What is the most least common disease? Unveiling the Rarest Human Illnesses

October 1, 2025 •

2 min read

With an estimated 7,000 to 10,000 rare diseases identified globally, pinpointing exactly what is the most least common disease is a challenging and often debated topic among medical experts. Prevalence data can be elusive, and new cases of ultra-rare conditions are sometimes identified decades after the first diagnosis, shifting the rankings.

Quick Summary

It is nearly impossible to declare a single rarest disease due to incomplete data and new discoveries, but contenders include Ribose-5-phosphate isomerase (RPI) deficiency and Fields Condition. These incredibly rare disorders, alongside others like Stone Man's Disease, highlight the vast and complex landscape of human illness and medical science.

Key Points

No Single Rarest Disease: Pinpointing one single rarest disease is challenging due to the constant discovery of new ultra-rare genetic and infectious conditions.
RPI Deficiency: Ribose-5-phosphate isomerase deficiency is frequently cited as one of the rarest, with only a handful of documented cases worldwide.
Fields Condition: Considered by some as the rarest, this condition affects only three known individuals, two of whom are identical twins.
Genetic Origins: Most rare diseases, including many of the rarest, have a genetic origin stemming from mutations passed down or occurring spontaneously.
Implications for All Health: Studying extremely rare diseases offers critical insights into broader biological mechanisms, potentially leading to new therapies for more common conditions.
FOP: Fibrodysplasia Ossificans Progressiva, or 'Stone Man's Disease,' is another candidate for extreme rarity, known for progressively turning connective tissue into bone.

The Challenge of Identifying the Rarest Disease

Pinpointing the absolute rarest disease is a complex task for several reasons. The definition of a 'rare disease' varies by region; in the United States, it is a condition affecting fewer than 200,000 people. Within this category, some disorders are exceptionally scarce, affecting only a handful of individuals globally. Their rarity often stems from unique genetic mutations. Difficulties in diagnosis and documentation also hinder reliable statistics. Genetic sequencing has improved identification, sometimes revealing more cases and altering perceived rarity.

Leading Contenders for the Rarest Title

Several disorders are often considered candidates for the rarest human disease, each presenting a significant medical challenge.

Ribose-5-Phosphate Isomerase (RPI) Deficiency

RPI Deficiency is an extremely rare metabolic disorder, with only a few cases confirmed over many years. It is caused by mutations in the RPIA gene and affects a key metabolic pathway. Symptoms include progressive neurological issues like epilepsy and spasticity.

Fields Condition

Fields Condition is another strong contender for the rarest title, with only three known individuals affected, including identical twins. Limited information is available, reflecting its extreme rarity.

Fibrodysplasia Ossificans Progressiva (FOP)

Also known as 'Stone Man's Disease,' FOP is a very rare genetic disorder where muscle and connective tissues turn into bone. Life expectancy is around 41 years due to restricted mobility. Malformed great toes at birth are a characteristic sign.

Kuru Disease

Kuru was a rare infectious prion disease historically found in the Fore tribe of Papua New Guinea, transmitted through ritualistic practices. It is now virtually extinct following the cessation of these practices.

Comparison of Ultra-Rare Diseases


Feature	Ribose-5-Phosphate Isomerase (RPI) Deficiency	Fields Condition	Fibrodysplasia Ossificans Progressiva (FOP)
Known Cases	Only a few cases documented over decades.	Three known individuals, including identical twins.	Approximately 800 cases worldwide.
Cause	Genetic mutation in the RPIA gene.	Cause not widely published, possibly genetic due to the twin cases.	Single genetic mutation, which can be triggered by trauma.
Key Symptom	Neurological decline including seizures, spasticity.	Details are scarce, pointing to its extreme rarity.	Conversion of connective tissue into bone.
Prevalence	Extremely low, often cited as one of the rarest.	Unprecedented scarcity, affects only a few individuals.	One in two million people.

The Impact of Medical Research

Studying ultra-rare diseases, despite affecting few people, provides crucial insights into fundamental biological processes. Research into conditions like RPI Deficiency and FOP can reveal mechanisms relevant to more common disorders, leading to broader medical advancements.

Conclusion

While definitively naming the single rarest disease is challenging due to ongoing discoveries and data limitations, conditions such as Ribose-5-phosphate isomerase deficiency and Fields Condition are strong contenders, representing the extreme end of human illness rarity. These rare conditions, though affecting few, are vital for advancing medical knowledge and can lead to discoveries benefiting a wider population. The study of these 'orphan' diseases remains essential for expanding our understanding of human health.

Learn more about rare diseases and the research being done at the National Human Genome Research Institute.

Frequently Asked Questions

In the United States, a rare disease is defined as one that affects fewer than 200,000 people. This definition helps determine eligibility for funding and research under the Orphan Drug Act.

No, not all rare diseases are genetic. While approximately 80% have a genetic origin, others can be caused by infections, exposure to toxins, or other environmental factors.

Estimates vary, but organizations like Global Genes suggest there are approximately 10,000 rare diseases worldwide. Many remain uncharacterized or unknown.

Orphan drugs are medications and treatments specifically developed to target and treat rare diseases. They are called 'orphan' because their small patient population makes them less financially viable to develop without government incentives.

Accurate prevalence data is difficult to collect due to several factors, including the extremely small number of patients, the possibility of undiagnosed cases, and frequent misdiagnoses.

Ribose-5-phosphate isomerase deficiency (RPI Deficiency) is an extremely rare metabolic disorder affecting the brain, causing neurological symptoms like seizures, stiffness, and developmental delay.

Fields Condition is an incredibly rare and poorly understood neurological disorder, named after the two identical twins who, along with one other individual, were the only known cases as of recent reports.