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Capability Disclosure: Population Allele Frequency Template Cannot Answer ClinVar Pathogenic vs Benign Frequency Question

Exact input: For TTR, do ClinVar-pathogenic variants sit at lower gnomAD population frequency than benign ones?

Execution template: population allele freq

execution observatory

Attempt 1 of 1

failed Failed · publish stage
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immutable execution contract

exact input
For TTR, do ClinVar-pathogenic variants sit at lower gnomAD population frequency than benign ones?
execution template
population allele freq
  1. scope
  2. dataset
  3. run
  4. write
  5. review
  6. correct
  7. publish

latest committed step

orchestration Opencode process exited.

wrapper_exited · run · observed · wrapper

committed steps
21
accepted / verified
4
warnings / rejects
1
elapsed
7 minutes
last recorded
tokens recorded
not recorded
data downloaded
not recorded

retained execution history

Every attempt

Latest attempt
  1. Attempt 1 failed Jul 26, 2026 · 09:07 Capability Disclosure: Population Allele Frequency Template Cannot Answer ClinVar Pathogenic vs Benign Frequency Question

canonical execution ledger

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Public execution facts only — never private model reasoning, prompts, or raw process output.

attempt-1-ledger hal9000/run/273fc27e/1 chronological · persisted · archived Reload
  1. 001 orchestration run_queued run · queued · rails Execution attempt 1 queued.
  2. 002 triage investigation_selected notice · observed · rails Capability gate passed with population_allele_freq. Selected by daily triage (score 10): Genomics hypothesis; measurable with public data or a reproducible computational experiment.
    reason code
    supported_template_match
    reference template
    population_allele_freq
  3. 003 exploration neighbor_ideas_accepted artifact · accepted · rails Explored the seed idea and queued 2 undervalued hypotheses for future runs.
    idea count
    2
  4. 004 orchestration run_claimed run · claimed · rails Engine claimed this execution attempt.
  5. 005 orchestration runner_launch_authorized run · started · rails Execution lease acquired; the runner may launch once.
  6. 006 orchestration wrapper_started run · started · wrapper Opencode process started for this exact attempt.
    timeout s
    1200
  7. 007 scoping scope_started action · started · agent Beginning scoping for this exact execution attempt.
  8. 008 scoping scope_proposed gate · proposed · agent Proposed one falsifiable scoped question using the supported reference analysis.
    question
    For TTR (transthyretin), do ClinVar-classified pathogenic variants have lower gnomAD population allele frequency than ClinVar-classified benign variants?
  9. 009 writing draft_started action · started · agent Building the initial paper from committed evidence.
    artifact role
    paper_draft
  10. 010 writing draft_written artifact · proposed · agent Wrote the initial paper draft from the available evidence.
    artifact role
    paper_draft
    sha256
    94ff6239b98867e18b2fdb14e02f7654c812e34464c88dd2ca5d39187a1ebb35
  11. 011 review review_started action · started · agent Adversarial review round 1 against every available source artifact.
    artifact role
    paper_review
  12. 012 review review_observed gate · observed · agent Round 1 review severity counts.
    blockers
    0
    majors
    0
    minors
    2
  13. 013 correction correction_started action · started · agent Evidence-preserving corrections for round 1 findings.
    artifact role
    corrected_paper
  14. 014 correction correction_observed gate · observed · agent Round 1 correction resolution counts.
    remaining
    0
    resolved
    2
  15. 015 publishing publication_started action · started · agent Assembling the corrected artifacts for terminal validation.
    artifact role
    terminal_payload
  16. 016 scoping scope_accepted gate · accepted · rails Accepted the run's scoped research question.
    question
    For TTR (transthyretin), do ClinVar-classified pathogenic variants have lower gnomAD population allele frequency than ClinVar-classified benign variants?
  17. 017 data datasets_accepted artifact · accepted · rails Accepted 0 dataset provenance records for this run.
    artifact role
    dataset_provenance
    dataset count
    0
  18. 018 publishing paper_accepted artifact · accepted · rails Accepted the run-owned paper for publication.
    artifact role
    paper
  19. 019 publishing run_published run · failed · rails Execution attempt 1 published with outcome failed.
  20. 020 orchestration wrapper_duration metric · observed · wrapper Measured opencode process duration.
    duration s
    432
  21. 021 orchestration wrapper_exited run · observed · wrapper Opencode process exited.
    exit status
    0

exact-attempt artifacts

Artifacts & paper

Nothing on this attempt is borrowed from a newer run.

Abstract

hal9000/run/273fc27e/attempt/1 · published Jul 26, 2026

This sprint investigated whether ClinVar-classified pathogenic variants in the TTR (transthyretin) gene have lower gnomAD population allele frequencies than ClinVar-classified benign variants — a question central to variant interpretation in hereditary transthyretin amyloidosis (hATTR). The capability gate assigned the population_allele_freq reference analysis template. This template uses 1000 Genomes phase-3 super-population allele frequencies and performs chi-square tests of allele-count homogeneity across five super-populations (AFR, AMR, EAS, EUR, SAS), plus pairwise Fst analysis. It cannot answer the proposed question because (1) it uses 1000 Genomes data, not gnomAD, (2) it does not incorporate ClinVar clinical significance annotations, and (3) it cannot stratify variants by pathogenic/benign classification. The required clinvar_gnomad_ensembl anchor template — which joins ClinVar clinical significance with gnomAD allele frequencies — is the appropriate tool for this question but was not assigned by the capability gate. No data was fetched and no analysis was performed. This paper is an honest disclosure of a capability mismatch.

Outcome: failed (capability mismatch — required template cannot answer the question)

Capability Disclosure: Population Allele Frequency Template Cannot Answer ClinVar Pathogenic vs Benign Frequency Question

Abstract

This sprint investigated whether ClinVar-classified pathogenic variants in the TTR (transthyretin) gene have lower gnomAD population allele frequencies than ClinVar-classified benign variants — a question central to variant interpretation in hereditary transthyretin amyloidosis (hATTR). The capability gate assigned the population_allele_freq reference analysis template. This template uses 1000 Genomes phase-3 super-population allele frequencies and performs chi-square tests of allele-count homogeneity across five super-populations (AFR, AMR, EAS, EUR, SAS), plus pairwise Fst analysis. It cannot answer the proposed question because (1) it uses 1000 Genomes data, not gnomAD, (2) it does not incorporate ClinVar clinical significance annotations, and (3) it cannot stratify variants by pathogenic/benign classification. The required clinvar_gnomad_ensembl anchor template — which joins ClinVar clinical significance with gnomAD allele frequencies — is the appropriate tool for this question but was not assigned by the capability gate. No data was fetched and no analysis was performed. This paper is an honest disclosure of a capability mismatch.

Outcome: failed (capability mismatch — required template cannot answer the question)

Introduction

Transthyretin (TTR) gene variants cause hereditary transthyretin amyloidosis (hATTR), a progressive and life-threatening disease. ClinVar annotates TTR variants with clinical significance (pathogenic, likely pathogenic, benign, likely benign, uncertain significance). gnomAD provides population allele frequency data. A natural question in variant interpretation is whether pathogenic variants tend to be rarer in the general population than benign ones — a pattern expected under purifying selection against disease-causing alleles.

Scoped Question

For TTR (transthyretin), do ClinVar-classified pathogenic variants have lower gnomAD population allele frequency than ClinVar-classified benign variants?

Required Template and Capability Mismatch

The capability gate assigned population_allele_freq as the required reference analysis template. This template is designed for a different question shape:

What population_allele_freq does:

  • Fetches 1000 Genomes phase-3 allele frequencies for a genomic region via tabix byte-range slicing
  • Compares allele frequencies across five super-populations (AFR, AMR, EAS, EUR, SAS)
  • Performs chi-square test of allele-count homogeneity across populations
  • Computes pairwise Fst (Weir-Cockerham style) for the most differentiated variant

What the question requires:

  • ClinVar variant-level clinical significance annotations (pathogenic vs benign)
  • gnomAD population allele frequencies at the variant level
  • Stratification of variants by clinical significance class
  • Comparison of allele frequency distributions between pathogenic and benign groups

Why the template cannot answer the question:

  1. Wrong data source: population_allele_freq uses 1000 Genomes, not gnomAD. While both provide allele frequencies, 1000 Genomes does not carry ClinVar clinical significance annotations.
  2. No ClinVar integration: The template has no mechanism to incorporate ClinVar variant classifications. It cannot distinguish pathogenic from benign variants.
  3. Wrong comparison axis: The template compares allele frequencies across populations (AFR vs EUR vs EAS, etc.), not across clinical significance classes (pathogenic vs benign). These are fundamentally different analytical questions.
  4. Wrong statistical test: Chi-square homogeneity across populations is inappropriate for comparing frequency distributions between two classes of variants.

The correct template would be: clinvar_gnomad_ensembl (the anchor), which joins ClinVar clinical significance with gnomAD allele frequencies and Ensembl gene coordinates. This template is specifically designed for the question shape: "For gene G, do pathogenic variants differ in population frequency from benign ones?"

What Was Done

No data was fetched. No analysis was performed. The capability mismatch was identified during scoping (Stage a), and this paper documents the mismatch as an honest failed disclosure.

Limitations

  • This sprint produced no computed results, no figure, and no dataset provenance.
  • The capability mismatch is inherent in the template assignment, not a recoverable error.
  • The question itself is scientifically sound and answerable with the clinvar_gnomad_ensembl template, but that template was not assigned by the capability gate.
  • A re-run with the clinvar_gnomad_ensembl template would be needed to answer this question.

Conclusion

The population_allele_freq reference analysis template cannot answer whether ClinVar pathogenic variants in TTR have lower gnomAD allele frequencies than benign variants. The template's design (1000 Genomes super-population comparison) is fundamentally incompatible with the question's requirements (ClinVar-stratified gnomAD frequency comparison). This sprint is a disclosed capability mismatch with no computed output. The question remains scientifically valid and answerable with the appropriate template (clinvar_gnomad_ensembl) in a future sprint.

Provenance

Field Value
Sprint ID 24
Run ID 25
Reference Template populationallelefreq
Question For TTR, do ClinVar-pathogenic variants sit at lower gnomAD population frequency than benign ones?
Outcome failed
Failure Reason Capability mismatch — required template cannot answer the question
Datasets Fetched None
Analysis Performed None
Figure Generated No
Provenance · exact attempt
attempt 1 · exact retained execution
exact input For TTR, do ClinVar-pathogenic variants sit at lower gnomAD population frequency than benign ones?
execution template population allele freq
script sha256 —
seed —
app git sha 90235e290363ee8922771b653ade6ffe7248ff2f
corrections none

No analysis script — sprint stopped before authoring one.

deterministic re-runs of this exact attempt

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Executor health and scientific verdict are separate. Public-safe summaries only; leases and raw process output are never shown.

No reproduction attempt recorded

This exact run has not yet entered the deterministic re-run queue. Its original ledger, artifacts, and provenance remain available above.

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