AlphaMissense

What It Does

• Predicts pathogenicity of missense variants (amino acid substitutions)
• Score 0-1: <0.34 likely benign, 0.34-0.564 ambiguous, >0.564 likely pathogenic
• Pre-computed for ALL possible missense variants in human proteome (71M variants)
• Based on protein language model + structural features

How to Use

### Web (via AlphaFold DB)

1. Go to https://alphafold.ebi.ac.uk/entry/Q7RTU9 (STRC)

2. Click "AlphaMissense" tab

3. View heatmap of all possible substitutions

4. Download full CSV

### Download Pre-computed Data

        # Full dataset (4.3GB)
        gsutil cp gs://dm_alphamissense/AlphaMissense_hg38.tsv.gz .
        
        # Or per-gene from AlphaFold DB API
        curl "https://alphafold.ebi.ac.uk/api/prediction/Q7RTU9" | python3 -c "
        import sys,json
        d = json.load(sys.stdin)[0]
        print(d.get('amAnnotationUrl', 'N/A'))
        "
        

### Python (from downloaded TSV)

        import pandas as pd
        am = pd.read_csv("AlphaMissense_hg38.tsv.gz", sep='\t', comment='#')
        strc = am[am['uniprot_id'] == 'Q7RTU9']
        e1659a = strc[(strc['protein_variant'] == 'E1659A')]
        print(e1659a)  # Score: 0.9016
        

Verified Status

VERIFIED — STRC E1659A score: 0.9016 (likely pathogenic, ≥0.840 threshold per Pejaver 2022). Used as PP3_Moderate evidence in ACMG classification.

STRC Research Usage

• STRC E1659A Conservation and Reclassification — PP3 evidence (score 0.9016)
• STRC Variant c.4976A>C — Misha — pathogenicity assessment
• Saturation mutagenesis: ALL 19 substitutions at position 1659 score 0.846-0.999 (all pathogenic)

Results (April 2026)

• Full STRC heatmap analyzed: 33,725 variants scored. E1659 region (1651-1700) is the most pathogenic-sensitive area in STRC — 69% of substitutions score as pathogenic.
• Regional pathogenicity: C-terminal (1476-1775): 43.1% pathogenic. mini-STRC region (700-1775): 39.6%. N-terminal (1-699): 27.1%.
• Still untapped: REVEL cross-validation at discordant positions, STRCP1-specific variant analysis

Results (April 2026)

• Full STRC heatmap analyzed: 33,725 variants scored. E1659 region (1651-1700) is the most pathogenic-sensitive area in STRC — 69% of substitutions score as pathogenic.
• Regional pathogenicity: C-terminal (1476-1775): 43.1% pathogenic. mini-STRC region (700-1775): 39.6%. N-terminal (1-699): 27.1%.
• Still untapped: REVEL cross-validation at discordant positions, STRCP1-specific variant analysis