gnomad-genetics-mcp-server

---

Overview

Population genetics over gnomAD (Broad Institute), with ClinVar clinical significance joined in from NCBI. Look up per-ancestry allele frequencies, gene loss-of-function constraint, gene variant catalogs, and sequencing coverage, then query large result sets with SQL.

Tools

Tool	Description
gnomad_get_variant	Full population record for one or more variants — AC/AN/AF overall and per genetic-ancestry group, homozygote/hemizygote counts, quality flags, transcript consequence, in-silico predictors, and joined ClinVar significance.
gnomad_get_gene_constraint	Gene loss-of-function constraint — pLI, LOEUF (oe_lof_upper) with confidence interval, observed/expected ratios, and Z-scores. By HGNC symbol or Ensembl gene ID.
gnomad_list_gene_variants	Every variant in a gene, transcript, or region with allele frequencies and predicted consequences, filterable by consequence class and max allele frequency.
gnomad_get_coverage	Sequencing coverage across a gene, transcript, or region — mean/median depth and the fraction of samples over depth thresholds, per callset track.
gnomad_search_clinvar	Gene-level ClinVar detail via NCBI E-utilities — classified variants, review status, conditions, submission counts, and gnomAD-compatible variant IDs, paged by offset.
gnomad_dataframe_query	Run a read-only SQL SELECT across canvas tables staged by the list tools.
gnomad_dataframe_describe	List the tables staged on a canvas and their columns before writing SQL.
gnomad_dataframe_drop	Drop a named table from a canvas to reclaim memory. Opt-in via GNOMAD_DATAFRAME_DROP_ENABLED=true — off by default.

Resources

Resource	Description
gnomad://variant/{dataset}/{variantId}	Population record for one variant — mirrors gnomad_get_variant.
gnomad://gene/{dataset}/{gene}/constraint	Gene loss-of-function constraint — mirrors gnomad_get_gene_constraint.

All resource data is also reachable via tools. The list tools (gnomad_list_gene_variants, gnomad_get_coverage, gnomad_search_clinvar) return analytical row sets rather than stable single-URI documents, so they are not exposed as resources — call the tools instead.

Upstream-backed tools and resource reads share one fixed 45 s deadline across queue waits, retries, response bodies, and chained requests. A variant batch shares that deadline across every item: completed results remain available and unfinished primary items report upstream_timeout. Caller cancellation rejects the call.

Prompts

Prompt	Description
gnomad_variant_triage	Guided rare-disease variant-triage workflow: population frequency → gene constraint → callability check, in order.

Capability reference

gnomad_get_variant _tool

• Up to 25 IDs per call (raise via GNOMAD_MAX_VARIANT_BATCH), each a chrom-pos-ref-alt variantId on chromosome 1–22, X, or Y with an optional chr prefix (e.g. 1-55051215-G-GA) or an rsID (e.g. rs11591147)
• A bad or absent ID lands in failed[] as { variant, error, reason, recovery } without failing the rest; mitochondrial IDs (M, MT, chrM) fail as mitochondrial_unsupported, and an ambiguous rsID adds candidates
• Returns the full per-ancestry frequency vector, the callset(s) carrying the variant, quality flags, consequence, predictor scores, and ClinVar significance. A validated population record survives ClinVar-only failure or expiry with clinvar: null and clinvar_unavailable: true
• Inspect each failed[].reason: only variant_not_found reports absence from the chosen dataset; timeouts and other failures leave presence unknown. Check gnomad_get_coverage before interpreting an absent variant

---

gnomad_get_gene_constraint _tool

• Accepts an HGNC symbol (PCSK9) or an Ensembl gene ID (ENSG00000169174)

• Returns pLI (>0.9 intolerant), LOEUF / oe_lof_upper with its lower bound, observed/expected ratios for LoF / missense / synonymous, the three Z-scores, and constraint_flags (e.g. no_exp_lof, syn_outlier)

• constraint_release names the release the metrics come from. Many genes have null constraint, reported as null:

  dataset	Source	constraint_release	LoF-intolerance guidance
  gnomad_r4	GRCh38 gnomAD constraint	gnomAD v4.1.2	LOEUF < 0.45
  gnomad_r3	GRCh38 gnomAD constraint (gnomAD publishes no v3 constraint)	gnomAD v4.1.2	LOEUF < 0.45
  gnomad_r2_1	GRCh37 gnomAD constraint	gnomAD v2.1.1	LOEUF < 0.35
  exac	GRCh37 ExAC constraint	ExAC r0.3	pLI only

• On exac the ratios and LOEUF are null and constraint_flags is empty

---

gnomad_list_gene_variants _tool

• Supply exactly one of gene, transcript_id, or region (chrom-start-stop, 1-based inclusive, chromosome 1–22, X, or Y with an optional chr prefix); a blank gene or transcript_id counts as omitted
• A region must span less than 2,500,000 bp and hold at most ~30,000 variants, otherwise it fails as invalid_region or region_too_large; mitochondrial targets fail as mitochondrial_unsupported
• Optional filters: one consequence_class (lof / missense / synonymous / other) and/or a maximum allele frequency
• A result too large to inline is staged on the gene_variants canvas table, returned as canvas_id and table_name beside a preview; inspect it with gnomad_dataframe_describe and query it with gnomad_dataframe_query. Passing a canvas_id always writes gene_variants there, replacing the previous table. With the canvas disabled (CANVAS_PROVIDER_TYPE=none), only the capped preview is returned

---

gnomad_get_coverage _tool

• Supply exactly one of gene, transcript_id, or region (same chrom-start-stop form and 2,500,000 bp limit as gnomad_list_gene_variants); a blank gene or transcript_id counts as omitted. Bad regions fail as invalid_region or region_too_large, and mitochondrial targets as mitochondrial_unsupported
• Returns mean and median read depth plus the mean fraction of samples covered at each threshold (1× through 100×), summarized per callset track, with bucket_size, bucket_count, observed positions, total target_positions, and unobserved missing_positions for each. Missing bases leave callability unknown; statistics describe only returned buckets, with no invented zero depths
• coverage_source narrows to one track (exome / genome); omit to return every available track
• Notices disclose partial targets and missing supported tracks. An explicitly requested unsupported track is identified separately (v3 has genome only; ExAC has exome only)

---

gnomad_search_clinvar _tool

• Takes an HGNC symbol only (an Ensembl gene ID returns guidance and searches nothing). Optional filters: clinical_significance (e.g. pathogenic) and min_review_stars (0–4)
• Returns clinical significance, review status with a 0–4 star rating, conditions, molecular consequences, submission counts, and gnomAD-compatible identifiers (canonical_spdi, rsids, grch38_variant_id). IDs ClinVar has no summary for are listed in unavailable_ids
• Pages up to 500 records per call with offset / limit (1–500); total_found, truncated, and next_offset say whether more remain. limit counts records before the filters, so a window can return fewer rows
• A window too large to inline is staged on the clinvar_variants canvas table (query it with gnomad_dataframe_describe and gnomad_dataframe_query); passing a canvas_id always writes it there, replacing the previous table. NCBI_API_KEY raises the rate limit from 3 to 10 req/s

---

gnomad_dataframe_query _tool

• Runs single-statement, read-only SQL SELECTs against a table staged by gnomad_list_gene_variants or gnomad_search_clinvar (gene_variants or clinvar_variants); writes, DDL, and file/HTTP table functions are rejected
• Pages with offset (default 0) and limit (default 100, max 500); returns rows, columns, total, truncated, and next_offset (follow it until null). Use an ORDER BY on a unique key for stable paging, and filter or aggregate in SQL to get past the CANVAS_DEFAULT_ROW_LIMIT cap (10,000 by default)
• A row over the 10,000-character page budget fails with row_too_large; with CANVAS_PROVIDER_TYPE=none it fails with canvas_disabled

---

gnomad_dataframe_describe _tool

• Lists every table staged on a canvas with its row count and column schema (name and DuckDB type)
• Call it before writing SQL for gnomad_dataframe_query
• Fails with a canvas_disabled error when the canvas is turned off (CANVAS_PROVIDER_TYPE=none)

---

gnomad_dataframe_drop _tool

• Drops a named table from a canvas to reclaim memory (destructiveHint: true)
• Opt-in via GNOMAD_DATAFRAME_DROP_ENABLED=true; absent from tools/list when off
• An unknown or expired canvas_id fails as canvas_not_found; with CANVAS_PROVIDER_TYPE=none it fails with canvas_disabled

---

gnomad://variant/{dataset}/{variantId} _resource

• Population record for one variant as application/json, mirroring gnomad_get_variant; variantId takes a chrom-pos-ref-alt ID or an rsID
• Typed errors: invalid_variant_id, mitochondrial_unsupported, variant_not_found, ambiguous_rsid (with candidates), graphql_error, upstream_build_mismatch, upstream_unavailable, upstream_timeout, upstream_access, and invalid_upstream_response, each with a recovery hint

---

gnomad://gene/{dataset}/{gene}/constraint _resource

• Gene loss-of-function constraint as application/json, mirroring gnomad_get_gene_constraint (same constraint_release per dataset); gene takes an HGNC symbol or Ensembl gene ID
• Typed errors: gene_not_found, invalid_constraint_data, graphql_error, upstream_unavailable, upstream_timeout, upstream_access, and invalid_upstream_response, each with a recovery hint

---

gnomad_variant_triage _prompt

• Arguments: variant required (chrom-pos-ref-alt or rsID; a malformed one is rejected); gene and dataset optional. dataset is one of gnomad_r4, gnomad_r3, gnomad_r2_1, exac, and the server default applies when omitted
• Emits a three-step chain as one user message: population frequency (gnomad_get_variant) → gene constraint (gnomad_get_gene_constraint) → callability check (gnomad_get_coverage on the exact position)

Features

Built on @cyanheads/mcp-ts-core: stdio and Streamable HTTP transports, pluggable auth (none / jwt / oauth), swappable storage (in-memory, filesystem, Supabase, Cloudflare KV/R2/D1), structured logging with optional OpenTelemetry tracing.

gnomAD-specific:

• Single keyless GraphQL source for the entire core surface — ClinVar significance is joined per variant inside gnomAD's own response
• dataset and reference_genome are distinct, coherence-validated parameters (v4/v3 ⇒ GRCh38, v2.1/ExAC ⇒ GRCh37); both are echoed in every tool's output so a wrong-build coordinate mismatch is visible
• Polite client — conservative concurrency cap (GNOMAD_MAX_CONCURRENCY, default 2) and exponential backoff against a community-funded, rate-limited API
• In-conversation SQL analytics: gnomad_list_gene_variants and gnomad_search_clinvar stage results too large to inline on a DuckDB-backed canvas table — gnomad_dataframe_describe lists its columns, gnomad_dataframe_query runs SQL over every row

Agent-friendly output:

• Per-ancestry allele-frequency vector returned in full, never collapsed to a single global AF
• gnomad_get_variant returns per-item failed[] rows instead of failing the whole batch
• Effective dataset and reference_genome echoed on every response; null upstream fields stay null
• Every error carries a typed reason (e.g. incoherent_build, invalid_target, variant_not_found, upstream_timeout, canvas_disabled) and a recovery hint

Getting started

Public Hosted Instance

A public instance is available at https://gnomad-genetics.caseyjhand.com/mcp — no installation required. It serves Streamable HTTP; each client takes its own config shape.

For Claude Code:

claude mcp add --transport http gnomad-genetics-mcp-server https://gnomad-genetics.caseyjhand.com/mcp

For Cline (cline_mcp_settings.json):

{
  "mcpServers": {
    "gnomad-genetics-mcp-server": {
      "type": "streamableHttp",
      "url": "https://gnomad-genetics.caseyjhand.com/mcp"
    }
  }
}

For Cursor (mcp.json):

{
  "mcpServers": {
    "gnomad-genetics-mcp-server": {
      "url": "https://gnomad-genetics.caseyjhand.com/mcp"
    }
  }
}

Claude Desktop adds remote servers under Settings → Connectors.

Self-Hosted / Local

Add the following to your MCP client configuration file. gnomAD is a free, keyless API — no credentials required.

{
  "mcpServers": {
    "gnomad-genetics-mcp-server": {
      "type": "stdio",
      "command": "bunx",
      "args": ["@cyanheads/gnomad-genetics-mcp-server@latest"],
      "env": {
        "MCP_TRANSPORT_TYPE": "stdio",
        "MCP_LOG_LEVEL": "info"
      }
    }
  }
}

Or with npx (no Bun required):

{
  "mcpServers": {
    "gnomad-genetics-mcp-server": {
      "type": "stdio",
      "command": "npx",
      "args": ["-y", "@cyanheads/gnomad-genetics-mcp-server@latest"],
      "env": {
        "MCP_TRANSPORT_TYPE": "stdio",
        "MCP_LOG_LEVEL": "info"
      }
    }
  }
}

Or with Docker:

{
  "mcpServers": {
    "gnomad-genetics-mcp-server": {
      "type": "stdio",
      "command": "docker",
      "args": [
        "run", "-i", "--rm",
        "-e", "MCP_TRANSPORT_TYPE=stdio",
        "ghcr.io/cyanheads/gnomad-genetics-mcp-server:latest"
      ]
    }
  }
}

For Streamable HTTP, set the transport and start the server:

MCP_TRANSPORT_TYPE=http MCP_HTTP_PORT=3010 bun run start:http
# Server listens at http://localhost:3010/mcp

The SQL analytics path runs on DuckDB by default — @duckdb/node-api ships as a dependency, so nothing extra to install. Set CANVAS_PROVIDER_TYPE=none to turn it off. The Claude Desktop bundle (.mcpb) ships without DuckDB's native bindings and runs with the canvas off.

Prerequisites

• Bun v1.4.0 or higher (or Node.js v24+).
• No API key — gnomAD's GraphQL endpoint is keyless. An optional NCBI_API_KEY raises the gnomad_search_clinvar rate limit.

Installation

1. Clone the repository:

git clone https://github.com/cyanheads/gnomad-genetics-mcp-server.git

2. Navigate into the directory:

cd gnomad-genetics-mcp-server

3. Install dependencies:

bun install

4. Configure environment:

cp .env.example .env
# all vars are optional — the server runs keyless out of the box

Configuration

All variables are optional; the server runs keyless with the defaults below.

Node and Bun load the working directory's .env before building tool definitions. Exported values take precedence; blank values use the schema defaults. The advertised variant cap, its input validation, and the drop-tool registration gate use those same settings. Invalid server configuration fails startup with a banner naming the variable; DEBUG=true includes the stack.

Variable	Description	Default
GNOMAD_API_BASE_URL	gnomAD GraphQL endpoint. Override for a private mirror or testing.	https://gnomad.broadinstitute.org/api
GNOMAD_DEFAULT_DATASET	Dataset used when a tool call omits dataset (gnomad_r4 / gnomad_r3 / gnomad_r2_1 / exac).	gnomad_r4
GNOMAD_REQUEST_TIMEOUT_MS	Per-attempt gnomAD/NCBI timeout in milliseconds, bounded by the shared 45 s call deadline.	30000
GNOMAD_MAX_CONCURRENCY	Cap on concurrent upstream requests — politeness against a community-funded API.	2
GNOMAD_MAX_VARIANT_BATCH	Maximum variant IDs accepted per gnomad_get_variant call.	25
CLINVAR_BASE_URL	NCBI E-utilities base URL for gnomad_search_clinvar.	https://eutils.ncbi.nlm.nih.gov/entrez/eutils
NCBI_API_KEY	Optional NCBI key. Raises the E-utilities rate limit from 3 to 10 req/s.	—
CANVAS_PROVIDER_TYPE	DataCanvas backend for the spill/SQL path behind the list tools. none disables it, and the list tools then return a capped inline preview.	duckdb
GNOMAD_DATAFRAME_DROP_ENABLED	Gate for the opt-in gnomad_dataframe_drop tool. Off by default.	false
MCP_TRANSPORT_TYPE	Transport: stdio or http.	stdio
MCP_HTTP_PORT	Port for the HTTP server.	3010
MCP_AUTH_MODE	Auth mode: none, jwt, or oauth.	none
MCP_LOG_LEVEL	Log level (RFC 5424).	info
OTEL_ENABLED	Enable OpenTelemetry instrumentation.	false

See .env.example for the full list of optional overrides.

Running the server

Local development

• Build and run:

  # One-time build
  bun run rebuild
  
  # Run the built server
  bun run start:stdio
  # or
  bun run start:http
  

• Run checks and tests:

  bun run devcheck   # Lint, format, typecheck, security
  bun run test       # Vitest test suite
  bun run lint:mcp   # Validate MCP definitions against spec
  

Docker

docker build -t gnomad-genetics-mcp-server .
docker run --rm -e MCP_TRANSPORT_TYPE=http -p 3010:3010 gnomad-genetics-mcp-server

The Dockerfile defaults to HTTP transport, stateless session mode, and logs to /var/log/gnomad-genetics-mcp-server. OpenTelemetry peer dependencies are installed by default — build with --build-arg OTEL_ENABLED=false to omit them.

Project structure

Directory	Purpose
src/index.ts	createApp() entry point — registers tools/resources/prompts and inits services.
src/config	Server-specific environment variable parsing and validation with Zod.
src/mcp-server/tools	Tool definitions (*.tool.ts) and shared input schemas.
src/mcp-server/resources	Resource definitions (*.resource.ts).
src/mcp-server/prompts	Prompt definitions (*.prompt.ts).
src/services/gnomad	gnomAD GraphQL client, query documents, and domain types.
src/services/clinvar	NCBI E-utilities client for the optional ClinVar tool.
src/services/canvas-accessor.ts	Module-level accessor for the framework's optional DataCanvas.

Development guide

See CLAUDE.md/AGENTS.md for development guidelines and architectural rules. The short version:

• Handlers throw, framework catches — no try/catch in tool logic
• Use ctx.log for request-scoped logging, ctx.state for tenant-scoped storage
• Register new tools and resources in the createApp() arrays in src/index.ts
• Wrap external API calls: validate raw → normalize to domain type → return output schema; never fabricate missing fields

Data attribution

gnomAD data is provided by the Genome Aggregation Database (Broad Institute). ClinVar data is provided by NCBI.

Contributing

Issues are welcome. Run checks and tests before submitting:

bun run devcheck
bun run test

License

Apache-2.0 — see LICENSE for details.