Axenfeld-Rieger syndrome type 3

Summary

Axenfeld-Rieger syndrome type 3 (MONDO:0011233) is a disease caused by FOXC1 (GenCC Definitive), with 5 cohort genes.

At a glance

• Causal gene: FOXC1 (GenCC Definitive)
• Cohort genes: 5
• ClinVar variants: 620

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Axenfeld-Rieger syndrome type 3
Mondo ID	MONDO:0011233
OMIM	602482
DOID	DOID:0110122
SNOMED CT	22155002
UMLS	C2678503
MedGen	394534
GARD	0009626
Is cancer (heuristic)	no

Also known as: anterior chamber cleavage syndrome · Axenfeld-Rieger syndrome caused by mutation in FOXC1 · Axenfeld-Rieger syndrome type 3 · Axenfeld-Rieger syndrome, type 3 · FOXC1 Axenfeld-Rieger syndrome · RIEG3

Data availability: 620 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Axenfeld-Rieger syndrome › Axenfeld-Rieger syndrome type 3

Related subtypes (2): Axenfeld-Rieger syndrome type 1, Axenfeld-Rieger syndrome type 2

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

600 retrieved; paginated sample, class counts are floors:

331 uncertain significance, 111 likely benign, 80 pathogenic, 25 conflicting classifications of pathogenicity, 18 likely pathogenic, 12 pathogenic/likely pathogenic, 11 benign/likely benign, 11 benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
375433	der(6)t(6;10)(p25.2;q26.3)		Pathogenic	no assertion criteria provided
1676308	GRCh37/hg19 6p25.3-25.2(chr6:375263-3655142)x1	BPHL	Pathogenic	no assertion criteria provided
560066	Single allele	COL18A1	Pathogenic	criteria provided, single submitter
2506536	GRCh37/hg19 6p25.3(chr6:491126-1624775)	EXOC2	Pathogenic	criteria provided, single submitter
100687	NM_001453.3(FOXC1):c.141C>G (p.Tyr47Ter)	FOXC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071356	NM_001453.3(FOXC1):c.51del (p.Tyr18fs)	FOXC1	Pathogenic	criteria provided, single submitter
1072188	NM_001453.3(FOXC1):c.244dup (p.Ser82fs)	FOXC1	Pathogenic	criteria provided, single submitter
1073152	NM_001453.3(FOXC1):c.81_100del (p.Ala28fs)	FOXC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076933	NM_001453.3(FOXC1):c.712C>T (p.Gln238Ter)	FOXC1	Pathogenic	criteria provided, single submitter
1224520	NM_001453.3(FOXC1):c.504GCG[4] (p.Arg173del)	FOXC1	Pathogenic	criteria provided, single submitter
1251979	NM_001453.3(FOXC1):c.246C>A (p.Ser82Arg)	FOXC1	Pathogenic	no assertion criteria provided
1453723	NM_001453.3(FOXC1):c.821dup (p.Ser276fs)	FOXC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1458299	NM_001453.3(FOXC1):c.143C>A (p.Ser48Ter)	FOXC1	Pathogenic	criteria provided, single submitter
1506339	NM_001453.3(FOXC1):c.399C>G (p.Asn133Lys)	FOXC1	Pathogenic	criteria provided, single submitter
1524543	NM_001453.3(FOXC1):c.256_267del (p.Leu86_Met89del)	FOXC1	Pathogenic	criteria provided, single submitter
1693137	NM_001453.3(FOXC1):c.65dup (p.Gln23fs)	FOXC1	Pathogenic	criteria provided, single submitter
1693138	NM_001453.3(FOXC1):c.176dup (p.Met60fs)	FOXC1	Pathogenic	criteria provided, single submitter
1693139	NM_001453.3(FOXC1):c.274C>T (p.Gln92Ter)	FOXC1	Pathogenic	criteria provided, multiple submitters, no conflicts
1693140	NM_001453.3(FOXC1):c.354del (p.Asn118fs)	FOXC1	Pathogenic	criteria provided, single submitter
1693141	NM_001453.3(FOXC1):c.366G>A (p.Trp122Ter)	FOXC1	Pathogenic	criteria provided, multiple submitters, no conflicts
1693142	NM_001453.3(FOXC1):c.502del (p.Leu168fs)	FOXC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1693143	NM_001453.3(FOXC1):c.816_817delinsA (p.Ser272fs)	FOXC1	Pathogenic	criteria provided, single submitter
1693144	NM_001453.3(FOXC1):c.821del (p.Pro274fs)	FOXC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1693145	NM_001453.3(FOXC1):c.965_977dup (p.Leu328fs)	FOXC1	Pathogenic	criteria provided, single submitter
1693147	NM_001453.3(FOXC1):c.1141dup (p.Ala381fs)	FOXC1	Pathogenic	criteria provided, single submitter
1693148	NM_001453.3(FOXC1):c.1193_1196dup (p.Met400fs)	FOXC1	Pathogenic	criteria provided, single submitter
1693149	NM_001453.3(FOXC1):c.1430del (p.Gln477fs)	FOXC1	Pathogenic	criteria provided, single submitter
1693150	NM_001453.3(FOXC1):c.1508del (p.Asn503fs)	FOXC1	Pathogenic	criteria provided, single submitter
1693151	NM_001453.3(FOXC1):c.241T>C (p.Tyr81His)	FOXC1	Pathogenic	criteria provided, single submitter
1693152	NM_001453.3(FOXC1):c.257T>G (p.Leu86Arg)	FOXC1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 11 · 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	Definitive	Autosomal dominant	Axenfeld-Rieger syndrome type 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
COL18A1	Orphanet:1571	Knobloch syndrome
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

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

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
COL18A1	HGNC:2195	ENSG00000182871	P39060	Collagen alpha-1(XVIII) chain	clinvar
EXOC2	HGNC:24968	ENSG00000112685	Q96KP1	Exocyst complex component 2	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.
COL18A1	Collagen alpha-1(XVIII) chain	Probably plays a major role in determining the retinal structure as well as in the closure of the neural tube.
EXOC2	Exocyst complex component 2	Component of the exocyst complex involved in the docking of exocytic vesicles with fusion sites on the plasma membrane.
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: 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
Antibody/Immunoglobulin	1	5.8×	0.515
Scaffold/PPI	1	3.5×	0.515
Transcription factor	1	1.6×	0.634
Other/Unknown	2	0.7×	0.877

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
COL18A1	Other/Unknown	no		Collagen, DUF959_COL18_N, Collagenase_NC10/endostatin
EXOC2	Antibody/Immunoglobulin	yes		IPT_dom, Ig-like_fold, Ig_E-set
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.

5 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
parotid gland	1
trigeminal ganglion	1
vena cava	1
adult mammalian kidney	1
liver	1
right lobe of liver	1
popliteal artery	1
right coronary artery	1
tibial artery	1
cortical plate	1
male germ line stem cell (sensu Vertebrata) in testis	1
middle temporal gyrus	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
COL18A1	266	ubiquitous	marker	right coronary artery, popliteal artery, tibial artery
EXOC2	255	ubiquitous	marker	male germ line stem cell (sensu Vertebrata) in testis, middle temporal gyrus, cortical plate
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
EXOC2	2,587
COL18A1	2,316
IFT140	1,602
BPHL	1,390

Structural data

PDB: 3 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
COL18A1	P39060	9
BPHL	Q86WA6	4
IFT140	Q96RY7	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
EXOC2	Q96KP1	80.82
FOXC1	Q12948	56.09

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 17. Enrichment computed across 5 evidence-associated genes (5 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 5 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	285.5×	0.038	FOXC1
VxPx cargo-targeting to cilium	1	103.8×	0.038	EXOC2
Formation of the ureteric bud	1	99.3×	0.038	FOXC1
Insulin processing	1	91.4×	0.038	EXOC2
Laminin interactions	1	76.1×	0.038	COL18A1
Activation of Matrix Metalloproteinases	1	61.7×	0.038	COL18A1
Collagen chain trimerization	1	51.9×	0.038	COL18A1
Phase I - Functionalization of compounds	1	43.9×	0.038	BPHL
Assembly of collagen fibrils and other multimeric structures	1	40.1×	0.038	COL18A1
Intraflagellar transport	1	40.1×	0.038	IFT140
Hedgehog ‘off’ state	1	35.7×	0.038	IFT140
Collagen degradation	1	35.1×	0.038	COL18A1
Collagen biosynthesis and modifying enzymes	1	34.1×	0.038	COL18A1
Translocation of SLC2A4 (GLUT4) to the plasma membrane	1	30.9×	0.039	EXOC2
Integrin cell surface interactions	1	26.9×	0.040	COL18A1
Biological oxidations	1	25.9×	0.040	BPHL
Metabolism	1	2.3×	0.362	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 5 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	3370.4×	0.011	FOXC1
positive regulation of hematopoietic stem cell differentiation	1	3370.4×	0.011	FOXC1
apoptotic process involved in outflow tract morphogenesis	1	1685.2×	0.011	FOXC1
negative regulation of apoptotic process involved in outflow tract morphogenesis	1	1685.2×	0.011	FOXC1
positive regulation of core promoter binding	1	1685.2×	0.011	FOXC1
negative regulation of lymphangiogenesis	1	1123.5×	0.011	FOXC1
positive regulation of hematopoietic progenitor cell differentiation	1	1123.5×	0.011	FOXC1
response to hydrostatic pressure	1	842.6×	0.011	COL18A1
paraxial mesoderm formation	1	674.1×	0.011	FOXC1
regulation of entry of bacterium into host cell	1	674.1×	0.011	EXOC2
neural tube patterning	1	561.7×	0.011	IFT140
mesenchymal cell development	1	481.5×	0.011	FOXC1
glycosaminoglycan metabolic process	1	481.5×	0.011	FOXC1
lacrimal gland development	1	421.3×	0.011	FOXC1
maintenance of lens transparency	1	421.3×	0.011	FOXC1
regulation of organ growth	1	421.3×	0.011	FOXC1
lymph vessel development	1	374.5×	0.011	FOXC1
primordial germ cell migration	1	374.5×	0.011	FOXC1
homocysteine metabolic process	1	374.5×	0.011	BPHL
obsolete vesicle tethering involved in exocytosis	1	374.5×	0.011	EXOC2
heart development	2	31.5×	0.011	FOXC1, IFT140
angiogenesis	2	25.0×	0.011	FOXC1, COL18A1
embryonic camera-type eye development	1	240.7×	0.015	IFT140
positive regulation of DNA binding	1	240.7×	0.015	FOXC1
intraciliary retrograde transport	1	224.7×	0.015	IFT140
endothelial cell morphogenesis	1	210.7×	0.015	COL18A1
photoreceptor cell outer segment organization	1	210.7×	0.015	IFT140
vascular endothelial growth factor signaling pathway	1	210.7×	0.015	FOXC1
cellular response to chemokine	1	198.3×	0.015	FOXC1
amino acid metabolic process	1	160.5×	0.016	BPHL

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 5

Druggability breadth: 2 of 5 evidence-associated genes (40%) 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
COL18A1	0	0
EXOC2	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: 5; 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	1	EXOC2
E	Difficult family or no structure, no drug	4	FOXC1, BPHL, COL18A1, IFT140

Undrugged target profiles

5 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	—
COL18A1	0	—
EXOC2	0	—
IFT140	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.