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Novel MC1R variants cause red hair and lighter skin color

Deepak K Kashyap1, Srashti J Agrawal2, Meenakshisundaram Karthikeyan3

  • 1CSIR-Centre for Cellular and Molecular Biology, Hyderabad, Telangana 500007, India; Tata Institute for Genetics and Society, Bengaluru, Karnataka 560065, India; Department of Genetic Engineering, College of Engineering and Technology, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu 603203, India.

HGG Advances
|April 5, 2026
PubMed

Insights

Ultra-rare variants in the melanocortin 1 receptor (MC1R) gene are identified as causes for the rare red hair color (RHC) phenotype in India. These variants, including p.Ala291Asp, were found in diverse Indian populations.

Area of Science:

  • Genetics
  • Human Pigmentation
  • Molecular Biology

Background:

  • The melanocortin 1 receptor (MC1R) gene is crucial for regulating mammalian skin and hair color.
  • The red hair color (RHC) phenotype is exceptionally rare in Indian populations.

Purpose of the Study:

  • To investigate the genetic basis of the rare RHC phenotype in India.
  • To identify and functionally characterize novel MC1R variants in diverse Indian populations.

Main Methods:

  • Screening of the complete coding region of MC1R in 11,021 individuals from 91 Indian populations.
  • In silico, in vitro, and Zebrafish-based functional analyses of identified MC1R variants.
  • Association study of MC1R variants with skin pigmentation in specific populations.

Main Results:

  • An ultra-rare pathogenic variant, p.Ala291Asp, was identified as a cause of RHC in an Indian child.
  • A total of 21 novel or ultra-rare MC1R variants were discovered across Indian populations.
  • p.Gly248Cys and p.Ala291Asp variants demonstrated loss-of-function effects.
  • The MC1R c.-226 A>T variant (rs3212363) is associated with lighter skin pigmentation in the Bodh population of Ladakh.

Conclusions:

  • Ultra-rare MC1R variants are potential causative factors for the RHC phenotype in India.
  • Functional validation confirms loss-of-function effects for key MC1R variants.
  • MC1R variant distribution varies significantly among Indian populations, influencing pigmentation traits.

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