Version Compatibility

Reference examples tested with: requests 2.31+, Ensembl REST API (release 110+); Ensembl release schedule is roughly quarterly

Before using code patterns, verify installed versions match. If versions differ:

• Python: pip show requests
• API surface: check release notes at https://rest.ensembl.org

Each Ensembl release has an archive REST endpoint (e.g. https://e110.rest.ensembl.org) for reproducibility.

Ensembl REST

"Pull Ensembl-native gene / transcript / variant data programmatically" -> Ensembl REST is distinct from NCBI Entrez and BioMart. It is the right answer for: stable Ensembl IDs, transcript / exon structure, VEP (Variant Effect Predictor) annotation, Compara orthologs at vertebrate scale, regulatory feature annotation, and any workflow rooted in Ensembl's coordinate system.

Two facts dominate Ensembl REST work: (1) the 15 req/sec / 55,000 req/hour rate limit — high enough for hundreds of queries, low enough that bulk work (>5,000) belongs in BioMart instead; (2) versioned archive endpoints — https://e110.rest.ensembl.org pins to release 110 for reproducibility, while https://rest.ensembl.org follows the current release.

• Python: requests.get('https://rest.ensembl.org/...')
• Web: https://rest.ensembl.org (interactive doc with try-it-now)
• R: biomaRt for bulk (see biomart-queries); REST via httr

Required Setup

import requests
import time

BASE = 'https://rest.ensembl.org'
HEADERS = {'Accept': 'application/json'}
SLEEP = 0.07   # 15 req/sec ceiling

No API key required. Respect Retry-After header on 429.

Ensembl divisions

Ensembl is divided by clade. Different REST hosts:

Division	Host	Scope
Vertebrates	https://rest.ensembl.org	Human, mouse, fish, etc. (the "main" Ensembl)
Plants	https://rest.ensembl.org (plants division also accessible)	Arabidopsis, rice, etc. via Ensembl Genomes
Fungi	https://rest.ensemblgenomes.org	Yeasts, Aspergillus, etc.
Metazoa	https://rest.ensemblgenomes.org	Insects, nematodes, etc.
Bacteria	https://rest.ensemblgenomes.org	Limited (most bacteria in NCBI)

For non-vertebrate work, check ensemblgenomes.org mirrors. As of 2024, Ensembl Genomes was being consolidated; check current host.

Version pinning

URL	Behavior
https://rest.ensembl.org	Current release (rolling)
https://e110.rest.ensembl.org	Pinned to release 110
https://e111.rest.ensembl.org	Pinned to release 111
https://grch37.rest.ensembl.org	Pinned to GRCh37 (legacy assembly)

For any published analysis, pin the release. Ensembl releases change gene model versions, exon coordinates, and transcript annotations — re-running a pipeline a year later against the live endpoint may produce different results.

Major endpoint groups

Group	Example	Purpose
Lookup	/lookup/symbol/human/BRCA1	Resolve symbol or ID to stable record
Sequence	/sequence/id/{id}	DNA/protein sequence for ID
Cross References	/xrefs/symbol/human/BRCA1	Cross-refs to other DBs
Homology / Compara	/homology/symbol/human/BRCA1	Orthologs and paralogs
Gene Tree	/genetree/id/{tree_id}	Compara gene tree
VEP	/vep/human/region/{region}/{allele}	Variant effect prediction
Overlap	/overlap/id/{id} or /overlap/region/{region}	Genes/regulatory in interval
Regulatory	/regulatory/species/{species}/feature/{id}	Regulatory features
Variant	/variation/{species}/{id}	dbSNP / 1000G / ClinVar via Ensembl
LD	/ld/{species}/pairwise/{var1}/{var2}	LD between variants
GA4GH	/ga4gh/...	GA4GH-compliant subset

Full reference: https://rest.ensembl.org (interactive).

The symbol-vs-ID stability problem

Gene symbols are unstable (MARCH1 -> MARCHF1 in 2020 due to Excel autocorrect; SEPT* family also renamed). Ensembl Gene IDs (ENSG...) are stable across releases when the gene model is preserved.

Best practice:

1. Resolve symbol -> Ensembl ID once at pipeline start: /lookup/symbol/{species}/{symbol}.
2. Persist the Ensembl ID.
3. Run downstream queries by ID, not symbol.

Symbol-based endpoints are convenient for interactive use; ID-based endpoints are for reproducible pipelines.

Rate-limit math

Limit	Value
Burst	15 req/sec
Hourly	55,000 req/hour
Concurrent	Not enforced; courtesy 1-2

Respect Retry-After header on HTTP 429. For >5,000 queries, switch to BioMart bulk export (see biomart-queries) — BioMart has separate, more permissive limits.

VEP (Variant Effect Predictor)

VEP via REST is the right call for ad hoc variant annotation. For batch variant annotation (>1000 variants), download VEP and run locally (variant-calling/variant-annotation skill).

REST modes:

• /vep/{species}/region/{region}/{allele} — single variant by coordinate
• /vep/{species}/id/{variant_id} — by dbSNP / Ensembl variant ID
• /vep/{species}/hgvs/{hgvs_notation} — by HGVS notation

VEP returns rich annotation: consequence (missense, synonymous, intron), SIFT/PolyPhen scores, gnomAD frequencies (if available), ClinVar significance.

Compara homology

Compara orthology calls via Ensembl REST are covered in detail in ortholog-inference (database-access view). The relevant endpoint:

• /homology/symbol/{species}/{symbol} — all orthologs across Ensembl species
• /homology/id/{ensembl_id} — same, by ID
• ?target_species= to restrict to one target
• ?type=orthologues or paralogues to filter

Code patterns

Symbol -> stable Ensembl Gene ID

Goal: Resolve a gene symbol to its current Ensembl Gene ID once, then use the ID for all downstream queries.

Approach: /lookup/symbol/{species}/{symbol} returns the canonical record.

Reference (requests 2.31+):

import requests
import time

BASE = 'https://rest.ensembl.org'
HEADERS = {'Accept': 'application/json'}


def get_with_retry(url, params=None, max_retries=3):
    for attempt in range(max_retries):
        r = requests.get(url, params=params, headers=HEADERS)
        if r.status_code == 429:
            time.sleep(int(r.headers.get('Retry-After', '5')))
            continue
        r.raise_for_status()
        return r
    raise RuntimeError(f'Failed after {max_retries} retries')


def symbol_to_ensembl(species, symbol):
    r = get_with_retry(f'{BASE}/lookup/symbol/{species}/{symbol}')
    return r.json()


info = symbol_to_ensembl('human', 'BRCA1')
print(f'  Ensembl Gene ID: {info["id"]}')
print(f'  Biotype:         {info["biotype"]}')
print(f'  Chromosome:      {info["seq_region_name"]}:{info["start"]}-{info["end"]}')
print(f'  Strand:          {info["strand"]}')

Sequence retrieval by Ensembl ID

def get_sequence(ensembl_id, seq_type='cdna'):
    '''seq_type: cdna, cds, protein, genomic'''
    r = get_with_retry(f'{BASE}/sequence/id/{ensembl_id}',
                       params={'type': seq_type, 'content-type': 'application/json'})
    return r.json()


prot = get_sequence('ENSG00000139618', seq_type='protein')
print(f'  Length: {len(prot["seq"])} aa')

Overlap: what genes are in this region

def genes_in_region(species, region):
    '''region as "chr:start-end" e.g. "17:43000000-44000000".'''
    r = get_with_retry(f'{BASE}/overlap/region/{species}/{region}',
                       params={'feature': 'gene'})
    return r.json()


for g in genes_in_region('human', '17:43000000-43200000'):
    print(f'  {g["external_name"]:<12} {g["id"]} {g["biotype"]:<20} {g["start"]}-{g["end"]}')

VEP for a single variant

Goal: Get full annotation for a variant by coordinate.

Approach: /vep/{species}/region/{region}/{allele} returns transcript consequences, SIFT/PolyPhen, frequencies.

Reference (Ensembl REST release 110+):

def vep_region(species, region, allele):
    r = get_with_retry(f'{BASE}/vep/{species}/region/{region}/{allele}')
    return r.json()


# BRCA1 missense variant in GRCh38 coordinates (rest.ensembl.org defaults to GRCh38);
# for GRCh37 coords use https://grch37.rest.ensembl.org instead.
results = vep_region('human', '17:43044295-43044295:1', 'A')
if results:
    for tc in results[0].get('transcript_consequences', [])[:5]:
        print(f'  {tc["gene_symbol"]:<8} {tc["consequence_terms"]}')
        if 'sift_prediction' in tc:
            print(f'    SIFT: {tc["sift_prediction"]} ({tc.get("sift_score", "?")})')

Compara orthologs (Compara via REST)

def orthologs(species, symbol, target_species=None):
    params = {'type': 'orthologues'}
    if target_species:
        params['target_species'] = target_species
    r = get_with_retry(f'{BASE}/homology/symbol/{species}/{symbol}', params=params)
    return r.json()['data'][0]['homologies']


for o in orthologs('human', 'BRCA1', target_species='mouse'):
    print(f'  {o["target"]["species"]:<15} {o["target"]["id"]}  type={o["type"]}  confidence={o.get("confidence")}')

Batch lookup with rate-limit handling

def batch_symbols(species, symbols):
    out = {}
    for sym in symbols:
        try:
            out[sym] = symbol_to_ensembl(species, sym)
        except requests.HTTPError as e:
            out[sym] = {'error': str(e)}
        time.sleep(0.07)  # 15 req/sec ceiling
    return out

Archive endpoint for reproducibility

# Pin to release 110
ARCHIVE = 'https://e110.rest.ensembl.org'
r = requests.get(f'{ARCHIVE}/lookup/symbol/human/BRCA1', headers={'Accept': 'application/json'})
print(r.json()['id'])
# Re-runs against e110 in 2030 will return the same Gene ID even if the live release has moved on.

LD between two variants

def ld_pairwise(species, var1, var2, population='1000GENOMES:phase_3:CEU'):
    r = get_with_retry(f'{BASE}/ld/{species}/pairwise/{var1}/{var2}',
                       params={'population_name': population})
    return r.json()

Failure modes

Symbol-based pipeline breaks on HGNC rename

• Trigger: /lookup/symbol/human/MARCH1 after the 2020 rename.
• Mechanism: HGNC renamed Excel-autocorrect-affected genes; Ensembl mirrors the rename.
• Symptom: 404 or wrong gene returned.
• Fix: Resolve symbol to Ensembl Gene ID once at pipeline start; use ID downstream.

No version pinning, results drift

• Trigger: Re-running a pipeline against https://rest.ensembl.org a year later.
• Mechanism: Live endpoint follows current release; gene models update quarterly.
• Symptom: Different transcript coordinates, exon counts, sometimes Gene ID changes.
• Fix: Pin to an archive endpoint (https://e110.rest.ensembl.org) for reproducibility.

Rate-limit cascade

• Trigger: Loop of 5,000 REST calls without sleep.
• Mechanism: 15 req/sec ceiling; 429 with Retry-After.
• Symptom: Pipeline stalls; cascade of failures.
• Fix: Sleep 0.07s between calls; honor Retry-After; for >5K queries use BioMart bulk export.

VEP for bulk variants

• Trigger: VEP REST for 100K variants.
• Mechanism: REST is per-variant; rate-limit makes this infeasible.
• Symptom: Days-long runtime; many 429s.
• Fix: Download VEP and run locally (variant-calling/variant-annotation skill); reserve REST for ad hoc <1K variants.

Wrong species name

• Trigger: Using Homo_sapiens instead of human, or arbitrary capitalization.
• Mechanism: Ensembl species names are lowercase with underscores or common names; case matters.
• Symptom: 404 or empty result.
• Fix: Use https://rest.ensembl.org/info/species to enumerate valid names.

Non-vertebrate species not in vertebrate host

• Trigger: Querying Arabidopsis on rest.ensembl.org.
• Mechanism: Plants live in Ensembl Genomes (rest.ensemblgenomes.org) as of 2024 (consolidation ongoing).
• Symptom: 404 or species not recognized.
• Fix: Check the right division host; use the lookup endpoint info/divisions to confirm.

Archive endpoint TLS / connectivity

• Trigger: Older archive endpoints (e80, e90) gradually decommissioned.
• Mechanism: Very old archives are retired ~5 years after release.
• Symptom: DNS failure or 503.
• Fix: Check the current archive list at https://www.ensembl.org/info/website/archives/index.html.

Common errors

Error / symptom	Cause	Solution
404 on symbol lookup	HGNC rename or wrong species	Resolve to Ensembl ID; check species code
HTTP 429	Rate limit	Sleep per Retry-After; cap to 15 req/sec
Different results 6 months later	No version pinning	Use archive endpoint (eXX.rest.ensembl.org)
404 on non-vertebrate	Wrong host division	Switch to rest.ensemblgenomes.org
VEP infeasible bulk	REST is per-variant	Local VEP for bulk
Old archive 503	Decommissioned	Use a current archive release

References

• Yates AD, Allen J, Amode RM, et al. (2022) Ensembl Genomes 2022: an expanding genome resource for non-vertebrates. Nucleic Acids Res 50:D996-D1003.
• Martin FJ, Amode MR, Aneja A, et al. (2023) Ensembl 2023. Nucleic Acids Res 51:D933-D941.
• McLaren W, Gil L, Hunt SE, et al. (2016) The Ensembl Variant Effect Predictor. Genome Biol 17:122.
• Yates A, Beal K, Keenan S, et al. (2015) The Ensembl REST API: Ensembl data for any language. Bioinformatics 31:143-145.

Related Skills

• biomart-queries - Ensembl BioMart for bulk (>5K) ID mapping
• ortholog-inference - Compara orthologs via Ensembl REST and other resources
• uniprot-access - Cross-reference Ensembl IDs in UniProt entries
• variant-calling/variant-annotation - Local VEP for bulk variant annotation
• ncbi-datasets-cli - NCBI alternative for genome / gene data
• entrez-search - NCBI alternative for non-Ensembl queries