Pachyonychia congenita 3

Summary

Pachyonychia congenita 3 (MONDO:0014324) is a disease caused by KRT6A (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: KRT6A (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 33

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	pachyonychia congenita 3
Mondo ID	MONDO:0014324
OMIM	615726
UMLS	C3714948
MedGen	811523
GARD	0016005
Is cancer (heuristic)	no

Also known as: KRT6A pachyonychia congenita · pachyonychia congenita 3 · pachyonychia congenita caused by mutation in KRT6A · pachyonychia congenita type 3 · PC3

Data availability: 33 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 3

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

33 retrieved; paginated sample, class counts are floors:

9 pathogenic, 9 likely pathogenic, 5 benign, 4 uncertain significance, 2 pathogenic/likely pathogenic, 2 benign/likely benign, 1 conflicting classifications of pathogenicity, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
14634	NM_005554.4(KRT6A):c.510CAA[2] (p.Asn172del)	KRT6A	Pathogenic	criteria provided, multiple submitters, no conflicts
14635	NM_005554.4(KRT6A):c.520T>G (p.Phe174Val)	KRT6A	Pathogenic	no assertion criteria provided
14636	NM_005554.4(KRT6A):c.1414G>A (p.Glu472Lys)	KRT6A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14637	NM_005554.4(KRT6A):c.1406T>G (p.Leu469Arg)	KRT6A	Pathogenic	no assertion criteria provided
3391301	NM_005554.4(KRT6A):c.1460-1G>C	KRT6A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
66576	NM_005554.4(KRT6A):c.1406T>C (p.Leu469Pro)	KRT6A	Pathogenic	criteria provided, single submitter
66579	NM_005554.4(KRT6A):c.487G>A (p.Glu163Lys)	KRT6A	Pathogenic	criteria provided, multiple submitters, no conflicts
66585	NM_005554.4(KRT6A):c.511A>G (p.Asn171Asp)	KRT6A	Pathogenic	criteria provided, single submitter
66588	NM_005554.4(KRT6A):c.512A>G (p.Asn171Ser)	KRT6A	Pathogenic	criteria provided, multiple submitters, no conflicts
66589	NM_005554.4(KRT6A):c.513C>A (p.Asn171Lys)	KRT6A	Pathogenic	criteria provided, multiple submitters, no conflicts
66591	NM_005554.4(KRT6A):c.521T>C (p.Phe174Ser)	KRT6A	Pathogenic	no assertion criteria provided
156022	NM_005554.4(KRT6A):c.1460-2A>C	KRT6A	Likely pathogenic	criteria provided, single submitter
1806290	NM_005554.4(KRT6A):c.817-2A>G	KRT6A	Likely pathogenic	criteria provided, single submitter
3574966	NM_005554.4(KRT6A):c.1382A>G (p.Glu461Gly)	KRT6A	Likely pathogenic	criteria provided, single submitter
3574967	NM_005554.4(KRT6A):c.520T>A (p.Phe174Ile)	KRT6A	Likely pathogenic	criteria provided, single submitter
3891533	NM_005554.4(KRT6A):c.1388C>T (p.Ala463Val)	KRT6A	Likely pathogenic	criteria provided, single submitter
4081480	NM_005554.4(KRT6A):c.1203+1G>A	KRT6A	Likely pathogenic	criteria provided, single submitter
66566	NM_005554.4(KRT6A):c.1381G>A (p.Glu461Lys)	KRT6A	Likely pathogenic	criteria provided, single submitter
66582	NM_005554.4(KRT6A):c.500T>A (p.Ile167Asn)	KRT6A	Likely pathogenic	criteria provided, single submitter
827961	NM_005554.4(KRT6A):c.1381G>T (p.Glu461Ter)	KRT6A	Likely pathogenic	criteria provided, single submitter
1312601	NM_005554.4(KRT6A):c.1157G>A (p.Arg386His)	KRT6A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1339080	NM_005554.4(KRT6A):c.1529G>T (p.Gly510Val)	KRT6A	Uncertain significance	criteria provided, single submitter
2665037	NM_005554.4(KRT6A):c.1650G>T (p.Lys550Asn)	KRT6A	Uncertain significance	criteria provided, multiple submitters, no conflicts
2716296	NM_005554.4(KRT6A):c.1124G>A (p.Arg375His)	KRT6A	Uncertain significance	criteria provided, multiple submitters, no conflicts
930292	NM_005554.4(KRT6A):c.1078-10T>C	KRT6A	Uncertain significance	criteria provided, single submitter
1233095	NM_005554.4(KRT6A):c.483T>C (p.Ala161=)	KRT6A	Benign	criteria provided, multiple submitters, no conflicts
1291209	NM_005554.4(KRT6A):c.1424+18A>C	KRT6A	Benign	criteria provided, multiple submitters, no conflicts
1300086	NM_005554.4(KRT6A):c.819T>C (p.Asp273=)	KRT6A	Benign	criteria provided, multiple submitters, no conflicts
1300087	NM_005554.4(KRT6A):c.62A>G (p.Asn21Ser)	KRT6A	Benign	criteria provided, multiple submitters, no conflicts
1580821	NM_005554.4(KRT6A):c.1203+13A>G	KRT6A	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · 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
KRT6A	Strong	Autosomal dominant	pachyonychia congenita 3	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KRT6A	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
KRT6A	HGNC:6443	ENSG00000205420	P02538	Keratin, type II cytoskeletal 6A	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KRT6A	Keratin, type II cytoskeletal 6A	Epidermis-specific type I keratin involved in wound healing.

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)
KRT6A	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
gingiva	1
gingival epithelium	1
squamous epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KRT6A	187	broad	marker	gingiva, gingival epithelium, squamous epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KRT6A	2,160

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KRT6A	P02538	1

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	KRT6A
Keratinization	1	55.7×	0.027	KRT6A
Developmental Biology	1	14.5×	0.069	KRT6A

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
negative regulation of entry of bacterium into host cell	1	5617.3×	0.002	KRT6A
morphogenesis of an epithelium	1	343.9×	0.007	KRT6A
killing of cells of another organism	1	271.8×	0.007	KRT6A
intermediate filament organization	1	240.7×	0.007	KRT6A
keratinization	1	234.1×	0.007	KRT6A
wound healing	1	227.7×	0.007	KRT6A
antimicrobial humoral immune response mediated by antimicrobial peptide	1	162.0×	0.009	KRT6A
defense response to Gram-positive bacterium	1	127.7×	0.010	KRT6A
positive regulation of cell population proliferation	1	33.6×	0.033	KRT6A
cell differentiation	1	29.1×	0.034	KRT6A

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
KRT6A	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	KRT6A

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)
KRT6A	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.