Rare Diseases and Mondo

The Global Challenge of Rare Diseases

An estimated 300 million people worldwide—nearly 4% of the global population—are affected by a rare disease. Despite this enormous collective impact, the majority of rare conditions have only a handful of recorded cases. This limited representation means there is often scarce information about symptoms, causes, and disease progression, leading many patients through a “diagnostic odyssey” of incorrect diagnoses, unnecessary tests, and delayed care.

Consider fibrodysplasia ossificans progressiva (FOP), also known as “Stoneman syndrome” (MONDO:0007606): with an estimated prevalence of 1 in 2 million and only about 700 reported cases worldwide, FOP patients endure a high rate of initial misdiagnosis (87%), with many undergoing unnecessary biopsies (67%) and receiving inappropriate therapies (68%) (PMID:31785620, PMID:16230464).

Mondo brings together the world’s rare disease resources to help shorten the diagnostic odysseys.

What Makes a Disease “Rare”?

There is no universal definition of “rare disease.” The concept is typically defined by prevalence—the number of affected individuals per population—but these thresholds vary significantly PMID:39261914:

Region	Prevalence Threshold	Equivalent
United States	Fewer than 200,000 people	~1 in 1,500
European Union	Fewer than 1 in 2,000	~250,000
Japan	Fewer than 1 in 2,500	~50,000

Beyond different thresholds, disease prevalence itself varies by geography. For example, Kawasaki disease affects approximately 1 in 6,500-20,500 children under 5 in Europe (considered “rare”), but 1 in 324 in Japan (considered “common”)(PMID:22307434, PMID:30786118).

Some organizations also require additional criteria, such as the disease being “life-threatening or chronically debilitating” (EU Orphan Drug Regulation (EC No 141/2000)).

Why This Matters

These differences have real consequences:

Research funding: Programs like the FDA’s Orphan Drug Designation provide incentives only for diseases classified as “rare”
Insurance coverage: Whether a disease is designated “rare” can affect treatment coverage
Clinical trials: Rare disease status influences eligibility for specialized trial pathways
Patient advocacy: Organizations focus resources based on rare disease classifications

How Mondo Handles Rare Diseases

Rather than imposing a single definition of “rare,” Mondo takes a pragmatic, inclusive approach:

Mondo integrates rare disease information from multiple authoritative sources and transparently tracks which sources consider each disease to be rare.

This means:

✅ You can access all diseases considered rare by any major authority
✅ You can filter to diseases considered rare by specific authorities relevant to your region or use case
✅ You always know the provenance of the “rare” designation

Sources of Rare Disease Information in Mondo

Source	What it provides	Subset annotation
Orphanet	European reference for rare diseases; comprehensive disease descriptions, diagnostic tests, orphan drug data	`orphanet_rare`
GARD	NIH’s Genetic and Rare Diseases Information Center; patient-friendly information for US audiences	`gard_rare`
NORD	National Organization for Rare Disorders; patient advocacy, education, and research support	`nord_rare`
Literature	Diseases reported as rare in peer-reviewed publications but not yet in authoritative lists	`mondo_rare`
Ontology inference	Children of rare disease terms inherit the “rare” designation	`inferred_rare`

Understanding the Overlap

Not all sources agree on which diseases are rare. Our analysis shows:

Only ~35% of diseases in Mondo’s rare subset are considered rare by all authoritative sources
~40% are recognized by Orphanet
Different sources use different criteria for what counts as a distinct “rare disease” (e.g., Orphanet counts only “disorders,” while NORD and GARD also count disease subtypes)

This reflects genuine scientific and policy disagreement—not a problem to solve, but a reality to represent accurately.

Finding Rare Diseases in Mondo

For Patients and Advocates

If you’re looking for information about a specific rare disease:

Search on Monarch Initiative: Visit monarchinitiative.org and search for your disease
Follow links to authoritative sources: Each Mondo term links to original sources (Orphanet, GARD, NORD, OMIM, etc.) for detailed information

For Researchers and Developers

Download the Rare Disease Subset

The Mondo rare disease subset includes all diseases considered rare by at least one authoritative source:

Format	Download Link
OBO	mondo-rare.obo
JSON	mondo-rare.json

Filter by Source

To get rare diseases according to a specific authority, filter by the in_subset annotation:

# Example: Get only Orphanet rare diseases
Filter where in_subset contains "orphanet_rare"

# Example: Get diseases rare in the US (GARD or NORD)
Filter where in_subset contains "gard_rare" OR "nord_rare"

Understanding Subset Annotations

Each rare disease term in Mondo has:

rare: Present on ALL terms in the rare disease subset (union of all sources)
orphanet_rare, gard_rare, nord_rare: Indicates the specific authority
mondo_rare: Manually curated from literature (community-reported)
inferred_rare: Inherited from a parent term that is rare
rare_grouping: Parent terms included for classification context (not themselves rare diseases)

Example: Calciphylaxis (MONDO:0017215) is annotated with nord_rare, gard_rare, and orphanet_rare—indicating consensus across all three authorities.

Real-World Applications

COVID-19 and Rare Disease Research

The National COVID Cohort Collaborative (N3C) used Mondo to study outcomes for rare disease patients during the pandemic:

Imported Mondo’s KGX format into the N3C research enclave
Selected terms with the “rare” designation
Leveraged Mondo’s mappings to clinical codes (SNOMED, ICD-10, MeSH) to identify patients
Created a rare disease dashboard enabling researchers to explore rare disease cohorts

Diagnostic Tools

Tools like Exomiser use Mondo’s rare disease classifications alongside phenotype data to help clinicians navigate diagnostic odysseys and identify potentially pathogenic variants.

Drug Repurposing

Mondo’s integration of rare diseases with broader disease classifications enables researchers to identify common biological pathways between rare and common diseases—opening opportunities for drug repurposing. Every Cure, for example, is using Mondo as the backbone for their drug-disease research.

How Rare Disease Data is Maintained

Mondo maintains rare disease annotations through automated pipelines that synchronize monthly with authoritative sources:

GARD and NORD: Partner organizations maintain spreadsheets with Mondo IDs; automated workflows update Mondo accordingly
Orphanet: Automated integration from Orphanet’s published data files
Community curation: Researchers can report rare diseases not yet in authoritative lists via GitHub issues

This system ensures:

Authoritative sources remain the “source of truth”
Updates propagate to Mondo within one month
Full transparency about data provenance

When Terms Change

If a Mondo term is obsoleted

The term will not appear in the rare disease subset. The relevant authoritative source(s) will be notified.

If a source removes a disease from their rare list

Only that source’s annotation is removed (e.g., gard_rare). Other source annotations remain unchanged.

If two Mondo terms are merged

Rare disease annotations will be transferred to the surviving term as soon as the update is made at the authoritative source.

Get Involved

Report a Missing Rare Disease

If you know of a rare disease not represented in Mondo or missing from the rare disease subset, please open a GitHub issue.

Connect with Rare Disease Communities

Mondo works closely with rare disease organizations worldwide. Contact us to discuss collaboration opportunities.

Rare Disease Day

Join us in recognizing Rare Disease Day on the last day of February each year, raising awareness for the 300 million people living with rare diseases worldwide.

Quick Reference

I want to…	Action
Find if my disease is considered rare	Search on Monarch Initiative and check subset annotations
Download all rare diseases	Get mondo-rare.obo or mondo-rare.json
Get rare diseases for a specific region	Filter by `orphanet_rare` (Europe), `gard_rare` or `nord_rare` (US)
Report a missing rare disease	Open a GitHub issue
Learn more about a specific rare disease	Follow cross-references to OMIM, Orphanet, GARD, or NORD