Anterior segment dysgenesis 3

Summary

Anterior segment dysgenesis 3 (MONDO:0024456) is a disease caused by FOXC1 (GenCC Strong), with 4 cohort genes.

At a glance

• Causal gene: FOXC1 (GenCC Strong)
• Cohort genes: 4
• ClinVar variants: 141

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	anterior segment dysgenesis 3
Mondo ID	MONDO:0024456
MeSH	C535535
OMIM	601631
DOID	DOID:0080608
UMLS	C5975707
MedGen	1875235
GARD	0002978
Is cancer (heuristic)	no

Also known as: anterior segment dysgenesis 3 · anterior segment dysgenesis 3, multiple subtypes · ASGD3 · FOXC1 iridogoniodysgenesis · glaucoma iridogoniodysgenesia · glaucoma iridogoniodysplasia, familial · IGDA · IGDA syndrome · IRID1 · iridogoniodysgenesis anomaly, autosomal dominant · iridogoniodysgenesis caused by mutation in FOXC1 · iridogoniodysgenesis type 1 · iridogoniodysgenesis, type 1 · iris hypoplasia with glaucoma

Data availability: 141 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › disorder of orbital region › eye disorder › uveal disorder › iris disorder › anterior segment dysgenesis 3

Related subtypes (7): pupil disorder, ciliary body disorder, iritis, exfoliation syndrome, aniridia, iris neoplasm, intraoperative floppy iris syndrome

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

141 retrieved; paginated sample, class counts are floors:

110 uncertain significance, 11 pathogenic, 5 likely pathogenic, 4 conflicting classifications of pathogenicity, 4 likely benign, 3 pathogenic/likely pathogenic, 2 benign, 1 benign/likely benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
100687	NM_001453.3(FOXC1):c.141C>G (p.Tyr47Ter)	FOXC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1685825	NM_001453.3(FOXC1):c.398_401del (p.Asn133fs)	FOXC1	Pathogenic	criteria provided, single submitter
1710334	NM_001453.3(FOXC1):c.1040dup (p.Leu348fs)	FOXC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3236698	NM_001453.3(FOXC1):c.235C>A (p.Pro79Thr)	FOXC1	Pathogenic	criteria provided, single submitter
375426	NM_001453.3(FOXC1):c.487G>T (p.Glu163Ter)	FOXC1	Pathogenic	criteria provided, single submitter
375429	NM_001453.3(FOXC1):c.718_719del (p.Leu240fs)	FOXC1	Pathogenic	criteria provided, multiple submitters, no conflicts
495293	NM_001453.3(FOXC1):c.349del (p.Asp117fs)	FOXC1	Pathogenic	criteria provided, single submitter
8451	NM_001453.3(FOXC1):c.153_163del (p.His52fs)	FOXC1	Pathogenic	no assertion criteria provided
8452	NM_001453.3(FOXC1):c.392C>T (p.Ser131Leu)	FOXC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
8453	NM_001453.3(FOXC1):c.378C>G (p.Ile126Met)	FOXC1	Pathogenic	no assertion criteria provided
8456	FOXC1, DUP	FOXC1	Pathogenic	no assertion criteria provided
8457	FOXC1, 22-BP INS, NT26	FOXC1	Pathogenic	no assertion criteria provided
8459	NM_001453.3(FOXC1):c.261C>G (p.Ile87Met)	FOXC1	Pathogenic	no assertion criteria provided
973776	GRCh37/hg19 6p25.3(chr6:1318643-1837594)x3	FOXQ1	Pathogenic	no assertion criteria provided
1333607	NM_001453.3(FOXC1):c.454T>C (p.Trp152Arg)	FOXC1	Likely pathogenic	criteria provided, single submitter
2629736	NM_001453.3(FOXC1):c.404G>A (p.Cys135Tyr)	FOXC1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3775503	NM_001453.3(FOXC1):c.824dup (p.Ser276fs)	FOXC1	Likely pathogenic	criteria provided, single submitter
4294515	NM_001453.3(FOXC1):c.1141del (p.Ala381fs)	FOXC1	Likely pathogenic	criteria provided, single submitter
992653	NM_001453.3(FOXC1):c.1157del (p.Gly386fs)	FOXC1	Likely pathogenic	criteria provided, single submitter
1355457	NM_001453.3(FOXC1):c.1486G>A (p.Gly496Ser)	FOXC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1507910	NM_001453.3(FOXC1):c.476ACA[1] (p.Asn160del)	FOXC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2231499	NM_001453.3(FOXC1):c.1334G>A (p.Ser445Asn)	FOXC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
469653	NM_001453.3(FOXC1):c.532G>C (p.Asp178His)	FOXC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1175734	NM_001453.3(FOXC1):c.1600C>T (p.Pro534Ser)	FOXC1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1213302	NM_001453.3(FOXC1):c.418C>T (p.Pro140Ser)	FOXC1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1299232	NM_001453.3(FOXC1):c.1337A>G (p.His446Arg)	FOXC1	Uncertain significance	criteria provided, multiple submitters, no conflicts
132835	NM_001453.3(FOXC1):c.1337_1342dup (p.Gly447_Gly448insAspGly)	FOXC1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1333591	NM_001453.3(FOXC1):c.337_339dup (p.Pro113dup)	FOXC1	Uncertain significance	criteria provided, single submitter
1344729	NM_001453.3(FOXC1):c.430AAG[1] (p.Lys145del)	FOXC1	Uncertain significance	criteria provided, single submitter
1344730	NM_001453.3(FOXC1):c.926_940del (p.Ser309_Ile313del)	FOXC1	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 10 · 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
FOXC1	Strong	Autosomal dominant	anterior segment dysgenesis 3	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FOXC1	Orphanet:250923	Isolated aniridia
FOXC1	Orphanet:708	Peters anomaly
FOXC1	Orphanet:782	Axenfeld-Rieger syndrome
FOXC1	Orphanet:91483	Rieger anomaly
FOXC1	Orphanet:98978	Axenfeld anomaly
IFT140	Orphanet:140969	Saldino-Mainzer syndrome
IFT140	Orphanet:474	Jeune syndrome
IFT140	Orphanet:65	Leber congenital amaurosis
IFT140	Orphanet:730	Autosomal dominant polycystic kidney disease
IFT140	Orphanet:791	Retinitis pigmentosa

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
FOXC1	HGNC:3800	ENSG00000054598	Q12948	Forkhead box protein C1	gencc,clinvar
BPHL	HGNC:1094	ENSG00000137274	Q86WA6	Serine hydrolase BPHL	clinvar
FOXQ1	HGNC:20951	ENSG00000164379	Q9C009	Forkhead box protein Q1	clinvar
IFT140	HGNC:29077	ENSG00000187535	Q96RY7	Intraflagellar transport protein 140 homolog	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FOXC1	Forkhead box protein C1	DNA-binding transcriptional factor that plays a role in a broad range of cellular and developmental processes such as eye, bones, cardiovascular, kidney and skin development.
BPHL	Serine hydrolase BPHL	Specific alpha-amino acid ester serine hydrolase that prefers small, hydrophobic, and aromatic side chains and does not have a stringent requirement for the leaving group other than preferring a primary alcohol.
FOXQ1	Forkhead box protein Q1	Plays a role in hair follicle differentiation.
IFT140	Intraflagellar transport protein 140 homolog	Component of the IFT complex A (IFT-A), a complex required for retrograde ciliary transport and entry into cilia of G protein-coupled receptors (GPCRs).

Protein-family classification

Druggable: 0 · Difficult: 3 · 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
Transcription factor	2	4.1×	0.223
Scaffold/PPI	1	4.3×	0.318
Other/Unknown	1	0.5×	0.962

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FOXC1	Transcription factor	no		Fork_head_dom, TF_fork_head_CS_1, TF_fork_head_CS_2
BPHL	Other/Unknown	no		AB_hydrolase_1, AB_hydrolase_fold
FOXQ1	Transcription factor	no		Fork_head_dom, TF_fork_head_CS_1, TF_fork_head_CS_2
IFT140	Scaffold/PPI	no		WD40_rpt, WD40/YVTN_repeat-like_dom_sf, WD40_repeat_dom_sf

Expression context

Cohort genes with no expression data: 0.

4 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
parotid gland	2
trigeminal ganglion	1
vena cava	1
adult mammalian kidney	1
liver	1
right lobe of liver	1
epithelial cell of pancreas	1
pylorus	1
left lobe of thyroid gland	1
right lobe of thyroid gland	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FOXC1	267	ubiquitous	marker	parotid gland, vena cava, trigeminal ganglion
BPHL	253	ubiquitous	marker	right lobe of liver, adult mammalian kidney, liver
FOXQ1	195	broad	marker	parotid gland, pylorus, epithelial cell of pancreas
IFT140	214	ubiquitous	marker	right uterine tube, right lobe of thyroid gland, left lobe of thyroid gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FOXC1	2,896
IFT140	1,602
BPHL	1,390
FOXQ1	1,262

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
BPHL	Q86WA6	4
IFT140	Q96RY7	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
FOXQ1	Q9C009	61.92
FOXC1	Q12948	56.09

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 4 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Formation of intermediate mesoderm	1	356.9×	0.022	FOXC1
Formation of the ureteric bud	1	124.1×	0.032	FOXC1
Phase I - Functionalization of compounds	1	54.9×	0.036	BPHL
Intraflagellar transport	1	50.1×	0.036	IFT140
Hedgehog ‘off’ state	1	44.6×	0.036	IFT140
Biological oxidations	1	32.4×	0.038	BPHL
Negative Regulation of CDH1 Gene Transcription	1	30.1×	0.038	FOXQ1
Metabolism	1	2.9×	0.302	BPHL

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
glomerular epithelium development	1	4213.0×	0.006	FOXC1
positive regulation of hematopoietic stem cell differentiation	1	4213.0×	0.006	FOXC1
apoptotic process involved in outflow tract morphogenesis	1	2106.5×	0.006	FOXC1
negative regulation of apoptotic process involved in outflow tract morphogenesis	1	2106.5×	0.006	FOXC1
positive regulation of core promoter binding	1	2106.5×	0.006	FOXC1
anatomical structure morphogenesis	2	69.6×	0.006	FOXC1, FOXQ1
negative regulation of lymphangiogenesis	1	1404.3×	0.007	FOXC1
positive regulation of hematopoietic progenitor cell differentiation	1	1404.3×	0.007	FOXC1
heart development	2	39.4×	0.008	FOXC1, IFT140
paraxial mesoderm formation	1	842.6×	0.008	FOXC1
neural tube patterning	1	702.2×	0.008	IFT140
mesenchymal cell development	1	601.9×	0.008	FOXC1
glycosaminoglycan metabolic process	1	601.9×	0.008	FOXC1
lacrimal gland development	1	526.6×	0.008	FOXC1
maintenance of lens transparency	1	526.6×	0.008	FOXC1
regulation of organ growth	1	526.6×	0.008	FOXC1
lymph vessel development	1	468.1×	0.008	FOXC1
primordial germ cell migration	1	468.1×	0.008	FOXC1
homocysteine metabolic process	1	468.1×	0.008	BPHL
embryonic camera-type eye development	1	300.9×	0.012	IFT140
positive regulation of DNA binding	1	300.9×	0.012	FOXC1
intraciliary retrograde transport	1	280.9×	0.012	IFT140
photoreceptor cell outer segment organization	1	263.3×	0.012	IFT140
vascular endothelial growth factor signaling pathway	1	263.3×	0.012	FOXC1
cellular response to chemokine	1	247.8×	0.012	FOXC1
amino acid metabolic process	1	200.6×	0.012	BPHL
neural crest cell development	1	200.6×	0.012	FOXC1
positive regulation of keratinocyte differentiation	1	200.6×	0.012	FOXC1
negative regulation of mitotic cell cycle	1	200.6×	0.012	FOXC1
embryonic brain development	1	200.6×	0.012	IFT140

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 4 evidence-associated genes (25%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FOXC1	0	0
BPHL	0	0
FOXQ1	0	0
IFT140	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
BPHL	4	Binding:4

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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	4	FOXC1, BPHL, FOXQ1, IFT140

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
FOXC1	0	—
BPHL	4	—
FOXQ1	0	—
IFT140	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.