Monilethrix-1

Summary

Monilethrix-1 (MONDO:0700343) is a disease caused by variants in KRT81 and KRT86, with 3 cohort genes. The dominant Reactome pathway is Formation of the cornified envelope (3 cohort genes).

At a glance

• Causal genes: KRT81 (GenCC Strong), KRT86 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 11

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	monilethrix-1
Mondo ID	MONDO:0700343
OMIM	158000
DOID	DOID:0061145
UMLS	C6012688
MedGen	1876529
GARD	0028017
Is cancer (heuristic)	no

Data availability: 11 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › monilethrix › monilethrix-1

Related subtypes (2): monilethrix-2, monilethrix-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

11 retrieved; paginated sample, class counts are floors:

8 uncertain significance, 2 conflicting classifications of pathogenicity, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
7611	NM_001320198.2(KRT86):c.1204G>A (p.Glu402Lys)	KRT86	Likely pathogenic	criteria provided, single submitter
561048	NM_002281.4(KRT81):c.846T>A (p.Tyr282Ter)	KRT81	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3891539	NM_002282.3(KRT83):c.72_78del (p.Pro25fs)	KRT83	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2433271	NM_002281.4(KRT81):c.2T>G (p.Met1Arg)	KRT81	Uncertain significance	criteria provided, single submitter
3116717	NM_002281.4(KRT81):c.1367C>A (p.Pro456Gln)	KRT81	Uncertain significance	criteria provided, multiple submitters, no conflicts
3865707	NM_002281.4(KRT81):c.127G>A (p.Gly43Arg)	KRT81	Uncertain significance	criteria provided, multiple submitters, no conflicts
3891537	NM_002281.4(KRT81):c.1300G>A (p.Gly434Arg)	KRT81	Uncertain significance	criteria provided, single submitter
3116740	NM_002282.3(KRT83):c.1361C>T (p.Thr454Met)	KRT83	Uncertain significance	criteria provided, multiple submitters, no conflicts
3891538	NM_002282.3(KRT83):c.1167C>A (p.Cys389Ter)	KRT83	Uncertain significance	criteria provided, single submitter
3891540	NM_001320198.2(KRT86):c.911T>C (p.Met304Thr)	KRT86	Uncertain significance	criteria provided, single submitter
3891541	NM_001320198.2(KRT86):c.212_235dup (p.Ile78_Thr79insSerGlyProSerProProCysIle)	KRT86	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 4 · 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
KRT81	Strong	Autosomal dominant	monilethrix-1	4
KRT86	Strong	Autosomal dominant	monilethrix	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KRT81	Orphanet:573	Monilethrix
KRT86	Orphanet:573	Monilethrix
KRT83	Orphanet:316	Progressive symmetric erythrokeratodermia
KRT83	Orphanet:573	Monilethrix

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
KRT81	HGNC:6458	ENSG00000205426	Q14533	Keratin, type II cuticular Hb1	gencc,clinvar
KRT86	HGNC:6463	ENSG00000170442	O43790	Keratin, type II cuticular Hb6	gencc,clinvar
KRT83	HGNC:6460	ENSG00000170523	P78385	Keratin, type II cuticular Hb3	clinvar

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · 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	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KRT81	Other/Unknown	no		Keratin_II, IF_conserved, Keratin_2_head
KRT86	Other/Unknown	no		Keratin_II, IF_conserved, Keratin_2_head
KRT83	Other/Unknown	no		Keratin_II, Growth_fac_rcpt_cys_sf, IF_conserved

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	3
diaphragm	2
hair follicle	1
right coronary artery	1
sperm	1
type B pancreatic cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KRT81	131	tissue_specific	marker	diaphragm, male germ line stem cell (sensu Vertebrata) in testis, hair follicle
KRT86	160	broad	marker	male germ line stem cell (sensu Vertebrata) in testis, sperm, right coronary artery
KRT83	73	tissue_specific	yes	diaphragm, type B pancreatic cell, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KRT81	1,077
KRT83	1,053
KRT86	244

Structural data

PDB: 0 · AlphaFold-only: 3 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
KRT86	O43790	75.50
KRT83	P78385	74.81
KRT81	Q14533	74.40

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 3 evidence-associated genes (3 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 3 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	3	87.8×	4e-06	KRT81, KRT86, KRT83
Keratinization	3	55.7×	9e-06	KRT81, KRT86, KRT83
Developmental Biology	3	14.5×	3e-04	KRT81, KRT86, KRT83

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 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	3	240.7×	1e-07	KRT81, KRT86, KRT83
keratinization	3	234.1×	1e-07	KRT81, KRT86, KRT83
hair cycle	1	312.1×	0.004	KRT83
epidermis development	1	70.2×	0.014	KRT83

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 3 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KRT81	0	0
KRT86	0	0
KRT83	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
KRT81	1	Binding:1
KRT86	1	Binding:1
KRT83	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	3	KRT81, KRT86, KRT83

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
KRT81	1	—
KRT86	1	—
KRT83	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.