Pachyonychia congenita: genes and variants

Genes linked to Pachyonychia congenita

• KRT6A: Keratin, type II cytoskeletal 6A

  It is induced in palmoplantar, nail-bed, and wound-response epithelia and helps reinforce keratinocytes under mechanical stress. Dominant pathogenic variants cause pachyonychia congenita, often with severe painful plantar keratoderma and nail dystrophy.

  12 disease-causing and 4 uncertain variants in KRT6A are linked to Pachyonychia congenita.

• KRT16: Keratin, type I cytoskeletal 16

  It is induced in mechanically stressed and repairing epithelia and helps reinforce keratinocyte intermediate filaments. Dominant pathogenic variants can cause pachyonychia congenita and focal palmoplantar keratoderma with painful hyperkeratosis.

  12 disease-causing and 6 uncertain variants in KRT16 are linked to Pachyonychia congenita.

• KRT17: Keratin, type I cytoskeletal 17

  It supports structural integrity of nail beds, hair follicles, glands, and stressed epithelia and also influences epithelial growth responses. Dominant pathogenic variants cause pachyonychia congenita and steatocystoma multiplex.

  7 disease-causing and 2 uncertain variants in KRT17 are linked to Pachyonychia congenita.

• KRT6B: Keratin, type II cytoskeletal 6B

  It contributes to stress-responsive keratin networks in nail, palmoplantar, and other specialized epithelia. Dominant pathogenic variants can cause pachyonychia congenita with nail dystrophy, painful keratoderma, and variable oral or follicular findings.

  3 disease-causing and 2 uncertain variants in KRT6B are linked to Pachyonychia congenita.

• KRT10: Keratin, type I cytoskeletal 10

  It forms intermediate filaments with keratin 1 in differentiating epidermal keratinocytes, protecting the upper epidermis from mechanical stress. Dominant pathogenic variants cause epidermolytic ichthyosis, while specific mechanisms can produce ichthyosis with confetti.

  0 disease-causing and 0 uncertain variants in KRT10 are linked to Pachyonychia congenita.

Where Pachyonychia congenita variants cluster

• KRT16 Coil 1A (positions 117–152): 12 of 12 disease-causing changes, 13.1× more than its size predicts.
• KRT17 Coil 1A (positions 84–120): 7 of 7 disease-causing changes, 11.7× more than its size predicts.
• KRT6A Coil 1A (positions 163–198): 7 of 12 disease-causing changes, 9.1× more than its size predicts.
• KRT6A Coil 2 (positions 334–472): 5 of 12 disease-causing changes, 1.7× more than its size predicts.

Known disease-causing variants in Pachyonychia congenita

Which prediction tools work for Pachyonychia congenita

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

• REVEL: 100 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 97 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• PolyPhen-2: 94 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 89 out of 100
• CADD: 88 out of 100
• phyloP: 72 out of 100

Diseases related to Pachyonychia congenita

• Ichthyosis and erythrokeratoderma, also linked to KRT10 and KRT16
• Epidermolytic palmoplantar keratoderma, 1, also linked to KRT10
• Epidermolytic hyperkeratosis 2A, autosomal dominant, also linked to KRT10
• Annular epidermolytic ichthyosis, also linked to KRT10
• Palmoplantar keratoderma, nonepidermolytic, focal 1, also linked to KRT16
• Epidermolytic ichthyosis, also linked to KRT10
• Autosomal dominant epidermolytic ichthyosis, also linked to KRT10
• Epidermolytic nevus, also linked to KRT10
• Steatocystoma multiplex, also linked to KRT17
• Ichthyosis, annular epidermolytic 1, also linked to KRT10
• Congenital reticular ichthyosiform erythroderma, also linked to KRT10

Frequently asked questions

Which genes are linked to Pachyonychia congenita?

In CATVariant, Pachyonychia congenita is linked to 5 analyzed proteins: KRT6A (Keratin, type II cytoskeletal 6A), KRT16 (Keratin, type I cytoskeletal 16), KRT17 (Keratin, type I cytoskeletal 17), KRT6B (Keratin, type II cytoskeletal 6B) and KRT10 (Keratin, type I cytoskeletal 10).

How many genetic variants are linked to Pachyonychia congenita?

80 variants: 34 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 14 are of uncertain significance or have conflicting reports.

Which uncertain variants in Pachyonychia congenita 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 Pachyonychia congenita?

Among tools not trained on clinical labels, SIFT separates this disease's known disease-causing variants from harmless ones best (AUROC 0.89, based on 25 disease-causing and 114 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.

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