Pachyonychia congenita 2

Summary

Pachyonychia congenita 2 (MONDO:0008174) is a disease caused by KRT17 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: KRT17 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 19

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	pachyonychia congenita 2
Mondo ID	MONDO:0008174
OMIM	167210
UMLS	C1721007
MedGen	314107
GARD	0015103
Is cancer (heuristic)	no

Also known as: KRT17 pachyonychia congenita · pachyonychia congenita 2 · pachyonychia congenita caused by mutation in KRT17 · pachyonychia congenita type 2 · pachyonychia congenita, Jackson-Lawler type · PC2

Data availability: 19 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › integumentary system disorder › skin disorder › keratosis › palmoplantar keratosis › hereditary palmoplantar keratoderma › focal palmoplantar keratoderma › pachyonychia congenita › pachyonychia congenita 2

Related subtypes (3): pachyonychia congenita 1, pachyonychia congenita 3, pachyonychia congenita 4

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

19 retrieved; paginated sample, class counts are floors:

11 pathogenic, 3 uncertain significance, 2 pathogenic/likely pathogenic, 1 benign, 1 benign/likely benign, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
14586	NM_000422.3(KRT17):c.274A>G (p.Asn92Asp)	KRT17	Pathogenic	criteria provided, multiple submitters, no conflicts
14587	NM_000422.3(KRT17):c.275A>G (p.Asn92Ser)	KRT17	Pathogenic	criteria provided, multiple submitters, no conflicts
14588	NM_000422.3(KRT17):c.292T>G (p.Tyr98Asp)	KRT17	Pathogenic	no assertion criteria provided
14590	NM_000422.3(KRT17):c.281G>A (p.Arg94His)	KRT17	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14591	NM_000422.3(KRT17):c.280C>T (p.Arg94Cys)	KRT17	Pathogenic	criteria provided, multiple submitters, no conflicts
14592	NM_000422.3(KRT17):c.263T>C (p.Met88Thr)	KRT17	Pathogenic	no assertion criteria provided
14593	NM_000422.3(KRT17):c.281_295del (p.Arg94_Tyr98del)	KRT17	Pathogenic	no assertion criteria provided
14594	NM_000422.3(KRT17):c.281G>C (p.Arg94Pro)	KRT17	Pathogenic	no assertion criteria provided
14595	NM_000422.3(KRT17):c.284T>A (p.Leu95Gln)	KRT17	Pathogenic	no assertion criteria provided
14596	NM_000422.3(KRT17):c.284T>C (p.Leu95Pro)	KRT17	Pathogenic	criteria provided, single submitter
14598	NM_000422.3(KRT17):c.296T>C (p.Leu99Pro)	KRT17	Pathogenic	criteria provided, single submitter
14599	NM_000422.3(KRT17):c.304G>A (p.Val102Met)	KRT17	Pathogenic	no assertion criteria provided
265321	NM_000422.3(KRT17):c.287CCT[1] (p.Ser97del)	KRT17	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
794186	NM_000422.3(KRT17):c.784A>T (p.Lys262Ter)	KRT17	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3779802	NM_000422.3(KRT17):c.161del (p.Gly54fs)	KRT17	Uncertain significance	criteria provided, multiple submitters, no conflicts
3891521	NM_000422.3(KRT17):c.1153C>T (p.Arg385Cys)	KRT17	Uncertain significance	criteria provided, single submitter
3891522	NM_000422.3(KRT17):c.902C>T (p.Ser301Leu)	KRT17	Uncertain significance	criteria provided, single submitter
773316	NM_000422.3(KRT17):c.834+5G>A	KRT17	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
518252	NM_005555.4(KRT6B):c.332G>A (p.Gly111Asp)	KRT6B	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 3 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
KRT17	Strong	Autosomal dominant	pachyonychia congenita 2	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KRT17	Orphanet:2309	Pachyonychia congenita
KRT17	Orphanet:841	Sebocystomatosis
KRT6B	Orphanet:2309	Pachyonychia congenita

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
KRT17	HGNC:6427	ENSG00000128422	Q04695	Keratin, type I cytoskeletal 17	gencc,clinvar
KRT6B	HGNC:6444	ENSG00000185479	P04259	Keratin, type II cytoskeletal 6B	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KRT17	Keratin, type I cytoskeletal 17	Type I keratin involved in the formation and maintenance of various skin appendages, specifically in determining shape and orientation of hair.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KRT17	Other/Unknown	no		Keratin_I, IF_conserved, IF_rod_dom
KRT6B	Other/Unknown	no		Keratin_II, IF_conserved, Keratin_2_head

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gingiva	2
gingival epithelium	2
lower esophagus mucosa	1
cervix squamous epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KRT17	224	broad	marker	gingival epithelium, gingiva, lower esophagus mucosa
KRT6B	168	tissue_specific	marker	gingiva, gingival epithelium, cervix squamous epithelium

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KRT17	2,523
KRT6B	1,692

Intra-cohort edges

A	B	Sources
KRT17	KRT6B	string_interaction

Structural data

PDB: 0 · AlphaFold-only: 2 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
KRT17	Q04695	79.28
KRT6B	P04259	69.76

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Formation of the cornified envelope	2	87.8×	5e-04	KRT17, KRT6B
Keratinization	2	55.7×	6e-04	KRT17, KRT6B
Developmental Biology	2	14.5×	0.006	KRT17, KRT6B
Developmental Lineage of Pancreatic Ductal Cells	1	114.2×	0.009	KRT17

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
intermediate filament organization	2	240.7×	8e-05	KRT17, KRT6B
keratinization	2	234.1×	8e-05	KRT17, KRT6B
positive regulation of hair follicle development	1	1203.7×	0.002	KRT17
ectoderm development	1	601.9×	0.004	KRT6B
hair follicle morphogenesis	1	247.8×	0.007	KRT17
morphogenesis of an epithelium	1	172.0×	0.009	KRT17
positive regulation of translation	1	113.9×	0.011	KRT17
positive regulation of cell growth	1	91.6×	0.011	KRT17
epithelial cell differentiation	1	87.8×	0.011	KRT17

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KRT17	0	0
KRT6B	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	KRT17, KRT6B

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
KRT17	0	—
KRT6B	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.