KRT9

Summary

KRT9 (keratin 9, HGNC:6447) is a protein-coding gene on chromosome 17q21.2, encoding Keratin, type I cytoskeletal 9 (P35527). May serve an important special function either in the mature palmar and plantar skin tissue or in the morphogenetic program of the formation of these tissues.

This gene encodes the type I keratin 9, an intermediate filament chain expressed only in the terminally differentiated epidermis of palms and soles. Mutations in this gene cause epidermolytic palmoplantar keratoderma.

Source: NCBI Gene 3857 — RefSeq curated summary.

At a glance

• Gene–disease (curated): epidermolytic palmoplantar keratoderma, 1 (Definitive, GenCC)
• Clinical variants (ClinVar): 236 total — 11 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 19
• MANE Select transcript: NM_000226

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6447
Approved symbol	KRT9
Name	keratin 9
Location	17q21.2
Locus type	gene with protein product
Status	Approved
Aliases	EPPK, K9, CK-9
Ensembl gene	ENSG00000171403
Ensembl biotype	protein_coding
OMIM	607606
Entrez	3857

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000246662, ENST00000588431

RefSeq mRNA: 1 — MANE Select: NM_000226 NM_000226

CCDS: CCDS32654

Canonical transcript exons

ENST00000246662 — 8 exons

Exon	Start	End
ENSE00000395530	41568508	41568633
ENSE00000723816	41569426	41569587
ENSE00000723819	41569859	41570015
ENSE00001118285	41567233	41567750
ENSE00001289693	41565836	41566152
ENSE00001305573	41568162	41568385
ENSE00001326363	41571351	41572059
ENSE00003500584	41570138	41570220

Expression profiles

Bgee: expression breadth broad, 59 present calls, max score 86.50.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 2.2500 / max 3582.8625, expressed in 49 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
165968	2.2500	49

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	86.50	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	78.90	gold quality
penis	UBERON:0000989	78.24	gold quality
amniotic fluid	UBERON:0000173	73.08	silver quality
gingival epithelium	UBERON:0001949	72.25	silver quality
mammalian vulva	UBERON:0000997	70.88	gold quality
sperm	CL:0000019	68.83	gold quality
buccal mucosa cell	CL:0002336	68.21	gold quality
male germ cell	CL:0000015	67.39	gold quality
hair follicle	UBERON:0002073	66.75	gold quality
gingiva	UBERON:0001828	66.09	silver quality
upper leg skin	UBERON:0004262	63.37	gold quality
thymus	UBERON:0002370	62.96	gold quality
zone of skin	UBERON:0000014	62.03	gold quality
skin of leg	UBERON:0001511	61.87	gold quality
skin of hip	UBERON:0001554	61.53	gold quality
skin of abdomen	UBERON:0001416	61.40	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	61.29	gold quality
cardia of stomach	UBERON:0001162	59.63	gold quality
secondary oocyte	CL:0000655	59.15	gold quality
tibialis anterior	UBERON:0001385	57.31	silver quality
superficial temporal artery	UBERON:0001614	56.42	gold quality
mucosa of paranasal sinus	UBERON:0005030	55.66	gold quality
esophagus squamous epithelium	UBERON:0006920	54.67	gold quality
epithelium of esophagus	UBERON:0001976	54.60	gold quality
quadriceps femoris	UBERON:0001377	54.40	gold quality
deltoid	UBERON:0001476	53.90	gold quality
tendon of biceps brachii	UBERON:0008188	53.65	gold quality
vastus lateralis	UBERON:0001379	53.49	gold quality
oocyte	CL:0000023	52.88	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.29

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ASCL4, DNMT1, ESR1, EZH2, ID1, IRF8, JARID2, KDM5C, KLF11, MYB, NEUROD4, NFKB, RARA, SPI1, TADA2A, TAL1, TCF12, TCF3, TP53, TTF1, ZBTB16, ZKSCAN7, ZNF699

miRNA regulators (miRDB)

19 targeting KRT9, 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-6721-5P	99.93	68.92	2981
HSA-MIR-6079	99.84	68.54	1170
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-671-5P	99.52	67.11	1277
HSA-MIR-4786-3P	99.36	68.35	1390
HSA-MIR-3125	99.14	68.49	2269
HSA-MIR-5587-5P	99.07	68.58	838
HSA-MIR-3916	98.99	68.04	2155
HSA-MIR-455-3P	98.94	67.68	878
HSA-MIR-9500	98.62	66.54	1845
HSA-MIR-1301-5P	98.09	66.62	495
HSA-MIR-6502-5P	98.09	66.73	495
HSA-MIR-744-3P	97.99	67.76	637
HSA-MIR-6793-3P	97.66	65.78	1084
HSA-MIR-2467-5P	97.36	67.71	991
HSA-MIR-1202	97.19	66.43	827
HSA-MIR-3972	97.19	66.46	808

Literature-anchored findings (GeneRIF, showing 32)

• Genetic studies have revealed that K9 gene mutations are responsible for epodermolytic palmoplantar keratoderma. (PMID:12532041)
• Keratin 9 is mutated in epidermolytic palmoplantar keratoderma (PMID:14675368)
• Keratin 9 gene mutation is associated with diffuse palmoplantar keratoderma. (PMID:16043929)
• A heterozygous nucleotide T–>C transition at position 500 in exon 1 of KRT9 was detected, which resulted in a leucine to serine (L167S) change. (PMID:17362238)
• A missense mutation in keratin 9 – Met157Arg in the 1A domain – was found in a Chinese family with EPPK (PMID:18477167)
• the first family from Northeast China affected by epidermolytic palmoplantar keratoderma (EPPK) in which we confirmed the presence of the N161S mutation as the result of a 548A>G transition in exon1 of the keratin 9 gene. (PMID:18573708)
• We show that in a family affected by EPPK and knuckle pad keratosis, carrying the R163W substitution, wild type (wt) and mutated K9 are strongly expressed in knuckle pads. This suggests that the knuckle pad phenotype is due to ectopical expression of K9. (PMID:19106041)
• The genomic DNA from the patient’s peripheral blood showed an R162W mutation in the keratin 9 gene. We therefore diagnosed the patient with Vorner type EPPK. (PMID:19451521)
• Prenatal diagnosis of epidermolytic palmoplantar keratoderma caused by c.T470C (p.M157T) of the keratin 9 gene. (PMID:19548225)
• The affected members of all five families possess mutations in the KRT9 gene that severely affect heterodimer formation with the type II keratin partner. (PMID:19874353)
• A c.T1206C substitution in the 2B domain of KRT 9 was identified. (PMID:20964665)
• identified mRNA transcripts from three genes CDSN, LOR and KRT9, showing strong over-expression in skin samples relative to samples from forensic body fluids, making them suitable markers for skin identification (PMID:21221983)
• Study provides evidence that epidermolytic palmoplantar keratoderma in a large Chinese family may result from a novel duplication mutation (c.495_503dupCTCTTACTT) in the 1A rod domain of KRT9. (PMID:21489919)
• KRT9 may play a complicated role in the genesis of epidermolytic palmoplantar keratoderma with knuckle pads and camptodactyly. (PMID:21715251)
• A substitution in arginine alters the charge and shape of KRT9 rod domain, disrupting the function of the helix initiation motif of keratins and compromising the integrity of filaments and weakening their stability in the epidermis of palms and soles. (PMID:22262370)
• A heterozygous transversional mutation, 488G–>A, was identified in exon 1 of KRT9 gene in all patients. (PMID:22678789)
• Data indicate that the node tumour burden could be accurately quantified based on the cytokeratin 19 (CK19) mRNA copy number. (PMID:23265708)
• Our findings indicate that knuckle pads can be associated with epidermolytic palmoplantar keratoderma and the R163W mutation in a family with a genetic background different from that described here. (PMID:23278372)
• We identified a novel Eidermolytic Palmoplantar Keratoderma-causing mutation located in a region of the KRT9 gene, encoding a poorly conserved region of the protein that is not routinely screened for diagnostic purposes. (PMID:23397986)
• A heterozygous missense mutation c.482A to G in the KRT9 gene. (PMID:24510562)
• KRT9 gene mutation as a reliable indicator in the prenatal molecular diagnosis of epidermolytic palmoplantar keratoderma. (PMID:24862219)
• Mutational analysis revealed a T to G transition in the coding DNA sequence, designated as c.470T>G (p.Met157Arg), a missense mutation in exon 1 of KRT9 in the proband and her brother, but not in unrelated healthy controls. (PMID:24899405)
• Findings suggest that dysregulated Keratin 9 expression is a consequence of Alzheimer’s disease (AD). (PMID:26973255)
• During analyzing the sequences of KRT9 gene of a epidermolytic palmoplantar keratoderma (EPPK) pedigree, we found a new heterozygous missense mutation (488G>T) of exon 1 of KRT9 gene, which has not been reported before and does not exist in healthy individuals of the family and 100 unrelated individuals. (PMID:27726289)
• Results identified the missense mutation KRT9 c.487C>T, as a potential causative mutation in the large Uygur family with epidermolytic palmoplantar keratoderma. (PMID:27864007)
• KRT9 expression is significantly downregulated in human masticatory mucosa during wound healing (PMID:28005267)
• Study identified a novel L164P mutation responsible for epidermolytic palmoplantar keratoderma (EPPK) in a large Chinese family and three recurrent mutations in another three Chinese families with EPPK. All these mutations are located in the highly conserved 1A rod domain of keratin 9. (PMID:29044727)
• A novel heterozygous c.1369C>T transition (p.Leu457Phe) in exon 6 of the KRT9 gene was identified in four patients in a Chinese Family with Epidermolytic Palmoplantar Keratoderma. (PMID:29719290)
• keratin 9 is an Hsp70 client protein and is expressed in human bladder cancer cells. (PMID:29802537)
• Exogenous dsRNA inhibits KRT9 expression in early passage volar keratinocytes or in vivo footpads of wild-type mice. Loss of DDX58 in passaged volar keratinocytes rescues KRT9 and inhibits KRT7 expression. (PMID:30120933)
• KRT9 L164P mutation is associated with epidermolytic palmoplantar keratoderma. (PMID:31525823)
• Cytokeratin 7 and 19 expression in oropharyngeal and oral squamous cell carcinoma. (PMID:34046748)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Krt9	ENSMUSG00000051617
rattus_norvegicus	Krt9	ENSRNOG00000014370

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 9 — P35527 (reviewed: P35527)

Alternative names: Cytokeratin-9, Keratin-9

All UniProt accessions (2): P35527, K7EQQ3

UniProt curated annotations — full annotation on UniProt →

Function. May serve an important special function either in the mature palmar and plantar skin tissue or in the morphogenetic program of the formation of these tissues. Plays a role in keratin filament assembly.

Subunit / interactions. Heterotetramer of two type I and two type II keratins.

Tissue specificity. Expressed in the terminally differentiated epidermis of palms and soles.

Disease relevance. Palmoplantar keratoderma, epidermolytic, 1 (EPPK1) [MIM:144200] A form of epidermolytic palmoplantar keratoderma, a dermatological disorder characterized by diffuse thickening of the epidermis on the entire surface of palms and soles sharply bordered with erythematous margins. Some patients may present knuckle pads, thick pads of skin appearing over the proximal phalangeal joints. EPPK1 inheritance is autosomal dominant. The disease is caused by variants affecting the gene represented in this entry.

Induction. Induced by intrinsic regulatory mechanisms and by extrinsic signals from a subset of dermal palmoplantar fibroblasts.

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_000217* (*=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 (44 total): sequence variant 22, region of interest 10, sequence conflict 4, compositionally biased region 3, modified residue 2, chain 1, domain 1, mutagenesis site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P35527-F1	66.43	0.41

Functional residue map

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

Post-translational modifications (2): 14, 57

Mutagenesis-validated functional residues (1):

Position	Phenotype
163	leads to aggregate formation.

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: 107 (showing top): GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, MYAATNNNNNNNGGC_UNKNOWN, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_INTERMEDIATE_FILAMENT_BASED_PROCESS, GOBP_INTERMEDIATE_FILAMENT_ORGANIZATION, RORA1_01, GOBP_MALE_GAMETE_GENERATION, GOBP_EPIDERMIS_DEVELOPMENT, GOBP_DEVELOPMENTAL_PROCESS_INVOLVED_IN_REPRODUCTION, PIT1_Q6, GOBP_SKIN_DEVELOPMENT, GOBP_TISSUE_MORPHOGENESIS, GOCC_INTERMEDIATE_FILAMENT_CYTOSKELETON, GOCC_KERATIN_FILAMENT, MATZUK_SPERMATID_DIFFERENTIATION

GO Biological Process (6): morphogenesis of an epithelium (GO:0002009), spermatogenesis (GO:0007283), epidermis development (GO:0008544), epithelial cell differentiation (GO:0030855), skin development (GO:0043588), intermediate filament organization (GO:0045109)

GO Molecular Function (3): structural constituent of cytoskeleton (GO:0005200), structural constituent of skin epidermis (GO:0030280), structural molecule activity (GO:0005198)

GO Cellular Component (8): obsolete extracellular space (GO:0005615), nucleus (GO:0005634), cytosol (GO:0005829), cytoskeleton (GO:0005856), 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
epithelium development	2
structural molecule activity	2
cellular anatomical structure	2
tissue morphogenesis	1
developmental process involved in reproduction	1
male gamete generation	1
tissue development	1
cell differentiation	1
animal organ development	1
intermediate filament cytoskeleton organization	1
supramolecular fiber organization	1
cytoskeleton	1
cytoskeleton organization	1
molecular_function	1
intracellular membrane-bounded organelle	1
cytoplasm	1
intracellular membraneless organelle	1
intermediate filament	1
extracellular vesicle	1
intermediate filament cytoskeleton	1
polymeric cytoskeletal fiber	1

Protein interactions and networks

STRING

1360 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KRT9	AAGAB	Q6PD74	729
KRT9	MTMR8	Q96EF0	640
KRT9	KRT20	P35900	626
KRT9	LIAT1	Q6ZQX7	595
KRT9	CTSC	P53634	590
KRT9	MTMR9	Q96QG7	588
KRT9	HOXA13	P31271	577
KRT9	DCD	P58461	537
KRT9	KRT6B	P04259	514
KRT9	GAPDH	P00354	498
KRT9	KRT1	P04264	493
KRT9	KRT8	P05787	484
KRT9	KRT2	P35908	475
KRT9	ACTB	P02570	471
KRT9	WNT5A	P41221	468

IntAct

81 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CFTR	KRT18	psi-mi:“MI:0914”(association)	0.710
CFTR	VIM	psi-mi:“MI:0914”(association)	0.610
AQP7	PLIN1	psi-mi:“MI:0914”(association)	0.570
CDH1	ACTN4	psi-mi:“MI:0915”(physical association)	0.500
PPP2R2B	DDX3X	psi-mi:“MI:0914”(association)	0.460
TSC22D1	KRT1	psi-mi:“MI:0914”(association)	0.460
APC	IGHA1	psi-mi:“MI:0915”(physical association)	0.400
YWHAQ	KRT9	psi-mi:“MI:0915”(physical association)	0.400
APOA1	CNMD	psi-mi:“MI:0914”(association)	0.350
ALB	CDC45	psi-mi:“MI:0914”(association)	0.350
IGHA1	PLG	psi-mi:“MI:0914”(association)	0.350
IGHM	APOL1	psi-mi:“MI:0914”(association)	0.350
IGHG1	PDPK1	psi-mi:“MI:0914”(association)	0.350
ALB	F2	psi-mi:“MI:0914”(association)	0.350
ALB	SH3BP5	psi-mi:“MI:0914”(association)	0.350
METTL3	TUBAL3	psi-mi:“MI:0914”(association)	0.350
WTAP	DDX39A	psi-mi:“MI:0914”(association)	0.350
METTL14	HMGB1P1	psi-mi:“MI:0914”(association)	0.350
APP	ESYT2	psi-mi:“MI:0914”(association)	0.350
Prdm16	ESYT2	psi-mi:“MI:0914”(association)	0.350
Mecom	ESYT2	psi-mi:“MI:0914”(association)	0.350
CAND1	GTPBP10	psi-mi:“MI:0914”(association)	0.350
CUL1	LGALS8	psi-mi:“MI:0914”(association)	0.350
CUL4A	HAX1	psi-mi:“MI:0914”(association)	0.350
DCUN1D1	RGSL1	psi-mi:“MI:0914”(association)	0.350

BioGRID (194): KRT9 (Affinity Capture-MS), KRT9 (Affinity Capture-MS), KRT9 (Reconstituted Complex), KRT9 (Affinity Capture-MS), KRT9 (Affinity Capture-MS), KRT9 (Affinity Capture-MS), KRT9 (Reconstituted Complex), KRT9 (Affinity Capture-MS), KRT9 (Affinity Capture-MS), KRT9 (Affinity Capture-MS), KRT9 (Affinity Capture-MS), KRT9 (Affinity Capture-MS), KRT9 (Affinity Capture-MS), KRT9 (Affinity Capture-MS), KRT9 (Affinity Capture-MS)

ESM2 similar proteins: A2ZJC9, A3C5A7, A3CG83, C0HM81, O18740, O22612, O48848, P02674, P05834, P06649, P09789, P0C5C7, P0DUT6, P10495, P10496, P11898, P12796, P13396, P13645, P17816, P19469, P19470, P22357, P35527, P37703, P37704, P86797, P86798, P86857, Q07202, Q09134, Q1HVF7, Q25055, Q3KSS4, Q3TTY5, Q54M35, Q54T37, Q5AMF7, Q6IG02, Q6RHW0

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

0 interactions.

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
Regulation of RAS by GAPs	5	14.0×	1e-03
Response to elevated platelet cytosolic Ca2+	5	11.8×	1e-03
Macroautophagy	6	10.0×	1e-03
Platelet activation, signaling and aggregation	6	9.2×	1e-03
Neddylation	12	8.2×	1e-05
Platelet degranulation	6	7.6×	2e-03
Cargo recognition for clathrin-mediated endocytosis	5	7.6×	5e-03
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	6	7.5×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
intrinsic apoptotic signaling pathway	7	29.9×	1e-06
autophagosome maturation	5	20.9×	6e-04
mitophagy	5	18.9×	7e-04
G1/S transition of mitotic cell cycle	7	16.7×	6e-05
autophagosome assembly	5	13.4×	3e-03
endocytosis	7	7.9×	3e-03
DNA damage response	11	7.0×	1e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	11
Likely pathogenic	4
Uncertain significance	130
Likely benign	22
Benign	24

Top pathogenic / likely-pathogenic (15)

Variant ID	HGVS	Classification
2998	NM_000226.4(KRT9):c.515A>C (p.Gln172Pro)	Pathogenic
2999	NM_000226.4(KRT9):c.481A>T (p.Asn161Tyr)	Pathogenic
3002	NM_000226.4(KRT9):c.469A>G (p.Met157Val)	Pathogenic
3003	NM_000226.4(KRT9):c.482A>G (p.Asn161Ser)	Pathogenic
3004	NM_000226.4(KRT9):c.503T>C (p.Leu168Ser)	Pathogenic
3005	NM_000226.4(KRT9):c.478C>G (p.Leu160Val)	Pathogenic
3007	NM_000226.4(KRT9):c.511G>A (p.Val171Met)	Pathogenic
3008	NM_000226.4(KRT9):c.478C>T (p.Leu160Phe)	Pathogenic
3009	NM_000226.4(KRT9):c.482A>T (p.Asn161Ile)	Pathogenic
66146	NM_000226.4(KRT9):c.1360T>C (p.Tyr454His)	Pathogenic
915270	NM_000226.4(KRT9):c.1674T>G (p.Tyr558Ter)	Pathogenic
1489909	NM_000226.4(KRT9):c.479T>C (p.Leu160Pro)	Likely pathogenic
1687438	NM_000226.4(KRT9):c.500A>C (p.Tyr167Ser)	Likely pathogenic
2308244	NM_000226.4(KRT9):c.512T>G (p.Val171Gly)	Likely pathogenic
3000	NM_000226.4(KRT9):c.483T>A (p.Asn161Lys)	Likely pathogenic

SpliceAI

1045 predictions. Top by Δscore:

Variant	Effect	Δscore
17:41567642:T:TA	donor_gain	1.0000
17:41567669:T:TA	donor_gain	1.0000
17:41567746:ATTCA:A	acceptor_gain	1.0000
17:41567747:TTCA:T	acceptor_gain	1.0000
17:41567748:TCA:T	acceptor_gain	1.0000
17:41567748:TCAC:T	acceptor_loss	1.0000
17:41567749:CA:C	acceptor_gain	1.0000
17:41567749:CAC:C	acceptor_gain	1.0000
17:41567751:C:CC	acceptor_gain	1.0000
17:41567751:CT:C	acceptor_loss	1.0000
17:41568145:AAT:A	donor_gain	1.0000
17:41568160:A:AC	donor_gain	1.0000
17:41568161:C:CT	donor_gain	1.0000
17:41568161:CAA:C	donor_gain	1.0000
17:41568161:CAAGT:C	donor_gain	1.0000
17:41568168:T:TA	donor_gain	1.0000
17:41568177:C:A	donor_gain	1.0000
17:41568207:T:TA	donor_gain	1.0000
17:41568247:ATT:A	donor_gain	1.0000
17:41568249:T:TA	donor_gain	1.0000
17:41568382:CTTT:C	acceptor_gain	1.0000
17:41568384:TT:T	acceptor_gain	1.0000
17:41568385:TCTA:T	acceptor_loss	1.0000
17:41568386:C:A	acceptor_loss	1.0000
17:41568386:C:CC	acceptor_gain	1.0000
17:41568629:GTTAT:G	acceptor_gain	1.0000
17:41568630:TTAT:T	acceptor_gain	1.0000
17:41568631:TAT:T	acceptor_gain	1.0000
17:41568632:AT:A	acceptor_gain	1.0000
17:41568634:C:CC	acceptor_gain	1.0000

AlphaMissense

4046 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:41569490:C:G	R327P	0.998
17:41568527:A:G	L384P	0.997
17:41569502:A:G	L323P	0.996
17:41569502:A:T	L323H	0.996
17:41569941:A:G	L267P	0.996
17:41569472:A:G	L333P	0.995
17:41570015:C:A	K242N	0.995
17:41570015:C:G	K242N	0.995
17:41568515:A:G	L388P	0.994
17:41568522:A:G	S386P	0.994
17:41568560:A:G	L373P	0.994
17:41569491:G:T	R327S	0.994
17:41569962:A:G	L260P	0.994
17:41569978:C:G	A255P	0.994
17:41571361:A:G	L211P	0.994
17:41571514:A:G	L160P	0.994
17:41569950:A:G	L264P	0.993
17:41568330:A:G	L409P	0.992
17:41568375:A:G	L394P	0.992
17:41570139:T:C	K242E	0.992
17:41571505:C:G	R163P	0.992
17:41569878:A:G	L288P	0.991
17:41569899:A:G	L281P	0.991
17:41570151:C:G	D238H	0.991
17:41571464:C:G	A177P	0.991
17:41569514:A:G	L319P	0.989
17:41569920:A:G	L274P	0.989
17:41568216:A:G	L447P	0.988
17:41569959:C:G	R261P	0.988
17:41570150:T:C	D238G	0.988

dbSNP variants (sampled 300 via entrez): RS1000295890 (17:41570680 C>T), RS1001712928 (17:41567484 C>T), RS1002081199 (17:41565829 G>A,T), RS1002757017 (17:41571318 G>A,T), RS1002839042 (17:41567891 C>T), RS1003139765 (17:41566658 A>C,T), RS1003170774 (17:41566276 C>T), RS1003790527 (17:41572219 C>T), RS1004261060 (17:41566072 C>A,G,T), RS1005082264 (17:41566938 G>A), RS1005459656 (17:41567249 G>A,C,T), RS1005745560 (17:41569607 G>T), RS1006051133 (17:41568526 C>A,T), RS1006179875 (17:41573743 C>T), RS1006420167 (17:41573512 C>T)

Disease associations

OMIM: gene MIM:607606 | disease phenotypes: MIM:144200

GenCC curated gene-disease

Disease	Classification	Inheritance
epidermolytic palmoplantar keratoderma, 1	Definitive	Autosomal dominant

Mondo (3): palmoplantar keratoderma, epidermolytic (MONDO:0968949), prostate cancer (MONDO:0008315), epidermolytic palmoplantar keratoderma, 1 (MONDO:0007758)

Orphanet (2): Familial prostate cancer (Orphanet:1331), Epidermolytic palmoplantar keratoderma (Orphanet:2199)

HPO phenotypes

19 total (19 of 19 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000962	Hyperkeratosis
HP:0000972	Palmoplantar hyperkeratosis
HP:0000975	Hyperhidrosis
HP:0001217	Clubbing
HP:0001220	Interphalangeal joint contracture of finger
HP:0001231	Abnormal fingernail morphology
HP:0003212	Increased circulating IgE concentration
HP:0007447	Diffuse palmoplantar hyperkeratosis
HP:0007556	Plantar hyperkeratosis
HP:0007559	Localized epidermolytic hyperkeratosis
HP:0008066	Abnormal blistering of the skin
HP:0010765	Palmar hyperkeratosis
HP:0010829	Impaired temperature sensation
HP:0010830	Impaired tactile sensation
HP:0012385	Camptodactyly
HP:0025092	Epidermal acanthosis
HP:0025114	Hypergranulosis
HP:0032541	Knuckle pad

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Cadmium	decreases reaction, increases abundance, increases palmitoylation, affects binding	2
Silicon Dioxide	affects secretion, increases expression	2
Cadmium Chloride	increases palmitoylation, increases expression, decreases reaction, increases abundance	2
bisphenol F	increases expression	1
9-hydroxyoctadecadienoic acid	decreases expression	1
bisphenol A	decreases expression	1
2-bromopalmitate	decreases reaction, increases abundance, increases palmitoylation	1
phenyl isocyanate	affects binding	1
2,3,5-(triglutathion-S-yl)hydroquinone	decreases ADP-ribosylation	1
abrine	increases expression	1
bromovanin	decreases expression	1
bisphenol AF	increases expression	1
Air Pollutants	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Copper	affects binding	1
Doxorubicin	affects expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Estradiol	increases expression	1
Ivermectin	decreases expression	1
Lead	affects binding	1
Mustard Gas	increases expression	1
Nickel	affects binding	1
Sodium Dodecyl Sulfate	decreases expression	1
Testosterone	increases expression	1
Tobacco Smoke Pollution	affects expression	1
Valproic Acid	affects expression	1
Zinc	affects binding	1
Aflatoxin B1	decreases methylation	1
Complex Mixtures	decreases expression	1
Particulate Matter	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00035997	PHASE4	COMPLETED	Open-label Trial on the Effect of I.V. Zoledronic Acid 4 mg on Bone Density in Hormone Sensitive Prostate Cancer Patients With Bone Metastasis
NCT00063609	PHASE4	COMPLETED	The Effect of Zoledronic Acid on Bone Loss in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy
NCT00103623	PHASE4	SUSPENDED	The Plenaxis® Experience Study
NCT00106392	PHASE4	COMPLETED	A Safety and Efficacy Study of Prograf in the Prevention of Erectile Dysfunction After Radical Prostatectomy
NCT00185029	PHASE4	UNKNOWN	MR-Lymphography and Lymph Node Staging in Prostate Cancer
NCT00199485	PHASE4	COMPLETED	Angelica Sinensis for the Treatment of Hot Flashes in Men Undergoing LHRH Therapy for Prostate Cancer
NCT00219219	PHASE4	COMPLETED	Zoledronic Acid in the Prevention of Skeletal-related Events in Hormone Refractory and Hormone-sensitive Prostate Cancer Patients With Bone Metastases
NCT00219271	PHASE4	COMPLETED	Effect Of Zoledronic Acid On Circulating And Bone Marrow-Residing Prostate Cancer Cells In Patients With Clinically Localized Prostate Cancer
NCT00237146	PHASE4	COMPLETED	Study to Evaluate Zoledronic Acid on Quality of Life and Skeletal-related Events as Adjuvant Treatment in Patients With Hormone-naïve Prostate Cancer and Bone Metastasis Who Have Undergone Orchiectomy
NCT00242554	PHASE4	COMPLETED	Open-label Phase IV Clinical Trial to Evaluate the Safety and Tolerability of Zoledronic Acid in Patients With Prostate Cancer and Bone Metastases
NCT00280098	PHASE4	COMPLETED	Docetaxel in the Treatment of Hormone Refractory Prostate Cancer
NCT00293696	PHASE4	COMPLETED	Casodex/Zoladex Biomarkers in Localised Prostate Cancer
NCT00334139	PHASE4	COMPLETED	Effect of Zoledronic Acid on Bone Metabolism in Patients With Bone Metastasis and Prostate or Breast Cancer
NCT00375765	PHASE4	COMPLETED	Effects On Dihydrotestosterone Regulated Gene Expression In Benign Prostatic Hyperplasia Or Prostate Cancer
NCT00391690	PHASE4	COMPLETED	Evaluation of Bone Markers as Diagnostic Tools for Early Detection of Bone Metastases in Patients With High Risk Prostate Cancer
NCT00422708	PHASE4	COMPLETED	Local Anesthesia for Prostate Biopsy
NCT00526331	PHASE4	COMPLETED	Evaluation of Arterial Pressure Based Cardiac Output for Goal-Directed Perioperative Therapy
NCT00590213	PHASE4	COMPLETED	Compare the Value of Prophylactic Versus Therapeutic Breast Radiotherapy in CASODEX
NCT00629330	PHASE4	TERMINATED	Dissemination of Prostate Cancer Screening to PCP’s in African American Communities
NCT00771966	PHASE4	COMPLETED	Radical Prostatectomy and Perioperative Fluid Therapy
NCT00805701	PHASE4	COMPLETED	Study Assessing The Efficacy And Safety Of Avodart (Dutasteride) At Improving Urinary Symptoms In Men With Prostate Cancer Who Are Undergoing Seed Implantation
NCT00859027	PHASE4	COMPLETED	Effect Of Risedronate On Bone Mass In Older Men Receiving Neoadjuvant Therapy For Prostate Cancer
NCT00906269	PHASE4	UNKNOWN	Can Hyperbaric Oxygen Improve Erectile Function Following Surgery for Prostate Cancer
NCT00953277	PHASE4	COMPLETED	Study of Nerve Reconstruction Using AVANCE in Subjects Who Undergo Robotic Assisted Prostatectomy for Treatment of Prostate Cancer
NCT00982800	PHASE4	COMPLETED	Does Postoperative Gabapentin Reduce Pain, Opioid Consumption and Anxiety and Have a Positive Effect on Health Related Quality of Life After Radical Prostatectomy?
NCT01083199	PHASE4	COMPLETED	Global Performance Evaluation of the AMS CONTINUUM™ Device
NCT01136226	PHASE4	COMPLETED	Evaluate Recovery of Testosterone for Patients Using Eligard
NCT01161563	PHASE4	COMPLETED	Randomized Crossover Trial to Assess the Tolerability of Gonadotropin Releasing Hormone (GnRH) Analogue Administration
NCT01230905	PHASE4	COMPLETED	Study to Monitor the Effects of Androgen Suppression Treatment on the Heart
NCT01296672	PHASE4	COMPLETED	3 Month Finasteride Challenge Test Can Significantly Improve the Performance of Screening for Prostate Cancer
NCT01365143	PHASE4	TERMINATED	Prospective Randomized Trial Comparing Robotic Versus Open Radical Prostatectomy
NCT01379742	PHASE4	UNKNOWN	Comparison of Between ThinSeed™ and OncoSeed™ for Permanent Prostate Brachytherapy
NCT01486563	PHASE4	COMPLETED	Hydroxyethyl Starch and Renal Function After Radical Prostatectomy
NCT01511874	PHASE4	COMPLETED	Efficacy and Safety Study of ELIGARD 22.5mg With Prostate Cancer
NCT01512472	PHASE4	TERMINATED	Firmagon (Degarelix) Intermittent Therapy
NCT01547416	PHASE4	COMPLETED	The Effect of Combined General/Epidural Anesthesia Versus General Anesthesia on Diaphragmatic Function
NCT01571544	PHASE4	COMPLETED	The Use of Thermal Suits as Preventing Hypothermia During Surgery
NCT01581749	PHASE4	UNKNOWN	Evaluation of Truebeam for Low-Intermediate Risk Prostate Cancer
NCT01649635	PHASE4	COMPLETED	Study of Cabazitaxel Combined With Prednisone and Prophylaxis of Neutropenia Complications in the Treatment of Patients With Metastatic Castration-resistant Prostate Cancer