Cataract 41

Summary

Cataract 41 (MONDO:0007287) is a disease caused by WFS1 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: WFS1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 467

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	cataract 41
Mondo ID	MONDO:0007287
OMIM	116400
DOID	DOID:0110241
UMLS	C3805412
MedGen	811742
GARD	0018234
Is cancer (heuristic)	no

Also known as: cataract 41 · cataract type 41 · CTRCT41 · early-onset non-syndromic cataract caused by mutation in WFS1 · WFS1 early-onset non-syndromic cataract

Data availability: 467 ClinVar variants · 1 GenCC gene-disease record.

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 › early-onset nuclear cataract › cataract 41

Related subtypes (3): cataract 27, cataract 35, autosomal recessive nonsyndromic congenital nuclear 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

467 retrieved; paginated sample, class counts are floors:

250 uncertain significance, 80 conflicting classifications of pathogenicity, 33 benign/likely benign, 30 likely benign, 29 pathogenic/likely pathogenic, 20 uncertain significance/uncertain risk allele, 12 pathogenic, 12 likely pathogenic, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1012716	NM_006005.3(WFS1):c.1096C>T (p.Gln366Ter)	WFS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1075961	NM_006005.3(WFS1):c.9dup (p.Asn4fs)	WFS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1179030	NM_006005.3(WFS1):c.76C>T (p.Arg26Ter)	WFS1	Pathogenic	criteria provided, multiple submitters, no conflicts
1179097	NM_006005.3(WFS1):c.1956C>G (p.Tyr652Ter)	WFS1	Pathogenic	criteria provided, multiple submitters, no conflicts
1179192	NM_006005.3(WFS1):c.2293del (p.Cys765fs)	WFS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1205588	NM_006005.3(WFS1):c.1549del (p.Arg517fs)	WFS1	Pathogenic	criteria provided, multiple submitters, no conflicts
1264331	NM_006005.3(WFS1):c.387G>A (p.Trp129Ter)	WFS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1298955	NM_006005.3(WFS1):c.1543TTC[1] (p.Phe516del)	WFS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1453842	NM_006005.3(WFS1):c.1525_1539del (p.Val509_Tyr513del)	WFS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1455530	NM_006005.3(WFS1):c.1558C>T (p.Gln520Ter)	WFS1	Pathogenic	criteria provided, multiple submitters, no conflicts
1456380	NM_006005.3(WFS1):c.1619G>A (p.Trp540Ter)	WFS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1458000	NM_006005.3(WFS1):c.1234_1237del (p.Val412fs)	WFS1	Pathogenic	criteria provided, multiple submitters, no conflicts
1458815	NM_006005.3(WFS1):c.1611_1624del (p.Cys537_Glu542delinsTer)	WFS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
189251	NM_006005.3(WFS1):c.124C>T (p.Arg42Ter)	WFS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
198835	NM_006005.3(WFS1):c.1672C>T (p.Arg558Cys)	WFS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
209207	NM_006005.3(WFS1):c.2648_2651del (p.Phe883fs)	WFS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
212612	NM_006005.3(WFS1):c.1692CCTCTT[1] (p.565LF[1])	WFS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
215376	NM_006005.3(WFS1):c.505G>A (p.Glu169Lys)	WFS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
215378	NM_006005.3(WFS1):c.631G>A (p.Asp211Asn)	WFS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
215399	NM_006005.3(WFS1):c.2254G>T (p.Glu752Ter)	WFS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
215405	NM_006005.3(WFS1):c.911_914dup (p.Asp305_Met306insTer)	WFS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
215406	NM_006005.3(WFS1):c.1243_1245del (p.Val415del)	WFS1	Pathogenic	criteria provided, multiple submitters, no conflicts
215409	NM_006005.3(WFS1):c.2643_2644del (p.Phe883fs)	WFS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2193625	NM_006005.3(WFS1):c.559C>T (p.Leu187Phe)	WFS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2203523	NM_006005.3(WFS1):c.1628T>G (p.Leu543Arg)	WFS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2418916	NM_006005.3(WFS1):c.643C>T (p.Gln215Ter)	WFS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2734648	NM_006005.3(WFS1):c.2314_2315insT (p.Arg772fs)	WFS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
349320	NM_006005.3(WFS1):c.1839G>A (p.Trp613Ter)	WFS1	Pathogenic	criteria provided, multiple submitters, no conflicts
3590689	NM_006005.3(WFS1):c.1355_1370del (p.Glu452fs)	WFS1	Pathogenic	criteria provided, single submitter
427051	NM_006005.3(WFS1):c.1673G>A (p.Arg558His)	WFS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 19 · Orphanet: 4 · 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
WFS1	Strong	Autosomal dominant	cataract 41	19

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
WFS1	Orphanet:3463	Wolfram syndrome
WFS1	Orphanet:411590	Wolfram-like syndrome
WFS1	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
WFS1	Orphanet:98991	Early-onset nuclear cataract

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
WFS1	HGNC:12762	ENSG00000109501	O76024	Wolframin	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
WFS1	Wolframin	Participates in the regulation of cellular Ca(2+) homeostasis, at least partly, by modulating the filling state of the endoplasmic reticulum Ca(2+) store.

Protein-family classification

Druggable: 0 · Difficult: 0 · 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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
WFS1	Other/Unknown	no		TPR-like_helical_dom_sf, Wolframin, Wolframin_fam

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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
body of uterus	1
left ovary	1
right ovary	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
WFS1	280	ubiquitous	marker	right ovary, left ovary, body of uterus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
WFS1	3,409

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
WFS1	O76024	73.85

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 1 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
XBP1(S) activates chaperone genes	1	215.5×	0.012	WFS1
Post-translational protein phosphorylation	1	100.2×	0.012	WFS1
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	1	86.5×	0.012	WFS1

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of ATF6-mediated unfolded protein response	1	8426.0×	0.003	WFS1
positive regulation of growth	1	4213.0×	0.003	WFS1
negative regulation of response to endoplasmic reticulum stress	1	2407.4×	0.003	WFS1
negative regulation of type B pancreatic cell apoptotic process	1	2106.5×	0.003	WFS1
olfactory behavior	1	1872.4×	0.003	WFS1
ER overload response	1	1532.0×	0.003	WFS1
nervous system process	1	1203.7×	0.003	WFS1
positive regulation of protein metabolic process	1	991.3×	0.003	WFS1
positive regulation of ERAD pathway	1	887.0×	0.003	WFS1
endoplasmic reticulum calcium ion homeostasis	1	842.6×	0.003	WFS1
negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway	1	842.6×	0.003	WFS1
negative regulation of programmed cell death	1	732.7×	0.003	WFS1
pancreas development	1	674.1×	0.003	WFS1
positive regulation of calcium ion transport	1	581.1×	0.004	WFS1
renal water homeostasis	1	510.7×	0.004	WFS1
calcium ion homeostasis	1	443.5×	0.004	WFS1
intrinsic apoptotic signaling pathway	1	358.6×	0.005	WFS1
endoplasmic reticulum unfolded protein response	1	295.6×	0.006	WFS1
positive regulation of protein ubiquitination	1	213.3×	0.007	WFS1
negative regulation of translation	1	195.9×	0.008	WFS1
ERAD pathway	1	181.2×	0.008	WFS1
response to endoplasmic reticulum stress	1	166.8×	0.008	WFS1
kidney development	1	140.4×	0.009	WFS1
glucose homeostasis	1	130.6×	0.010	WFS1
negative regulation of neuron apoptotic process	1	110.9×	0.011	WFS1
sensory perception of sound	1	100.9×	0.011	WFS1
visual perception	1	79.5×	0.014	WFS1
protein stabilization	1	66.9×	0.016	WFS1
negative regulation of apoptotic process	1	34.8×	0.030	WFS1
negative regulation of transcription by RNA polymerase II	1	17.7×	0.056	WFS1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
WFS1	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
WFS1	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	1	WFS1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
WFS1	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.