UniProt CAUTION notes

Using curators' written warnings to find over-annotated GO functions

AI Gene Review · projects/UNIPROT_CAUTION_NOTE · 2026

Bottom line

  • 14,830 CAUTION notes on 14,513 reviewed UniProt entries; 7,219 flag contested, reclassified, pseudoenzyme, retracted or artifact functions.
  • Two queries turn them into GO flags. Locally, strong flags matched curators' actions 8 of 11 times; UniProt-wide they rediscovered known pseudoenzymes.
  • 13 human genes reviewed; nine pseudoenzymes (CRMP family, ILK, ROR1, CASP12, AZIN2) each had an inferred catalytic row removed.

What a CAUTION note is

  • A free-text CC -!- CAUTION: comment in the UniProt flat file: the curator warns the reader.
  • Distinct from the structured SEQUENCE CAUTION block (gene-model issues), which we exclude.
  • Example (S. pombe Epe1): "lacks the iron catalytic His … has no histone demethylase activity in vitro".
  • These are exactly the cases where IEA/IBA domain-to-function mappings go wrong.

What the notes are about

Query A: positive parent, NOT-ed child

Query B: the CAUTION paper, cited positively

  • A CAUTION cites a PMID; GO uses the same PMID for a positive annotation, with no NOT from it.
  • 69 flags / 39 local genes; 1,140 UniProt-wide.
  • Real catches: CHMP1A metallopeptidase from a mistranslated ORF (REMOVE); ENDOU serine peptidase from a refuted paper; HDAC6 histone deacetylase.
  • Over-flags: a paper makes several claims and only one is doubted. Needs activity-level matching, not PMID matching.

Pseudoenzymes reviewed

Gene Removed inferred catalytic term Real core role
DPYSL2/3, CRMP1, DPYSL5 hydrolase activity (IEA) cytoskeletal regulators, semaphorin signalling
DPYSL4 cyclic-amide hydrolase (IBA); hydrolase UNDECIDED same family
ILK protein kinase activity IPP-complex scaffold
ROR1 protein kinase activity Wnt coreceptor
CASP12 cysteine-type peptidase activity inflammasome modulator
AZIN2 catalytic activity antizyme inhibitor

Status and next steps

  • Done: survey, 4,046-candidate worklist, Queries A/B local + UniProt-wide, 13 validated reviews.
  • Pending: report 9 local + 97 UniProt-wide same-term GOA conflicts (positive and NOT on one term) upstream; audit 255 retracted-reference candidates; shrink the 7,605-note "other" bucket.
  • Lesson: the GO NOT is the curated twin of a CAUTION. CAUTIONs with no NOT are the best targets.

Read more: projects/UNIPROT_CAUTION_NOTE.md · projects/UNIPROT_CAUTION_NOTE/uniprot_wide_queries.md