KRT16

Summary

KRT16 (keratin 16, HGNC:6423) is a protein-coding gene on chromosome 17q21.2, encoding Keratin, type I cytoskeletal 16 (P08779). Epidermis-specific type I keratin that plays a key role in skin.

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.

Source: NCBI Gene 3868 — RefSeq curated summary.

At a glance

• Gene–disease (curated): pachyonychia congenita 1 (Strong, GenCC) — +3 more curated relationships
• Clinical variants (ClinVar): 183 total — 15 pathogenic, 5 likely-pathogenic
• Phenotypes (HPO): 47
• MANE Select transcript: NM_005557

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6423
Approved symbol	KRT16
Name	keratin 16
Location	17q21.2
Locus type	gene with protein product
Status	Approved
Aliases	NEPPK
Ensembl gene	ENSG00000186832
Ensembl biotype	protein_coding
OMIM	148067
Entrez	3868

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 3 protein_coding, 1 retained_intron

ENST00000301653, ENST00000588319, ENST00000590990, ENST00000593067

RefSeq mRNA: 1 — MANE Select: NM_005557 NM_005557

CCDS: CCDS11401

Canonical transcript exons

ENST00000301653 — 8 exons

Exon	Start	End
ENSE00001118266	41611069	41611230
ENSE00001118302	41610854	41610979
ENSE00001325556	41609778	41610029
ENSE00001723397	41612158	41612767
ENSE00002404289	41610190	41610236
ENSE00002411630	41610331	41610551
ENSE00003648691	41611345	41611501
ENSE00003650696	41611639	41611721

Expression profiles

Bgee: expression breadth ubiquitous, 176 present calls, max score 99.96.

FANTOM5 (CAGE): breadth broad, TPM avg 56.1534 / max 28849.4074, expressed in 436 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
165992	55.8905	436
165989	0.1359	29
165991	0.0999	29
165990	0.0271	7

Top tissues by expression

289 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
gingival epithelium	UBERON:0001949	99.96	gold quality
gingiva	UBERON:0001828	99.94	gold quality
lower esophagus mucosa	UBERON:0035834	99.66	gold quality
tongue squamous epithelium	UBERON:0006919	99.56	gold quality
hair follicle	UBERON:0002073	98.65	gold quality
esophagus mucosa	UBERON:0002469	97.92	gold quality
buccal mucosa cell	CL:0002336	97.60	gold quality
amniotic fluid	UBERON:0000173	97.10	gold quality
skin of abdomen	UBERON:0001416	96.40	gold quality
skin of leg	UBERON:0001511	95.65	gold quality
periodontal ligament	UBERON:0008266	95.51	gold quality
zone of skin	UBERON:0000014	94.64	gold quality
squamous epithelium	UBERON:0006914	93.70	gold quality
cervix epithelium	UBERON:0004801	92.96	gold quality
body of tongue	UBERON:0011876	92.92	gold quality
epithelium of esophagus	UBERON:0001976	92.54	gold quality
penis	UBERON:0000989	92.50	gold quality
esophagus squamous epithelium	UBERON:0006920	92.33	gold quality
mammalian vulva	UBERON:0000997	90.56	gold quality
oral cavity	UBERON:0000167	89.84	gold quality
tongue	UBERON:0001723	89.63	gold quality
vagina	UBERON:0000996	87.23	gold quality
cervix squamous epithelium	UBERON:0006922	86.58	gold quality
nipple	UBERON:0002030	84.81	gold quality
pharyngeal mucosa	UBERON:0000355	82.94	gold quality
upper arm skin	UBERON:0004263	82.00	gold quality
superior surface of tongue	UBERON:0007371	81.06	gold quality
seminal vesicle	UBERON:0000998	80.98	gold quality
tonsil	UBERON:0002372	80.82	gold quality
popliteal artery	UBERON:0002250	79.99	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-8142	yes	12152.50
E-HCAD-1	yes	234.15
E-MTAB-10596	no	19390.49
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, EP300, JUN, KAT7, KDM5B, KMT2A, MBD2, NFE2L2, PITX2, SMAD2, SP1, TCF3

miRNA regulators (miRDB)

5 targeting KRT16, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-4695-5P	99.06	64.87	1151
HSA-MIR-4451	98.82	68.17	1455
HSA-MIR-4536-5P	98.47	64.39	657
HSA-MIR-1226-3P	97.51	66.32	1063

Literature-anchored findings (GeneRIF, showing 31)

• disease-associated keratin 16 expression is induced by epidermal growth factor is regulated through cooperation of transcription factors Sp1 and c-Jun (PMID:12954631)
• K16 expression is observed in non-lesional psoriatic skin and may serve as a marker of preclinical psoriasis. (PMID:15239676)
• ERK2-mediated C-terminal serine phosphorylation of p300 was a key event in the regulation of EGF-induced keratin 16 expression. (PMID:17623675)
• Four new missense and five known mutations in K6a, one new deletion and three previously identified missense mutations in K16, plus one known mutation in K17 are reported in pachyonychia congenita. (PMID:17719747)
• K14 and K16 were detected in the tumour cells, suggesting differentiation towards the outer root sheath beneath the orifice of the sebaceous duct. (PMID:18005116)
• PC-1 is due to mutations of the KRT16 gene or its expression partner KRT6A, wheres PC-2 is caused by mutations in the KRT17 or KRT6B genes. (PMID:18489596)
• DPPIV-expression and enzyme activity, Ki-67 antigen and K16 are significantly upregulated in the centre and inner margin of the psoriatic lesion compared to clinically uninvolved skin and the healthy volunteers skin. (PMID:18496701)
• Antikeratin 16 autoAbs are involved in psoriasis, by exaggerating the innate immune response of keratinocytes. (PMID:18557933)
• Infection by HPV stimulates the expression of K16 (PMID:19515043)
• coinheritance of mutations in KRT16 and filaggrin may aggravate the pachyonychia congenita phenotype (PMID:19785597)
• these data highlight the possibility of a physiological role for K6/K16 heterodimers in keratinocyte cell migration, in addition to the heterodimer’s known functions in cell differentiation and mechanical resilience. (PMID:20403371)
• Data suggest that an immune response to trichohyalin and K16 may have a role in the pathogenesis of the enigmatic disorder. (PMID:20722389)
• Patients with p.Asn125Asp and p.Arg127Pro mutations in KRT16 exhibited more severe disease than patients carrying p.Asn125Ser and p.Arg127Cys mutations in terms of age of onset of symptoms, extent of nail involvement, and impact on daily quality of life. (PMID:21160496)
• Phenotypic differences exist between KRT6A and KRT16 mutations support adoption of a new classification system. (PMID:22098151)
• We found that the KRT16 mutation carriers developed plantar keratoderma at a similar age to KRT6A carriers wheras KRT6B and KRT17 carriers were significantly more likely to report later onset. (PMID:22264670)
• Genotype-phenotype correlations among PC patients with codon-125 mutation in KRT16 were established, while the phenotypes caused by the IVS8-2A>C mutation in KRT6A need further studies to confirm the rare feature of fissured tongue (PMID:22668561)
• Data established a seven-gene (AR, ESR2, GATA3, GBX2, KRT16, MMP28 and WNT11) prognostic signature to define a subset of triple-negative breast cancer (TNBC). (PMID:23549873)
• analysis of a new p.Leu421Pro (c.1262T>C) mutation in the highly conserved helix termination motif of K16 in a large Spanish family that may have a role in pachyonychia congenita (PMID:24118415)
• Keratin 16 regulates innate immunity in response to epidermal barrier breach. (PMID:24218583)
• The wider spectrum of KRT16 mutations suggests that changes in codons 125, 127, and 132 are most commonly responsible for PC-1 and that proline substitution mutations at codons 127 or 128 may produce more severe disease (PMID:24357266)
• Study identified iRHOM2 as a novel regulator of K16 in humans and mice, with important implications for palmoplantar keratodermas, wound healing, inflammatory skin disease and cancers. (PMID:28128203)
• inflammatory cytokines promoted Nrf2 nuclear translocation in psoriatic epidermis, which led to elevated expression of K6, K16, and K17, thus promoting keratinocyte proliferation and contributing to the pathogenesis of psoriasis. (PMID:28576737)
• results suggest a conditional regulation of KRT16 gene by ATF4 that may be inhibited in normal cells, but engaged during cancer progression. Potential roles of KRT16, FAM129A and HKDC1 genes upregulation in adaptive stress responses and pathologies are discussed (PMID:29420561)
• Targeting a novel miR-365-3p/EHF/KRT16/beta5-integrin/c-Met signaling pathway could improve treatment efficacy in OSCC. (PMID:30782177)
• The mutation found in this study is the first report in China. So far, 25 mutations in KRT16 have been reportedly associated with Pachyonychia congenita. Twenty-one mutations are located on exon 1, and four mutations on exon 6. (PMID:30859684)
• Silencing KRT16 inhibits keratinocyte proliferation and VEGF secretion in psoriasis via inhibition of ERK signaling pathway. (PMID:30942529)
• TFAP2A induced KRT16 overexpression promotes tumorigenicity in lung adenocarcinoma via epithelial-mesenchymal transition (PMID:31337972)
• BarH-like homeobox 2 represses the transcription of keratin 16 and affects Ras signaling pathway to suppress nasopharyngeal carcinoma progression. (PMID:35037835)
• A novel KRT16 frameshift variant causing pachyonychia congenita by re-initiation of translation. (PMID:36149327)
• Targeting the KRT16-vimentin axis for metastasis in lung cancer. (PMID:37315823)
• GLI Transcriptional Targets S100A7 and KRT16 Show Upregulated Expression Patterns in Epidermis Overlying the Tumor Mass in Melanoma Samples. (PMID:38892279)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Krt16	ENSMUSG00000053797
rattus_norvegicus	Krt15	ENSRNOG00000003899

Paralogs (68): KRT33A (ENSG00000006059), VIM (ENSG00000026025), KRT31 (ENSG00000094796), NEFM (ENSG00000104722), KRT23 (ENSG00000108244), KRT37 (ENSG00000108417), KRT32 (ENSG00000108759), KRT18 (ENSG00000111057), LMNB1 (ENSG00000113368), KRT36 (ENSG00000126337), KRT17 (ENSG00000128422), GFAP (ENSG00000131095), KRT34 (ENSG00000131737), KRT33B (ENSG00000131738), NES (ENSG00000132688), PRPH (ENSG00000135406), KRT85 (ENSG00000135443), KRT7 (ENSG00000135480), KRT71 (ENSG00000139648), INA (ENSG00000148798), LMNTD1 (ENSG00000152936), LMNA (ENSG00000160789), KRT84 (ENSG00000161849), KRT82 (ENSG00000161850), KRT80 (ENSG00000167767), KRT1 (ENSG00000167768), KRT24 (ENSG00000167916), KRT8 (ENSG00000170421), KRT78 (ENSG00000170423), KRT86 (ENSG00000170442), KRT75 (ENSG00000170454), KRT6C (ENSG00000170465), KRT4 (ENSG00000170477), KRT74 (ENSG00000170484), KRT72 (ENSG00000170486), KRT83 (ENSG00000170523), BFSP2 (ENSG00000170819), KRT19 (ENSG00000171345), KRT15 (ENSG00000171346), KRT38 (ENSG00000171360)

Protein

Protein identifiers

Keratin, type I cytoskeletal 16 — P08779 (reviewed: P08779)

Alternative names: Cytokeratin-16, Keratin-16

All UniProt accessions (3): P08779, K7ENV3, K7ENW6

UniProt curated annotations — full annotation on UniProt →

Function. Epidermis-specific type I keratin that plays a key role in skin. Acts as a regulator of innate immunity in response to skin barrier breach: required for some inflammatory checkpoint for the skin barrier maintenance.

Subunit / interactions. Heterodimer of a type I and a type II keratin. KRT16 associates with KRT6 isomers (KRT6A or KRT6B). Interacts with TCHP. Interacts with TRADD.

Tissue specificity. Expressed in the corneal epithelium (at protein level).

Disease relevance. Pachyonychia congenita 1 (PC1) [MIM:167200] An autosomal dominant ectodermal dysplasia characterized by hypertrophic nail dystrophy resulting in onchyogryposis (thickening and increase in curvature of the nail), palmoplantar keratoderma, follicular hyperkeratosis, and oral leukokeratosis. Hyperhidrosis of the hands and feet is usually present. The disease is caused by variants affecting the gene represented in this entry. Keratoderma, palmoplantar, non-epidermolytic, focal 1 (FNEPPK1) [MIM:613000] A dermatological disorder characterized by non-epidermolytic palmoplantar keratoderma limited to the pressure points on the balls of the feet, with later mild involvement on the palms. Oral, genital and follicular keratotic lesions are often present. The disease is caused by variants affecting the gene represented in this entry. KRT16 and KRT17 are coexpressed only in pathological situations such as metaplasias and carcinomas of the uterine cervix and in psoriasis vulgaris.

Miscellaneous. There are two types of cytoskeletal and microfibrillar keratin, I (acidic) and II (neutral to basic) (40-55 and 56-70 kDa, respectively).

Similarity. Belongs to the intermediate filament family.

RefSeq proteins (1): NP_005548* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002957	Keratin_I	Family
IPR018039	IF_conserved	Conserved_site
IPR039008	IF_rod_dom	Domain

Pfam: PF00038

UniProt features (37 total): sequence variant 16, sequence conflict 9, region of interest 8, compositionally biased region 2, chain 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P08779-F1	74.26	0.53

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-6805567	Keratinization
R-HSA-6809371	Formation of the cornified envelope
R-HSA-1266738	Developmental Biology

MSigDB gene sets: 244 (showing top): GSE45365_NK_CELL_VS_CD11B_DC_DN, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_INTERMEDIATE_FILAMENT_BASED_PROCESS, YAGI_AML_WITH_INV_16_TRANSLOCATION, GOBP_INTERMEDIATE_FILAMENT_ORGANIZATION, GOBP_INFLAMMATORY_RESPONSE, JAEGER_METASTASIS_DN, HUMMERICH_BENIGN_SKIN_TUMOR_UP, HUMMERICH_MALIGNANT_SKIN_TUMOR_UP, SARRIO_EPITHELIAL_MESENCHYMAL_TRANSITION_DN, HUMMERICH_SKIN_CANCER_PROGRESSION_UP, DOANE_BREAST_CANCER_CLASSES_DN, GOBP_AMEBOIDAL_TYPE_CELL_MIGRATION, GOBP_EPIDERMAL_CELL_DIFFERENTIATION

GO Biological Process (12): morphogenesis of an epithelium (GO:0002009), inflammatory response (GO:0006954), cytoskeleton organization (GO:0007010), keratinocyte differentiation (GO:0030216), negative regulation of cell migration (GO:0030336), keratinization (GO:0031424), hair cycle (GO:0042633), innate immune response (GO:0045087), intermediate filament organization (GO:0045109), keratinocyte migration (GO:0051546), establishment of skin barrier (GO:0061436), intermediate filament cytoskeleton organization (GO:0045104)

GO Molecular Function (4): structural constituent of cytoskeleton (GO:0005200), structural constituent of skin epidermis (GO:0030280), structural molecule activity (GO:0005198), protein binding (GO:0005515)

GO Cellular Component (7): cornified envelope (GO:0001533), nucleus (GO:0005634), cytosol (GO:0005829), cytoskeleton (GO:0005856), intermediate filament (GO:0005882), keratin filament (GO:0045095), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Developmental Biology	1
Keratinization	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoskeleton organization	2
structural molecule activity	2
tissue morphogenesis	1
epithelium development	1
defense response	1
organelle organization	1
epidermal cell differentiation	1
skin development	1
cell migration	1
regulation of cell migration	1
negative regulation of cell motility	1
keratinocyte differentiation	1
multicellular organismal process	1
molting cycle	1
immune response	1
defense response to symbiont	1
intermediate filament cytoskeleton organization	1
supramolecular fiber organization	1
epithelial cell migration	1
skin epidermis development	1
intermediate filament-based process	1
cytoskeleton	1
molecular_function	1
binding	1
plasma membrane	1
intracellular membrane-bounded organelle	1
cytoplasm	1
cellular anatomical structure	1
intracellular membraneless organelle	1
intermediate filament cytoskeleton	1
polymeric cytoskeletal fiber	1
intermediate filament	1
extracellular vesicle	1

Protein interactions and networks

STRING

1716 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KRT16	KRT6A	P02538	775
KRT16	S100A7	P31151	737
KRT16	KRT6B	P04259	696
KRT16	CCHCR1	Q8TD31	683
KRT16	IVL	P07476	609
KRT16	FLG	P20930	607
KRT16	FLG2	Q5D862	594
KRT16	LORICRIN	P23490	581
KRT16	S100A7A	Q86SG5	577
KRT16	CDSN	Q15517	554
KRT16	KRT72	Q14CN4	538
KRT16	TGM1	P22735	525
KRT16	SPRR1B	P22528	507
KRT16	RHBDF2	Q6PJF5	485
KRT16	KRT7	P08729	484

IntAct

224 interactions, top by confidence:

A	B	Type	Score
KRT16	SGF29	psi-mi:“MI:0915”(physical association)	0.670
KRT16	KRT73	psi-mi:“MI:0915”(physical association)	0.560
KRT16	KRT71	psi-mi:“MI:0915”(physical association)	0.560
KRT16	PPP1R18	psi-mi:“MI:0915”(physical association)	0.560
KRT16	CCDC146	psi-mi:“MI:0915”(physical association)	0.560
KRT16	PRPH	psi-mi:“MI:0915”(physical association)	0.560
KRT16	KRT4	psi-mi:“MI:0915”(physical association)	0.560
KRT16	AIRIM	psi-mi:“MI:0915”(physical association)	0.560
MBD3	KRT16	psi-mi:“MI:0915”(physical association)	0.560
KRT16	KRT79	psi-mi:“MI:0915”(physical association)	0.560
KRT16	CCNC	psi-mi:“MI:0915”(physical association)	0.560
KRT16	PKN1	psi-mi:“MI:0915”(physical association)	0.560
KRT16	KRT2	psi-mi:“MI:0915”(physical association)	0.560
KRT16	TTC23	psi-mi:“MI:0915”(physical association)	0.560
KRT16	KLC4	psi-mi:“MI:0915”(physical association)	0.560
SNAPIN	KRT16	psi-mi:“MI:0915”(physical association)	0.560
KRT16	TCHP	psi-mi:“MI:0915”(physical association)	0.560
KRT16	LMO1	psi-mi:“MI:0915”(physical association)	0.560
KRT16	CYTH4	psi-mi:“MI:0915”(physical association)	0.560
GAS8	KRT16	psi-mi:“MI:0915”(physical association)	0.560
KRT16	KRT81	psi-mi:“MI:0915”(physical association)	0.560
KRT86	KRT16	psi-mi:“MI:0915”(physical association)	0.560
KRT16	KRT72	psi-mi:“MI:0915”(physical association)	0.560
AMOT	KRT16	psi-mi:“MI:0915”(physical association)	0.560
KRT16	KRT3	psi-mi:“MI:0915”(physical association)	0.560
KRT16	PRKAA2	psi-mi:“MI:0915”(physical association)	0.560
KRT16	KIFC3	psi-mi:“MI:0915”(physical association)	0.560
KRT16	KRT85	psi-mi:“MI:0915”(physical association)	0.560
KRT16	USHBP1	psi-mi:“MI:0915”(physical association)	0.560
KRT1	KRT16	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (235): KRT16 (Affinity Capture-MS), KRT16 (Affinity Capture-MS), KRT16 (Affinity Capture-MS), KRT16 (Co-fractionation), KRT16 (Co-fractionation), KRT16 (Co-fractionation), KRT16 (Co-fractionation), KRT16 (Affinity Capture-MS), KRT16 (Affinity Capture-MS), KRT16 (Proximity Label-MS), KRT16 (Affinity Capture-MS), KRT16 (Affinity Capture-MS), KRT16 (Affinity Capture-MS), KRT16 (Affinity Capture-MS), KRT16 (Affinity Capture-MS)

ESM2 similar proteins: A1L317, A1L595, A5A6N2, A6BLY7, B1AQ75, E1AB55, O76013, P02533, P08730, P08779, P13646, P19012, Q0P5J4, Q0P5J6, Q0P5J7, Q148H5, Q148H6, Q148H8, Q2M2I5, Q3UV17, Q497I4, Q61414, Q61781, Q64291, Q6IFU7, Q6IFU8, Q6IFV1, Q6IFV3, Q6IFV4, Q6IFW6, Q6IFW8, Q6IFX0, Q6IFX1, Q6IFX2, Q6NXH9, Q6R649, Q6R650, Q7Z3Y7, Q7Z3Y8, Q7Z3Y9

Diamond homologs: A1KQY9, A1L317, A1L595, A5A6M0, A5A6M5, A5A6N2, A5A6P3, A6BLY7, A6QQQ9, A7YWM2, B0LKP1, B1AQ75, O57607, O57611, O76009, O76013, O77727, O93256, P02533, P02534, P02535, P02537, P05781, P05783, P05784, P06394, P08727, P08728, P08730, P08777, P08778, P08779, P08802, P13645, P13646, P19001, P19012, P25030, P25690, P35527

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
SP1	“up-regulates quantity by expression”	KRT16	“transcriptional regulation”
EP300	“up-regulates quantity by expression”	KRT16	“transcriptional regulation”
JUN	“up-regulates quantity by expression”	KRT16	“transcriptional regulation”
NFE2L2	“up-regulates quantity by expression”	KRT16	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 101 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Formation of the cornified envelope	20	24.8×	2e-20
Keratinization	20	15.7×	1e-16
Macroautophagy	6	9.8×	3e-03

GO biological processes:

GO term	Partners	Fold	FDR
intermediate filament organization	20	54.1×	3e-27
keratinization	19	50.0×	2e-25
autophagosome maturation	6	23.7×	4e-05
mitophagy	5	17.9×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

183 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	15
Likely pathogenic	5
Uncertain significance	71
Likely benign	45
Benign	20

Top pathogenic / likely-pathogenic (20)

Variant ID	HGVS	Classification
14600	NM_005557.4(KRT16):c.395T>C (p.Leu132Pro)	Pathogenic
14601	NM_005557.4(KRT16):c.379C>T (p.Arg127Cys)	Pathogenic
14602	NM_005557.4(KRT16):c.374A>G (p.Asn125Ser)	Pathogenic
14603	NM_005557.4(KRT16):c.386CCT[1] (p.Ser130del)	Pathogenic
14604	NM_005557.4(KRT16):c.380G>C (p.Arg127Pro)	Pathogenic
14605	NM_005557.4(KRT16):c.365A>C (p.Gln122Pro)	Pathogenic
14606	NM_005557.4(KRT16):c.371T>G (p.Leu124Arg)	Pathogenic
14609	NM_005557.4(KRT16):c.383T>A (p.Leu128Gln)	Pathogenic
14610	NM_005557.4(KRT16):c.1244_1270delinsGGC (p.Ala415_Glu424delinsGlyGln)	Pathogenic
156024	NM_005557.4(KRT16):c.373_374delinsGG (p.Asn125Gly)	Pathogenic
265217	NM_005557.4(KRT16):c.379C>G (p.Arg127Gly)	Pathogenic
265486	NM_005557.4(KRT16):c.383T>C (p.Leu128Pro)	Pathogenic
3722722	NM_005557.4(KRT16):c.380G>A (p.Arg127His)	Pathogenic
419351	NM_005557.4(KRT16):c.362T>G (p.Met121Arg)	Pathogenic
66608	NM_005557.4(KRT16):c.373A>G (p.Asn125Asp)	Pathogenic
216955	NM_005557.4(KRT16):c.365A>G (p.Gln122Arg)	Likely pathogenic
2671710	NM_005557.4(KRT16):c.39del (p.Ser13_Met14insTer)	Likely pathogenic
3581944	NM_005557.4(KRT16):c.375T>G (p.Asn125Lys)	Likely pathogenic
4526742	NM_005557.4(KRT16):c.1252_1255delinsACCTCCAGCGGCG (p.Arg418_Arg419delinsThrSerSerGlyGly)	Likely pathogenic
4681892	NM_005557.4(KRT16):c.1_4dup (p.Thr2fs)	Likely pathogenic

SpliceAI

610 predictions. Top by Δscore:

Variant	Effect	Δscore
17:41610025:GAAGA:G	acceptor_gain	1.0000
17:41610027:AGA:A	acceptor_gain	1.0000
17:41610028:GA:G	acceptor_gain	1.0000
17:41610030:C:CC	acceptor_gain	1.0000
17:41610188:AC:A	donor_gain	1.0000
17:41610189:CC:C	donor_gain	1.0000
17:41610237:C:CC	acceptor_gain	1.0000
17:41610314:AGGGG:A	donor_gain	1.0000
17:41610328:CA:C	donor_loss	1.0000
17:41610329:A:AC	donor_gain	1.0000
17:41610329:AC:A	donor_loss	1.0000
17:41610330:C:CA	donor_gain	1.0000
17:41610330:CT:C	donor_gain	1.0000
17:41610330:CTG:C	donor_gain	1.0000
17:41610330:CTGGG:C	donor_gain	1.0000
17:41610337:T:TA	donor_gain	1.0000
17:41610548:CTTT:C	acceptor_gain	1.0000
17:41610549:TTT:T	acceptor_gain	1.0000
17:41610550:TT:T	acceptor_gain	1.0000
17:41610552:C:CC	acceptor_gain	1.0000
17:41610553:T:C	acceptor_loss	1.0000
17:41610555:CAAG:C	acceptor_gain	1.0000
17:41610556:A:T	acceptor_gain	1.0000
17:41610558:G:C	acceptor_gain	1.0000
17:41610558:G:GC	acceptor_gain	1.0000
17:41610812:A:AC	donor_gain	1.0000
17:41610813:C:CC	donor_gain	1.0000
17:41610850:ATAC:A	donor_loss	1.0000
17:41610851:TAC:T	donor_loss	1.0000
17:41610852:A:AC	donor_gain	1.0000

AlphaMissense

3092 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:41610352:A:G	L420P	1.000
17:41610382:A:G	L410P	1.000
17:41612306:A:G	L128P	1.000
17:41612306:A:T	L128Q	1.000
17:41612309:C:G	R127P	1.000
17:41612318:A:G	L124P	1.000
17:41612318:A:T	L124H	1.000
17:41610358:C:G	R418P	0.999
17:41610362:A:G	Y417H	0.999
17:41610370:A:C	I414S	0.999
17:41610373:T:A	E413V	0.999
17:41610382:A:T	L410Q	0.999
17:41610454:A:G	L386P	0.999
17:41610873:A:G	L347P	0.999
17:41611670:C:G	A195P	0.999
17:41612168:A:G	L174P	0.999
17:41612243:A:G	I149T	0.999
17:41612255:A:G	L145P	0.999
17:41612268:C:G	A141P	0.999
17:41612276:A:G	L138P	0.999
17:41612294:A:G	L132P	0.999
17:41612310:G:T	R127S	0.999
17:41612314:A:C	N125K	0.999
17:41612314:A:T	N125K	0.999
17:41612315:T:A	N125I	0.999
17:41612319:G:A	L124F	0.999
17:41610349:A:G	L421P	0.998
17:41610362:A:C	Y417D	0.998
17:41610368:C:G	A415P	0.998
17:41610370:A:T	I414N	0.998

dbSNP variants (sampled 300 via entrez): RS1000136710 (17:41610860 G>A), RS1000630222 (17:41614756 G>A), RS1003043093 (17:41614671 C>T), RS1003093953 (17:41614347 G>A), RS1003377256 (17:41613236 C>G,T), RS1003429508 (17:41612958 G>A,C), RS1003868383 (17:41612940 C>T), RS1006664370 (17:41614313 G>A,C), RS1007046084 (17:41613604 A>C), RS1010771404 (17:41613341 T>C), RS1011260549 (17:41613599 G>A), RS1013088476 (17:41609307 G>A), RS1013529129 (17:41614730 T>TC), RS1013575991 (17:41611779 A>G,T), RS1013911461 (17:41610773 G>A)

Disease associations

OMIM: gene MIM:148067 | disease phenotypes: MIM:613000, MIM:167200, MIM:144200

GenCC curated gene-disease

Disease	Classification	Inheritance
pachyonychia congenita 1	Strong	Autosomal dominant
palmoplantar keratoderma, nonepidermolytic, focal 1	Strong	Autosomal dominant
pachyonychia congenita	Supportive	Autosomal dominant
isolated focal non-epidermolytic palmoplantar keratoderma	Supportive	Autosomal dominant

Mondo (5): palmoplantar keratoderma, nonepidermolytic, focal 1 (MONDO:0013073), pachyonychia congenita 1 (MONDO:0008173), palmoplantar keratoderma, epidermolytic (MONDO:0968949), pachyonychia congenita (MONDO:0016471), isolated focal non-epidermolytic palmoplantar keratoderma (MONDO:0014622)

Orphanet (1): Pachyonychia congenita (Orphanet:2309)

HPO phenotypes

47 total (30 of 47 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000695	Natal tooth
HP:0000962	Hyperkeratosis
HP:0000972	Palmoplantar hyperkeratosis
HP:0000975	Hyperhidrosis
HP:0000982	Palmoplantar keratoderma
HP:0001217	Clubbing
HP:0001220	Interphalangeal joint contracture of finger
HP:0001231	Abnormal fingernail morphology
HP:0001508	Failure to thrive
HP:0001596	Alopecia
HP:0001609	Hoarse voice
HP:0001805	Onychogryphosis
HP:0001818	Paronychia
HP:0002098	Respiratory distress
HP:0002745	Oral leukoplakia
HP:0003621	Juvenile onset
HP:0006288	Advanced eruption of teeth
HP:0007410	Palmoplantar hyperhidrosis
HP:0007446	Palmoplantar blistering
HP:0007447	Diffuse palmoplantar hyperkeratosis
HP:0007475	Congenital bullous ichthyosiform erythroderma
HP:0007490	Linear arrays of macular hyperkeratoses in flexural areas
HP:0007502	Follicular hyperkeratosis
HP:0008066	Abnormal blistering of the skin
HP:0008401	Onychogryphosis of toenails
HP:0008404	Nail dystrophy
HP:0010765	Palmar hyperkeratosis
HP:0010829	Impaired temperature sensation
HP:0010830	Impaired tactile sensation

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D053549	Pachyonychia Congenita	C16.131.077.350.856; C16.131.831.350.856; C16.320.850.250.856; C17.800.529.594; C17.800.804.350.856; C17.800.827.250.856

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

61 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Tobacco Smoke Pollution	affects expression, increases expression	6
Calcitriol	decreases expression, increases expression, affects cotreatment	4
sodium arsenite	increases expression, increases reaction, decreases expression	3
Cadmium	affects expression, increases abundance, increases expression, affects binding	3
Benzo(a)pyrene	decreases methylation, increases expression, increases methylation	2
Estradiol	affects cotreatment, increases expression	2
Lead	affects binding, increases expression	2
Mustard Gas	increases cleavage, increases reaction, increases alkylation, increases expression	2
Nickel	affects binding, increases expression	2
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
Particulate Matter	decreases expression, increases abundance, affects cotreatment, increases expression	2
beauvericin	affects cotreatment, decreases expression	1
pyrogallol 1,3-dimethyl ether	decreases expression, affects cotreatment, affects localization	1
2,3-pentanedione	increases expression	1
2,4,5,2’,4’,5’-hexachlorobiphenyl	increases expression	1
beta-lapachone	increases expression	1
phenyl isocyanate	affects binding	1
sulindac sulfide	increases expression	1
cupric chloride	increases expression	1
phenanthrene	decreases expression	1
ethyl-p-((E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propenyl)benzoic acid	decreases expression	1
isobutyl alcohol	increases abundance, increases expression, affects cotreatment	1
calcipotriene	decreases expression	1
4-((3-bromophenyl)amino)-6,7-dimethoxyquinazoline	affects cotreatment, affects expression, decreases expression	1
chloropicrin	decreases expression	1
enniatins	affects cotreatment, decreases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	increases expression	1
tofacitinib	decreases expression	1
abrine	decreases expression	1
apilimod	decreases expression	1

Clinical trials (associated diseases)

12 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT04520750	PHASE3	COMPLETED	VALO-2: Study Evaluating the Safety and Efficacy of PTX022 in the Treatment of Adults With Pachyonychia Congenita
NCT05180708	PHASE3	COMPLETED	A Multicenter, Phase 3 Randomized, Double-Blind, Vehicle-Controlled Study Evaluating the Safety and Efficacy of QTORIN 3.9% Rapamycin Anhydrous Gel in the Treatment of Pachyonychia Congenita
NCT05643872	PHASE3	RECRUITING	A Study Evaluating the Safety and Pharmacokinetics of QTORIN Rapamycin 3.9% Anhydrous Gel in the Treatment of Adults With Pachyonychia Congenita
NCT00716014	PHASE1	COMPLETED	Study of TD101, a Small Interfering RNA (siRNA) Designed for Treatment of Pachyonychia Congenita
NCT02152007	PHASE1	COMPLETED	Topical Sirolimus for the Treatment of Pachyonychia Congenita (PC)
NCT02592954	PHASE1	COMPLETED	Effect of Broccoli Sprout Extract on Keratinocyte Differentiation in Normal Skin
NCT05435638	PHASE1	COMPLETED	Study Designed to Evaluate Safety and Efficacy of 1% Topical Formulation of KM-001 on Type 1 Punctate Palmoplantar Keratoderma or Pachyonychia Congenita Diseases
NCT05956314	PHASE1	COMPLETED	Assessment of KM-001 - Safety, Tolerability, and Efficacy in Patients With PPPK1 or PC
NCT03920228	PHASE2/PHASE3	COMPLETED	Phase 2/3 Study Evaluating the Safety and Efficacy of PTX-022 in Treatment of Adults With Pachyonychia Congenita
NCT06545695	PHASE1/PHASE2	NOT_YET_RECRUITING	Epidermal Growth Factor Receptor Inhibition for Keratinopathies
NCT01382511	Not specified	UNKNOWN	Simvastatin Treatment of Pachyonychia Congenita
NCT02321423	Not specified	RECRUITING	International Pachyonychia Congenita Research Registry