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Alphagenome Variant Impact Score

Google DeepMindOfficialPublished by Google DeepMind

  • Skill
  • Tool integration
  • Science and research
  • Apache-2.0
  • Low risk
  • Has scripts
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From the author

Score, annotate, and analyze the functional impact of genetic variants using AlphaGenome Variant Impact (AVI) scores. Query variants in chr:pos:ref>alt format, annotate VCF/tabular callsets, perform saturation mutagenesis window scans (1-based closed chr:start-end), and extract GENCODE v46 GTF gene/exon/junction coordinates all via the AlphaGenome Atlas API.
— the description by Google DeepMind

AutoGineer summary

Written by AutoGineer from the skill’s own files, not by the author

The AlphaGenome Variant Impact (AVI) skill provides a programmatic interface to the AlphaGenome Atlas API for scoring, annotating, and analyzing the functional impact of genetic variants. It supports querying individual variants, annotating large callsets, performing saturation mutagenesis scans, and retrieving detailed gene structure information from GENCODE v46. The tool is strictly for research purposes and emphasizes molecular and functional interpretation over clinical diagnosis.

What it does

  • Scores genetic variants using AVI models with Phred-scaled impact metrics.
  • Annotates VCF and tabular variant files with functional impact data.
  • Performs saturation mutagenesis window scans to identify high-impact hotspots.
  • Retrieves GENCODE v46 gene, exon, and splice junction coordinates.
  • Provides attribution weights for 18 biological feature modalities.
  • Integrates with the AlphaGenome Atlas for deep-linking and track visualization.

When to use it

  • When you need to prioritize genetic variants based on predicted functional impact.
  • When analyzing the potential effect of variants on splicing or transcription factor binding.
  • When performing large-scale variant annotation for research datasets.
  • When investigating the functional consequences of mutations within a specific genomic window.

Advantages

  • Provides standardized, calibrated Phred-scaled impact scores.
  • Offers granular attribution to specific biological modalities like splicing or chromatin accessibility.
  • Supports high-throughput annotation of large variant callsets.
  • Ensures consistency by using built-in GENCODE v46 annotations.

Usage examples

“Score the variant chr9:128225994:G>A and provide feature importance.”
The agent executes the query command and returns the AVI Phred score, quantile, and the top contributing biological feature.
“Annotate my variants.vcf file and output the top 20 candidates.”
The agent runs the annotation script on the provided file, generating an annotated VCF and a JSON file containing the top-ranked variants.

Install

  1. Download the skill as a ZIP:

    https://mp-staging.autogineer.com/agent-skills/google-deepmind/alphagenome-variant-impact-score/download

  2. Unzip it into the cross-client skills folder of your project:

    mkdir -p .agents/skills && unzip alphagenome-variant-impact-score.zip -d .agents/skills

Documentation by Google DeepMind

AlphaGenome Variant Impact (AVI) Analysis

Score and prioritize genetic variants using AlphaGenome Variant Impact (AVI) models via scripts/alphagenome_atlas_avi.py.

[!IMPORTANT] Research Use Only & Clinical Safety Rules: The AlphaGenome AVI Skill and the underlying AlphaGenome model/Atlas are strictly research tools. Access to outputs requires an AlphaGenome API key subject to terms of service prohibiting clinical use.

  1. No Medical Advice or Clinical Diagnosis: You MUST NOT provide medical advice, clinical diagnoses, disease management strategies, or treatment recommendations based on outputs from this skill or the AlphaGenome Atlas.

  2. Strict Molecular & Functional Framing: A high AVI score reflects predicted molecular/functional impact (e.g., disruption of splicing, alteration of transcription factor binding, chromatin accessibility changes, or coding consequences). Frame all findings in terms of molecular mechanisms and biological annotations—never as clinical diagnoses or medical conclusions.

  3. No Diagnostic Leaps: Never extrapolate high functional impact to clinical disease causation, penetrance, or patient prognosis. If a user asks a clinical or diagnostic question, explicitly clarify that AlphaGenome is a research tool and restrict your answer to the predicted molecular and functional effects.

[!IMPORTANT] Always Use AlphaGenome GENCODE v46 GTF (scripts/alphagenome_atlas_avi.py gtf) for Gene Annotations: When retrieving gene models, transcript IDs, exon coordinates, CDS/UTR regions, or splice junction donor/acceptor boundaries, always use the built-in scripts/alphagenome_atlas_avi.py gtf command. Do NOT query external sources (e.g., Ensembl REST API, UCSC, external GTF databases, or NCBI) for gene annotations or transcript coordinates. This ensures that the annotations match the scores and website.

Prerequisites

Run scripts/alphagenome_atlas_avi.py using uv run:

# Display CLI help:
uv run scripts/alphagenome_atlas_avi.py --help

[!TIP] Agent & Programmatic Execution Format: When invoking the CLI in agent workflows, prefer --format json or direct file export (-o <file>) for deterministic, structured parsing rather than extracting fields from stdout markdown tables.

1. Query Variants (query)

Query single or multiple variants in 1-based chr:pos:ref>alt format to inspect scores and the 18 biological feature attribution weights:

# Query single variant with basic feature importances (stdout JSON preview):
uv run scripts/alphagenome_atlas_avi.py query "chr9:128225994:G>A" --format json

# Query variant with exact underlying Atlas track indices, biosamples, and target genes:
uv run scripts/alphagenome_atlas_avi.py query "chr9:128225994:G>A" --include_track_info --format json

# Query multiple variants and export full track info to a file (prevents stdout overflow):
uv run scripts/alphagenome_atlas_avi.py query "chr9:128225994:G>A" "chr22:36201698:A>C" \
  --include_track_info --format json -o query_results.json

  • Output Size & Redirection: Single variant table/JSON queries are compact (~1.0–1.5 KB). When querying $>3$ variants or passing --include_track_info --format json (which generates ~3.9 KB per variant), always export directly to a file using -o <file.json> or -o <file.tsv> to avoid exceeding context window limits.

  • Typical Runtime: ~0.5–1.0 s per variant (~12–15 s total including environment startup). Single calls with $>100$ variants take $>1$ minute.

2. Annotate & Rank Variant Files (annotate)

Annotate a VCF (or CSV/TSV/Parquet) in standard Ensembl VEP CSQ format:

uv run scripts/alphagenome_atlas_avi.py annotate \
  --input test_data/example_variants.vcf \
  --output annotated_variants.vcf \
  --top_k 20 \
  --min_phred 15.0 \
  --top_output top_variants.json

  • Output Size & Redirection: annotate streams the full callset directly to disk via --output (.vcf, .vcf.gz, .parquet, .tsv, .csv). Stdout displays a bounded summary (top candidate table + top 3 modality breakdowns, ~4.0–5.5 KB). Use --top_output <file.json> when downstream tools need machine-readable top candidate data.

  • Typical Runtime & Callset Scaling: Throughput is ~10 variants/s (default) and ~5 variants/s (with track info). Small callsets ($\le 100$ variants) take ~15 s. Callsets $\ge 500$ variants execute silently for $>1$ minute (e.g., 1,000 variants take ~2–3 min; 10,000 variants take ~20 min).

3. Saturation Mutagenesis Window Scan (region)

Scan a 1-based closed genomic window (chr:start-end) to score all possible single nucleotide substitutions ($3 \times N$ variants for an $N$-bp window):

uv run scripts/alphagenome_atlas_avi.py region \
  --region chr9:128225990-128226000 \
  --min_phred 15.0 \
  --top_k 20 \
  --output region_hotspots.tsv

  • Output Size & Redirection: Scanning a 100 bp window produces 300 SNVs (~42 KB TSV / ~105 KB JSON), while a 1,000 bp window produces 3,000 SNVs (~421 KB TSV / ~1.06 MB JSON). Always specify --output <file.tsv|parquet> to save the complete dataset; stdout will only show a top-20 candidate preview.

  • Typical Runtime: Queries precomputed dense scores over gRPC in 1.5–3.0 s for up to 1,000 bp (default --max_window_size).

4. Inspect Atlas Database Metadata (metadata)

Dump or search registered scorers, the 18 biological feature definitions, or experimental track catalogs:

# List all registered scorers:
uv run scripts/alphagenome_atlas_avi.py metadata --scorers --format json

# List the 18 biological feature attribution modalities:
uv run scripts/alphagenome_atlas_avi.py metadata --features --format json

# Search experimental tracks by query keyword with a controlled preview (top 20):
uv run scripts/alphagenome_atlas_avi.py metadata --tracks --query "GATA1" --top_n 20

# Dump complete 9,440-track catalog to Parquet or TSV for offline search:
uv run scripts/alphagenome_atlas_avi.py metadata --tracks --output atlas_tracks.parquet

  • Output Size & Redirection: --features (~1.3 KB) and --scorers table (~1.7 KB) are safely under 4 KB. The experimental track catalog contains 9,440 tracks (~972 KB table / ~2.55 MB JSON). Never dump unfiltered tracks to stdout; always supply a narrow --query, specify --top_n 20, or export to --output atlas_tracks.parquet.

  • Typical Runtime: ~1.5–2.5 s.

5. Inspect Gene Structure & Splice Junctions (gtf)

Query GENCODE v46 gene annotations, extract 1-based exon boundaries with donor/acceptor coordinates, and compute canonical and exon-skipping splice junction coordinates:

# Query MANE Select exon boundaries for a gene (stdout JSON preview):
uv run scripts/alphagenome_atlas_avi.py gtf --gene CAPN3 --exons --format json

# Query canonical and exon-skipping splice junctions for a variant locus:
uv run scripts/alphagenome_atlas_avi.py gtf --variant "chr15:42387805:C>G" --junctions --format json

# Extract CDS and UTR segments for an Ensembl transcript ID:
uv run scripts/alphagenome_atlas_avi.py gtf --transcript_id ENST00000397163.8 --cds --utr --format json

  • Output Size & Redirection: Single-gene MANE Select queries with --exons are compact (<2.5 KB). Always export to --output <file.tsv|parquet>or redirect (> gtf_out.json) when passing --all_transcripts(30–500 KB),--region($>50\text{ kb}$),--format json, or querying genes with $>30$ exons (e.g.TTN, DMD).

  • Typical Runtime & Memory: Ingests the 318 MB GENCODE v46 feather dataset (~4.37 GB RAM). Cached queries execute in ~4–6 s. Cold-start runs downloading the file from GCS take ~5–10 s on corp/Cloudtop networks, but can take up to 60–90 s on external networks. Do not kill the process prematurely during initial download.

Programmatic Python SDK Usage

When querying AlphaGenome programmatically in Python:

  1. Client Factory: Always instantiate the client using atlas.create(api_key) — do NOT instantiate atlas.AtlasClient() directly (which requires an internal gRPC stub).

  2. Coordinate System: genome.Interval operates with 0-based half-open indexing ([start, end)). When querying a 1-based closed interval chr:start_1_based-end_1_based, pass start = start_1_based - 1 and end = end_1_based.

  3. Single Variants: genome.Variant.from_str("chr:pos:ref>alt") expects 1-based position coordinates.

import os
from alphagenome.atlas import atlas
from alphagenome.data import genome
import dotenv

dotenv.load_dotenv(os.path.expanduser('~/.env'))
client = atlas.create(os.environ['ALPHAGENOME_API_KEY'])

# Query 1-based closed interval chr11:5225727-5226575 using 0-based half-open [5225726, 5226575)
interval = genome.Interval(chromosome='chr11', start=5225726, end=5226575)
results = client.query_interval(
    interval,
    requested_scorers=['AVI_SCORE', 'AVI_SCORE_FEATURE_IMPORTANCE'],
)

# Query single variant with 1-based coordinate
variant = genome.Variant.from_str('chr11:5225488:A>T')
variant_scores = client.query_variant(
    variant,
    requested_scorers=['AVI_SCORE', 'AVI_SCORE_FEATURE_IMPORTANCE'],
)

Output Schemas & Response Structures

1. VCF CSQ & INFO Tag Schema (annotate)

When writing annotated VCF files, the following annotations are injected:

  • Ensembl VEP CSQ Format String: Allele|AVI_PHRED|AVI_RAW|AVI_QUANTILE|AVI_TOP_PERCENTILE|AVI_TOP_FEATURE

  • Subfield Definitions:

    • Allele (string): Alternate allele base(s) (e.g. A).

    • AVI_PHRED (float): Calibrated Phred impact score ($\text{Phred} = -10 \cdot \log_{10}(1.0 - \text{quantile})$). Range: [0.0, ~70.0]. Higher = greater functional impact.

    • AVI_RAW (float): Raw continuous model prediction.

    • AVI_QUANTILE (float): Calibrated tail quantile ($1 - \text{CDF}$). Range: (0.0, 1.0].

    • AVI_TOP_PERCENTILE (float): Top percentile of genome-wide SNVs ($10^{-\text{Phred}/10} \times 100%$, e.g. 0.0380 for Top 0.038%).

    • AVI_TOP_FEATURE (string): Display name of the top contributing biological modality (e.g. Splicing, AlphaMissense, ChIP-TF, DNASE-seq, Cactus).

  • Standalone INFO Tags (unless --vep_csq_only): AVI_PHRED=Float, AVI_RAW=Float, AVI_QUANTILE=Float, AVI_TOP_PERCENTILE=Float, AVI_TOP_FEATURE=String.

2. Tabular & JSON Record Schema (query, region, --top_output)

Output records exported to JSON, TSV, CSV, or Parquet contain the following fields:

  • rank (integer, present in --top_output and region tabular exports): 1-based candidate rank sorted by Phred descending.

  • variant (string): Genomic variant string in chr:pos_1_based:ref>alt format (e.g. chr9:128225994:G>A, where coordinate is 1-based).

  • chromosome (string): Contig name with chr prefix (e.g. chr9).

  • position (integer): 1-based genomic coordinate.

  • ref (string): Reference allele base(s).

  • alt (string): Alternate allele base(s).

  • avi_phred (float): Calibrated Phred-scaled score.

  • avi_raw (float): Raw continuous model score.

  • avi_quantile (float): Tail quantile ($1 - \text{CDF}$).

  • top_percentile (float): Exact top percentile value (e.g. 0.3421 for Top 0.34%).

  • top_modality (string): Display name of the top contributing biological modality (e.g. Splicing, AlphaMissense, ChIP-TF).

  • top_feature_importance (float): Attribution weight (SHAP value) of the top modality.

  • Optional Attribution Weights (--include_features): 18 columns fi_<MODALITY> (e.g. fi_MERGED_SPLICING, fi_ALPHAMISSENSE, fi_MAX_ABS_RNA_SEQ, fi_CACTUS_241_WAY).

  • Optional Track Provenance (--include_track_info): track_idx_<MODALITY>, track_name_<MODALITY>, track_biosample_<MODALITY>, track_gene_<MODALITY>.

3. GTF Query Schema (gtf)

When querying gene structure with gtf --format json, each transcript object provides:

  • Gene & Transcript Metadata: gene_name, gene_id, transcript_id, transcript_type, chromosome, start, end, strand, is_mane_select, num_exons (coordinates are 1-based closed).

  • Exons Array (--exons):

    • exon_number (int): 1-based exon index in 5' to 3' transcript order.

    • start, end, width (int): 1-based closed exon coordinates and length in bp.

    • acceptor, donor (int): 1-based 5' splice acceptor and 3' splice donor coordinates.

    • overlaps_variant (bool): True if overlapping the query mutation site.

  • Junctions Array (--junctions):

    • type (string): Canonical Intron {i} or Exon {k} Skipping.

    • upstream_exon, downstream_exon (int): 1-based flanking exon numbers in 5' to 3' transcript order.

    • junction_start, junction_end (int): 1-based genomic donor and acceptor coordinates.

    • intron_length (int): Intron length in bp.

    • score_id (string): Constructed Atlas track comparison token.

    • atlas_url (string): Clickable deep-link to Atlas track predictions.

  • CDS & UTR Arrays (--cds, --utr): 1-based closed start, end, width (int).

Score Metrics & Interpretation

  • AVI Phred: Calibrated score (Phred = -10 * log10(1.0 - quantile)):

    • Phred >= 40: Top 0.01% predicted impact of all genome-wide SNVs.

    • Phred >= 30: Top 0.10% predicted impact of all genome-wide SNVs.

    • Phred >= 20: Top 1.0% predicted impact of all genome-wide SNVs.

    • Phred >= 15: Top 3.16% predicted impact of all genome-wide SNVs.

    • Phred >= 10: Top 10.0% predicted impact of all genome-wide SNVs.

    • Phred < 10: Bottom 90% of all genome-wide SNVs.

  • Top Percentile: Exact percentage of genome-wide SNVs with equal or greater impact: Top Percentile = 10^(-Phred/10) * 100% (e.g. Phred 29.7 $\implies$ Top 0.11%).

  • Top Modality: Leading biological feature attribution (metadata --features).

Visualizations & Atlas Deep-Linking

[!IMPORTANT] Mandatory Atlas Deep-Linking with Variant Scores: Whenever reporting, discussing, or displaying an AVI score for a variant (whether for a single variant query, a ranked candidate table, or a genomic region scan), you MUST always provide a clickable deep-link to the AlphaGenome Atlas for each variant.

  1. User Context Prioritization: Always prioritize context from the user first (e.g., disease, tissue, or relevant cell types). When absent, use --include_track_info with query to discover the driving biosample, cell line, ontology CURIE, and track index.

  2. Mandatory Splicing & RNA-seq Co-Plotting Rule: Whenever plotting or visualizing splicing variants, always plot continuous RNA-seq expression alongside splicing tracks (SPLICE_JUNCTIONS, SPLICE_SITE_USAGE, SPLICE_SITES) to evaluate both structural splice disruption and resulting transcript abundance changes.

  3. Atlas Link Construction: Use the alphagenome-atlas-website-links skill (scripts/alphagenome_atlas_links.py) for all URL generation, layout configuration (lItems), biosample filtering (f), and /atlas/track-predictions comparison chart links.

Files

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Requirements and compatibility

Works with: Claude Code, Claude apps, OpenAI Codex, GitHub Copilot, Cursor, Gemini CLI, Kiro, OpenCode, Goose, Amp, Roo Code, JetBrains Junie, Factory Droid, Devin (ex-Windsurf), Mistral Vibe, OpenHands, Letta

“Works with” means the tool reads the open Agent Skills format; a skill written for one tool may use features others lack.

Needs: Needs an API key, Needs Python

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Published by
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Google DeepMind (Official)
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google-deepmind/science-skills · skills/alphagenome_variant_impact_score · commit 4de6786
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