corneal dystrophy, Fuchs endothelial, 3

Summary

corneal dystrophy, Fuchs endothelial, 3 (MONDO:0013203) is a disease caused by TCF4 (GenCC Strong), with 1 cohort gene and 1 clinical trial.

At a glance

• Causal gene: TCF4 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 26
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	corneal dystrophy, Fuchs endothelial, 3
Mondo ID	MONDO:0013203
MeSH	C567678
OMIM	613267
UMLS	C2750451
MedGen	442479
GARD	0018218
Is cancer (heuristic)	no

Also known as: corneal dystrophy, Fuchs endothelial, 3 · corneal dystrophy, Fuchs endothelial, type 3 · FECD3 · Fuchs’ endothelial dystrophy caused by mutation in TCF4 · TCF4 Fuchs’ endothelial dystrophy

Data availability: 26 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › disorder of orbital region › eye disorder › corneal disorder › corneal dystrophy › corneal endothelial dystrophy › Fuchs’ endothelial dystrophy › corneal dystrophy, Fuchs endothelial, 3

Related subtypes (7): corneal dystrophy, Fuchs endothelial, 1, corneal dystrophy, fuchs endothelial, 2, corneal dystrophy, Fuchs endothelial, 4, corneal dystrophy, fuchs endothelial, 5, corneal dystrophy, Fuchs endothelial, 6, corneal dystrophy, fuchs endothelial, 7, corneal dystrophy, Fuchs endothelial, 8

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

26 retrieved; paginated sample, class counts are floors:

8 pathogenic, 7 uncertain significance, 4 likely pathogenic, 3 benign, 2 benign/likely benign, 1 conflicting classifications of pathogenicity, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
204360	NG_011716.2:g.54765TGC[51_?]	TCF4	Pathogenic	no assertion criteria provided
235853	NM_001083962.2(TCF4):c.520C>T (p.Arg174Ter)	TCF4	Pathogenic	criteria provided, multiple submitters, no conflicts
3024315	NM_001083962.2(TCF4):c.306_307del (p.Ser102fs)	TCF4	Pathogenic	criteria provided, single submitter
3024324	NM_001083962.2(TCF4):c.710_711insT (p.Tyr238fs)	TCF4	Pathogenic	criteria provided, single submitter
3383034	NM_001083962.2(TCF4):c.1739G>T (p.Arg580Leu)	TCF4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
562214	NM_001083962.2(TCF4):c.696del (p.Gly232_Met233insTer)	TCF4	Pathogenic	criteria provided, single submitter
620020	NM_001083962.2(TCF4):c.1705C>T (p.Arg569Trp)	TCF4	Pathogenic	criteria provided, multiple submitters, no conflicts
7372	NM_001083962.2(TCF4):c.1153C>T (p.Arg385Ter)	TCF4	Pathogenic	criteria provided, multiple submitters, no conflicts
93542	NM_001083962.2(TCF4):c.1733G>A (p.Arg578His)	TCF4	Pathogenic	reviewed by expert panel
2664214	NM_001083962.2(TCF4):c.775_776dup (p.Glu261fs)	TCF4	Likely pathogenic	criteria provided, single submitter
3382238	NM_001083962.2(TCF4):c.1417_1418delinsT (p.Pro473fs)	TCF4	Likely pathogenic	criteria provided, single submitter
3393035	NM_001083962.2(TCF4):c.980C>A (p.Ala327Glu)	TCF4	Likely pathogenic	criteria provided, single submitter
828013	NM_001083962.2(TCF4):c.1118dup (p.Pro373_Asn374insTer)	TCF4	Likely pathogenic	criteria provided, single submitter
3235863	NM_001083962.2(TCF4):c.1706G>A (p.Arg569Gln)	TCF4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1302472	NM_001083962.2(TCF4):c.650T>C (p.Met217Thr)	TCF4	Uncertain significance	criteria provided, multiple submitters, no conflicts
1691007	NM_001083962.2(TCF4):c.550-22780G>A	TCF4	Uncertain significance	criteria provided, single submitter
3583370	NM_001083962.2(TCF4):c.1649+6A>G	TCF4	Uncertain significance	criteria provided, single submitter
468954	NM_001083962.2(TCF4):c.1990G>T (p.Ala664Ser)	TCF4	Uncertain significance	criteria provided, multiple submitters, no conflicts
536803	NM_001083962.2(TCF4):c.182A>G (p.Asn61Ser)	TCF4	Uncertain significance	criteria provided, multiple submitters, no conflicts
548609	NM_001083962.2(TCF4):c.785G>A (p.Arg262His)	TCF4	Uncertain significance	criteria provided, single submitter
560270	NM_001083962.2(TCF4):c.-21+2T>A	TCF4	Uncertain significance	criteria provided, multiple submitters, no conflicts
139413	NM_001083962.2(TCF4):c.*5-10C>T	TCF4	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
160083	NM_001083962.2(TCF4):c.305-165C>T	TCF4	Benign	criteria provided, multiple submitters, no conflicts
160089	NM_001083962.2(TCF4):c.789+23C>T	TCF4	Benign	criteria provided, multiple submitters, no conflicts
381239	NM_001083962.2(TCF4):c.923-17G>T	TCF4	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
93544	NM_001083962.2(TCF4):c.1941A>G (p.Ser647=)	TCF4	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · 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
TCF4	Strong	Autosomal dominant	corneal dystrophy, Fuchs endothelial, 3	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TCF4	Orphanet:171	Primary sclerosing cholangitis
TCF4	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
TCF4	Orphanet:2896	Pitt-Hopkins syndrome
TCF4	Orphanet:98974	Fuchs endothelial corneal dystrophy

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
TCF4	HGNC:11634	ENSG00000196628	P15884	Transcription factor 4	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TCF4	Transcription factor 4	Transcription factor that binds to the immunoglobulin enhancer Mu-E5/KE5-motif.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TCF4	Transcription factor	no	7.6.2.3	bHLH_dom, HLH_DNA-bd_sf, NeuroDiff_E-box_TFs

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
endothelial cell	1
pericardium	1
skin of hip	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TCF4	292	ubiquitous	marker	endothelial cell, skin of hip, pericardium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TCF4	3,342

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TCF4	P15884	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. 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
TGFBR3 expression	1	456.8×	0.007	TCF4
Myogenesis	1	380.7×	0.007	TCF4
Signaling by TGFBR3	1	368.4×	0.007	TCF4
Formation of the beta-catenin:TCF transactivating complex	1	120.2×	0.012	TCF4
Signaling by TGFB family members	1	115.3×	0.012	TCF4
CHD1 and CHD2 subfamily	1	108.8×	0.012	TCF4
Developmental Biology	1	14.5×	0.079	TCF4
Signal Transduction	1	10.2×	0.098	TCF4

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
protein-DNA complex assembly	1	5617.3×	0.001	TCF4
positive regulation of neuron differentiation	1	198.3×	0.018	TCF4
nervous system development	1	45.9×	0.050	TCF4
cell differentiation	1	29.1×	0.050	TCF4
positive regulation of DNA-templated transcription	1	27.9×	0.050	TCF4
positive regulation of transcription by RNA polymerase II	1	14.9×	0.078	TCF4
regulation of transcription by RNA polymerase II	1	11.7×	0.086	TCF4

Therapeutics

Drug target analysis

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

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
TCF4	1	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
SALINOMYCIN	2	TCF4

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
TCF4	31	Binding:31

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TCF4	7.6.2.3	ABC-type glutathione-S-conjugate transporter

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

1 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)
SALINOMYCIN	2	TCF4

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	1	TCF4
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05052554	PHASE1	WITHDRAWN	Study With QR-504a to Evaluate Safety, Tolerability & Corneal Endothelium Molecular Biomarker(s) in Subjects With FECD3