Cataract 3 multiple types

Summary

Cataract 3 multiple types (MONDO:0011104) is a disease caused by CRYBB2 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: CRYBB2 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 65

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	cataract 3 multiple types
Mondo ID	MONDO:0011104
MeSH	C563294
OMIM	601547
DOID	DOID:0110269
UMLS	C1832175
MedGen	321901
GARD	0015335
Is cancer (heuristic)	no

Also known as: cataract (disease) caused by mutation in CRYBB2 · cataract 3, multiple types · CRYBB2 cataract (disease) · CTRCT3

Data availability: 65 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 › lens disorder › cataract › cataract 3 multiple types

Related subtypes (28): immature cataract, diabetic cataract, mature cataract, tetanic cataract, myotonic cataract, senile cataract, diabetes mellitus type 2 associated cataract, cataract 4 multiple types, cataract 29, cataract 1 multiple types, early-onset non-syndromic cataract, cataract 9 multiple types, cataract 28, cataract 18, cataract 12 multiple types, cataract 34 multiple types, cataract 36, bhaskar jagannathan syndrome, autosomal dominant cataract, craniostenosis cataract, Kozlowski Rafinski Klicharska syndrome, cataract 49, cataract 48, hypermature cataract, nuclear cataract, cortical cataract, cataract 2, multiple types, cataract 50 with or without glaucoma

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

65 retrieved; paginated sample, class counts are floors:

37 uncertain significance, 8 likely benign, 6 likely pathogenic, 5 pathogenic, 5 benign, 2 pathogenic/likely pathogenic, 1 conflicting classifications of pathogenicity, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1210294	NM_000496.3(CRYBB2):c.562C>T (p.Arg188Cys)	CRYBB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16949	NM_000496.3(CRYBB2):c.463C>T (p.Gln155Ter)	CRYBB2	Pathogenic	criteria provided, multiple submitters, no conflicts
16950	NM_000496.3(CRYBB2):c.471C>T (p.Pro157=)	CRYBB2	Pathogenic	no assertion criteria provided
1708137	NM_000496.3(CRYBB2):c.470C>T (p.Pro157Leu)	CRYBB2	Pathogenic	criteria provided, single submitter
242473	NM_000496.3(CRYBB2):c.355G>A (p.Gly119Arg)	CRYBB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
280142	NM_000496.3(CRYBB2):c.563G>A (p.Arg188His)	CRYBB2	Pathogenic	criteria provided, multiple submitters, no conflicts
4278000	NM_000496.3(CRYBB2):c.54+1G>A	CRYBB2	Pathogenic	criteria provided, single submitter
1210343	NM_000496.3(CRYBB2):c.173C>T (p.Pro58Leu)	CRYBB2	Likely pathogenic	criteria provided, single submitter
1803265	NM_000496.3(CRYBB2):c.427T>C (p.Ser143Pro)	CRYBB2	Likely pathogenic	criteria provided, single submitter
3897839	NM_000496.3(CRYBB2):c.230G>T (p.Gly77Val)	CRYBB2	Likely pathogenic	criteria provided, single submitter
463969	NM_000496.3(CRYBB2):c.161T>G (p.Val54Gly)	CRYBB2	Likely pathogenic	criteria provided, single submitter
463971	NM_000496.3(CRYBB2):c.551T>G (p.Val184Gly)	CRYBB2	Likely pathogenic	criteria provided, single submitter
952559	NM_000496.3(CRYBB2):c.446G>T (p.Gly149Val)	CRYBB2	Likely pathogenic	criteria provided, single submitter
1039314	NM_000496.3(CRYBB2):c.559G>A (p.Val187Met)	CRYBB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1038716	NM_000496.3(CRYBB2):c.173+1G>T	CRYBB2	Uncertain significance	criteria provided, single submitter
1297040	NM_000496.3(CRYBB2):c.565_572delinsTGCATCCA (p.Arg189_Arg191delinsCysIleHis)	CRYBB2	Uncertain significance	criteria provided, single submitter
1366735	NM_000496.3(CRYBB2):c.431T>A (p.Val144Glu)	CRYBB2	Uncertain significance	criteria provided, single submitter
1478290	NM_000496.3(CRYBB2):c.384T>G (p.Asp128Glu)	CRYBB2	Uncertain significance	criteria provided, single submitter
1709845	NM_000496.3(CRYBB2):c.359AGA[1] (p.Lys121del)	CRYBB2	Uncertain significance	criteria provided, single submitter
1718159	NM_000496.3(CRYBB2):c.479G>C (p.Arg160Pro)	CRYBB2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1947443	NM_000496.3(CRYBB2):c.174-12T>A	CRYBB2	Uncertain significance	criteria provided, single submitter
2085530	NM_000496.3(CRYBB2):c.389C>G (p.Pro130Arg)	CRYBB2	Uncertain significance	criteria provided, single submitter
2316067	NM_000496.3(CRYBB2):c.170G>A (p.Gly57Glu)	CRYBB2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2440573	NM_000496.3(CRYBB2):c.152C>T (p.Ser51Phe)	CRYBB2	Uncertain significance	criteria provided, single submitter
2440574	NM_000496.3(CRYBB2):c.112T>C (p.Cys38Arg)	CRYBB2	Uncertain significance	criteria provided, single submitter
2442008	NM_000496.3(CRYBB2):c.325A>T (p.Ile109Phe)	CRYBB2	Uncertain significance	criteria provided, single submitter
2628849	NM_000496.3(CRYBB2):c.433C>T (p.Arg145Trp)	CRYBB2	Uncertain significance	criteria provided, single submitter
2767531	NM_000496.3(CRYBB2):c.449+6T>A	CRYBB2	Uncertain significance	criteria provided, single submitter
2823220	NM_000496.3(CRYBB2):c.434G>C (p.Arg145Pro)	CRYBB2	Uncertain significance	criteria provided, single submitter
2833640	NM_000496.3(CRYBB2):c.292_293delinsCC (p.Arg98Pro)	CRYBB2	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · 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
CRYBB2	Definitive	Autosomal dominant	cataract 3 multiple types	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CRYBB2	Orphanet:1377	Cataract-microcornea syndrome
CRYBB2	Orphanet:441447	Early-onset posterior subcapsular cataract
CRYBB2	Orphanet:98984	Pulverulent cataract
CRYBB2	Orphanet:98985	Early-onset sutural cataract
CRYBB2	Orphanet:98989	Cerulean cataract
CRYBB2	Orphanet:98991	Early-onset nuclear cataract
CRYBB2	Orphanet:98994	Total early-onset cataract
RAG1	Orphanet:157949	Combined immunodeficiency with granulomatosis
RAG1	Orphanet:231154	Combined immunodeficiency due to partial RAG1 deficiency
RAG1	Orphanet:331206	Severe combined immunodeficiency due to complete RAG1/2 deficiency
RAG1	Orphanet:39041	Omenn syndrome

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CRYBB2	HGNC:2398	ENSG00000244752	P43320	Beta-crystallin B2	gencc,clinvar
RAG1	HGNC:9831	ENSG00000166349	P15918	V(D)J recombination-activating protein 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CRYBB2	Beta-crystallin B2	Crystallins are the dominant structural components of the vertebrate eye lens.
RAG1	V(D)J recombination-activating protein 1	Catalytic component of the RAG complex, a multiprotein complex that mediates the DNA cleavage phase during V(D)J recombination.

Protein-family classification

Druggable: 0 · Difficult: 1 · 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	1	4.1×	0.455
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CRYBB2	Other/Unknown	no		Beta/gamma_crystallin, G_crystallin-like, Beta/Gamma-Crystallin
RAG1	Transcription factor	no		Znf_RING, Znf_RING/FYVE/PHD, Znf_RING_CS

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gluteal muscle	1
trabecular bone tissue	1
triceps brachii	1
buccal mucosa cell	1
male germ line stem cell (sensu Vertebrata) in testis	1
thymus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CRYBB2	144	tissue_specific	yes	triceps brachii, gluteal muscle, trabecular bone tissue
RAG1	164	broad	marker	thymus, buccal mucosa cell, 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
RAG1	3,549
CRYBB2	548

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CRYBB2	P43320	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
RAG1	P15918	81.68

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 2 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Interleukin-7 signaling	1	317.2×	0.006	RAG1
MAPK6/MAPK4 signaling	1	135.9×	0.007	RAG1

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
pre-B cell allelic exclusion	1	2808.7×	0.004	RAG1
regulation of behavioral fear response	1	2106.5×	0.004	RAG1
V(D)J recombination	1	1053.2×	0.005	RAG1
negative regulation of thymocyte apoptotic process	1	842.6×	0.005	RAG1
T cell homeostasis	1	227.7×	0.010	RAG1
positive regulation of T cell differentiation	1	227.7×	0.010	RAG1
T cell differentiation in thymus	1	205.5×	0.010	RAG1
lens development in camera-type eye	1	187.2×	0.010	CRYBB2
DNA recombination	1	168.5×	0.010	RAG1
thymus development	1	168.5×	0.010	RAG1
visual learning	1	153.2×	0.010	RAG1
protein autoubiquitination	1	117.0×	0.012	RAG1
B cell differentiation	1	109.4×	0.012	RAG1
chromatin organization	1	49.6×	0.024	RAG1
adaptive immune response	1	42.1×	0.027	RAG1
visual perception	1	39.8×	0.027	CRYBB2
immune response	1	23.5×	0.042	RAG1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CRYBB2	0	0
RAG1	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
CRYBB2	9	Binding:9

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	2	CRYBB2, RAG1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CRYBB2	9	—
RAG1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.