Keratoconus 1

Summary

Keratoconus 1 (MONDO:0007851) is a disease with 5 cohort genes.

At a glance

• Cohort genes: 5
• ClinVar variants: 47

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	keratoconus 1
Mondo ID	MONDO:0007851
MeSH	C563649
OMIM	148300
UMLS	C1835677
MedGen	372103
GARD	0024582
Is cancer (heuristic)	no

Also known as: keratoconus (disease) caused by mutation in VSX1 · keratoconus 1 · keratoconus type 1 · KTCN1 · VSX1 keratoconus (disease)

Data availability: 47 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › disorder of orbital region › eye disorder › corneal disorder › keratoconus › keratoconus 1

Related subtypes (10): acute hydrops keratoconus, keratoconus, stable condition, keratoconus 3, keratoconus 2, keratoconus 4, keratoconus 5, keratoconus 6, keratoconus 8, keratoconus 7, keratoconus 9

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

47 retrieved; paginated sample, class counts are floors:

16 uncertain significance, 14 conflicting classifications of pathogenicity, 6 likely benign, 4 pathogenic, 3 benign, 2 likely pathogenic, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
126931	NM_001367624.2(ZNF469):c.77G>C (p.Ser26Thr)	ZNF469	Pathogenic	no assertion criteria provided
126939	NM_001367624.2(ZNF469):c.2699C>G (p.Pro900Arg)	ZNF469	Pathogenic	no assertion criteria provided
126942	NM_001367624.2(ZNF469):c.337G>A (p.Glu113Lys)	ZNF469	Pathogenic	no assertion criteria provided
126944	NM_001367624.2(ZNF469):c.5681A>T (p.Gln1894Leu)	ZNF469	Pathogenic	no assertion criteria provided
126917	NM_001367624.2(ZNF469):c.10927C>T (p.Leu3643=)	ZNF469	Likely pathogenic	no assertion criteria provided
126930	NM_001367624.2(ZNF469):c.720G>A (p.Glu240=)	ZNF469	Likely pathogenic	no assertion criteria provided
337958	NM_014588.6(VSX1):c.740C>G (p.Pro247Arg)	VSX1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
337959	NM_014588.6(VSX1):c.731A>G (p.His244Arg)	VSX1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
126915	NM_001367624.2(ZNF469):c.1020C>T (p.Gly340=)	ZNF469	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
126918	NM_001367624.2(ZNF469):c.11185G>A (p.Gly3729Ser)	ZNF469	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
126922	NM_001367624.2(ZNF469):c.2699C>T (p.Pro900Leu)	ZNF469	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
126925	NM_001367624.2(ZNF469):c.4447G>T (p.Ala1483Ser)	ZNF469	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
126927	NM_001367624.2(ZNF469):c.6091G>A (p.Glu2031Lys)	ZNF469	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
126928	NM_001367624.2(ZNF469):c.6179C>A (p.Ser2060Tyr)	ZNF469	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
126932	NM_001367624.2(ZNF469):c.8996G>T (p.Gly2999Val)	ZNF469	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
126935	NM_001367624.2(ZNF469):c.9919A>G (p.Thr3307Ala)	ZNF469	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
126937	NM_001367624.2(ZNF469):c.1627G>A (p.Gly543Ser)	ZNF469	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
126943	NM_001367624.2(ZNF469):c.5144G>A (p.Arg1715Lys)	ZNF469	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
126945	NM_001367624.2(ZNF469):c.7831G>A (p.Glu2611Lys)	ZNF469	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
126946	NM_001367624.2(ZNF469):c.7931G>A (p.Arg2644Gln)	ZNF469	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
225703	NM_025130.4(HKDC1):c.850G>A (p.Gly284Ser)	HKDC1	Uncertain significance	criteria provided, single submitter
225702	NM_014443.3(IL17B):c.527G>A (p.Cys176Tyr)	IL17B	Uncertain significance	no assertion criteria provided
225701	NM_001161546.2(PROB1):c.671G>A (p.Gly224Asp)	LOC129994769	Uncertain significance	no assertion criteria provided
225700	NM_170679.3(SKP1):c.456+19T>G	SKP1	Uncertain significance	no assertion criteria provided
3707468	NM_014588.6(VSX1):c.1039G>T (p.Gly347Ter)	VSX1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3892862	NM_014588.6(VSX1):c.581G>A (p.Arg194Gln)	VSX1	Uncertain significance	criteria provided, single submitter
3892863	NM_014588.6(VSX1):c.627+31G>A	VSX1	Uncertain significance	criteria provided, single submitter
5247	NM_014588.6(VSX1):c.496C>T (p.Arg166Trp)	VSX1	Uncertain significance	criteria provided, single submitter
126919	NM_001367624.2(ZNF469):c.11699C>T (p.Pro3900Leu)	ZNF469	Uncertain significance	criteria provided, single submitter
126923	NM_001367624.2(ZNF469):c.290C>T (p.Pro97Leu)	ZNF469	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 2 · 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
VSX1	Moderate	Autosomal dominant	keratoconus 1	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
VSX1	Orphanet:98973	Posterior polymorphous corneal dystrophy
ZNF469	Orphanet:90354	Brittle cornea syndrome

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
VSX1	HGNC:12723	ENSG00000100987	Q9NZR4	Visual system homeobox 1	gencc,clinvar
SKP1	HGNC:10899	ENSG00000113558	P63208	S-phase kinase-associated protein 1	clinvar
ZNF469	HGNC:23216	ENSG00000225614	Q96JG9	Zinc finger protein 469	clinvar
HKDC1	HGNC:23302	ENSG00000156510	Q2TB90	Hexokinase HKDC1	clinvar
IL17B	HGNC:5982	ENSG00000127743	Q9UHF5	Interleukin-17B	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
VSX1	Visual system homeobox 1	Binds to the 37-bp core of the locus control region (LCR) of the red/green visual pigment gene cluster.
SKP1	S-phase kinase-associated protein 1	Essential component of the SCF (SKP1-CUL1-F-box protein) ubiquitin ligase complex, which mediates the ubiquitination of proteins involved in cell cycle progression, signal transduction and transcription.
ZNF469	Zinc finger protein 469	May be involved in transcriptional regulation.
HKDC1	Hexokinase HKDC1	Catalyzes the phosphorylation of hexose to hexose 6-phosphate, although at very low level compared to other hexokinases.
IL17B	Interleukin-17B	Stimulates the release of tumor necrosis factor alpha and IL-1-beta from the monocytic cell line THP-1.

Protein-family classification

Druggable: 1 · Difficult: 2 · Unknown: 2 · Druggable fraction: 0.2

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
Kinase	1	5.5×	0.252
Transcription factor	2	3.3×	0.252
Other/Unknown	2	0.7×	0.877

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
VSX1	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS
SKP1	Other/Unknown	no		SKP1-like, SKP1/BTB/POZ_sf, Skp1_comp_dimer
ZNF469	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, ZNF469
HKDC1	Kinase	yes	2.7.1.1	Hexokinase, Hexokinase_BS, Hexokinase_N
IL17B	Other/Unknown	no		IL-17_fam, IL-17_chr, Cystine-knot_cytokine

Expression context

Cohort genes with no expression data: 0.

3 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cerebellar hemisphere	2
tibia	2
cerebellar cortex	1
right hemisphere of cerebellum	1
prefrontal cortex	1
right frontal lobe	1
cartilage tissue	1
upper arm skin	1
duodenum	1
jejunal mucosa	1
male germ line stem cell (sensu Vertebrata) in testis	1
oocyte	1
tibial nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
VSX1	110	tissue_specific	marker	cerebellar hemisphere, cerebellar cortex, right hemisphere of cerebellum
SKP1	295	ubiquitous	marker	prefrontal cortex, cerebellar hemisphere, right frontal lobe
ZNF469	211	broad	yes	tibia, upper arm skin, cartilage tissue
HKDC1	162	broad	marker	jejunal mucosa, duodenum, male germ line stem cell (sensu Vertebrata) in testis
IL17B	165	tissue_specific	yes	tibia, oocyte, tibial nerve

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SKP1	2,031
HKDC1	1,393
VSX1	1,133
ZNF469	954
IL17B	669

Intra-cohort edges

A	B	Sources
VSX1	ZNF469	string_interaction

Structural data

PDB: 1 · AlphaFold-only: 4 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SKP1	P63208	72

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
HKDC1	Q2TB90	93.37
IL17B	Q9UHF5	78.34
VSX1	Q9NZR4	61.61
ZNF469	Q96JG9

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 115. Enrichment computed across 5 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
FBXW7 Mutants and NOTCH1 in Cancer	1	5710.0×	0.017	SKP1
Loss of Function of FBXW7 in Cancer and NOTCH1 Signaling	1	1142.0×	0.017	SKP1
Regulation of BACH1 activity	1	519.1×	0.017	SKP1
Downstream signaling events of B Cell Receptor (BCR)	1	407.9×	0.017	SKP1
Prolactin receptor signaling	1	380.7×	0.017	SKP1
MAP3K8 (TPL2)-dependent MAPK1/3 activation	1	356.9×	0.017	SKP1
TCR signaling	1	248.3×	0.017	SKP1
Signaling by NOTCH4	1	248.3×	0.017	SKP1
Signaling by NOTCH1 PEST Domain Mutants in Cancer	1	203.9×	0.017	SKP1
Signaling by NOTCH1 in Cancer	1	203.9×	0.017	SKP1
Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer	1	203.9×	0.017	SKP1
G1 Phase	1	196.9×	0.017	SKP1
Signaling by NOTCH1	1	178.4×	0.017	SKP1
R-HSA-400253	1	173.0×	0.017	SKP1
Iron uptake and transport	1	173.0×	0.017	SKP1
Signaling by the B Cell Receptor (BCR)	1	173.0×	0.017	SKP1
Host Interactions of HIV factors	1	167.9×	0.017	SKP1
APC/C-mediated degradation of cell cycle proteins	1	167.9×	0.017	SKP1
Regulation of mitotic cell cycle	1	167.9×	0.017	SKP1
Nuclear events mediated by NFE2L2	1	167.9×	0.017	SKP1
Nuclear events stimulated by ALK signaling in cancer	1	163.1×	0.017	SKP1
Regulation of APC/C activators between G1/S and early anaphase	1	154.3×	0.017	SKP1
MAP kinase activation	1	154.3×	0.017	SKP1
Switching of origins to a post-replicative state	1	150.3×	0.017	SKP1
Synthesis of DNA	1	150.3×	0.017	SKP1
Cyclin E associated events during G1/S transition	1	142.8×	0.017	SKP1
Glycolysis	1	142.8×	0.017	HKDC1
Fc epsilon receptor (FCERI) signaling	1	135.9×	0.017	SKP1
Interleukin-1 family signaling	1	135.9×	0.017	SKP1
Signaling by ALK in cancer	1	135.9×	0.017	SKP1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
retinal bipolar neuron differentiation	1	561.7×	0.026	VSX1
regulation of extracellular matrix organization	1	374.5×	0.026	ZNF469
glucose 6-phosphate metabolic process	1	259.3×	0.026	HKDC1
maintenance of protein location in nucleus	1	224.7×	0.026	SKP1
neuron maturation	1	160.5×	0.029	VSX1
intracellular glucose homeostasis	1	116.2×	0.030	HKDC1
positive regulation of cytokine production involved in inflammatory response	1	108.7×	0.030	IL17B
glycolytic process	1	76.6×	0.033	HKDC1
SCF-dependent proteasomal ubiquitin-dependent protein catabolic process	1	74.9×	0.033	SKP1
protein monoubiquitination	1	68.8×	0.033	SKP1
glucose metabolic process	1	51.1×	0.037	HKDC1
neuron development	1	51.1×	0.037	VSX1
protein K48-linked ubiquitination	1	33.7×	0.052	SKP1
protein polyubiquitination	1	23.1×	0.070	SKP1
visual perception	1	15.9×	0.094	VSX1
chromatin remodeling	1	14.6×	0.094	SKP1
cell-cell signaling	1	13.9×	0.094	IL17B
proteasome-mediated ubiquitin-dependent protein catabolic process	1	10.4×	0.118	SKP1
immune response	1	9.4×	0.123	IL17B
protein ubiquitination	1	8.3×	0.132	SKP1
inflammatory response	1	7.5×	0.138	IL17B
regulation of DNA-templated transcription	1	6.3×	0.155	VSX1
negative regulation of transcription by RNA polymerase II	1	3.5×	0.252	ZNF469

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 5 evidence-associated genes (40%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
SKP1	SELEXIPAG
HKDC1	CHLORHEXIDINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
HKDC1	2	4
SKP1	1	4
VSX1	0	0
ZNF469	0	0
IL17B	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
SELEXIPAG	4	SKP1
CHLORHEXIDINE	4	HKDC1
EBSELEN	3	HKDC1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
HKDC1	7	Functional:6, Binding:1
SKP1	4	Binding:4

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
HKDC1	2.7.1.1	hexokinase

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

3 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.

Compound	Max phase	Cohort target (bioactivity)
SELEXIPAG	4	SKP1
CHLORHEXIDINE	4	HKDC1
EBSELEN	3	HKDC1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	SKP1, HKDC1
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	VSX1, ZNF469, IL17B

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)
VSX1	0	—
ZNF469	0	—
IL17B	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.