Cataract 14 multiple types

Summary

Cataract 14 multiple types (MONDO:0011162) is a disease caused by GJA3 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: GJA3 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 218

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	cataract 14 multiple types
Mondo ID	MONDO:0011162
MeSH	C566608
OMIM	601885
DOID	DOID:0110253
UMLS	C1866078
MedGen	356152
GARD	0024777
Is cancer (heuristic)	no

Also known as: cataract 14, multiple types · CTRCT14 · early-onset non-syndromic cataract caused by mutation in GJA3 · GJA3 early-onset non-syndromic cataract

Data availability: 218 ClinVar variants · 3 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 14 multiple types

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, pulverulent cataract, cataract 31 multiple types, cataract 26 multiple types, cataract 22 multiple types, cataract 21 multiple types, cataract 23, 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

218 retrieved; paginated sample, class counts are floors:

121 uncertain significance, 34 benign, 25 likely pathogenic, 10 likely benign, 9 pathogenic/likely pathogenic, 9 conflicting classifications of pathogenicity, 6 benign/likely benign, 4 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1184602	NM_021954.4(GJA3):c.184G>A (p.Glu62Lys)	GJA3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1481592	NM_021954.4(GJA3):c.226C>T (p.Arg76Cys)	GJA3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16979	NM_021954.4(GJA3):c.1137dup (p.Ser380fs)	GJA3	Pathogenic	criteria provided, single submitter
2028307	NM_021954.4(GJA3):c.609C>A (p.Phe203Leu)	GJA3	Pathogenic	criteria provided, single submitter
217339	NM_021954.4(GJA3):c.176C>T (p.Pro59Leu)	GJA3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
252944	NM_021954.4(GJA3):c.56C>T (p.Thr19Met)	GJA3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2735992	NM_021954.4(GJA3):c.7G>T (p.Asp3Tyr)	GJA3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3064923	NM_021954.4(GJA3):c.175C>G (p.Pro59Ala)	GJA3	Pathogenic	criteria provided, single submitter
3253681	NM_021954.4(GJA3):c.139G>A (p.Asp47Asn)	GJA3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3253713	NM_021954.4(GJA3):c.64G>A (p.Gly22Ser)	GJA3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4277287	NM_021954.4(GJA3):c.140A>G (p.Asp47Gly)	GJA3	Pathogenic	criteria provided, single submitter
50945	NM_021954.4(GJA3):c.427G>A (p.Gly143Arg)	GJA3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
639312	NM_021954.4(GJA3):c.130G>A (p.Val44Met)	GJA3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1184603	NM_021954.4(GJA3):c.148T>C (p.Ser50Pro)	GJA3	Likely pathogenic	criteria provided, single submitter
1345145	NM_021954.4(GJA3):c.178G>A (p.Gly60Ser)	GJA3	Likely pathogenic	criteria provided, single submitter
1474368	NM_021954.4(GJA3):c.151G>C (p.Asp51His)	GJA3	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1527965	NM_021954.4(GJA3):c.98G>T (p.Arg33Leu)	GJA3	Likely pathogenic	criteria provided, multiple submitters, no conflicts
16978	NM_021954.4(GJA3):c.188A>G (p.Asn63Ser)	GJA3	Likely pathogenic	criteria provided, single submitter
16980	NM_021954.4(GJA3):c.560C>T (p.Pro187Leu)	GJA3	Likely pathogenic	criteria provided, single submitter
16981	NM_021954.4(GJA3):c.227G>A (p.Arg76His)	GJA3	Likely pathogenic	criteria provided, single submitter
2055275	NM_021954.4(GJA3):c.196T>C (p.Tyr66His)	GJA3	Likely pathogenic	criteria provided, single submitter
217334	NM_021954.4(GJA3):c.260C>T (p.Thr87Met)	GJA3	Likely pathogenic	criteria provided, single submitter
3253655	NM_021954.4(GJA3):c.1A>G (p.Met1Val)	GJA3	Likely pathogenic	criteria provided, single submitter
3253669	NM_021954.4(GJA3):c.96C>A (p.Phe32Leu)	GJA3	Likely pathogenic	criteria provided, single submitter
3253680	NM_021954.4(GJA3):c.134G>C (p.Trp45Ser)	GJA3	Likely pathogenic	criteria provided, single submitter
3253683	NM_021954.4(GJA3):c.143A>G (p.Glu48Gly)	GJA3	Likely pathogenic	criteria provided, single submitter
3253692	NM_021954.4(GJA3):c.584C>T (p.Ser195Phe)	GJA3	Likely pathogenic	criteria provided, single submitter
3253695	NM_021954.4(GJA3):c.771dup (p.Ser258fs)	GJA3	Likely pathogenic	criteria provided, single submitter
3253697	NM_021954.4(GJA3):c.32T>C (p.Leu11Ser)	GJA3	Likely pathogenic	criteria provided, single submitter
3253698	NM_021954.4(GJA3):c.950dup (p.His318fs)	GJA3	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 3 · 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
GJA3	Definitive	Autosomal dominant	cataract 14 multiple types	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GJA3	Orphanet:98984	Pulverulent cataract
GJA3	Orphanet:98991	Early-onset nuclear cataract
GJA3	Orphanet:98993	Early-onset posterior polar 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
GJA3	HGNC:4277	ENSG00000121743	Q9Y6H8	Gap junction alpha-3 protein	gencc,clinvar
CRYL1	HGNC:18246	ENSG00000165475	Q9Y2S2	Lambda-crystallin homolog	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GJA3	Gap junction alpha-3 protein	Structural component of lens fiber gap junctions.
CRYL1	Lambda-crystallin homolog	Catalyzes the conversion of L-gulonate to 3-dehydro-L-gulonate.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GJA3	Other/Unknown	no		Connexin, Connexin46, Connexin_N
CRYL1	Other/Unknown	no		3HC_DH_C, 3-OHacyl-CoA_DH_NAD-bd, 3-OHacyl-CoA_DH_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
heart right ventricle	1
left ventricle myocardium	1
myocardium	1
C1 segment of cervical spinal cord	1
adult mammalian kidney	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GJA3	75	broad	yes	left ventricle myocardium, heart right ventricle, myocardium
CRYL1	268	ubiquitous	marker	adult mammalian kidney, right lobe of liver, C1 segment of cervical spinal cord

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CRYL1	2,064
GJA3	449

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CRYL1	Q9Y2S2	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
GJA3	Q9Y6H8	69.53

Function

Pathway analysis

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

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Formation of xylulose-5-phosphate	1	951.7×	0.002	CRYL1
Gap junction assembly	1	146.4×	0.007	GJA3

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
obsolete D-glucuronate catabolic process to D-xylulose 5-phosphate	1	1404.3×	0.002	CRYL1
gap junction-mediated intercellular transport	1	1404.3×	0.002	GJA3
fatty acid metabolic process	1	96.8×	0.017	CRYL1
visual perception	1	39.8×	0.029	GJA3
cell-cell signaling	1	34.8×	0.029	GJA3

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
GJA3	0	0
CRYL1	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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	GJA3, CRYL1

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)
GJA3	0	—
CRYL1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.