A developmental-context variant pathogenicity scoring method
Weights mutation impact by spatiotemporal gene expression across human development

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What is DevScore?

Existing tools like CADD, SIFT, and PolyPhen-2 predict pathogenicity from evolutionary conservation or protein-level impact alone. They treat every developmental window as equal — but a mutation in a gene critical during gastrulation is fundamentally different from one in a gene expressed only in adults.

DevScore is the first metric to explicitly incorporate when and where a gene is expressed during human development, weighted by the criticality of that developmental stage.

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The formula

DevScore = V × E_peak × C_stage × D_domain × 100

Component	Range	Source	What it captures
V — variant severity	0–1	CADD PHRED + ClinVar	Combined pathogenicity from conservation, protein impact, and clinical annotation
E_peak — peak expression	0–1	Expression Atlas (E-MTAB-6814)	Maximum developmental TPM across 10 stages, normalised to 10,000 TPM ceiling
C_stage — stage criticality	0.25–1.0	Curated developmental biology	Gastrulation & neurulation = 1.0 · organogenesis = 0.95 · fetalearly = 0.65 · fetallate = 0.50 · adult = 0.25
D_domain — domain essentiality	0.2–1.0	UniProt	DNA-binding & catalytic = 1.0 · structural = 0.7 · regulatory = 0.5 · disordered = 0.4 · UTR = 0.2

A DevScore > 8.5 (Youden threshold) indicates likely developmental pathogenicity. Scores range 0–100.

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Validation

Benchmarked on 110 variants across developmental-disorder and adult-onset genes.

Results

Comparison	AUC		Improvement
DevScore (all variants, n=110)	0.928	⬤ —
CADD (paired, n=110)	0.457	⬤	+0.471
SIFT (missense-only, n=66)	0.397	⬤	+0.536
PolyPhen-2 (missense-only, n=66)	0.446	⬤	+0.487

Mann-Whitney U: U = 2784.5, p = 6.38 × 10⁻¹⁵  ·  Cohen's d: 1.77 (very large effect)  ·  Median DevScore: developmental = 16.6 vs adult-onset = 4.0

Conventional conservation tools systematically over-predict pathogenicity for adult-onset genes (TP53, BRCA1, etc.) because protein constraint alone cannot resolve developmental timing. DevScore fills this gap through spatiotemporal criticality weighting (C_stage). Spearman ρ(DevScore, CADD) = 0.156 (p = 0.103) — orthogonal information.

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Figure gallery

ROC curves DevScore (AUC 0.928) vs CADD (0.457), SIFT (0.397), PolyPhen-2 (0.446) across 110 benchmark variants	Score distributions Developmental-disorder variants (median 16.6) vs adult-onset controls (median 4.0), p = 6.38 × 10⁻¹⁵
Case studies SOX2 (DevScore 52.8), MECP2 (23.3), BRCA1 (3.8) — component contributions	Component breakdown V, E_peak, C_stage, D_domain across the benchmark cohort
Peak developmental stage Distribution of peak expression stages across benchmark genes — gastrulation overrepresented in developmental-disorder genes	DevScore vs CADD Spearman ρ = 0.156 — DevScore captures orthogonal developmental signal not present in conservation-based scores
AUC comparison summary DevScore outperforms CADD (+0.471), SIFT (+0.536), and PolyPhen-2 (+0.487) across all pairwise comparisons	DevScore vs CADD detail Paired AUC comparison illustrating the magnitude of improvement from incorporating developmental context

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Quick start

# Backend
cd backend
pip install -r requirements.txt
uvicorn app.main:app --reload          # → http://localhost:8000

# Frontend (separate terminal)
cd frontend
npm install
npm run dev                             # → http://localhost:5173

Score a variant

curl -X POST http://localhost:8000/api/score \
  -H "Content-Type: application/json" \
  -d '{"gene": "SOX2", "hgvs": "c.70C>T", "position": 24}'

{
  "gene": "SOX2",
  "variant": "c.70C>T",
  "score": 52.8,
  "V": 0.91,
  "E_peak": 0.58,
  "C_stage": 1.0,
  "D_domain": 1.0,
  "peak_stage": "gastrulation",
  "component_explanation": {
    "V":        "ClinVar: pathogenic · CADD PHRED: 34.0",
    "E_peak":   "SOX2 peaks at 5800 TPM during gastrulation",
    "C_stage":  "Gastrulation (C_stage = 1.0) is the most critical developmental window",
    "D_domain": "HMG-box DNA-binding domain (D_domain = 1.0)"
  }
}

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Web app

Try the live demo at devmutdb.vercel.app.

1. Enter a gene symbol — autocomplete searches 150+ curated genes
2. Type an HGVS variant (e.g. c.70C>T), or click Pick variant to browse pre-loaded ClinVar entries
3. View results — score ring, component breakdown, 10-stage expression heatmap, and comparison table vs CADD / SIFT / PolyPhen-2
4. Export PDF — citable variant summary report

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Data sources

Source	Data	Access
Ensembl VEP	Variant consequences, SIFT, PolyPhen-2	REST API
NCBI ClinVar	Clinical significance classifications	REST API
Expression Atlas (E-MTAB-6814)	Developmental transcriptome (Cardoso-Moreira et al. 2019, Nature)	REST API
UniProt	Protein domains and functional regions	REST API
gnomAD v4	Population allele frequencies	REST API
CADD	Combined Annotation Dependent Depletion	Scaling API

Genes absent from the E-MTAB-6814 developmental transcriptome receive class-informed expression estimates based on known developmental or adult-onset patterns.

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Project structure

DevMutDB/
├── backend/                 # FastAPI server + DevScore engine
│   ├── app/
│   │   ├── main.py          # API routes (/score, /genes, /health)
│   │   ├── devscore/        # Core formula, stage index, domain weights
│   │   └── clients/         # Ensembl, ClinVar, gnomAD, Expression Atlas, UniProt
│   └── requirements.txt
├── frontend/                # React + Vite + Tailwind CSS
│   └── src/
│       ├── pages/           # Search, Results, Methodology, API Docs
│       └── components/      # ScoreRing, StageTimeline, ComparisonTable
├── validation/              # Benchmark dataset + scoring pipeline
│   ├── run_validation.py    # Batch scoring script
│   └── figures/             # ROC curves, distributions, case studies
└── paper/                   # Preprint manuscript (draft)

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Citation

@software{ghrieb2026devmutdb,
  author = {Abdelkarim Hani Ghrieb},
  title  = {{DevScore}: A Spatiotemporal Criticality Index for Improved Pathogenicity Prediction of Developmental Variants},
  year   = {2026},
  doi    = {10.1101/2025.xx.xx},
  url    = {https://github.com/Ghrieb/DevMutDB}
}

License

Code (backend, frontend, validation pipeline): All Rights Reserved — commercial use, modification, distribution, and patent use prohibited without prior written consent.
Manuscript and figures: Creative Commons Attribution 4.0 International (CC BY 4.0)

_{Research prototype — not intended for clinical diagnosis without independent validation}