Early onset severe obesity: genes and variants

Genes linked to Early onset severe obesity

• MC4R: Melanocortin receptor 4

  Its melanocortin signaling in hypothalamic circuits suppresses appetite and helps regulate energy expenditure and body weight. Loss-of-function variants are the most common known cause of monogenic obesity and typically produce early hyperphagia.

  9 disease-causing and 17 uncertain variants in MC4R are linked to Early onset severe obesity.

Weakly linked (only a few uncertain records): NTRK2, LEPR, PCSK1, BBS2 and GNAS.

Where Early onset severe obesity variants cluster

• MC4R Cytoplasmic (positions 146–166): 4 of 9 disease-causing changes, 7.0× more than its size predicts.

Known disease-causing variants in Early onset severe obesity

Which prediction tools work for Early onset severe obesity

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• CADD: 98 out of 100
• PolyPhen-2: 94 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 92 out of 100
• CATVariant: 89 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• REVEL: 89 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• phyloP: 75 out of 100
• MetaLR: 73 out of 100 (learned from overlapping clinical labels, so this is optimistic)

Same protein, different disease

• BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20 is also caused by MC4R variants; they fall mostly in different places as the Early onset severe obesity variants (8 disease-causing).
• Obesity due to melanocortin 4 receptor deficiency is also caused by MC4R variants; they fall mostly in different places as the Early onset severe obesity variants (6 disease-causing).

Diseases related to Early onset severe obesity

• Type 2 diabetes mellitus, also linked to MC4R
• BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20, also linked to MC4R
• Obesity due to melanocortin 4 receptor deficiency, also linked to MC4R

Frequently asked questions

Which genes are linked to Early onset severe obesity?

In CATVariant, Early onset severe obesity is linked to 1 analyzed protein: MC4R (Melanocortin receptor 4).

How many genetic variants are linked to Early onset severe obesity?

37 variants: 9 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 27 are of uncertain significance or have conflicting reports.

Which uncertain variants in Early onset severe obesity look disease-causing?

None of the uncertain variants currently reaches the likely-pathogenic range on computable evidence alone.

Which variant effect predictor works best for Early onset severe obesity?

Among tools not trained on clinical labels, CADD separates this disease's known disease-causing variants from harmless ones best (AUROC 0.98, based on 8 disease-causing and 44 harmless variants).

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

Download every variant as CSV · Browse all diseases · Methods · About the Center