Leber congenital amaurosis 4

Summary

Leber congenital amaurosis 4 (MONDO:0011458) is a disease caused by AIPL1 (GenCC Definitive), with 3 cohort genes and 11 clinical trials. Top therapeutic interventions include cholesterol.

At a glance

• Causal gene: AIPL1 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 519
• Clinical trials: 11

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Leber congenital amaurosis 4
Mondo ID	MONDO:0011458
MeSH	C565778
OMIM	604393
DOID	DOID:0110332
UMLS	C1858386
MedGen	346808
GARD	0009662
Is cancer (heuristic)	no

Also known as: AIPL1 Leber congenital amaurosis · amaurosis congenita of Leber, type 4 · cone-rod dystrophy · LCA4 · Leber congenital amaurosis 4 · Leber congenital amaurosis caused by mutation in AIPL1 · Leber congenital amaurosis type 4

Data availability: 519 ClinVar variants · 2 GenCC gene-disease records · 2 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › retinal disorder › retinal degeneration › inherited retinal dystrophy › cone-rod dystrophy › Leber congenital amaurosis 4

Related subtypes (27): cone-rod dystrophy 2, macular degeneration, X-linked atrophic, cone-rod dystrophy 1, cone-rod dystrophy 5, cone-rod dystrophy 6, cone dystrophy 3, cone-rod dystrophy 7, cone-rod dystrophy 3, cone-rod dystrophy 8, Newfoundland cone-rod dystrophy, cone-rod dystrophy 13, cone-rod dystrophy 10, cone-rod dystrophy 11, retinal cone dystrophy 4, cone-rod dystrophy 12, cone-rod dystrophy 9, cone-rod dystrophy 15, cone-rod dystrophy 16, cone-rod dystrophy 17, cone-rod dystrophy 18, cone-rod dystrophy 19, cone-rod dystrophy 20, cone-rod dystrophy 21, X-linked cone-rod dystrophy, cone-rod dystrophy 22, cone-rod dystrophy 14, cone-rod dystrophy 24

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

519 retrieved; paginated sample, class counts are floors:

203 uncertain significance, 191 likely benign, 48 pathogenic, 30 conflicting classifications of pathogenicity, 16 likely pathogenic, 15 benign, 11 benign/likely benign, 4 pathogenic/likely pathogenic, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1071352	NM_014336.5(AIPL1):c.512dup (p.Asn171fs)	AIPL1	Pathogenic	criteria provided, single submitter
1213953	NM_014336.5(AIPL1):c.643-2A>T	AIPL1	Pathogenic	criteria provided, single submitter
1398909	NM_014336.5(AIPL1):c.488_498del (p.Gln163fs)	AIPL1	Pathogenic	criteria provided, single submitter
1451640	NM_014336.5(AIPL1):c.276+1G>A	AIPL1	Pathogenic	reviewed by expert panel
1451781	NM_014336.5(AIPL1):c.826G>T (p.Glu276Ter)	AIPL1	Pathogenic	criteria provided, single submitter
1458331	NM_014336.5(AIPL1):c.325C>T (p.Gln109Ter)	AIPL1	Pathogenic	criteria provided, single submitter
2013018	NM_014336.5(AIPL1):c.778dup (p.His260fs)	AIPL1	Pathogenic	criteria provided, single submitter
2024868	NM_014336.5(AIPL1):c.2T>C (p.Met1Thr)	AIPL1	Pathogenic	criteria provided, single submitter
2425944	NC_000017.10:g.(?6331618)(6338424_?)del	AIPL1	Pathogenic	criteria provided, single submitter
2733148	NM_001285403.4(AIPL1):c.466-24_466-21del	AIPL1	Pathogenic	criteria provided, single submitter
2736405	NM_014336.5(AIPL1):c.809G>A (p.Arg270His)	AIPL1	Pathogenic	reviewed by expert panel
2736406	NM_014336.5(AIPL1):c.572T>C (p.Leu191Pro)	AIPL1	Pathogenic	criteria provided, single submitter
2753703	NM_014336.5(AIPL1):c.88G>T (p.Gly30Ter)	AIPL1	Pathogenic	criteria provided, single submitter
2769284	NM_014336.5(AIPL1):c.867dup (p.Val290fs)	AIPL1	Pathogenic	criteria provided, single submitter
2799552	NM_014336.5(AIPL1):c.454G>T (p.Glu152Ter)	AIPL1	Pathogenic	criteria provided, single submitter
2803843	NM_014336.5(AIPL1):c.1A>G (p.Met1Val)	AIPL1	Pathogenic	criteria provided, single submitter
2837105	NM_014336.5(AIPL1):c.621C>A (p.Cys207Ter)	AIPL1	Pathogenic	criteria provided, single submitter
2843538	NM_014336.5(AIPL1):c.289_292del (p.Tyr97fs)	AIPL1	Pathogenic	criteria provided, single submitter
2863637	NM_014336.5(AIPL1):c.142_145del (p.Val48fs)	AIPL1	Pathogenic	criteria provided, single submitter
2875208	NM_014336.5(AIPL1):c.59del (p.Gly20fs)	AIPL1	Pathogenic	criteria provided, single submitter
3243055	NC_000017.10:g.(?6338309)(6338424_?)del	AIPL1	Pathogenic	criteria provided, single submitter
3243056	NC_000017.10:g.(?6337219)(6337438_?)del	AIPL1	Pathogenic	criteria provided, single submitter
3649117	NM_014336.5(AIPL1):c.905_906del (p.Arg302fs)	AIPL1	Pathogenic	criteria provided, single submitter
3678853	NM_014336.5(AIPL1):c.950dup (p.Glu318fs)	AIPL1	Pathogenic	criteria provided, single submitter
4277794	NM_014336.5(AIPL1):c.178dup (p.His60fs)	AIPL1	Pathogenic	criteria provided, single submitter
4735544	NM_014336.5(AIPL1):c.267C>A (p.Cys89Ter)	AIPL1	Pathogenic	criteria provided, single submitter
5565	NM_014336.5(AIPL1):c.834G>A (p.Trp278Ter)	AIPL1	Pathogenic	reviewed by expert panel
5566	NM_014336.5(AIPL1):c.1010_1011del (p.Glu337fs)	AIPL1	Pathogenic	reviewed by expert panel
566075	NM_014336.5(AIPL1):c.238C>T (p.Arg80Trp)	AIPL1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
574505	NM_014336.5(AIPL1):c.265T>C (p.Cys89Arg)	AIPL1	Pathogenic	reviewed by expert panel

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
AIPL1	Definitive	Autosomal recessive	Leber congenital amaurosis 4	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
AIPL1	Orphanet:1872	Cone rod dystrophy
AIPL1	Orphanet:65	Leber congenital amaurosis
PITPNM3	Orphanet:1872	Cone rod dystrophy

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
AIPL1	HGNC:359	ENSG00000129221	Q9NZN9	Aryl-hydrocarbon-interacting protein-like 1	gencc,clinvar
PITPNM3	HGNC:21043	ENSG00000091622	Q9BZ71	Membrane-associated phosphatidylinositol transfer protein 3	clinvar
TXNDC17	HGNC:28218	ENSG00000129235	Q9BRA2	Thioredoxin domain-containing protein 17	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
AIPL1	Aryl-hydrocarbon-interacting protein-like 1	May be important in protein trafficking and/or protein folding and stabilization.
PITPNM3	Membrane-associated phosphatidylinositol transfer protein 3	Catalyzes the transfer of phosphatidylinositol and phosphatidylcholine between membranes (in vitro).
TXNDC17	Thioredoxin domain-containing protein 17	Disulfide reductase.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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
Enzyme (other)	1	4.0×	0.460
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
AIPL1	Other/Unknown	no		TPR-like_helical_dom_sf, TPR_rpt, AIP/AIPL1/TTC9
PITPNM3	Other/Unknown	no		PI_transfer, DDHD_dom, HAD_sf
TXNDC17	Enzyme (other)	yes	1.8.1.6	TXNDC17_dom, Thioredoxin-like_sf, TXNDC17-like

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
pancreatic ductal cell	3
buccal mucosa cell	1
tendon of biceps brachii	1
Brodmann (1909) area 23	1
endothelial cell	1
esophagus mucosa	1
lower esophagus mucosa	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
AIPL1	62	tissue_specific	marker	buccal mucosa cell, pancreatic ductal cell, tendon of biceps brachii
PITPNM3	222	broad	marker	pancreatic ductal cell, endothelial cell, Brodmann (1909) area 23
TXNDC17	255	ubiquitous	marker	pancreatic ductal cell, lower esophagus mucosa, esophagus mucosa

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TXNDC17	1,013
AIPL1	891
PITPNM3	817

Intra-cohort edges

A	B	Sources
AIPL1	PITPNM3	string_interaction

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
AIPL1	Q9NZN9	6
PITPNM3	Q9BZ71	1
TXNDC17	Q9BRA2	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 3 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
Synthesis of PI	1	2284.0×	4e-04	PITPNM3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
protein farnesylation	1	1872.4×	0.005	AIPL1
regulation of opsin-mediated signaling pathway	1	561.7×	0.006	AIPL1
phototransduction, visible light	1	432.1×	0.006	AIPL1
retina homeostasis	1	374.5×	0.006	AIPL1
phosphatidylinositol biosynthetic process	1	122.1×	0.014	PITPNM3
tumor necrosis factor-mediated signaling pathway	1	110.1×	0.014	TXNDC17
visual perception	1	26.5×	0.048	AIPL1
negative regulation of apoptotic process	1	11.6×	0.094	AIPL1
apoptotic process	1	9.6×	0.101	AIPL1

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
AIPL1	0	0
PITPNM3	0	0
TXNDC17	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
TXNDC17	3	Binding:3
AIPL1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TXNDC17	1.8.1.6	cystine reductase

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	TXNDC17
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	AIPL1, PITPNM3

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
AIPL1	1	—
PITPNM3	0	—
TXNDC17	3	—

Clinical trials & evidence

Clinical trials

Clinical trials: 11.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	8
PHASE1/PHASE2	2
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01773278	PHASE2	RECRUITING	Cholesterol and Antioxidant Treatment in Patients With Smith-Lemli-Opitz Syndrome (SLOS)
NCT06467344	PHASE1/PHASE2	RECRUITING	Study to Evaluate ACDN-01 in ABCA4-related Stargardt Retinopathy (STELLAR)
NCT06789445	PHASE1/PHASE2	RECRUITING	A Study to Investigate the Safety of OpCT-001 in Adults Who Have Primary Photoreceptor Disease (CLARICO)
NCT02435940	Not specified	RECRUITING	Inherited Retinal Degenerative Disease Registry
NCT05355415	Not specified	RECRUITING	Adaptive Optics Imaging of Outer Retinal Diseases
NCT06445322	Not specified	RECRUITING	Prescreening Study to Identify Potential Stargardt Participants for ACDN-01 Clinical Trials (STARPATH)
NCT07548944	Not specified	RECRUITING	Observational Study to Investigate the Short-term Effects of Transcorneal Electrical Stimulation on Visual Performance
NCT00427180	Not specified	UNKNOWN	IRIS PILOT - Extended Pilot Study With a Retinal Implant System
NCT01864486	Not specified	COMPLETED	Restoring Vision With the Intelligent Retinal Implant System (IRIS V1)in Patients With Retinal Dystrophy
NCT02670980	Not specified	COMPLETED	Compensation for Blindness With the Intelligent Retinal Implant System (IRIS V2) in Patients With Retinal Dystrophy
NCT04658251	Not specified	TERMINATED	Study of New Mutations in Cone Disorders

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
CHOLESTEROL	2	1
CHEMBL1867358	0	1
CHEMBL3184306	0	1