Transcription factor binding, cis-regulatory elements (cCREs), chromatin accessibility, and regulatory annotation using JASPAR (motifs), ENCODE (cCREs, ChIP-seq), RegulomeDB (regulatory variant scoring), UCSC — plus sequence-based deep-learning prediction of regulatory activity and non-coding variant effects (AlphaGenome, Enformer, Borzoi, ChromBPNet, Evo 2). Use for regulatory element annotation, TF-binding-site prediction, regulatory-region functional impact assessment, and predicting how a non-coding variant or a raw DNA sequence affects expression/chromatin/accessibility. Use this whenever a user asks what regulates a gene, whether a SNP hits a regulatory element, or to predict a non-coding variant's functional effect from sequence.

Rare disease genomics — disease identification (Orphanet), causative gene discovery, gene-disease validity (GenCC), variant interpretation (ClinVar), and translational research (ClinicalTrials.gov, drug repurposing for orphans). Use for rare-disease-gene curation, novel-gene-discovery analysis, and rare-disease drug-development support.

Rare disease differential diagnosis from patient phenotype — HPO term matching to candidate diseases (Orphanet, OMIM), gene panel prioritization, ACMG variant interpretation, and structure-based variant analysis. Use for diagnostic odyssey assistance, phenotype-to-disease ranking, and genetic-counseling differential generation.

Find and retrieve proteomics datasets from MassIVE and ProteomeXchange. Search by species, keyword, or accession; retrieve detailed metadata (instruments, publications, species, PTMs studied). Use for locating public proteomics datasets to reanalyze, comparing instrument/protocol coverage across studies, and pre-download dataset evaluation.

Mass-spec proteomics analysis — protein identification, quantification (LFQ, TMT, iTRAQ), differential expression (tumor vs normal, treatment vs control), PTM identification, and pathway enrichment on protein lists. Use when you have proteomics MS output, asking about protein abundance differences, or doing systems-level proteomic interpretation.

AI-guided de novo protein design — RFdiffusion backbone generation, ProteinMPNN sequence design, structure validation (pLDDT, pTM, MPNN scores). Use for designing therapeutic protein binders, novel scaffolds, enzyme variants, and miniprotein/protein-interface design before experimental validation.

Protein structure retrieval from RCSB PDB, PDBe, and AlphaFold with disambiguation, quality assessment (resolution, R-factor, pLDDT), and metadata. Distinguishes high-quality experimental (X-ray under 2 Angstrom) vs predicted vs medium-quality structures. Use for fetching protein structures, structure-quality comparison, and selecting structures for drug design or modeling.

Protein 3D structure prediction from sequence — ESMFold de novo prediction, AlphaFold database retrieval, experimental structures from RCSB, ProtVar variant impact assessment, ProtParam sequence properties. Use for structure prediction when no experimental structure exists, fold-confidence scoring, and structure-guided variant interpretation.

Given a PDB structure, produce a per-residue annotation table: which residues sit at a binding interface (vs a partner chain), which line a ligand pocket, which are buried (core) vs solvent-exposed (surface), and optionally secondary structure. This is the structural track drawn under a DMS heatmap and the structural prior SAE feature drops are read against. Use when you need to anchor a variant-interpretation or DMS analysis to the protein's actual physical context.

Interpret a missense variant via ESMC-6B Sparse Autoencoder (SAE) feature activations. For a given protein + variant, computes which interpretable SAE features (catalytic, ligand-binding, PTM, structural motif, domain, etc.) are lost or gained at the mutation site. Use when standard pathogenicity scores (AlphaMissense, ClinVar) say a variant is damaging but you need a MECHANISTIC explanation — e.g. 'why is this variant LoF?' Complements (does not replace) variant-interpretation and variant-to-mechanism skills, which focus on ACMG classification or regulatory mechanism.

Post-translational modification (PTM) analysis — phosphorylation, ubiquitination, acetylation, glycosylation, methylation. Uses iPTMnet (sites + enzymes), ProtVar (functional consequences), UniProt (baseline), STRING, ELM (linear motifs), MassIVE/ProteomeXchange (experimental). Use for PTM site annotation, kinase-substrate identification, and PTM-disease associations.

Propose the mechanism by which a missense variant causes loss-of-function (LoF), synthesizing evidence from 5 independent layers: AlphaMissense pathogenicity, AlphaFold structural context, ESMC sequence likelihood, SAE feature disruption, and DynaMut2 stability ΔΔG. Distinguishes 'structural stability LoF' (mis-folding) from 'direct functional disruption' (catalytic / binding / PTM site damage). Use for coding missense variants where you need a mechanistic causal model, not just a pathogenicity score.

Protein-protein interaction (PPI) network analysis — STRING (predicted + experimental), BioGRID (curated), SASBDB (small-angle scattering). Distinguishes physical interactions (binding) from functional associations (co-expression, co-regulation). Use for interactome queries, complex partner identification, and pathway-level interaction analysis.

Post-market safety surveillance and recall/adverse-event RETRIEVAL across the full spectrum of FDA-regulated products that are NOT covered by the drug-AE signal skills: medical devices, food / dietary supplements / cosmetics, veterinary drugs, and drug supply (shortages). Orchestrates openFDA endpoints (MAUDE device adverse events + device recalls + 510(k), CAERS food/supplement/ cosmetic adverse events, veterinary adverse events, drug shortages, and cross-product enforcement/recall reports). USE WHEN the user asks: "are there adverse events for [device / pacemaker / infusion pump / insulin pump]", "device recalls for [firm/product]", "supplement / vitamin / cosmetic adverse reactions", "is [drug] in shortage", "what injectables are on shortage", "veterinary / animal adverse events for [drug] in [dog/cat/horse]", "food recall for listeria", "MAUDE report for [device]", "CAERS reactions for [brand]". DO NOT USE for drug adverse-event SIGNAL detection or disproportionality (PRR / ROR /...

PCR / qPCR primer and oligo design — design forward/reverse primers for a target region (SantaLucia nearest-neighbor thermodynamics), compute melting temperature (Tm) and annealing temperature (Ta), check GC content, and screen an oligo for hairpins and primer-dimers. Use when you need primers for a sequence, want to QC an existing primer pair, or need the Tm of an oligo. Covers the primer-design rules (Tm matching, GC clamp, 3'-end, length) and the tools' constraint quirks.

Cancer treatment recommendations from molecular profile (mutations + cancer type + biomarkers) — FDA-approved + investigational therapies, resistance mechanisms, matching clinical trials, prognosis. Uses CIViC, ClinVar, OpenTargets, ClinicalTrials.gov. Use for tumor-board treatment recommendations, evidence-tiered actionability assessment, and FDA-precedent-driven therapy selection.

Patient stratification for precision medicine — integrate genomic, clinical, and therapeutic data to split patients into responder/non-responder groups, risk tiers, or treatment-decision groups. Use for stratification-by-biomarker, treatment-selection logic, and personalized therapeutic strategy reports per patient subgroup.

Population genetics analysis — allele frequencies (gnomAD, 1000 Genomes), Hardy-Weinberg equilibrium testing, Fst between populations, GWAS associations, evolutionary constraint scores. Use for cross-population variant comparison, ancestry-aware allele frequency lookups, and population-level evolutionary analysis.

Population genetics using the 1000 Genomes Project (IGSR) — superpopulation/population search, sample metadata, variant frequencies across AFR/AMR/EAS/EUR/SAS, ancestry-specific analyses. Use for ancestry comparison, population-aware allele frequency lookups, and 1000-Genomes-cohort-specific analyses (distinct from gnomAD which has different sample composition).

Build and interpret polygenic risk scores (PRS) for complex diseases using GWAS summary statistics. Covers PRS construction (clumping/thresholding, PRS-CS), validation in independent cohorts, ancestry-aware adjustment, and clinical interpretation (population-relative risk, not absolute prediction). Use for PRS-based risk stratification.