KRT16

Chr 17AD

keratin 16

Also known as: CK16, FNEPPK, K16, K1CP, KRT16A, NEPPK, PC1

NCBI Gene: 3868 ENSG00000186832 UniProt: P08779

The protein encoded by this gene is a member of the keratin gene family. The keratins are intermediate filament proteins responsible for the structural integrity of epithelial cells and are subdivided into cytokeratins and hair keratins. Most of the type I cytokeratins consist of acidic proteins which are arranged in pairs of heterotypic keratin chains and are clustered in a region of chromosome 17q12-q21. This keratin has been coexpressed with keratin 14 in a number of epithelial tissues, including esophagus, tongue, and hair follicles. Mutations in this gene are associated with type 1 pachyonychia congenita, non-epidermolytic palmoplantar keratoderma and unilateral palmoplantar verrucous nevus. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Pachyonychia congenita 1MIM #167200

Palmoplantar keratoderma, nonepidermolytic, focalMIM #613000

UniProtKeratoderma, palmoplantar, non-epidermolytic, focal 1

Active trials

Pathogenic / LP

180

ClinVar variants

Pubs (1 yr)

-0.3

Missense Z

1.61

LOEUF

Clinical Summary— KRT16

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

29 Pathogenic / Likely Pathogenic· 71 VUS of 180 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

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GeneReview available — KRT16

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

1.61LOEUF

pLI 0.000

Z-score -0.46

OE 1.12 (0.78–1.61)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

-0.31Z-score

OE missense 1.05 (0.96–1.16)

294 obs / 279.3 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.1.12 (0.78–1.61)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.05 (0.96–1.16)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.26

0≤1.21.6

LoF obs/exp: 20 / 17.9Missense obs/exp: 294 / 279.3Syn Z: -2.22

0.94top 5%

GOF

0.91top 5%

LOF

0.2385th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median · 1 literature citation

GOFprediction above median · 1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNThese findings together with our data suggest that both the dominant negative disruption of intermediate filaments as well as the exclusion of keratins from the network can contribute to PPK pathogenesis.PMID:22336941

GOFOur findings call into question the view that PC-related PPK arises exclusively as a gain-of-function on account of dominantly acting mutated keratins, and highlight the key role of modifiers in the clinical heterogeneity of PC symptoms.PMID:22336941

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.