Cataract 23

Summary

Cataract 23 (MONDO:0012489) is a disease caused by CRYBA4 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: CRYBA4 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 68

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	cataract 23
Mondo ID	MONDO:0012489
OMIM	610425
DOID	DOID:0110271
UMLS	C3808012
MedGen	814342
GARD	0024869
Is cancer (heuristic)	no

Also known as: cataract 23 · cataract type 23 · CRYBA4 early-onset non-syndromic cataract · CTRCT23 · early-onset non-syndromic cataract caused by mutation in CRYBA4

Data availability: 68 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 › early-onset non-syndromic cataract › cataract 23

Related subtypes (28): cataract 32 multiple types, cataract 8 multiple types, cataract 42, cataract 20 multiple types, cataract 6 multiple types, cataract 13 with adult I phenotype, cataract 5 multiple types, cataract 46 juvenile-onset, cataract 40, cataract 10 multiple types, cataract 14 multiple types, pulverulent cataract, cataract 31 multiple types, cataract 26 multiple types, cataract 22 multiple types, cataract 21 multiple types, cataract 11 multiple types, cataract 33, cataract 17 multiple types, cataract 38, cataract 39 multiple types, cataract 15 multiple types, cataract 19 multiple types, cataract 43, cataract 44, cataract 45, early-onset partial cataract, total early-onset 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

ClinVar germline variants

68 retrieved; paginated sample, class counts are floors:

26 uncertain significance, 20 likely benign, 8 benign, 5 benign/likely benign, 4 conflicting classifications of pathogenicity, 3 pathogenic, 2 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
16946	NM_001886.3(CRYBA4):c.281T>C (p.Phe94Ser)	CRYBA4	Pathogenic	no assertion criteria provided
16947	NM_001886.3(CRYBA4):c.206T>C (p.Leu69Pro)	CRYBA4	Pathogenic	no assertion criteria provided
427575	NM_001886.3(CRYBA4):c.190G>T (p.Gly64Trp)	CRYBA4	Pathogenic	no assertion criteria provided
1343240	NM_001886.3(CRYBA4):c.277T>C (p.Ser93Pro)	CRYBA4	Likely pathogenic	criteria provided, single submitter
965311	NM_001886.3(CRYBA4):c.198_200del (p.Gln66_Tyr67delinsHis)	CRYBA4	Likely pathogenic	criteria provided, single submitter
1477377	NM_001886.3(CRYBA4):c.148del (p.Val49_Leu50insTer)	CRYBA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2377228	NM_001886.3(CRYBA4):c.89C>T (p.Thr30Met)	CRYBA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
732871	NM_001886.3(CRYBA4):c.61G>A (p.Gly21Ser)	CRYBA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
856281	NM_001886.3(CRYBA4):c.262G>T (p.Ala88Ser)	CRYBA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1024884	NM_001886.3(CRYBA4):c.214G>A (p.Gly72Ser)	CRYBA4	Uncertain significance	criteria provided, single submitter
1027167	NM_001886.3(CRYBA4):c.26C>T (p.Ala9Val)	CRYBA4	Uncertain significance	criteria provided, single submitter
1399289	NM_001886.3(CRYBA4):c.300+2T>C	CRYBA4	Uncertain significance	criteria provided, single submitter
2013236	NM_001886.3(CRYBA4):c.442G>T (p.Ala148Ser)	CRYBA4	Uncertain significance	criteria provided, single submitter
2020622	NM_001886.3(CRYBA4):c.169T>A (p.Phe57Ile)	CRYBA4	Uncertain significance	criteria provided, single submitter
2040983	NM_001886.3(CRYBA4):c.34T>A (p.Trp12Arg)	CRYBA4	Uncertain significance	criteria provided, single submitter
2847247	NM_001886.3(CRYBA4):c.300+1del	CRYBA4	Uncertain significance	criteria provided, single submitter
2863146	NM_001886.3(CRYBA4):c.211C>T (p.Arg71Ter)	CRYBA4	Uncertain significance	criteria provided, single submitter
3019176	NM_001886.3(CRYBA4):c.504C>G (p.His168Gln)	CRYBA4	Uncertain significance	criteria provided, single submitter
3381932	NM_001886.3(CRYBA4):c.169T>C (p.Phe57Leu)	CRYBA4	Uncertain significance	criteria provided, single submitter
3667958	NM_001886.3(CRYBA4):c.331G>A (p.Glu111Lys)	CRYBA4	Uncertain significance	criteria provided, single submitter
3704651	NM_001886.3(CRYBA4):c.158C>T (p.Ala53Val)	CRYBA4	Uncertain significance	criteria provided, single submitter
3715282	NM_001886.3(CRYBA4):c.219A>C (p.Glu73Asp)	CRYBA4	Uncertain significance	criteria provided, single submitter
4712076	NM_001886.3(CRYBA4):c.579_580delinsTT (p.Arg193_Ile194delinsSerPhe)	CRYBA4	Uncertain significance	criteria provided, single submitter
4714941	NM_001886.3(CRYBA4):c.236C>A (p.Ala79Asp)	CRYBA4	Uncertain significance	criteria provided, single submitter
4730944	NM_001886.3(CRYBA4):c.284G>C (p.Arg95Pro)	CRYBA4	Uncertain significance	criteria provided, single submitter
4810247	NM_001886.3(CRYBA4):c.217G>A (p.Glu73Lys)	CRYBA4	Uncertain significance	criteria provided, single submitter
4847004	NM_001886.3(CRYBA4):c.386T>C (p.Leu129Pro)	CRYBA4	Uncertain significance	criteria provided, single submitter
566141	NM_001886.3(CRYBA4):c.352A>G (p.Lys118Glu)	CRYBA4	Uncertain significance	criteria provided, single submitter
658406	NM_001886.3(CRYBA4):c.65T>C (p.Phe22Ser)	CRYBA4	Uncertain significance	criteria provided, multiple submitters, no conflicts
661895	NM_001886.3(CRYBA4):c.227G>C (p.Ser76Thr)	CRYBA4	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 2 · 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
CRYBA4	Definitive	Autosomal dominant	cataract 23	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CRYBA4	Orphanet:1377	Cataract-microcornea syndrome
CRYBA4	Orphanet:441452	Early-onset lamellar cataract

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
CRYBA4	HGNC:2396	ENSG00000196431	P53673	Beta-crystallin A4	gencc,clinvar
SEZ6L	HGNC:10763	ENSG00000100095	Q9BYH1	Seizure 6-like protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CRYBA4	Beta-crystallin A4	Crystallins are the dominant structural components of the vertebrate eye lens.
SEZ6L	Seizure 6-like protein	May contribute to specialized endoplasmic reticulum functions in neurons.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Complement	1	134.0×	0.015
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CRYBA4	Other/Unknown	no		Beta/gamma_crystallin, G_crystallin-like, Beta/Gamma-Crystallin
SEZ6L	Complement	yes		Sushi_SCR_CCP_dom, CUB_dom, Sperma_CUB_dom_sf

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
frontal pole	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1
endothelial cell	1
ganglionic eminence	1
lateral nuclear group of thalamus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CRYBA4	72	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, frontal pole
SEZ6L	167	broad	marker	ganglionic eminence, endothelial cell, lateral nuclear group of thalamus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SEZ6L	2,443
CRYBA4	601

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CRYBA4	P53673	1
SEZ6L	Q9BYH1	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. 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
Attenuation phase	1	407.9×	0.004	CRYBA4
HSF1 activation	1	380.7×	0.004	CRYBA4
HSF1-dependent transactivation	1	317.2×	0.004	CRYBA4
Regulation of HSF1-mediated heat shock response	1	139.3×	0.007	CRYBA4

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
cerebellar Purkinje cell layer development	1	766.0×	0.006	SEZ6L
synapse maturation	1	468.1×	0.006	SEZ6L
lens development in camera-type eye	1	187.2×	0.008	CRYBA4
camera-type eye development	1	179.3×	0.008	CRYBA4
adult locomotory behavior	1	150.5×	0.008	SEZ6L
visual perception	1	39.8×	0.025	CRYBA4

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CRYBA4	0	0
SEZ6L	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	1	SEZ6L
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	CRYBA4

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)
CRYBA4	0	—
SEZ6L	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.