported role is Ca-dependent ciliary beat regulation. **Recommended edits:** none to YAML. [MAP]: flag ER-proteostasis "Protein disulfide isomerases" group GO:0003756 as requiring gene-level catalytic gating; AGR3 (DCYQS, no CXXC) should be excluded/`no_mapping`.