This sprint did not produce a computed result. The capability gate selected population_allele_freq as the required execution template, but that template cannot honestly answer the proposed question. The idea asks whether ClinVar-pathogenic variants in the F5 gene have lower gnomAD population frequencies than benign ones — a comparison across variant-class groups using two distinct data sources (ClinVar and gnomAD). The gated template is designed to test whether a single variant's frequency differs across 1000 Genomes super-populations (a population-genetics differentiation question). These are fundamentally different analyses. No honest adaptation of population_allele_freq can produce the required comparison without fabricating data or substituting a different template. Per the sprint rules, an explicit failed capability disclosure is published instead.

Sprint 27, Run 28 — Failed Capability Disclosure

Original Idea

For F5, do ClinVar-pathogenic variants sit at lower gnomAD population frequency than benign ones?

Scoped Question (determined during Stage a)

Capability mismatch: the required execution template population_allele_freq compares allele frequencies across 1000 Genomes super-populations (AFR, AMR, EAS, EUR, SAS) for a single variant or genomic region. It has no concept of ClinVar pathogenicity classifications, does not ingest ClinVar data, and operates on 1000 Genomes allele frequencies, not gnomAD frequencies. The original idea requires (a) ClinVar variant annotations with clinical-significance labels, (b) gnomAD population-frequency data per variant, and (c) a statistical comparison between the pathogenic and benign variant groups — none of which the gated template supports.

Abstract

This sprint did not produce a computed result. The capability gate selected population_allele_freq as the required execution template, but that template cannot honestly answer the proposed question. The idea asks whether ClinVar-pathogenic variants in the F5 gene have lower gnomAD population frequencies than benign ones — a comparison across variant-class groups using two distinct data sources (ClinVar and gnomAD). The gated template is designed to test whether a single variant's frequency differs across 1000 Genomes super-populations (a population-genetics differentiation question). These are fundamentally different analyses. No honest adaptation of population_allele_freq can produce the required comparison without fabricating data or substituting a different template. Per the sprint rules, an explicit failed capability disclosure is published instead.

Methods (required template)

The execution template mandated by the capability gate is population_allele_freq
(reference analysis reference_analyses/population_allele_freq.py). This template:

1. Fetches 1000 Genomes phase-3 allele frequencies for a genomic region via fetch_1000g.py (output: CSV with per-variant allele frequencies across five super-populations: AFR, AMR, EAS, EUR, SAS).
2. Identifies the lead variant — the one with the largest allele-frequency spread across populations (max minus min AF).
3. Computes a chi-square test of allele-count homogeneity on a 2×5 contingency table (alt vs ref counts across five populations), using the public 1000G phase-3 sample sizes to reconstruct counts from frequencies.
4. Computes pairwise Hudson-style Fst values between each population pair.
5. Renders a grouped bar chart of per-population AF for the lead variant.

What this template tests: whether a single variant's frequency differs
across 1000 Genomes super-populations — a population-genetics differentiation
question. It does not involve ClinVar, does not distinguish pathogenic from
benign variants, and does not use gnomAD data.

Capability Mismatch

The original idea asks: "For F5, do ClinVar-pathogenic variants sit at lower
gnomAD population frequency than benign ones?" This requires:

• ClinVar variant annotations with clinical-significance classifications.
• gnomAD per-variant population frequencies (or equivalent group frequencies).
• A statistical comparison between variant classes (pathogenic vs benign), not across human populations.

The population_allele_freq template cannot satisfy any of these requirements:

Requirement	What template provides
Pathogenicity labels	None — template has no ClinVar data
gnomAD frequencies	None — template uses 1000 Genomes frequencies
Two-group comparison (pathogenic vs benign)	None — template tests homogeneity across 5 super-populations for one variant

To answer the proposed question, the analysis would need to (a) replace the 1000
Genomes fetcher with a ClinVar fetcher and a gnomAD fetcher, (b) introduce a
variant-classification grouping step, and (c) change the statistical test from
chi-square-of-homogeneity-across-populations to a two-group comparison
(Mann–Whitney/Wilcoxon). This amounts to writing an entirely new analysis —
specifically, the clinvar_gnomad_ensembl template already allowlisted in the
toolbox. The sprint rules explicitly forbid substituting a different allowlisted
template or reshaping the question to fit another template. The capability
gate's decision to select population_allele_freq for this question is a
genuine mismatch.

Outcome

failed — capability mismatch. No analysis was executed, no data was fetched, and no figure was rendered. A re-run with the correct template (clinvar_gnomad_ensembl) would be required to answer the proposed question.

Limitations

• No dataset was fetched because the gated template does not use ClinVar or gnomAD data.
• No analysis script was run because the gated template cannot compute the required comparison.
• This disclosure is based entirely on the documented interface and behavior of the population_allele_freq reference analysis, not on a failed computation.

What a Re-run Would Need

1. Re-scope the idea with execution template clinvar_gnomad_ensembl instead of population_allele_freq.
2. Fetch Ensembl gene coordinates for F5, gnomAD v4 population frequencies for that gene's variants, and ClinVar annotations for F5 variants.
3. Run the anchor clinvar_gnomad_ensembl analysis which is designed to compare pathogenic-vs-benign allele frequency distributions using a Mann–Whitney U test.

Provenance

Item	Value
Sprint ID	27
Run ID	28
Idea	For F5, do ClinVar-pathogenic variants sit at lower gnomAD population frequency than benign ones?
Required template	population_allele_freq
Outcome	failed (capability mismatch)
Datasets fetched	None
Analysis executed	None
Seed	N/A