Axenfeld-Rieger syndrome type 1

Summary

Axenfeld-Rieger syndrome type 1 (MONDO:0008386) is a disease caused by PITX2 (GenCC Definitive), with 5 cohort genes.

At a glance

• Causal gene: PITX2 (GenCC Definitive)
• Cohort genes: 5
• ClinVar variants: 165

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Axenfeld-Rieger syndrome type 1
Mondo ID	MONDO:0008386
OMIM	180500
DOID	DOID:0110120
NCIT	C75015
UMLS	C3714873
MedGen	811487
GARD	0010281
Is cancer (heuristic)	no

Also known as: Axenfeld-Rieger syndrome caused by mutation in PITX2 · Axenfeld-Rieger syndrome type 1 · Axenfeld-Rieger syndrome, type 1 · PITX2 Axenfeld-Rieger syndrome · RIEG1 · Rieger syndrome type 1

Data availability: 165 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 1

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

165 retrieved; paginated sample, class counts are floors:

56 uncertain significance, 50 pathogenic, 14 conflicting classifications of pathogenicity, 12 likely pathogenic, 12 benign/likely benign, 11 likely benign, 6 pathogenic/likely pathogenic, 4 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
375444	GRCh37/hg19 4q25(chr4:111528916-111888401)x1	ENPEP	Pathogenic	no assertion criteria provided
1071052	NM_000325.6(PITX2):c.286C>T (p.Arg96Trp)	PITX2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1398374	NM_000325.6(PITX2):c.316G>T (p.Glu106Ter)	PITX2	Pathogenic	criteria provided, single submitter
1449912	NM_000325.6(PITX2):c.522C>G (p.Tyr174Ter)	PITX2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1455159	NM_000325.6(PITX2):c.700_716dup (p.Thr239_Gly240insCysProGlnGlnTer)	PITX2	Pathogenic	criteria provided, single submitter
1456258	NC_000004.11:g.(?111539281)(111554154_?)del	PITX2	Pathogenic	criteria provided, single submitter
1458040	NM_000325.6(PITX2):c.448_449del (p.Arg150fs)	PITX2	Pathogenic	criteria provided, multiple submitters, no conflicts
1693121	NM_000325.6(PITX2):c.220C>T (p.Gln74Ter)	PITX2	Pathogenic	criteria provided, single submitter
1693122	NM_000325.6(PITX2):c.503_506del (p.Asn168fs)	PITX2	Pathogenic	criteria provided, single submitter
1693123	NM_000325.6(PITX2):c.515del (p.Gln172fs)	PITX2	Pathogenic	criteria provided, multiple submitters, no conflicts
1693124	NM_000325.6(PITX2):c.525del (p.Asp175fs)	PITX2	Pathogenic	criteria provided, single submitter
1693125	NM_000325.6(PITX2):c.557G>A (p.Trp186Ter)	PITX2	Pathogenic	criteria provided, single submitter
1693126	NM_000325.6(PITX2):c.663del (p.Asn222fs)	PITX2	Pathogenic	criteria provided, single submitter
1693127	NM_000325.6(PITX2):c.790del (p.Val264fs)	PITX2	Pathogenic	criteria provided, single submitter
1693128	NM_000325.6(PITX2):c.791_792dup (p.Pro265fs)	PITX2	Pathogenic	criteria provided, single submitter
1693129	NM_000325.6(PITX2):c.867_889del (p.Ser290fs)	PITX2	Pathogenic	criteria provided, single submitter
1693130	NM_000325.6(PITX2):c.293dup (p.His98fs)	PITX2	Pathogenic	criteria provided, single submitter
1693133	NM_000325.6(PITX2):c.417G>T (p.Trp139Cys)	PITX2	Pathogenic	criteria provided, single submitter
1693135	NM_000325.6(PITX2):c.428G>C (p.Arg143Pro)	PITX2	Pathogenic	criteria provided, single submitter
1693136	NM_000325.6(PITX2):c.302_303del (p.Ser101fs)	PITX2	Pathogenic	criteria provided, single submitter
1693146	NM_000325.6(PITX2):c.384G>A (p.Trp128Ter)	PITX2	Pathogenic	criteria provided, single submitter
1693156	NM_000325.6(PITX2):c.412-1G>A	PITX2	Pathogenic	criteria provided, single submitter
2019449	NM_000325.6(PITX2):c.470_476dup (p.Cys159Ter)	PITX2	Pathogenic	criteria provided, single submitter
2203569	NM_000325.6(PITX2):c.350C>G (p.Pro117Arg)	PITX2	Pathogenic	criteria provided, single submitter
2942566	NM_000325.6(PITX2):c.376G>C (p.Ala126Pro)	PITX2	Pathogenic	criteria provided, single submitter
2950646	NM_000325.6(PITX2):c.250G>T (p.Glu84Ter)	PITX2	Pathogenic	criteria provided, single submitter
30197	NM_000325.6(PITX2):c.421A>G (p.Lys141Glu)	PITX2	Pathogenic	no assertion criteria provided
375436	NM_000325.6(PITX2):c.343_364del (p.Arg115fs)	PITX2	Pathogenic	no assertion criteria provided
375437	NM_000325.6(PITX2):c.350C>T (p.Pro117Leu)	PITX2	Pathogenic	no assertion criteria provided
375440	NM_000325.6(PITX2):c.714_735del (p.Thr239fs)	PITX2	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 15 · Orphanet: 8 · 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
PITX2	Definitive	Autosomal dominant	Axenfeld-Rieger syndrome type 1	15

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PITX2	Orphanet:334	Hereditary atrial fibrillation
PITX2	Orphanet:708	Peters anomaly
PITX2	Orphanet:782	Axenfeld-Rieger syndrome
PITX2	Orphanet:91481	Ring dermoid of cornea
PITX2	Orphanet:91483	Rieger anomaly
PITX2	Orphanet:98978	Axenfeld anomaly
ALPK1	Orphanet:313800	Retinal dystrophy-optic nerve edema-splenomegaly-anhidrosis-migraine headache syndrome
PRDM5	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
PITX2	HGNC:9005	ENSG00000164093	Q99697	Pituitary homeobox 2	gencc,clinvar
ALPK1	HGNC:20917	ENSG00000073331	Q96QP1	Alpha-protein kinase 1	clinvar
ADH1A	HGNC:249	ENSG00000187758	P07327	Alcohol dehydrogenase 1A	clinvar
ENPEP	HGNC:3355	ENSG00000138792	Q07075	Glutamyl aminopeptidase	clinvar
PRDM5	HGNC:9349	ENSG00000138738	Q9NQX1	PR domain zinc finger protein 5	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PITX2	Pituitary homeobox 2	May play a role in myoblast differentiation.
ALPK1	Alpha-protein kinase 1	Serine/threonine-protein kinase that detects bacterial pathogen-associated molecular pattern metabolites (PAMPs) and initiates an innate immune response, a critical step for pathogen elimination and engagement of adaptive immunity.
ADH1A	Alcohol dehydrogenase 1A	Alcohol dehydrogenase.
ENPEP	Glutamyl aminopeptidase	Regulates central hypertension through its calcium-modulated preference to cleave N-terminal acidic residues from peptides such as angiotensin II.
PRDM5	PR domain zinc finger protein 5	Sequence-specific DNA-binding transcription factor.

Protein-family classification

Druggable: 2 · Difficult: 2 · Unknown: 1 · Druggable fraction: 0.4

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
Protease	1	7.3×	0.224
Kinase	1	5.5×	0.224
Transcription factor	2	3.3×	0.224
Other/Unknown	1	0.4×	0.983

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PITX2	Transcription factor	no		HD, OAR_dom, Homeodomain-like_sf
ALPK1	Kinase	yes		a-kinase_dom, Kinase-like_dom_sf, ALPK1
ADH1A	Other/Unknown	no		ADH_Zn_CS, GroES-like_sf, ADH-like_C
ENPEP	Protease	yes	3.4.11.7	Peptidase_M1, Peptidase_M1_dom, ERAP1-like_C_dom
PRDM5	Transcription factor	no		SET_dom, Znf_C2H2_type, Znf_PRDM5-like

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
male germ line stem cell (sensu Vertebrata) in testis	2
biceps brachii	1
gingiva	1
gingival epithelium	1
blood	1
buccal mucosa cell	1
tendon of biceps brachii	1
liver	1
right lobe of liver	1
jejunal mucosa	1
metanephric glomerulus	1
renal glomerulus	1
calcaneal tendon	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PITX2	166	broad	marker	gingiva, biceps brachii, gingival epithelium
ALPK1	245	ubiquitous	marker	buccal mucosa cell, tendon of biceps brachii, blood
ADH1A	160	tissue_specific	marker	right lobe of liver, liver, male germ line stem cell (sensu Vertebrata) in testis
ENPEP	215	broad	marker	jejunal mucosa, renal glomerulus, metanephric glomerulus
PRDM5	206	ubiquitous	marker	calcaneal tendon, sural nerve, 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
PITX2	2,389
ADH1A	2,041
ENPEP	1,801
PRDM5	1,303
ALPK1	446

Structural data

PDB: 5 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ENPEP	Q07075	7
PITX2	Q99697	3
ALPK1	Q96QP1	3
ADH1A	P07327	2
PRDM5	Q9NQX1	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 39. Enrichment computed across 5 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
Abacavir metabolism	1	713.8×	0.027	ADH1A
TFAP2 (AP-2) family regulates transcription of other transcription factors	1	713.8×	0.027	PITX2
Abacavir ADME	1	356.9×	0.033	ADH1A
Alpha-protein kinase 1 signaling pathway	1	259.6×	0.033	ALPK1
Ethanol oxidation	1	237.9×	0.033	ADH1A
Metabolism of Angiotensinogen to Angiotensins	1	158.6×	0.035	ENPEP
RA biosynthesis pathway	1	119.0×	0.035	ADH1A
Signaling by Retinoic Acid	1	102.0×	0.035	ADH1A
TAK1-dependent IKK and NF-kappa-B activation	1	75.1×	0.035	ALPK1
Peptide hormone metabolism	1	68.0×	0.035	ENPEP
Interleukin-1 family signaling	1	68.0×	0.035	ALPK1
Drug ADME	1	57.1×	0.035	ADH1A
Phase I - Functionalization of compounds	1	54.9×	0.035	ADH1A
Toll Like Receptor 10 (TLR10) Cascade	1	53.9×	0.035	ALPK1
Toll Like Receptor 5 (TLR5) Cascade	1	53.9×	0.035	ALPK1
MyD88 cascade initiated on plasma membrane	1	51.0×	0.035	ALPK1
Toll Like Receptor 3 (TLR3) Cascade	1	48.4×	0.035	ALPK1
TRIF (TICAM1)-mediated TLR4 signaling	1	47.6×	0.035	ALPK1
TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation	1	47.6×	0.035	ALPK1
MyD88 dependent cascade initiated on endosome	1	47.6×	0.035	ALPK1
MyD88-independent TLR4 cascade	1	46.0×	0.035	ALPK1
Toll Like Receptor 7/8 (TLR7/8) Cascade	1	46.0×	0.035	ALPK1
Toll Like Receptor 9 (TLR9) Cascade	1	43.9×	0.035	ALPK1
Toll Like Receptor TLR6:TLR2 Cascade	1	43.9×	0.035	ALPK1
Toll Like Receptor 2 (TLR2) Cascade	1	43.3×	0.035	ALPK1
Toll Like Receptor TLR1:TLR2 Cascade	1	42.0×	0.035	ALPK1
MyD88:MAL(TIRAP) cascade initiated on plasma membrane	1	38.1×	0.038	ALPK1
Toll Like Receptor 4 (TLR4) Cascade	1	32.8×	0.040	ALPK1
Biological oxidations	1	32.4×	0.040	ADH1A
Toll-like Receptor Cascades	1	31.0×	0.040	ALPK1

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
subthalamic nucleus development	1	3370.4×	0.005	PITX2
superior vena cava morphogenesis	1	3370.4×	0.005	PITX2
hypothalamus cell migration	1	1685.2×	0.005	PITX2
prolactin secreting cell differentiation	1	1685.2×	0.005	PITX2
left lung morphogenesis	1	1685.2×	0.005	PITX2
pulmonary vein morphogenesis	1	1685.2×	0.005	PITX2
cell proliferation involved in outflow tract morphogenesis	1	1685.2×	0.005	PITX2
pulmonary myocardium development	1	1123.5×	0.005	PITX2
vascular associated smooth muscle cell differentiation	1	1123.5×	0.005	PITX2
deltoid tuberosity development	1	1123.5×	0.005	PITX2
endodermal digestive tract morphogenesis	1	1123.5×	0.005	PITX2
atrioventricular valve development	1	842.6×	0.006	PITX2
somatotropin secreting cell differentiation	1	842.6×	0.006	PITX2
regulation of systemic arterial blood pressure by renin-angiotensin	1	674.1×	0.007	ENPEP
extraocular skeletal muscle development	1	561.7×	0.007	PITX2
embryonic heart tube left/right pattern formation	1	561.7×	0.007	PITX2
cardiac neural crest cell migration involved in outflow tract morphogenesis	1	481.5×	0.007	PITX2
alcohol metabolic process	1	481.5×	0.007	ADH1A
atrial cardiac muscle tissue morphogenesis	1	481.5×	0.007	PITX2
hair cell differentiation	1	421.3×	0.007	PITX2
iris morphogenesis	1	374.5×	0.008	PITX2
regulation of extracellular matrix organization	1	374.5×	0.008	PRDM5
ventricular cardiac muscle cell development	1	306.4×	0.009	PITX2
angiotensin maturation	1	259.3×	0.010	ENPEP
glomerulus development	1	259.3×	0.010	ENPEP
embryonic camera-type eye development	1	240.7×	0.010	PITX2
left/right axis specification	1	240.7×	0.010	PITX2
peptide catabolic process	1	210.7×	0.011	ENPEP
embryonic digestive tract morphogenesis	1	187.2×	0.012	PITX2
cytoplasmic pattern recognition receptor signaling pathway	1	177.4×	0.012	ALPK1

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
PITX2	0	0
ALPK1	0	0
ADH1A	0	0
ENPEP	0	0
PRDM5	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
ADH1A	18	Binding:17, Functional:1
ENPEP	9	Binding:8, ADMET:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ENPEP	3.4.11.7	glutamyl aminopeptidase

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	2	ALPK1, ENPEP
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	PITX2, ADH1A, PRDM5

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)
PITX2	0	—
ALPK1	0	—
ADH1A	18	—
ENPEP	9	—
PRDM5	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.