Early-onset posterior polar cataract

Summary

Early-onset posterior polar cataract (MONDO:0020378) is a disease with 9 cohort genes.

At a glance

• Cohort genes: 9

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	early-onset posterior polar cataract
Mondo ID	MONDO:0020378
Orphanet	98993
UMLS	C0858617
MedGen	163646
GARD	0016889
Is cancer (heuristic)	no

Data availability: 8 GenCC gene-disease records.

Disease family

Classification path: human disease › disease by body system or component › disorder of orbital region › eye disorder › lens disorder › cataract › early-onset non-syndromic cataract › early-onset partial cataract › early-onset zonular cataract › cataract 16 multiple types › early-onset posterior polar cataract

Related subtypes (1): early-onset lamellar cataract

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

No tiered GWAS variants or ClinVar records for this disease.

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 76 · Orphanet: 28 · 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
CRYBA1	Definitive	Autosomal dominant	cataract 10 multiple types	7
EPHA2	Definitive	Autosomal dominant	cataract 6 multiple types	10
GJA3	Definitive	Autosomal dominant	cataract 14 multiple types	6
MIP	Definitive	Autosomal dominant	cataract 15 multiple types	10
TNPO1	Definitive	Autosomal dominant	cataract 15 multiple types	11
CHMP4B	Strong	Autosomal dominant	cataract 31 multiple types	5
CRYAB	Strong	Autosomal dominant	cataract 16 multiple types	16
PITX3	Strong	Autosomal dominant	cataract 11 multiple types	7
PANK4	Moderate	Autosomal dominant	cataract 49	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CHMP4B	Orphanet:441447	Early-onset posterior subcapsular cataract
CHMP4B	Orphanet:98993	Early-onset posterior polar cataract
PANK4	Orphanet:98993	Early-onset posterior polar cataract
CRYAB	Orphanet:154	Familial isolated dilated cardiomyopathy
CRYAB	Orphanet:280553	Fatal infantile hypertonic myofibrillar myopathy
CRYAB	Orphanet:399058	Alpha-B crystallin-related late-onset myopathy
CRYAB	Orphanet:441452	Early-onset lamellar cataract
CRYAB	Orphanet:98991	Early-onset nuclear cataract
CRYAB	Orphanet:98993	Early-onset posterior polar cataract
CRYBA1	Orphanet:441452	Early-onset lamellar cataract
CRYBA1	Orphanet:98985	Early-onset sutural cataract
CRYBA1	Orphanet:98991	Early-onset nuclear cataract
CRYBA1	Orphanet:98993	Early-onset posterior polar cataract
EPHA2	Orphanet:441447	Early-onset posterior subcapsular cataract
EPHA2	Orphanet:98991	Early-onset nuclear cataract
EPHA2	Orphanet:98993	Early-onset posterior polar cataract
EPHA2	Orphanet:98994	Total early-onset cataract
GJA3	Orphanet:98984	Pulverulent cataract
GJA3	Orphanet:98991	Early-onset nuclear cataract
GJA3	Orphanet:98993	Early-onset posterior polar cataract
MIP	Orphanet:441452	Early-onset lamellar cataract
MIP	Orphanet:98985	Early-onset sutural cataract
MIP	Orphanet:98989	Cerulean cataract
MIP	Orphanet:98991	Early-onset nuclear cataract
MIP	Orphanet:98993	Early-onset posterior polar cataract
MIP	Orphanet:98994	Total early-onset cataract
PITX3	Orphanet:162	Congenital cataract-anterior segment dysgenesis syndrome
PITX3	Orphanet:98993	Early-onset posterior polar cataract

Cohort genes → proteins

9 cohort genes, 9 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	9

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CHMP4B	HGNC:16171	ENSG00000101421	Q9H444	Charged multivesicular body protein 4b	gencc
PANK4	HGNC:19366	ENSG00000157881	Q9NVE7	4’-phosphopantetheine phosphatase	gencc
CRYAB	HGNC:2389	ENSG00000109846	P02511	Alpha-crystallin B chain	gencc
CRYBA1	HGNC:2394	ENSG00000108255	P05813	Beta-crystallin A3	gencc
EPHA2	HGNC:3386	ENSG00000142627	P29317	Ephrin type-A receptor 2	gencc
GJA3	HGNC:4277	ENSG00000121743	Q9Y6H8	Gap junction alpha-3 protein	gencc
TNPO1	HGNC:6401	ENSG00000083312	Q92973	Transportin-1	gencc
MIP	HGNC:7103	ENSG00000135517	P30301	Lens fiber major intrinsic protein	gencc
PITX3	HGNC:9006	ENSG00000107859	O75364	Pituitary homeobox 3	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CHMP4B	Charged multivesicular body protein 4b	Probable core component of the endosomal sorting required for transport complex III (ESCRT-III) which is involved in multivesicular bodies (MVBs) formation and sorting of endosomal cargo proteins into MVBs.
PANK4	4’-phosphopantetheine phosphatase	Phosphatase which shows a preference for 4’-phosphopantetheine and its oxidatively damaged forms (sulfonate or S-sulfonate), providing strong indirect evidence that the phosphatase activity pre-empts damage in the coenzyme A (CoA) pathway.
CRYAB	Alpha-crystallin B chain	May contribute to the transparency and refractive index of the lens.
CRYBA1	Beta-crystallin A3	Crystallins are the dominant structural components of the vertebrate eye lens.
EPHA2	Ephrin type-A receptor 2	Receptor tyrosine kinase which binds promiscuously membrane-bound ephrin-A family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells.
GJA3	Gap junction alpha-3 protein	Structural component of lens fiber gap junctions.
TNPO1	Transportin-1	Functions in nuclear protein import as nuclear transport receptor.
MIP	Lens fiber major intrinsic protein	Aquaporins form homotetrameric transmembrane channels, with each monomer independently mediating water transport across the plasma membrane along its osmotic gradient.
PITX3	Pituitary homeobox 3	Transcriptional regulator which is important for the differentiation and maintenance of meso-diencephalic dopaminergic (mdDA) neurons during development.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 7 · Druggable fraction: 0.11

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	3.1×	0.422
Other/Unknown	7	1.4×	0.422
Transcription factor	1	0.9×	0.687

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CHMP4B	Other/Unknown	no		Snf7_fam
PANK4	Other/Unknown	no		ARMT1-like_metal-bd, Type_II_PanK, PanK_long
CRYAB	Other/Unknown	no		Alpha-crystallin/sHSP_animal, A-crystallin/Hsp20_dom, Alpha-crystallin_N
CRYBA1	Other/Unknown	no		Beta/gamma_crystallin, G_crystallin-like, Beta/Gamma-Crystallin
EPHA2	Kinase	yes	2.7.10.1	Prot_kinase_dom, EPH_LBD, Ser-Thr/Tyr_kinase_cat_dom
GJA3	Other/Unknown	no		Connexin, Connexin46, Connexin_N
TNPO1	Other/Unknown	no		Importin-beta_N, ARM-like, ARM-type_fold
MIP	Other/Unknown	no		MIP, MIP_CS, Aquaporin-like
PITX3	Transcription factor	no		HD, OAR_dom, Homeodomain-like_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)	9
unknown	0

Top tissues across cohort

Tissue	Cohort genes
primordial germ cell in gonad	3
left ventricle myocardium	2
male germ line stem cell (sensu Vertebrata) in testis	2
ileal mucosa	1
tibialis anterior	1
upper arm skin	1
apex of heart	1
blood	1
right hemisphere of cerebellum	1
cardiac ventricle	1
middle frontal gyrus	1
lens of camera-type eye	1
esophagus mucosa	1
lower esophagus mucosa	1
pharyngeal mucosa	1
heart right ventricle	1
myocardium	1
caput epididymis	1
cauda epididymis	1
corpus epididymis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CHMP4B	259	ubiquitous	marker	ileal mucosa, upper arm skin, tibialis anterior
PANK4	134	ubiquitous	yes	apex of heart, right hemisphere of cerebellum, blood
CRYAB	289	ubiquitous	marker	middle frontal gyrus, left ventricle myocardium, cardiac ventricle
CRYBA1	138	tissue_specific	yes	lens of camera-type eye, primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis
EPHA2	224	ubiquitous	marker	lower esophagus mucosa, esophagus mucosa, pharyngeal mucosa
GJA3	75	broad	yes	left ventricle myocardium, heart right ventricle, myocardium
TNPO1	295	ubiquitous	marker	corpus epididymis, caput epididymis, cauda epididymis
MIP	91	tissue_specific	yes	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, right lobe of liver
PITX3	64	tissue_specific	yes	hindlimb stylopod muscle, triceps brachii, primordial germ cell in gonad

Protein interactions among cohort

Intra-cohort edges: 8.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
EPHA2	4,794
CRYAB	3,368
TNPO1	3,147
CHMP4B	3,043
MIP	2,496
PANK4	1,249
PITX3	1,186
CRYBA1	925
GJA3	449

Intra-cohort edges

A	B	Sources
CHMP4B	CRYBA1	string_interaction
CHMP4B	GJA3	string_interaction
CRYAB	CRYBA1	string_interaction
CRYAB	PITX3	string_interaction
CRYBA1	GJA3	string_interaction
CRYBA1	PITX3	string_interaction
GJA3	MIP	string_interaction
GJA3	PITX3	string_interaction

Structural data

PDB: 4 · AlphaFold-only: 5 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
EPHA2	P29317	103
CRYAB	P02511	21
TNPO1	Q92973	21
CHMP4B	Q9H444	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MIP	P30301	91.08
CRYBA1	P05813	88.27
PANK4	Q9NVE7	87.21
GJA3	Q9Y6H8	69.53
PITX3	O75364	63.71

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 30. Enrichment computed across 9 evidence-associated genes (7 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 7 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Passive transport by Aquaporins	1	125.5×	0.040	MIP
Translation of Replicase and Assembly of the Replication Transcription Complex	1	125.5×	0.040	CHMP4B
Translation of Replicase and Assembly of the Replication Transcription Complex	1	116.5×	0.040	CHMP4B
Vitamin B5 (pantothenate) metabolism	1	108.8×	0.040	PANK4
Tristetraprolin (TTP, ZFP36) binds and destabilizes mRNA	1	90.6×	0.040	TNPO1
Pyroptosis	1	60.4×	0.040	CHMP4B
Budding and maturation of HIV virion	1	58.3×	0.040	CHMP4B
Postmitotic nuclear pore complex (NPC) reformation	1	58.3×	0.040	TNPO1
EPHA-mediated growth cone collapse	1	54.4×	0.040	EPHA2
Aquaporin-mediated transport	1	52.6×	0.040	MIP
Endosomal Sorting Complex Required For Transport (ESCRT)	1	52.6×	0.040	CHMP4B
Sealing of the nuclear envelope (NE) by ESCRT-III	1	49.4×	0.040	CHMP4B
Late endosomal microautophagy	1	46.6×	0.040	CHMP4B
HSF1-dependent transactivation	1	45.3×	0.040	CRYAB
Gap junction assembly	1	41.8×	0.040	GJA3
RHOV GTPase cycle	1	40.8×	0.040	EPHA2
RHOU GTPase cycle	1	39.8×	0.040	EPHA2
RND1 GTPase cycle	1	37.9×	0.040	EPHA2
RND3 GTPase cycle	1	37.1×	0.040	EPHA2
RND2 GTPase cycle	1	37.1×	0.040	EPHA2
EPH-ephrin mediated repulsion of cells	1	31.4×	0.045	EPHA2
Intraflagellar transport	1	28.6×	0.047	TNPO1
EPH-Ephrin signaling	1	23.6×	0.054	EPHA2
RHOG GTPase cycle	1	21.2×	0.058	EPHA2
RAC2 GTPase cycle	1	18.1×	0.065	EPHA2
RAC3 GTPase cycle	1	17.0×	0.066	EPHA2
Macroautophagy	1	16.5×	0.066	CHMP4B
HCMV Late Events	1	14.1×	0.074	CHMP4B
RAC1 GTPase cycle	1	8.7×	0.113	EPHA2
Transport of small molecules	1	3.6×	0.247	MIP

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 9 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
lens development in camera-type eye	4	166.4×	7e-07	CRYAB, CRYBA1, MIP, PITX3
gap junction-mediated intercellular transport	2	624.1×	2e-04	GJA3, MIP
maintenance of lens transparency	2	468.1×	3e-04	CHMP4B, MIP
visual perception	3	26.5×	0.005	CRYBA1, GJA3, MIP
microtubule polymerization or depolymerization	1	1872.4×	0.012	CRYAB
notochord cell development	1	1872.4×	0.012	EPHA2
negative regulation of gliogenesis	1	936.2×	0.013	PITX3
axial mesoderm formation	1	936.2×	0.013	EPHA2
response to methamphetamine hydrochloride	1	936.2×	0.013	PITX3
positive regulation of cell proliferation in midbrain	1	936.2×	0.013	PITX3
cellular response to glial cell derived neurotrophic factor	1	936.2×	0.013	PITX3
notochord formation	1	624.1×	0.015	EPHA2
negative regulation of intracellular transport	1	624.1×	0.015	CRYAB
negative regulation of lymphangiogenesis	1	624.1×	0.015	EPHA2
cAMP metabolic process	1	468.1×	0.019	EPHA2
obsolete ubiquitin-independent protein catabolic process via the multivesicular body sorting pathway	1	374.5×	0.020	CHMP4B
pericyte cell differentiation	1	374.5×	0.020	EPHA2
regulation of programmed cell death	1	312.1×	0.021	CRYAB
regulation of blood vessel endothelial cell migration	1	312.1×	0.021	EPHA2
apoptotic process involved in morphogenesis	1	312.1×	0.021	CRYAB
blood vessel endothelial cell proliferation involved in sprouting angiogenesis	1	267.5×	0.021	EPHA2
pantothenate metabolic process	1	234.1×	0.021	PANK4
negative regulation of chemokine production	1	234.1×	0.021	EPHA2
lens fiber cell morphogenesis	1	234.1×	0.021	EPHA2
regulation of lamellipodium assembly	1	208.1×	0.021	EPHA2
viral budding	1	208.1×	0.021	CHMP4B
positive regulation of anoikis	1	208.1×	0.021	CRYBA1
tubulin complex assembly	1	187.2×	0.021	CRYAB
homotypic cell-cell adhesion	1	187.2×	0.021	MIP
positive regulation of bicellular tight junction assembly	1	187.2×	0.021	EPHA2

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 8

Druggability breadth: 4 of 9 evidence-associated genes (44%) 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
EPHA2	PONATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
EPHA2	50	4
CHMP4B	0	0
PANK4	0	0
CRYAB	0	0
CRYBA1	0	0
GJA3	0	0
TNPO1	0	0
MIP	0	0
PITX3	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PONATINIB	4	EPHA2
FEDRATINIB	4	EPHA2
TIVOZANIB	4	EPHA2
SORAFENIB	4	EPHA2
DASATINIB ANHYDROUS	4	EPHA2
REGORAFENIB	4	EPHA2
CABOZANTINIB	4	EPHA2
VANDETANIB	4	EPHA2
NILOTINIB	4	EPHA2
BOSUTINIB	4	EPHA2
TOVORAFENIB	4	EPHA2
NINTEDANIB	4	EPHA2
DASATINIB	4	EPHA2
CRIZOTINIB	4	EPHA2
SARACATINIB	3	EPHA2
LINIFANIB	3	EPHA2
TESEVATINIB	3	EPHA2
ALVOCIDIB	3	EPHA2
ALISERTIB	3	EPHA2
LESTAURTINIB	3	EPHA2
DORAMAPIMOD	2	EPHA2
NEFLAMAPIMOD	2	EPHA2
FORETINIB	2	EPHA2
ILORASERTIB	2	EPHA2
CEP-32496	2	EPHA2
BAFETINIB	2	EPHA2
SAPITINIB	2	EPHA2
OSI-632	2	EPHA2
GOLVATINIB	2	EPHA2
PEXMETINIB	2	EPHA2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
EPHA2	567	Binding:565, Functional:1, ADMET:1
CRYAB	13	Binding:13
TNPO1	7	Binding:7
CHMP4B	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
EPHA2	2.7.10.1	receptor protein-tyrosine kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
EPHA2	567

Pharmacogenomics

Cohort genes with a PharmGKB record: 9; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

30 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)
PONATINIB	4	EPHA2
FEDRATINIB	4	EPHA2
TIVOZANIB	4	EPHA2
SORAFENIB	4	EPHA2
DASATINIB ANHYDROUS	4	EPHA2
REGORAFENIB	4	EPHA2
CABOZANTINIB	4	EPHA2
VANDETANIB	4	EPHA2
NILOTINIB	4	EPHA2
BOSUTINIB	4	EPHA2
TOVORAFENIB	4	EPHA2
NINTEDANIB	4	EPHA2
DASATINIB	4	EPHA2
CRIZOTINIB	4	EPHA2
SARACATINIB	3	EPHA2
LINIFANIB	3	EPHA2
TESEVATINIB	3	EPHA2
ALVOCIDIB	3	EPHA2
ALISERTIB	3	EPHA2
LESTAURTINIB	3	EPHA2
DORAMAPIMOD	2	EPHA2
NEFLAMAPIMOD	2	EPHA2
FORETINIB	2	EPHA2
ILORASERTIB	2	EPHA2
CEP-32496	2	EPHA2
BAFETINIB	2	EPHA2
SAPITINIB	2	EPHA2
OSI-632	2	EPHA2
GOLVATINIB	2	EPHA2
PEXMETINIB	2	EPHA2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	EPHA2
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	8	CHMP4B, PANK4, CRYAB, CRYBA1, GJA3, TNPO1, MIP, PITX3

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CHMP4B	1	—
PANK4	0	—
CRYAB	13	—
CRYBA1	0	—
GJA3	0	—
TNPO1	7	—
MIP	0	—
PITX3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.