The 3 Main Types of Gene Mutations and Their Impact on Human Health

The 3 Main Types of Gene Mutations and Their Impact on Human Health

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Last Updated: July 26, 2025

Introduction

Our DNA is an incredibly complex instruction manual, and like any manual, a single typo can have profound consequences. In genetics, these typos are called mutations. But not all mutations are created equal; their impact on health depends entirely on how they alter the genetic code. Some are like a minor spelling error, while others delete an entire chapter. Understanding the different types of gene mutations is fundamental to diagnosing inherited diseases and developing targeted therapies. This article will break down the three most significant types—missense, splice site, and frameshift—using real-world genetic mutation examples from the research of Sadaqat Ijaz to show how they lead to disease.

Thesis Excerpt & Analysis

What is a Missense Mutation? A Pathogenic Genetic Variant Example

A missense mutation is one of the most common types of gene mutations. It is a point mutation where a single nucleotide change results in a codon that codes for a different amino acid. This is like swapping one word for another in a sentence. Sometimes the new word makes sense in context, but other times it changes the entire meaning.

The missense mutation impact depends on how different the new amino acid is from the original. A key example is the p.T325M mutation in the FAH gene, which causes Tyrosinemia Type 1.

• The Change: A single nucleotide substitution (C>T) at position 974 of the gene causes the amino acid threonine to be replaced by methionine at position 325 of the protein.
• The Impact: Threonine is a smaller, more hydrophobic amino acid capable of forming crucial hydrogen bonds that stabilize the protein’s structure. Methionine is larger and cannot form the same bonds. This single substitution is located in a domain critical for the enzyme’s activity, disrupting its function and leading to disease.
• The Result: Bioinformatics tools predict this change as “damaging,” confirming it as a disease-causing mutation. This illustrates how even a subtle, single-amino-acid swap can have severe consequences for protein function.

Splice Site Mutation Explained: When Genetic Instructions are Misread

Our genes contain coding regions (exons) and non-coding regions (introns). Before a protein is made, the introns must be precisely “spliced” out of the messenger RNA (mRNA). A splice site mutation is an error at the boundary between an exon and an intron. This disrupts the splicing machinery, leading to a faulty mRNA blueprint.

A classic example is the IVS12+5G>A mutation in the FAH gene. This is one of the most common pathogenic genetic variants causing Tyrosinemia Type 1 worldwide.

• The Change: A single nucleotide change (G>A) occurs five positions into intron 12, a critical location for the splicing signal.
• The Impact: This error confuses the cell’s splicing machinery, leading to three different incorrect versions of the mRNA:
  1. One version is missing exon 12 entirely.
  2. Another is missing both exons 12 and 13.
  3. A third version incorrectly retains 105 base pairs of the intron.
• The Result: All three outcomes lead to a non-functional or unstable FAH protein. This splice site mutation explained here shows how an error in a non-coding region can have a devastating effect on the final protein product.

The Devastating Frameshift Mutation Effects: Creating a Truncated Protein

Perhaps the most severe of all types of gene mutations is a frameshift mutation. The genetic code is read in three-letter “words” called codons. A frameshift occurs when nucleotides are inserted or deleted in a number that is not a multiple of three. This shifts the entire reading frame, scrambling every codon downstream from the mutation.

The novel c.609_612delAAAA deletion found in the FBP1 gene (causing Fructose-1,6-bisphosphatase deficiency) is a perfect example of the drastic frameshift mutation effects.

• The Change: The deletion of four “A” nucleotides in exon 6.
• The Impact: Because four is not a multiple of three, the entire genetic sentence is misread from that point onward. This results in a string of incorrect amino acids followed quickly by a premature stop codon.
• The Result: The cell stops protein production far too early, creating a severely shortened, non-functional, and unstable protein. This is known as a truncated protein. Frameshift mutations almost always result in a complete loss of protein function, making them one of the most severe disease-causing mutations.

Conclusion

From a single amino acid swap to a catastrophic shift in the reading frame, the specific type of genetic error dictates the biological outcome. Understanding the different types of gene mutations—missense, splice site, and frameshift—is therefore essential for the molecular diagnosis of inherited diseases. As these genetic mutation examples show, this knowledge allows scientists to predict disease severity, counsel families on genetic risk, and develop therapies that target the specific molecular defect at the heart of a condition.

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Source & Citations

Thesis Title: MOLECULAR CHARACTERIZATION AND COMPARATIVE GENOMIC STUDIES OF RECESSIVE METABOLIC DISORDERS RELATED GENES FAH, FBP1 AND IDUA
Researcher: SADAQAT IJAZ
Guide (Supervisor): Dr. Muhammad Yasir Zahoor
University: UNIVERSITY OF VETERINARY AND ANIMAL SCIENCES, LAHORE, PAKISTAN
Year of Compilation: 2018
Excerpt Page Numbers:

• Missense Mutation (p.T325M in FAH): Pages 60, 77, 116-117
• Splice Site Mutation (IVS12+5G>A in FAH): Pages 56-57, 73, 115-116
• Frameshift Mutation (c.609_612delAAAA in FBP1): Pages 73, 89-90, 118-119

Disclaimer: Some sentences have been lightly edited for SEO and readability. For the full, original research, please refer to the complete thesis PDF linked in the section above.

Author Bio: This analysis is based on the doctoral research of Sadaqat Ijaz, a specialist in Molecular Biology and Biotechnology from the University of Veterinary and Animal Sciences, Lahore, Pakistan. Her work provides critical insights into the various mutations that cause rare metabolic disorders.

Which of these mutation types do you find most interesting from a biological standpoint, and why? Share your thoughts in the comments below!