KRT6A

Summary

KRT6A (keratin 6A, HGNC:6443) is a protein-coding gene on chromosome 12q13.13, encoding Keratin, type II cytoskeletal 6A (P02538). Epidermis-specific type I keratin involved in wound healing.

The protein encoded by this gene is a member of the keratin gene family. The type II cytokeratins consist of basic or neutral proteins which are arranged in pairs of heterotypic keratin chains coexpressed during differentiation of simple and stratified epithelial tissues. As many as six of this type II cytokeratin (KRT6) have been identified; the multiplicity of the genes is attributed to successive gene duplication events. The genes are expressed with family members KRT16 and/or KRT17 in the filiform papillae of the tongue, the stratified epithelial lining of oral mucosa and esophagus, the outer root sheath of hair follicles, and the glandular epithelia. This KRT6 gene in particular encodes the most abundant isoform. Mutations in these genes have been associated with pachyonychia congenita. In addition, peptides from the C-terminal region of the protein have antimicrobial activity against bacterial pathogens. The type II cytokeratins are clustered in a region of chromosome 12q12-q13.

Source: NCBI Gene 3853 — RefSeq curated summary.

At a glance

• Gene–disease (curated): palmoplantar keratoderma, nonepidermolytic, focal or diffuse (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 477 total — 18 pathogenic, 10 likely-pathogenic
• Phenotypes (HPO): 35
• MANE Select transcript: NM_005554

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6443
Approved symbol	KRT6A
Name	keratin 6A
Location	12q13.13
Locus type	gene with protein product
Status	Approved
Aliases	CK6C, K6C, CK6D, K6D
Ensembl gene	ENSG00000205420
Ensembl biotype	protein_coding
OMIM	148041
Entrez	3853

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 4 retained_intron, 1 protein_coding

ENST00000330722, ENST00000548735, ENST00000549600, ENST00000549754, ENST00000549898

RefSeq mRNA: 1 — MANE Select: NM_005554 NM_005554

CCDS: CCDS41786

Canonical transcript exons

ENST00000330722 — 9 exons

Exon	Start	End
ENSE00001288498	52487176	52487955
ENSE00001403739	52492649	52493257
ENSE00001681496	52489943	52490068
ENSE00001692358	52488328	52488548
ENSE00001764626	52488069	52488103
ENSE00003477866	52490569	52490733
ENSE00003599571	52490858	52490953
ENSE00003618967	52491112	52491172
ENSE00003660727	52491522	52491736

Expression profiles

Bgee: expression breadth ubiquitous, 187 present calls, max score 99.96.

FANTOM5 (CAGE): breadth broad, TPM avg 178.1875 / max 15154.4399, expressed in 257 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
131057	177.3733	256
131054	0.4190	79
131056	0.1386	62
131051	0.0839	50
131055	0.0808	38
131053	0.0596	37
131052	0.0323	14

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
gingiva	UBERON:0001828	99.96	gold quality
gingival epithelium	UBERON:0001949	99.96	gold quality
squamous epithelium	UBERON:0006914	99.93	gold quality
esophagus squamous epithelium	UBERON:0006920	99.93	gold quality
tongue squamous epithelium	UBERON:0006919	99.91	gold quality
cervix squamous epithelium	UBERON:0006922	99.89	gold quality
lower esophagus mucosa	UBERON:0035834	99.83	gold quality
amniotic fluid	UBERON:0000173	99.75	gold quality
cervix epithelium	UBERON:0004801	99.73	gold quality
hair follicle	UBERON:0002073	99.71	gold quality
mammalian vulva	UBERON:0000997	99.53	gold quality
esophagus mucosa	UBERON:0002469	99.53	gold quality
body of tongue	UBERON:0011876	99.33	gold quality
oral cavity	UBERON:0000167	99.23	gold quality
pharyngeal mucosa	UBERON:0000355	99.21	gold quality
epithelium of esophagus	UBERON:0001976	99.14	gold quality
penis	UBERON:0000989	99.03	gold quality
upper arm skin	UBERON:0004263	98.18	gold quality
upper leg skin	UBERON:0004262	97.85	gold quality
skin of abdomen	UBERON:0001416	97.37	gold quality
periodontal ligament	UBERON:0008266	97.10	gold quality
zone of skin	UBERON:0000014	96.81	gold quality
skin of leg	UBERON:0001511	96.57	gold quality
tongue	UBERON:0001723	96.33	gold quality
epithelium of nasopharynx	UBERON:0001951	96.11	gold quality
nasal cavity epithelium	UBERON:0005384	95.24	gold quality
vagina	UBERON:0000996	94.29	gold quality
palpebral conjunctiva	UBERON:0001812	93.11	gold quality
buccal mucosa cell	CL:0002336	92.32	gold quality
superior surface of tongue	UBERON:0007371	91.04	gold quality

Single-cell (SCXA)

Detected in 9 experiment(s), a significant marker in 8.

Experiment	Marker?	Max mean expression
E-HCAD-1	yes	14079.32
E-MTAB-10855	yes	9800.28
E-MTAB-8142	yes	9783.09
E-CURD-114	yes	7109.76
E-MTAB-6308	yes	5990.12
E-MTAB-6653	yes	5687.47
E-GEOD-86618	yes	2815.67
E-MTAB-10596	no	14498.37
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

31 targeting KRT6A, 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-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-544A	99.84	68.66	1965
HSA-MIR-212-3P	99.73	70.65	1424
HSA-MIR-377-5P	99.70	65.28	712
HSA-MIR-6086	99.70	65.38	699
HSA-MIR-4677-5P	99.70	70.09	1940
HSA-MIR-7156-5P	99.64	68.81	1369
HSA-MIR-4756-3P	99.62	66.30	1319
HSA-MIR-5003-5P	99.61	69.13	1624
HSA-MIR-12117	99.50	67.57	868
HSA-MIR-3612	99.45	66.02	1333
HSA-MIR-650	99.45	65.77	1309
HSA-MIR-4273	99.45	67.93	1206
HSA-MIR-32-3P	99.36	68.20	2517
HSA-MIR-544B	99.18	67.41	1632
HSA-MIR-661	99.09	65.94	2062
HSA-MIR-4686	98.77	66.87	964
HSA-MIR-7851-3P	98.72	64.88	980
HSA-MIR-31-5P	98.58	68.35	1239
HSA-MIR-3928-5P	98.50	67.48	980
HSA-MIR-6806-3P	98.50	67.31	980
HSA-MIR-4443	98.02	66.25	1928
HSA-MIR-4438	97.96	63.70	947
HSA-MIR-4257	97.86	68.05	1190
HSA-MIR-4759	97.39	65.86	608
HSA-MIR-3907	96.76	65.04	662

Literature-anchored findings (GeneRIF, showing 36)

• CK5/6 and/or EGFR expressing tumor types have a persistently poorer prognosis over the longer term. (PMID:17650314)
• 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)
• 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)
• Three novel and four recurrent keratin 6A (KRT6A) mutations were found in Chinese patients with pachyonychia congenita type 1 (PMID:19416275)
• Rapamycin selectively inhibits expression of an inducible keratin (K6a) in human keratinocytes and improves symptoms in pachyonychia congenita patients. (PMID:19699613)
• Studies show that the intrinsic molecular signature of five markers, ER, PR, HER-2, CK 5/6, and EGFR, demonstrated specificity of 100% and sensitivity of 75%, compared with classification by gene expression profiling. (PMID:19720911)
• Mutations Y465H and N171D of the KRT16A gene were detected in the sporadic pachyonychia congenita cases. (PMID:19806570)
• The mutation of 521T–> C in the K6A gene is the causing mutation in pachyonychia congenita type I. (PMID:20140871)
• 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)
• Focal palmoplantar keratoderma is associated with mutations in keratin K6c in 3 families. 2 unrelated families have Asn172 del and the other has a deletion of AA 462-470. Review. (PMID:20470930)
• This report is the first case of pachyonychia congenita with laryngeal obstruction in which the gene mutation has been established (a deletional mutation in keratin 6a). (PMID:21554383)
• Phenotypic differences exist between KRT6A and KRT16 mutations support adoption of a new classification system. (PMID:22098151)
• We observed a higher likelihood of oral leukokeratosis in individuals harboring KRT6A mutations. (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)
• Keratin-derived antimicrobial peptides (KDAMPs) and their synthetic analogs exhibit antimicrobial activity against bacterial pathogens. (PMID:23006328)
• Data show that calretinin and CK5/6 were positive in 100 and 64% of mesotheliomas, and 92 and 31% of reactive effusions, respectively, and desmin was negative in all malignant cases and positive in 85% of reactive effusions. (PMID:23075894)
• CK5/6, but not c-Met expression, seems to be important in lymphatic metastasis (PMID:24326984)
• we here describe a family with pachyonychia congenita K6a, manifesting atypical symptoms of impaired wound healing and cheilitis. (PMID:24708461)
• KRT6A genetic mutation is associate with the development of Pachyonychia Congenita in patients in Australia. (PMID:27041546)
• Manipulating K6a phosphorylation or ubiquitin-proteasome system (UPS) activity may provide opportunities to harness the innate immunity of epithelia against infection. (PMID:29191848)
• Several missense polymorphisms in KRT6A, KRT6B and KRT6C that lead to a higher risk for dental caries. (PMID:29357356)
• Data indicate that cytokeratin 5/6 (CK5/6) is an independent prognostic biomarker in urothelial carcinoma and therefore can be used in the prognostic stratification of the patients with bladder cancer. (PMID:29587848)
• Cytokeratin 5/6 and CK8/18 immunohistochemistry on 150 cases of triple negative breast cancers was performed and association with various clinicopathological features was evaluated. (PMID:29884220)
• KRT6A silencing suppressed cell viability, invasion and metastasis of NPC cells via beta-catenin/TCF pathway. (PMID:30896882)
• Keratin 6a mutations lead to impaired mitochondrial quality control. (PMID:31004504)
• Anti-tumour effects of Keratin 6A in lung adenocarcinoma. (PMID:32162441)
• KRT6A Promotes EMT and Cancer Stem Cell Transformation in Lung Adenocarcinoma. (PMID:32329414)
• Non-Muscle-Invasive Bladder Carcinoma with Respect to Basal Versus Luminal Keratin Expression. (PMID:33086575)
• Comprehensive Gene Expression Analyses of Immunohistochemically Defined Subgroups of Muscle-Invasive Urinary Bladder Urothelial Carcinoma. (PMID:33435173)
• A KRT6A mutation p.Ile462Asn in a Chinese family with pachyonychia congenita, and identification of maternal mosaicism: a case report. (PMID:34724947)
• KRT6A expedites bladder cancer progression, regulated by miR-31-5p. (PMID:35311447)
• Cytokeratin 5/6 expression in pT1 bladder cancer predicts intravesical recurrence in patients treated with bacillus Calmette-Guerin instillation. (PMID:35527047)
• The expression pattern of cytokeratin 6a in epithelial cells of different origin in dermo-epidermal skin substitutes in vivo. (PMID:37766482)
• KRT6A Inhibits IL-1beta-Mediated Pyroptosis of Keratinocytes via Blocking IL-17 Signaling. (PMID:38505868)
• ECM1 and KRT6A are involved in tumor progression and chemoresistance in the effect of dexamethasone on pancreatic cancer. (PMID:38613239)
• Keratin 6A Is Expressed at the Invasive Front and Enhances the Progression of Colorectal Cancer. (PMID:38729352)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
mus_musculus	Krt6b	ENSMUSG00000023041
mus_musculus	Krt6a	ENSMUSG00000058354
mus_musculus	Gm5414	ENSMUSG00000064232
rattus_norvegicus	AABR07001416.1	ENSRNOG00000059050
rattus_norvegicus	LOC102553726	ENSRNOG00000067545
rattus_norvegicus	LOC100365213	ENSRNOG00000068586
rattus_norvegicus	LOC120093742	ENSRNOG00000068784
rattus_norvegicus	Krt6c	ENSRNOG00000070470

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 II cytoskeletal 6A — P02538 (reviewed: P02538)

Alternative names: Cytokeratin-6A, Cytokeratin-6D, Keratin-6A, Type-II keratin Kb6

All UniProt accessions (2): P02538, A0A0S2Z428

UniProt curated annotations — full annotation on UniProt →

Function. Epidermis-specific type I keratin involved in wound healing. Involved in the activation of follicular keratinocytes after wounding, while it does not play a major role in keratinocyte proliferation or migration. Participates in the regulation of epithelial migration by inhibiting the activity of SRC during wound repair.

Subunit / interactions. Heterodimer of a type I and a type II keratin. KRT6 isomers associate with KRT16 and/or KRT17. Interacts with TCHP.

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

Disease relevance. Pachyonychia congenita 3 (PC3) [MIM:615726] An autosomal dominant genodermatosis characterized by hypertrophic nail dystrophy, painful and highly debilitating plantar keratoderma, oral leukokeratosis, and a variety of epidermal cysts. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. There are at least six isoforms of human type II keratin-6 (K6), K6A being the most abundant representing about 77% of all forms found in epithelia. 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_005545* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003054	Keratin_II	Family
IPR018039	IF_conserved	Conserved_site
IPR032444	Keratin_2_head	Domain
IPR039008	IF_rod_dom	Domain

Pfam: PF00038, PF16208

UniProt features (51 total): sequence variant 28, region of interest 8, sequence conflict 7, helix 2, initiator methionine 1, chain 1, compositionally biased region 1, site 1, modified residue 1, domain 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
5KI0	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P02538-F1	69.16	0.42

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 414 (stutter)

Post-translational modifications (1): 2

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: 223 (showing top): GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_ANTIMICROBIAL_HUMORAL_RESPONSE, GOBP_INTERMEDIATE_FILAMENT_BASED_PROCESS, GU_PDEF_TARGETS_DN, GOBP_INTERMEDIATE_FILAMENT_ORGANIZATION, JAEGER_METASTASIS_DN, GCM_PRKCG, GOBP_WOUND_HEALING, GOBP_EPIDERMAL_CELL_DIFFERENTIATION, GCM_RING1, RICKMAN_METASTASIS_DN, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, RICKMAN_TUMOR_DIFFERENTIATED_WELL_VS_POORLY_DN, GOBP_REGULATION_OF_BIOLOGICAL_PROCESS_INVOLVED_IN_SYMBIOTIC_INTERACTION

GO Biological Process (10): morphogenesis of an epithelium (GO:0002009), positive regulation of cell population proliferation (GO:0008284), cell differentiation (GO:0030154), keratinization (GO:0031424), killing of cells of another organism (GO:0031640), wound healing (GO:0042060), intermediate filament organization (GO:0045109), defense response to Gram-positive bacterium (GO:0050830), antimicrobial humoral immune response mediated by antimicrobial peptide (GO:0061844), negative regulation of entry of bacterium into host cell (GO:2000536)

GO Molecular Function (3): structural constituent of cytoskeleton (GO:0005200), structural constituent of skin epidermis (GO:0030280), protein binding (GO:0005515)

GO Cellular Component (6): nucleus (GO:0005634), cytosol (GO:0005829), membrane (GO:0016020), keratin filament (GO:0045095), extracellular exosome (GO:0070062), intermediate filament (GO:0005882)

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
structural molecule activity	2
cellular anatomical structure	2
tissue morphogenesis	1
epithelium development	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
cellular developmental process	1
keratinocyte differentiation	1
multicellular organismal process	1
cell killing	1
disruption of cell in another organism	1
response to wounding	1
tissue regeneration	1
intermediate filament cytoskeleton organization	1
supramolecular fiber organization	1
defense response to bacterium	1
antimicrobial humoral response	1
entry of bacterium into host cell	1
negative regulation of biological process	1
regulation of entry of bacterium into host cell	1
cytoskeleton	1
cytoskeleton organization	1
binding	1
intracellular membrane-bounded organelle	1
cytoplasm	1
intermediate filament	1
extracellular vesicle	1
intermediate filament cytoskeleton	1
polymeric cytoskeletal fiber	1

Protein interactions and networks

STRING

1724 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KRT6A	KRT16	P08779	775
KRT6A	CCHCR1	Q8TD31	648
KRT6A	S100A7	P31151	530
KRT6A	SPRR1B	P22528	505
KRT6A	SPRR3	Q9UBC9	495
KRT6A	LAMC2	Q13753	480
KRT6A	SPRR1A	P35321	474
KRT6A	CDSN	Q15517	471
KRT6A	GJB3	O75712	462
KRT6A	SCARB1	Q8WTV0	457
KRT6A	DSG3	P32926	449
KRT6A	SERPINB13	Q9UIV8	445
KRT6A	ASPM	Q8IZT6	442
KRT6A	DCBLD2	Q96PD2	440
KRT6A	S100A7A	Q86SG5	427

IntAct

240 interactions, top by confidence:

A	B	Type	Score
KRT15	KRT6A	psi-mi:“MI:0915”(physical association)	0.930
KRT6A	KRT15	psi-mi:“MI:0915”(physical association)	0.930
KRT6A	KRT38	psi-mi:“MI:0915”(physical association)	0.890
KRT38	KRT6A	psi-mi:“MI:0915”(physical association)	0.890
KRT6A	KRT40	psi-mi:“MI:0915”(physical association)	0.870
KRT40	KRT6A	psi-mi:“MI:0915”(physical association)	0.870

BioGRID (196): KRT6A (Two-hybrid), KRT6A (Two-hybrid), KRT6A (Two-hybrid), KRT13 (Two-hybrid), KRT15 (Two-hybrid), KRT31 (Two-hybrid), SGTA (Two-hybrid), KRT38 (Two-hybrid), HGS (Two-hybrid), TFIP11 (Two-hybrid), TRIM54 (Two-hybrid), KRT40 (Two-hybrid), KRT6A (Affinity Capture-MS), KRT6A (Affinity Capture-MS), KRT6A (Affinity Capture-MS)

ESM2 similar proteins: A5A6M6, A5A6M8, O95678, P02535, P02537, P02538, P04104, P04259, P04264, P06394, P07744, P08776, P12035, P13645, P13647, P16878, P18520, P19013, P35527, P35908, P48668, P50446, Q01546, Q08D91, Q148H7, Q29426, Q2M2I5, Q3TTY5, Q3UV17, Q4FZU2, Q5XQN5, Q6EIY9, Q6EIZ0, Q6EIZ1, Q6IFW6, Q6IFZ6, Q6IG00, Q6IG01, Q6IG02, Q6IG05

Diamond homologs: A0A8C0N8E3, A5A6M8, A5A6N0, A6QQJ3, B4F721, O62654, O77788, O93532, O95678, P02538, P02540, P02541, P02542, P02543, P02544, P02547, P02548, P03995, P04259, P05786, P05787, P07196, P07197, P08551, P08552, P08553, P08670, P08729, P08776, P09654, P11679, P12035, P12036, P12839, P13647, P14136, P15331, P16053, P16878, P16884

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 54 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	16	36.0×	2e-19
Keratinization	16	22.9×	2e-16

GO biological processes:

GO term	Partners	Fold	FDR
morphogenesis of an epithelium	15	109.8×	2e-25
intermediate filament organization	15	76.8×	4e-23
epithelial cell differentiation	14	52.3×	4e-19

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	18
Likely pathogenic	10
Uncertain significance	236
Likely benign	87
Benign	76

Top pathogenic / likely-pathogenic (28)

Variant ID	HGVS	Classification
126525	NM_173086.5(KRT6C):c.510CAA[2] (p.Asn172del)	Pathogenic
14634	NM_005554.4(KRT6A):c.510CAA[2] (p.Asn172del)	Pathogenic
14635	NM_005554.4(KRT6A):c.520T>G (p.Phe174Val)	Pathogenic
14637	NM_005554.4(KRT6A):c.1406T>G (p.Leu469Arg)	Pathogenic
418765	NM_005554.4(KRT6A):c.529_531del (p.Phe177del)	Pathogenic
419468	NM_005554.4(KRT6A):c.511A>C (p.Asn171His)	Pathogenic
452212	NM_005554.4(KRT6A):c.490C>T (p.Arg164Cys)	Pathogenic
4695093	NM_005554.4(KRT6A):c.1393T>G (p.Tyr465Asp)	Pathogenic
66570	NM_005554.4(KRT6A):c.1387G>C (p.Ala463Pro)	Pathogenic
66572	NM_005554.4(KRT6A):c.1393T>C (p.Tyr465His)	Pathogenic
66576	NM_005554.4(KRT6A):c.1406T>C (p.Leu469Pro)	Pathogenic
66579	NM_005554.4(KRT6A):c.487G>A (p.Glu163Lys)	Pathogenic
66584	NM_005554.4(KRT6A):c.508C>T (p.Leu170Phe)	Pathogenic
66585	NM_005554.4(KRT6A):c.511A>G (p.Asn171Asp)	Pathogenic
66588	NM_005554.4(KRT6A):c.512A>G (p.Asn171Ser)	Pathogenic
66589	NM_005554.4(KRT6A):c.513C>A (p.Asn171Lys)	Pathogenic
66591	NM_005554.4(KRT6A):c.521T>C (p.Phe174Ser)	Pathogenic
66966	NM_173086.5(KRT6C):c.1384_1410del (p.Ile462_Glu470del)	Pathogenic
156022	NM_005554.4(KRT6A):c.1460-2A>C	Likely pathogenic
1806290	NM_005554.4(KRT6A):c.817-2A>G	Likely pathogenic
2109726	NM_005554.4(KRT6A):c.1418dup (p.Cys474fs)	Likely pathogenic
3574966	NM_005554.4(KRT6A):c.1382A>G (p.Glu461Gly)	Likely pathogenic
3574967	NM_005554.4(KRT6A):c.520T>A (p.Phe174Ile)	Likely pathogenic
3891533	NM_005554.4(KRT6A):c.1388C>T (p.Ala463Val)	Likely pathogenic
4081480	NM_005554.4(KRT6A):c.1203+1G>A	Likely pathogenic
66566	NM_005554.4(KRT6A):c.1381G>A (p.Glu461Lys)	Likely pathogenic
66582	NM_005554.4(KRT6A):c.500T>A (p.Ile167Asn)	Likely pathogenic
827961	NM_005554.4(KRT6A):c.1381G>T (p.Glu461Ter)	Likely pathogenic

SpliceAI

544 predictions. Top by Δscore:

Variant	Effect	Δscore
12:52488064:CTT:C	donor_loss	1.0000
12:52488065:TTACA:T	donor_loss	1.0000
12:52488067:A:AC	donor_gain	1.0000
12:52488067:ACAG:A	donor_loss	1.0000
12:52488068:C:CA	donor_gain	1.0000
12:52488068:CAG:C	donor_gain	1.0000
12:52488068:CAGA:C	donor_gain	1.0000
12:52488068:CAGAT:C	donor_gain	1.0000
12:52488104:C:CC	acceptor_gain	1.0000
12:52488323:CCCA:C	donor_loss	1.0000
12:52488324:CCA:C	donor_loss	1.0000
12:52488325:CA:C	donor_loss	1.0000
12:52488327:C:G	donor_loss	1.0000
12:52488544:GCGCA:G	acceptor_gain	1.0000
12:52488545:CGCA:C	acceptor_gain	1.0000
12:52488545:CGCAC:C	acceptor_gain	1.0000
12:52488546:GCA:G	acceptor_gain	1.0000
12:52488547:CA:C	acceptor_gain	1.0000
12:52488547:CAC:C	acceptor_gain	1.0000
12:52488549:C:CC	acceptor_gain	1.0000
12:52489938:CATAC:C	donor_loss	1.0000
12:52489941:AC:A	donor_loss	1.0000
12:52489942:CCTG:C	donor_gain	1.0000
12:52490065:CGTA:C	acceptor_gain	1.0000
12:52490069:C:CC	acceptor_gain	1.0000
12:52490077:C:CT	acceptor_gain	1.0000
12:52490078:A:T	acceptor_gain	1.0000
12:52490566:CACC:C	donor_loss	1.0000
12:52490568:C:CA	donor_loss	1.0000
12:52490590:AG:A	donor_gain	1.0000

AlphaMissense

3686 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:52491115:C:A	K271N	1.000
12:52491115:C:G	K271N	1.000
12:52491127:A:C	F267L	1.000
12:52491127:A:T	F267L	1.000
12:52491129:A:G	F267L	1.000
12:52492667:A:C	F174L	1.000
12:52492667:A:T	F174L	1.000
12:52492669:A:G	F174L	1.000
12:52488518:C:G	A412P	0.999
12:52489974:A:G	L391P	0.999
12:52489989:C:G	R386P	0.999
12:52490025:A:G	L374P	0.999
12:52490058:A:G	L363P	0.999
12:52490592:C:G	A352P	0.999
12:52490600:C:G	R349P	0.999
12:52490612:G:T	A345D	0.999
12:52490613:C:G	A345P	0.999
12:52490631:C:G	A339P	0.999
12:52490919:A:G	L284P	0.999
12:52491117:T:C	K271E	0.999
12:52491128:A:G	F267S	0.999
12:52491141:C:G	A263P	0.999
12:52491149:C:G	R260P	0.999
12:52491150:G:T	R260S	0.999
12:52491527:C:A	K250N	0.999
12:52491527:C:G	K250N	0.999
12:52492668:A:C	F174C	0.999
12:52492668:A:G	F174S	0.999
12:52488349:A:G	L468P	0.998
12:52488355:C:G	R466P	0.998

dbSNP variants (sampled 300 via entrez): RS1000362591 (12:52486992 A>C,G), RS1000673667 (12:52493479 C>A,G,T), RS1000866132 (12:52490421 T>C), RS1001710787 (12:52491176 C>T), RS1002056222 (12:52489823 T>A,C), RS1002195008 (12:52494779 T>C), RS1002226083 (12:52494557 C>T), RS1002534928 (12:52493503 G>A), RS1002566070 (12:52493212 A>T), RS1004133967 (12:52488927 A>T), RS1004521699 (12:52494438 G>C), RS1004806206 (12:52494653 C>T), RS1005100191 (12:52488406 TG>T), RS1005337280 (12:52492202 G>T), RS1005371687 (12:52491980 T>A,C)

Disease associations

OMIM: gene MIM:148041 | disease phenotypes: MIM:615726, MIM:615735

GenCC curated gene-disease

Disease	Classification	Inheritance
palmoplantar keratoderma, nonepidermolytic, focal or diffuse	Strong	Autosomal dominant
pachyonychia congenita 3	Strong	Autosomal dominant
pachyonychia congenita	Supportive	Autosomal dominant

Mondo (4): pachyonychia congenita 3 (MONDO:0014324), focal palmoplantar keratoderma (MONDO:0017672), palmoplantar keratoderma, nonepidermolytic, focal or diffuse (MONDO:0014327), pachyonychia congenita (MONDO:0016471)

Orphanet (3): Pachyonychia congenita (Orphanet:2309), Focal palmoplantar keratoderma (Orphanet:307837), Autosomal dominant focal non-epidermolytic palmoplantar keratoderma with plantar blistering (Orphanet:402003)

HPO phenotypes

35 total (30 of 35 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000221	Furrowed tongue
HP:0000230	Gingivitis
HP:0000695	Natal tooth
HP:0000972	Palmoplantar hyperkeratosis
HP:0000975	Hyperhidrosis
HP:0000982	Palmoplantar keratoderma
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:0006288	Advanced eruption of teeth
HP:0007410	Palmoplantar hyperhidrosis
HP:0007446	Palmoplantar blistering
HP:0007490	Linear arrays of macular hyperkeratoses in flexural areas
HP:0007502	Follicular hyperkeratosis
HP:0007556	Plantar hyperkeratosis
HP:0008401	Onychogryphosis of toenails
HP:0008404	Nail dystrophy
HP:0010765	Palmar hyperkeratosis
HP:0011968	Feeding difficulties
HP:0012035	Steatocystoma multiplex
HP:0012514	Lower limb pain
HP:0025245	Cutaneous cyst
HP:0025248	Eruptive vellus hair cyst
HP:0030268	Hyperplastic callus formation
HP:0030318	Angular cheilitis

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST010148_19	Cutaneous squamous cell carcinoma	2.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:1001927	cutaneous squamous cell carcinoma

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

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	5
Estradiol	affects cotreatment, increases expression, decreases expression	5
Benzo(a)pyrene	decreases expression, decreases methylation, increases expression, increases methylation	3
Tetrachlorodibenzodioxin	affects cotreatment, decreases expression, increases expression	3
bisphenol A	decreases expression, decreases methylation	2
Cadmium	increases expression, affects binding	2
Progesterone	affects cotreatment, increases expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
4-oxoretinoic acid	decreases expression	1
methyleugenol	decreases expression	1
titanium dioxide	decreases expression, decreases reaction	1
pyrogallol 1,3-dimethyl ether	affects localization, decreases expression, affects cotreatment	1
ascorbate-2-phosphate	affects cotreatment, increases expression, affects binding	1
beta-lapachone	increases expression	1
arsenite	increases expression	1
perfluorooctanoic acid	decreases expression	1
cupric chloride	increases expression	1
4-(2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic acid	affects cotreatment, increases expression	1
dibenzo(a,l)pyrene	decreases expression	1
2,3-dimethoxy-1,4-naphthoquinone	increases expression	1
4-((3-bromophenyl)amino)-6,7-dimethoxyquinazoline	affects cotreatment, affects expression, decreases expression	1
CGP 52608	increases reaction, affects binding	1
chloropicrin	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
Chir 99021	affects cotreatment, increases expression, affects binding	1
abrine	increases expression, decreases expression	1
bromovanin	decreases expression	1
XAV939	affects binding, affects cotreatment, increases expression	1
LDN 193189	increases expression, affects cotreatment	1
3-(4-pyridyl)-1H-indole	affects cotreatment, increases 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