Pachyonychia congenita 4

Summary

Pachyonychia congenita 4 (MONDO:0014325) is a disease caused by KRT6B (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: KRT6B (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 12

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	pachyonychia congenita 4
Mondo ID	MONDO:0014325
OMIM	615728
UMLS	C3714949
MedGen	811524
GARD	0016006
Is cancer (heuristic)	no

Also known as: KRT6B pachyonychia congenita · pachyonychia congenita 4 · pachyonychia congenita caused by mutation in KRT6B · pachyonychia congenita type 4 · PC4

Data availability: 12 ClinVar variants · 4 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 4

Related subtypes (3): pachyonychia congenita 1, pachyonychia congenita 2, pachyonychia congenita 3

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

12 retrieved; paginated sample, class counts are floors:

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

ClinVar	Variant (HGVS)	Gene	Classification	Review
14633	NM_005555.4(KRT6B):c.1414G>A (p.Glu472Lys)	KRT6B	Pathogenic	criteria provided, multiple submitters, no conflicts
66599	NM_005555.4(KRT6B):c.1381G>A (p.Glu461Lys)	KRT6B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
66600	NM_005555.4(KRT6B):c.510CAA[2] (p.Asn172del)	KRT6B	Pathogenic	criteria provided, multiple submitters, no conflicts
816696	NM_005555.4(KRT6B):c.1406T>G (p.Leu469Arg)	KRT6B	Pathogenic	no assertion criteria provided
2170364	NM_005555.4(KRT6B):c.1484G>A (p.Ser495Asn)	KRT6B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2063996	NM_005555.4(KRT6B):c.1124G>A (p.Arg375His)	KRT6B	Uncertain significance	criteria provided, multiple submitters, no conflicts
3891534	NM_005555.4(KRT6B):c.1243C>A (p.Arg415Ser)	KRT6B	Uncertain significance	criteria provided, single submitter
1269785	NM_005555.4(KRT6B):c.1221C>T (p.Ala407=)	KRT6B	Benign	criteria provided, multiple submitters, no conflicts
1300088	NM_005555.4(KRT6B):c.1093A>G (p.Ile365Val)	KRT6B	Benign	criteria provided, multiple submitters, no conflicts
1300089	NM_005555.4(KRT6B):c.62A>G (p.Asn21Ser)	KRT6B	Benign	criteria provided, multiple submitters, no conflicts
1631880	NM_005555.4(KRT6B):c.1186G>A (p.Asp396Asn)	KRT6B	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
802862	NM_005555.4(KRT6B):c.1495G>A (p.Gly499Ser)	KRT6B	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 1 · 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
KRT6B	Strong	Autosomal dominant	pachyonychia congenita 4	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KRT6B	Orphanet:2309	Pachyonychia congenita

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
KRT6B	HGNC:6444	ENSG00000185479	P04259	Keratin, type II cytoskeletal 6B	gencc,clinvar

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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	1	1.8×	0.558

Per-gene assignment

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

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cervix squamous epithelium	1
gingiva	1
gingival epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KRT6B	168	tissue_specific	marker	gingiva, gingival epithelium, cervix squamous epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KRT6B	1,692

Structural data

PDB: 0 · AlphaFold-only: 1 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
KRT6B	P04259	69.76

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 1 evidence-associated genes (1 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 1 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	1	87.8×	0.027	KRT6B
Keratinization	1	55.7×	0.027	KRT6B
Developmental Biology	1	14.5×	0.069	KRT6B

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
ectoderm development	1	1203.7×	0.002	KRT6B
intermediate filament organization	1	240.7×	0.004	KRT6B
keratinization	1	234.1×	0.004	KRT6B

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 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
KRT6B	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	1	KRT6B

Undrugged target profiles

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

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.