AlphaGenome and the AlphaGenome Atlas

AlphaGenome is DeepMind's sequence-to-function model: 1 Mb of DNA in, predictions at modality-specific resolutions for eleven assay types across thousands of human and mouse tracks out. The AlphaGenome Atlas (released 2026-09-08) is that model run once over every possible single-nucleotide change in GRCh38, about 9 billion variants, stored with a single ranking number, the AlphaGenome Variant Impact (AVI) score, its genome-wide percentile, and an 18-way attribution of what drives it. Both are reached through one pip install alphagenome and one API key.

Research and theoretical modelling only. API outputs must not be used to train other models, and are not for diagnostic procedures or medical decisions. Permissive-use downloads have separate terms; check the artifact licence.

When to use which

Setup

uv pip install alphagenome                     # PyPI; tested on Python 3.12 and 3.13, alphagenome 0.9.0
export ALPHAGENOME_API_KEY="..."               # https://deepmind.google.com/science/alphagenome
cd skills/alphagenome/scripts
python atlas_query.py scorers                  # proves key + network in one call

Shell examples quote variant strings because > otherwise redirects output. Network examples below are illustrative and were checked against SDK 0.9.0 contracts, without authenticated prediction/Atlas calls during this review.

Never put the key on a command line or in a file you commit; the scripts only read it from the environment. Authentication failures may surface as ValueError or PermissionError, depending on the gRPC status returned by the service.

The coordinate contract

• A variant is 1-based chr:pos:ref>alt (chr22:36201698:A>C). gnomAD (22-36201698-A-C), GTEx (chr22_36201698_A_C_b38), and Open Targets spellings are autodetected by the scripts. In the SDK, pass the matching variant_format=genome.VariantFormat.GNOMAD (or GTEX, OPEN_TARGETS, OPEN_TARGETS_BIGQUERY); from_str defaults to chr:pos:ref>alt.
• An interval on the command line is 1-based closed chr:start-end; the SDK's genome.Interval is 0-based half-open. The scripts convert.
• Human is GRCh38 only. The Atlas key is chr:pos:alt; REF is implied by the reference. Swapping REF/ALT can cause a miss; a wrong REF or build can misidentify a record. The scripts reject a returned variant that differs from the request, but cannot validate the build. Check REF against GRCh38 FASTA.
• rsIDs are not accepted by the API or the portal. Resolve them to coordinates.
• Use the chr prefix; MT becomes chrM.

Atlas workflow

1. Rank with AVI

python atlas_query.py avi --variant "chr22:36201698:A>C" "chr9:128225994:G>A"
python atlas_query.py avi --input candidates.vcf --min-phred 20 -o avi.tsv
python atlas_query.py avi --interval chr11:5225727-5226575 --top-k 25 -o hbb_window.tsv
python atlas_query.py avi --input credible_set.tsv --with-tracks -o avi_tracks.tsv

Output, one row per variant:

The Atlas report's advice: rank, do not threshold, and pick thresholds by region or application. Pathogenic regulatory variants sit in lower AVI bins than protein-truncating or splice-motif variants, so a single genome-wide cut-off under-calls exactly the variants this resource was built for.

Read the attribution before the number. MERGED_SPLICING or ALPHAMISSENSE on top means a splice or coding mechanism; MAX_ABS_DNASE, MAX_ABS_CHIP_TF, MAX_ABS_RNA_SEQ mean a regulatory mechanism you can resolve by track; CACTUS_241_WAY or PHASTCONS_470_WAY on top means conservation is carrying the score and the molecular mechanism is not resolved.

2. Resolve the mechanism by track

python atlas_query.py scorers                                   # what the server serves right now
python atlas_query.py tracks --scorer RNA_SEQ --query colon     # find ontology CURIEs
python atlas_query.py scores --variant "chr22:36201698:A>C" \
    --scorers RNA_SEQ DNASE SPLICE_SITE_USAGE --ontology UBERON:0001157 -o colon.tsv
python atlas_query.py scores --interval chr11:5225727-5226575 --scorers CHIP_TF -o hbb_tf.tsv

One row per variant x track (x gene or splice junction where applicable), with raw_score and, where served, quantile_score. Track-level scorer names: ATAC, DNASE, CHIP_TF, CHIP_HISTONE, CAGE, PROCAP, RNA_SEQ, POLYADENYLATION, SPLICE_SITES, SPLICE_SITE_USAGE, SPLICE_JUNCTIONS, CONTACT_MAPS, plus *_ACTIVE variants; scorers is the authority on the live list. Filter by the tissue the question is about, not by the genome-wide maximum: 9,440 scorer-track entries mean something may be extreme somewhere.

3. Send the reader to the portal

python atlas_link.py variant "chr22:36201698:A>C" --biosample "colon" --modalities RNA_SEQ,DNASE,CHIP_TF
python atlas_link.py locus chr11:5225727-5226575 --tf GATA1
python atlas_link.py gene HBB --markdown

No key, no network. The site shows the AVI track, per-modality heatmaps over every biosample, REF-vs-ALT prediction tracks, and motif instances. Attach a link to every variant you report.

In Python

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

client = atlas.create(os.environ["ALPHAGENOME_API_KEY"], timeout=30)
scores = client.query_variant(
    genome.Variant.from_str("chr22:36201698:A>C"),
    requested_scorers=["AVI_SCORE", "AVI_SCORE_FEATURE_IMPORTANCE", "RNA_SEQ"],
    ontology_terms=["UBERON:0001157"],          # optional; ignored for scorers without ontology metadata
)
avi = scores["AVI_SCORE"]                        # AnnData: X (1,1) raw; layers['quantiles'] (1,1) cdf
fi = scores["AVI_SCORE_FEATURE_IMPORTANCE"]      # AnnData: X (1,18); var['name'] = feature keys
rna = scores["RNA_SEQ"]                          # AnnData: obs = variant x gene, var = tracks, X = natural-log FC
client.query_interval(genome.Interval("chr11", 5225726, 5226575), requested_scorers=["AVI_SCORE"])

query_interval returns up to 3 SNVs per non-N base, in 32 bp chunks. Keep windows to about 1 kb (3,000 variants); atlas_query.py refuses more unless --max-window is raised. query_variants raises if any submitted lookup fails; completion order is not input order; the script makes separate variant requests so misses become error cells.

Model workflow

Score variants the Atlas does not hold

python score_variants.py --variant "chr22:36201698:A>C" -o scores.tsv                   # 12 recommended scorers, 1 Mb
python score_variants.py --input indels.vcf --scorers RNA_SEQ SPLICE_SITE_USAGE \
    --ontology UBERON:0001157 --min-abs-quantile 0.99 -o colon.tsv
python score_variants.py --organism mouse --variant "chr7:45000000:A>G" --scorers RNA_SEQ --sequence-length 500KB -o mouse.tsv
python score_variants.py --list-scorers
python score_variants.py --list-tracks --output-type RNA_SEQ --query liver -o tracks.tsv

Output is the official tidy table from variant_scorers.tidy_scores: one row per variant x scorer x track (x gene) with raw_score and quantile_score, sorted by |raw|. Default scorers are the 12 recommended difference scorers; --include-active adds the seven *_ACTIVE activity scorers. At most 20 scorers per request. Mouse has no calibrated quantiles; use raw scores there. --min-abs-quantile uses the supplied signed quantile magnitude (unsigned scorers use their upper-tail quantile); it never treats zero as an extreme.

from alphagenome.models import dna_client, variant_scorers
model = dna_client.create(os.environ["ALPHAGENOME_API_KEY"])
variant = genome.Variant.from_str("chr22:36201698:A>C")
interval = variant.reference_interval.resize(dna_client.SEQUENCE_LENGTH_1MB)
adatas = model.score_variant(interval, variant, variant_scorers=[variant_scorers.RECOMMENDED_VARIANT_SCORERS["RNA_SEQ"]])
df = variant_scorers.tidy_scores(adatas)         # filter df.ontology_curie afterwards; score_variant takes no ontology_terms

Predict tracks and mutagenise

vo = model.predict_variant(interval, variant,
                           requested_outputs=[dna_client.OutputType.RNA_SEQ, dna_client.OutputType.DNASE],
                           ontology_terms=["UBERON:0001157"])
vo.reference.rna_seq.values, vo.alternate.rna_seq.values      # (1048576, n_tracks)

window = genome.Interval("chr20", 3_753_000, 3_753_400).resize(dna_client.SEQUENCE_LENGTH_16KB)
ism = model.score_ism_variants(interval=window, ism_interval=window.resize(256),
                               variant_scorers=[variant_scorers.CenterMaskScorer(
                                   requested_output=dna_client.OutputType.DNASE, width=501,
                                   aggregation_type=variant_scorers.AggregationType.DIFF_MEAN)])

Supported windows: 16 kb, 100 kb, 500 kb, 1 Mb (2**14 to 2**20); 1 Mb is the recommended default for full context; the recommended contact-map scorer uses a 1 Mb mask. Shorter windows lose distal sequence context. Ontology terms are CURIEs (UBERON:0002048 lung, CL:0000084 T cell); discover them with --list-tracks or model.output_metadata(...).concatenate(). Plotting, gene annotation (GENCODE v46 Feather on GCS), splicing and haplotype recipes: references/model-api.md.

Reading the numbers

Always report raw score and quantile or Phred, with the scorer, track, biosample CURIE, and gene. raw_score is the effect size on the scorer's scale (RNA_SEQ is ln(mean ALT + 0.001) - ln(mean REF + 0.001): -1 is about 0.37x the pseudocount-adjusted REF signal). quantile_score ranks against common variants: signed scorers use [-1, 1], unsigned scorers [0, 1], with finite calibration limits near 1. AVI instead uses a genome-wide SNV CDF. A quantile above 0.99 with |raw| < 0.1 can reflect a narrow background in a quiet region; inspect REF/ALT tracks and report the small predicted change without declaring biological absence of effect. Raw-score thresholds are scorer-specific; quantiles are ranks, not p-values. Unsigned scorers (SPLICE_*, POLYADENYLATION, CONTACT_MAPS, *_ACTIVE) have no direction. "AlphaGenome predicts no appreciable change in the queried tracks" is a complete answer, and a variant inside a peak whose REF and ALT tracks are identical is not "disrupting" anything. Full rules, tissue matching, and the reporting checklist: references/interpretation.md.

Model limitations include trans effects, poorly represented non-polyadenylated RNAs (training includes both poly(A)+ and total RNA tracks), absent cell types, and protein-level consequences (AlphaMissense is folded into AVI for that), RNA structure and miRNA biology, diploid dosage, developmental time, species other than human and mouse.

Limits, quota, terms

• Atlas: GRCh38 SNVs only for now; indels were scored for the paper and are promised later. Reference N bases were never scored.
• Quotas are per key and unpublished; the Atlas is documented as having a larger query rate than on-demand prediction. Transient RESOURCE_EXHAUSTED and UNAVAILABLE are retried. Atlas also retries DEADLINE_EXCEEDED (up to 5 attempts, 60 s call deadline); model streaming RPCs use a separate retry policy. --timeout controls channel setup only, not total query time.
• Access tiers (Atlas report): AVI scores are also a permissively licensed Tabix download at https://alphagenome.google/downloads; feature attributions and splicing scores are non-commercial downloads; all other raw track scores are API-only and non-commercial. Commercial Atlas access is announced as coming soon; the base model is already available through Google Cloud Model Garden. See the current official FAQ.
• The alphagenome client is Apache-2.0; model weights and outputs carry DeepMind's terms. Cite Avsec et al., Nature 649:1206 (2026) and the Atlas report (Cheng et al., medRxiv, 2026, doi:10.64898/2026.09.16.26363192).

References

• references/atlas.md - what the Atlas contains, the 19 scorer configurations with track counts, AVI training and the 18 features, quantile to Phred, the client API and AnnData layout, error mapping, access tiers, portal URL grammar, GTF and download locations.
• references/model-api.md - dna_client cheat sheet: coordinates, sequence lengths, output types and track counts, ontology metadata, predict and score calls, recommended scorer configurations, ISM, gene annotation, plotting.
• references/interpretation.md - raw versus quantile, AVI thresholds, tissue matching, negative results, model blind spots, coordinate hygiene, reporting checklist.
• Scripts: scripts/atlas_query.py (Atlas: avi, scores, scorers, tracks), scripts/score_variants.py (model scoring, --list-scorers, --list-tracks), scripts/atlas_link.py (portal deep links, offline).