AIPL1

Summary

AIPL1 (AIP like 1 HSP90 co-chaperone, HGNC:359) is a protein-coding gene on chromosome 17p13.2, encoding Aryl-hydrocarbon-interacting protein-like 1 (Q9NZN9). May be important in protein trafficking and/or protein folding and stabilization.

Leber congenital amaurosis (LCA) is the most severe inherited retinopathy with the earliest age of onset and accounts for at least 5% of all inherited retinal diseases. Affected individuals are diagnosed at birth or in the first few months of life with nystagmus, severely impaired vision or blindness and an abnormal or flat electroretinogram. The photoreceptor/pineal-expressed gene, AIPL1, encoding aryl-hydrocarbon interacting protein-like 1, is located within the LCA4 candidate region. The encoded protein contains three tetratricopeptide motifs, consistent with chaperone or nuclear transport activity. Mutations in this gene may cause approximately 20% of recessive LCA. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 23746 — RefSeq curated summary.

At a glance

• Gene–disease (curated): AIPL1-related retinopathy (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 8
• Clinical variants (ClinVar): 620 total — 53 pathogenic, 29 likely-pathogenic
• Phenotypes (HPO): 47
• Druggable target: yes
• MANE Select transcript: NM_014336

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:359
Approved symbol	AIPL1
Name	AIP like 1 HSP90 co-chaperone
Location	17p13.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000129221
Ensembl biotype	protein_coding
OMIM	604392
Entrez	23746

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 10 protein_coding, 1 nonsense_mediated_decay

ENST00000250087, ENST00000381128, ENST00000381129, ENST00000570466, ENST00000570584, ENST00000571740, ENST00000574506, ENST00000574913, ENST00000575265, ENST00000576307, ENST00000576776

RefSeq mRNA: 8 — MANE Select: NM_014336 NM_001033054, NM_001033055, NM_001285399, NM_001285400, NM_001285401, NM_001285402, NM_001285403, NM_014336

CCDS: CCDS11075, CCDS32539, CCDS32540, CCDS67130, CCDS67131, CCDS67132, CCDS67133

Canonical transcript exons

ENST00000381129 — 6 exons

Exon	Start	End
ENSE00002643632	6435009	6435121
ENSE00002656031	6423738	6425830
ENSE00003565902	6426881	6427057
ENSE00003574014	6426615	6426756
ENSE00003662461	6433919	6434098
ENSE00003675057	6428318	6428506

Expression profiles

Bgee: expression breadth broad, 62 present calls, max score 76.92.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 2.1221 / max 917.3371, expressed in 56 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
164048	1.9849	54
164049	0.1372	8

Top tissues by expression

263 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	76.92	silver quality
pancreatic ductal cell	CL:0002079	75.06	silver quality
tendon of biceps brachii	UBERON:0008188	65.77	gold quality
retina	UBERON:0000966	64.31	gold quality
pigmented layer of retina	UBERON:0001782	64.30	gold quality
ileal mucosa	UBERON:0000331	60.40	silver quality
mucosa of urinary bladder	UBERON:0001259	59.25	gold quality
endothelial cell	CL:0000115	58.32	gold quality
tibialis anterior	UBERON:0001385	58.11	silver quality
secondary oocyte	CL:0000655	57.79	gold quality
pineal body	UBERON:0001905	56.80	silver quality
deltoid	UBERON:0001476	56.66	silver quality
decidua	UBERON:0002450	56.55	gold quality
nasal cavity epithelium	UBERON:0005384	56.10	gold quality
myocardium	UBERON:0002349	55.90	gold quality
parotid gland	UBERON:0001831	54.33	gold quality
tibia	UBERON:0000979	54.21	gold quality
medial globus pallidus	UBERON:0002477	54.04	gold quality
lateral nuclear group of thalamus	UBERON:0002736	53.95	gold quality
epithelial cell of pancreas	CL:0000083	53.80	silver quality
choroid plexus epithelium	UBERON:0003911	53.77	silver quality
heart right ventricle	UBERON:0002080	53.24	gold quality
globus pallidus	UBERON:0001875	52.93	gold quality
hair follicle	UBERON:0002073	52.86	gold quality
lateral globus pallidus	UBERON:0002476	52.85	gold quality
substantia nigra pars reticulata	UBERON:0001966	52.36	gold quality
quadriceps femoris	UBERON:0001377	51.40	gold quality
skin of abdomen	UBERON:0001416	50.72	gold quality
vastus lateralis	UBERON:0001379	50.70	gold quality
cervix squamous epithelium	UBERON:0006922	50.57	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-GEOD-137537	yes	6253.13
E-MTAB-7316	yes	5053.80
E-GEOD-135922	yes	4603.58
E-MTAB-11121	yes	2303.89
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

62 targeting AIPL1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-8067	99.86	69.59	2260
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4756-5P	99.84	64.98	1809
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-548AZ-5P	99.83	69.94	3230
HSA-MIR-548T-5P	99.83	69.91	3220
HSA-MIR-3150A-3P	99.76	64.44	1640
HSA-MIR-6763-5P	99.76	64.68	1767
HSA-MIR-2681-5P	99.75	67.64	1655
HSA-MIR-6885-3P	99.75	70.36	3187
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-298	99.63	67.56	1916
HSA-MIR-548AV-5P	99.60	70.84	2107
HSA-MIR-548K	99.60	70.84	2107
HSA-MIR-3942-3P	99.57	69.03	2854
HSA-MIR-486-3P	99.51	66.82	1901
HSA-MIR-143-3P	99.49	69.05	1457
HSA-MIR-4770	99.49	69.09	1451
HSA-MIR-8054	99.48	70.81	2084
HSA-MIR-19B-1-5P	99.36	67.07	1669
HSA-MIR-19B-2-5P	99.36	67.07	1669

Literature-anchored findings (GeneRIF, showing 33)

• Phenotype-genotype correlations of AIPL1-associated Leber’s congenital amaurosis (LCA) (PMID:11548141)
• AIPL1 performs a function essential to the maintenance of rod photoreceptor function (PMID:11929855)
• The inherited blindness associated protein AIPL1 interacts with the cell cycle regulator protein NUB1 in the retina. (PMID:12374762)
• Interacts with and aids in processing of farnesylated proteins in the retina. (PMID:14555765)
• interaction between NUB1 and AIPL1 is affected in patients with Leber congenital amaurosis (PMID:15081406)
• Plays role in cytosolic stability and/or nuclear transport of NUB1 during regulation of cell cyle during photoreceptor development. (PMID:15180275)
• The phenotype of LCA (Leber congenital amaurosis) in patients with AIPL1 mutations is relatively severe, with a maculopathy in most patients and keratoconus and cataract in a large subset. (PMID:15249368)
• Data show that aryl hydrocarbon receptor-interacting protein-like 1 (AIPL1) can modulate protein translocation and act in a chaperone-like manner and suggest that AIPL1 is an important modulator of NEDD8 ultimate buster protein 1 (NUB1) cellular function. (PMID:15347646)
• aryl hydrocarbon interacting protein-like 1 (AIPL1) mutations may have a role in inherited retinal dystrophies (PMID:15469903)
• AIPL1, CRB1, GUCY2D, RPE65, and RPGRIP1 mutations may have roles in juvenile retinitis pigmentosa (PMID:16272259)
• AIPL1 may cooperate with both Hsp70 and Hsp90 within retina-specific chaperone heterocomplex, and specialized role of AIPL1 in photoreceptors may therefore be facilitated by these molecular chaperones. (PMID:18408180)
• Variations of macular microstructures were observed among LCA (Leber congenital amaurosis) patients with different genotypes. (PMID:19959640)
• AIPL1 is needed for the proper functioning and survival of cone photoreceptors. (PMID:20042464)
• AIPL1-Leber congenital amaurosis (LCA), unlike some other forms of LCA with equally severe visual disturbance, shows profound loss of foveal as well as extrafoveal photoreceptors. (PMID:20702822)
• Patients with mutations in AIPL1 may present with Leber congenital amaurosis and residual ERGs (electroretinography) characterized by slow insensitive scotopic responses. (PMID:21900377)
• implicate FAT10 in retinal cell biology and Leber congenital amaurosis pathogenesis, and reveal a new role of AIPL1 in regulating the FAT10 pathway. (PMID:22347407)
• The unique proline-rich domain of AIPL1 is important for its chaperone function as its truncation severely affects the ability of AIPL1 to bind non-native proteins. (PMID:23418749)
• In this chapter, using results obtained from multiple lines of animal models, we discuss the role for AIPL1 in photoreceptors. (PMID:24664679)
• Mutations in the AIPL1 and RDH12 genes associated with leber congenital amaurosis in two Turkish families. (PMID:25148430)
• The authors established a transgenic mouse model for cone-rod dystrophy carrying human AIPL1 gene with deletion in the C-terminal proline-rich region. (PMID:25274777)
• Gene therapy based approach may be worthy of consideration in a small group of selected patients with preserved outer retinal structure in AIPL1 Leber’s congenital amaurosis. (PMID:25596619)
• Findings suggest that AIPL1 function in retinal photoreceptor cells is not related to the role of EB proteins in microtubule dynamics or primary ciliogenesis, but their association may be related to a specific role in the retinal photoreceptors. (PMID:25799540)
• findings offer critical insights into the mechanisms that underlie AIPL1 function in health and disease, and highlight the structural and functional diversity of the FKBPs (PMID:28739921)
• This review summarizes important recent advances in understanding the mechanisms underlying normal function of AIPL1 and the protein perturbations caused by pathogenic mutations (PMID:28939106)
• Authors characterized the functional deficits of AIPL1 variations, some of which induce aberrant pre-mRNA AIPL1 splicing leading to the production of alternative AIPL1 isoforms and investigated the ability of the AIPL1 variants to mediate an interaction with HSP90 and modulate the rod cGMP PDE6 stability and activity. (PMID:28973376)
• AIPL1 functions as a photoreceptor-specific molecular co-chaperone that interacts specifically with the molecular chaperones HSP90 and HSP70 to facilitate the correct folding and assembly of the retinal cGMP phosphodiesterase (PDE6) holoenzyme. The absence of AIPL1 leads to a dramatic degeneration of rod and cone cells and a complete loss of any light-dependent electrical response. Review. (PMID:29721967)
• A Novel AIPL1 Nonsense Mutation: Case Report of Three Siblings Diagnosed with Leber Congenital Amaurosis. (PMID:31342828)
• This study sheds new light on the versatility of tetratricopeptide repeat domain (TPR) domains in protein folding by describing a novel TPR-protein binding partner, Pgamma, and revealing that this subunit imparts AIPL1 selectivity for its client. (PMID:31488544)
• Mutation in the AIPL1 gene is associated with Leber congenital amaurosis 4. (PMID:31576779)
• Two novel compound heterozygous AIPL1 variants were detected in two patients with cone-rod dystrophy (PMID:31703130)
• Retinal Organoids derived from hiPSCs of an AIPL1-LCA Patient Maintain Cytoarchitecture despite Reduced levels of Mutant AIPL1. (PMID:32214115)
• Pathogenic variants of AIPL1, MERTK, GUCY2D, and FOXE3 in Pakistani families with clinically heterogeneous eye diseases. (PMID:32976546)
• Clinical and functional analyses of AIPL1 variants reveal mechanisms of pathogenicity linked to different forms of retinal degeneration. (PMID:33067476)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	aipl1	ENSDARG00000075067
mus_musculus	Aipl1	ENSMUSG00000040554
rattus_norvegicus	Aipl1	ENSRNOG00000007889
drosophila_melanogaster	CG1847	FBGN0030345
caenorhabditis_elegans		WBGENE00016966

Paralogs (1): AIP (ENSG00000110711)

Protein

Protein identifiers

Aryl-hydrocarbon-interacting protein-like 1 — Q9NZN9 (reviewed: Q9NZN9)

All UniProt accessions (8): Q9NZN9, F1T0B5, F1T0B6, F1T0C4, I3L3R9, J3KPI5, K7EPF4, Q7Z3H1

UniProt curated annotations — full annotation on UniProt →

Function. May be important in protein trafficking and/or protein folding and stabilization.

Subunit / interactions. Interacts with NUB1.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Highly expressed in retina. Specifically localized to the developing photoreceptor layer and within the photoreceptors of the adult retina.

Disease relevance. Leber congenital amaurosis 4 (LCA4) [MIM:604393] A severe dystrophy of the retina, typically becoming evident in the first years of life. Visual function is usually poor and often accompanied by nystagmus, sluggish or near-absent pupillary responses, photophobia, high hyperopia and keratoconus. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (5)

UniProt ID	Names	Canonical?
Q9NZN9-1	1	yes
Q9NZN9-2	2
Q9NZN9-3	3, AIPL2
Q9NZN9-4	4
Q9NZN9-5	5

RefSeq proteins (8): NP_001028226, NP_001028227, NP_001272328, NP_001272329, NP_001272330, NP_001272331, NP_001272332, NP_055151* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011990	TPR-like_helical_dom_sf	Homologous_superfamily
IPR019734	TPR_rpt	Repeat
IPR039663	AIP/AIPL1/TTC9	Family
IPR046357	PPIase_dom_sf	Homologous_superfamily
IPR056277	PPIase_AIP	Domain

Pfam: PF23322

UniProt features (49 total): helix 14, strand 9, sequence variant 7, mutagenesis site 6, splice variant 4, repeat 3, sequence conflict 2, chain 1, domain 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
6PX0	X-RAY DIFFRACTION	1.55
5U9J	X-RAY DIFFRACTION	2.1
5U9I	X-RAY DIFFRACTION	2.3
5V35	X-RAY DIFFRACTION	2.5
5U9A	X-RAY DIFFRACTION	2.7
5U9K	X-RAY DIFFRACTION	2.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NZN9-F1	83.42	0.62

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Mutagenesis-validated functional residues (6):

Position	Phenotype
53	no interaction with nub1.
79	no interaction with nub1.
96	no interaction with nub1.
197	no significant effect on interaction with nub1.
206	no significant effect on interaction with nub1.
262	no interaction with nub1.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 168 (showing top): PEREZ_TP63_TARGETS, GOBP_CELLULAR_RESPONSE_TO_LIGHT_STIMULUS, GOBP_PHOTOTRANSDUCTION, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM1, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM5, GOBP_PHOTOTRANSDUCTION_VISIBLE_LIGHT, GOBP_SENSORY_PERCEPTION_OF_LIGHT_STIMULUS, GOBP_RESPONSE_TO_RADIATION, GOBP_DETECTION_OF_LIGHT_STIMULUS, GOBP_RESPONSE_TO_ABIOTIC_STIMULUS, GOBP_DETECTION_OF_ABIOTIC_STIMULUS, GOBP_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS, GOBP_DETECTION_OF_STIMULUS, GOBP_CELLULAR_RESPONSE_TO_RADIATION, GOBP_MULTICELLULAR_ORGANISMAL_LEVEL_HOMEOSTASIS

GO Biological Process (7): retina homeostasis (GO:0001895), apoptotic process (GO:0006915), visual perception (GO:0007601), phototransduction, visible light (GO:0007603), protein farnesylation (GO:0018343), regulation of opsin-mediated signaling pathway (GO:0022400), negative regulation of apoptotic process (GO:0043066)

GO Molecular Function (4): farnesylated protein binding (GO:0001918), peptidyl-prolyl cis-trans isomerase activity (GO:0003755), obsolete unfolded protein binding (GO:0051082), protein binding (GO:0005515)

GO Cellular Component (6): photoreceptor inner segment (GO:0001917), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), nuclear speck (GO:0016607)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
tissue homeostasis	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
sensory perception of light stimulus	1
phototransduction	1
detection of visible light	1
protein prenylation	1
regulation of G protein-coupled receptor signaling pathway	1
G protein-coupled opsin signaling pathway	1
regulation of response to external stimulus	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
protein binding	1
cis-trans isomerase activity	1
catalytic activity, acting on a protein	1
binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1
nuclear ribonucleoprotein granule	1

Protein interactions and networks

STRING

808 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AIPL1	GUCY2D	Q02846	971
AIPL1	RPGRIP1	Q96KN7	943
AIPL1	SPATA7	Q9P0W8	930
AIPL1	TULP1	O00294	915
AIPL1	NUB1	Q9Y5A7	910
AIPL1	CRX	O43186	906
AIPL1	RPE65	Q16518	902
AIPL1	RDH12	Q96NR8	889
AIPL1	LRAT	O95237	888
AIPL1	RD3	Q7Z3Z2	863
AIPL1	LCA5	Q86VQ0	854
AIPL1	CEP290	O15078	829
AIPL1	IMPDH1	P20839	822
AIPL1	PITPNM3	Q9BZ71	805
AIPL1	PRPH2	P23942	791

IntAct

36 interactions, top by confidence:

A	B	Type	Score
SEPTIN2	SEPTIN8	psi-mi:“MI:0914”(association)	0.670
AIPL1	PDE5A	psi-mi:“MI:0914”(association)	0.640
PLSCR3	AIPL1	psi-mi:“MI:0915”(physical association)	0.560
LBX1	AIPL1	psi-mi:“MI:0915”(physical association)	0.560
SMAP1	AIPL1	psi-mi:“MI:0915”(physical association)	0.560
TXNL4B	AIPL1	psi-mi:“MI:0915”(physical association)	0.560
AIPL1	TINF2	psi-mi:“MI:0915”(physical association)	0.510
AIPL1	SUPT5H	psi-mi:“MI:0914”(association)	0.510
NUB1	AIPL1	psi-mi:“MI:0915”(physical association)	0.510
AIPL1	NUB1	psi-mi:“MI:0915”(physical association)	0.510
AIPL1		psi-mi:“MI:0915”(physical association)	0.400
AIPL1	ACD	psi-mi:“MI:0915”(physical association)	0.370
AIPL1	POT1	psi-mi:“MI:0915”(physical association)	0.370
KPNA5	SPOP	psi-mi:“MI:0914”(association)	0.350
TINF2	AIPL1	psi-mi:“MI:0915”(physical association)	0.000
SUPT5H	AIPL1	psi-mi:“MI:0915”(physical association)	0.000
SEC16A	AIPL1	psi-mi:“MI:0915”(physical association)	0.000
PDE5A	AIPL1	psi-mi:“MI:0915”(physical association)	0.000
CEP43	AIPL1	psi-mi:“MI:0915”(physical association)	0.000
TP53	AIPL1	psi-mi:“MI:0915”(physical association)	0.000
BLM	AIPL1	psi-mi:“MI:0915”(physical association)	0.000
FKBP15	AIPL1	psi-mi:“MI:0915”(physical association)	0.000
RADX	AIPL1	psi-mi:“MI:0915”(physical association)	0.000
WASF1	AIPL1	psi-mi:“MI:0915”(physical association)	0.000
WDR24	AIPL1	psi-mi:“MI:0915”(physical association)	0.000
PATZ1	AIPL1	psi-mi:“MI:0915”(physical association)	0.000
MIOS	AIPL1	psi-mi:“MI:0915”(physical association)	0.000
AIPL1	PLSCR3	psi-mi:“MI:0915”(physical association)	0.000
AIPL1	LBX1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (47): NUB1 (Affinity Capture-Western), AIPL1 (Affinity Capture-MS), AIPL1 (Affinity Capture-MS), AIPL1 (Affinity Capture-MS), AIPL1 (Affinity Capture-MS), AIPL1 (Affinity Capture-MS), AIPL1 (Affinity Capture-MS), AIPL1 (Affinity Capture-MS), AIPL1 (Affinity Capture-MS), AIPL1 (Affinity Capture-MS), AIPL1 (Affinity Capture-MS), AIPL1 (Affinity Capture-MS), AIPL1 (Affinity Capture-MS), AIPL1 (Two-hybrid), LBX1 (Two-hybrid)

ESM2 similar proteins: A1A5P5, A1Z8E9, A4QP73, A8BS40, A8JA42, B5X0I6, D4A6D7, O00170, O08915, O09012, O70525, O97628, P50542, P91240, Q16JL4, Q17DK2, Q1RMV0, Q20255, Q24314, Q294E0, Q29L58, Q2KI89, Q2M2R8, Q38DX5, Q5FWY5, Q5ZI13, Q5ZMQ9, Q6DKK2, Q6DRJ9, Q7PYI4, Q7YRC1, Q8CC21, Q8SYD0, Q90830, Q920N5, Q95MN7, Q95MN8, Q95MN9, Q9M1J1, Q9NZN9

Diamond homologs: O00170, O08915, O35450, O97628, Q554J3, Q5FWY5, Q6MG81, Q7YRC1, Q924K1, Q95MN7, Q95MN8, Q95MN9, Q95MP0, Q95MP1, Q9JLG9, Q9NZN9, Q9QVC8, Q9UIM3, Q07617, Q43207, Q9FJL3, Q9LDC0, Q9XSI2

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

620 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	53
Likely pathogenic	29
Uncertain significance	248
Likely benign	197
Benign	39

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1071352	NM_014336.5(AIPL1):c.512dup (p.Asn171fs)	Pathogenic
1213953	NM_014336.5(AIPL1):c.643-2A>T	Pathogenic
1398909	NM_014336.5(AIPL1):c.488_498del (p.Gln163fs)	Pathogenic
1451640	NM_014336.5(AIPL1):c.276+1G>A	Pathogenic
1451781	NM_014336.5(AIPL1):c.826G>T (p.Glu276Ter)	Pathogenic
1458331	NM_014336.5(AIPL1):c.325C>T (p.Gln109Ter)	Pathogenic
2013018	NM_014336.5(AIPL1):c.778dup (p.His260fs)	Pathogenic
2024868	NM_014336.5(AIPL1):c.2T>C (p.Met1Thr)	Pathogenic
2425944	NC_000017.10:g.(?6331618)(6338424_?)del	Pathogenic
2733148	NM_001285403.4(AIPL1):c.466-24_466-21del	Pathogenic
2736405	NM_014336.5(AIPL1):c.809G>A (p.Arg270His)	Pathogenic
2736406	NM_014336.5(AIPL1):c.572T>C (p.Leu191Pro)	Pathogenic
2753703	NM_014336.5(AIPL1):c.88G>T (p.Gly30Ter)	Pathogenic
2769284	NM_014336.5(AIPL1):c.867dup (p.Val290fs)	Pathogenic
2799552	NM_014336.5(AIPL1):c.454G>T (p.Glu152Ter)	Pathogenic
2803843	NM_014336.5(AIPL1):c.1A>G (p.Met1Val)	Pathogenic
2837105	NM_014336.5(AIPL1):c.621C>A (p.Cys207Ter)	Pathogenic
2843538	NM_014336.5(AIPL1):c.289_292del (p.Tyr97fs)	Pathogenic
2863637	NM_014336.5(AIPL1):c.142_145del (p.Val48fs)	Pathogenic
2875208	NM_014336.5(AIPL1):c.59del (p.Gly20fs)	Pathogenic
3243055	NC_000017.10:g.(?6338309)(6338424_?)del	Pathogenic
3243056	NC_000017.10:g.(?6337219)(6337438_?)del	Pathogenic
3649117	NM_014336.5(AIPL1):c.905_906del (p.Arg302fs)	Pathogenic
3678853	NM_014336.5(AIPL1):c.950dup (p.Glu318fs)	Pathogenic
395716	GRCh37/hg19 17p13.3-13.1(chr17:1113102-6742486)	Pathogenic
4087767	NM_014336.5(AIPL1):c.618_619dup (p.Cys207fs)	Pathogenic
4087769	NM_014336.5(AIPL1):c.126T>A (p.Cys42Ter)	Pathogenic
4087770	NM_014336.5(AIPL1):c.216G>A (p.Trp72Ter)	Pathogenic
4277794	NM_014336.5(AIPL1):c.178dup (p.His60fs)	Pathogenic
4533378	NM_014336.5(AIPL1):c.653G>A (p.Trp218Ter)	Pathogenic

SpliceAI

1013 predictions. Top by Δscore:

Variant	Effect	Δscore
17:6425828:TGC:T	acceptor_gain	1.0000
17:6425828:TGCC:T	acceptor_loss	1.0000
17:6425829:GC:G	acceptor_gain	1.0000
17:6425829:GCC:G	acceptor_loss	1.0000
17:6425830:CC:C	acceptor_gain	1.0000
17:6425831:C:CC	acceptor_gain	1.0000
17:6425831:C:CG	acceptor_loss	1.0000
17:6426611:GCAC:G	donor_loss	1.0000
17:6426612:CACC:C	donor_loss	1.0000
17:6426614:C:G	donor_loss	1.0000
17:6426634:A:AC	donor_gain	1.0000
17:6426752:TTCTC:T	acceptor_gain	1.0000
17:6426754:CTC:C	acceptor_gain	1.0000
17:6426755:TC:T	acceptor_gain	1.0000
17:6426756:CC:C	acceptor_gain	1.0000
17:6426756:CCTG:C	acceptor_loss	1.0000
17:6426762:C:CT	acceptor_gain	1.0000
17:6426762:C:T	acceptor_gain	1.0000
17:6426877:TGAC:T	donor_loss	1.0000
17:6426879:A:AC	donor_gain	1.0000
17:6426879:ACCT:A	donor_loss	1.0000
17:6426880:C:CC	donor_gain	1.0000
17:6426880:C:CT	donor_loss	1.0000
17:6426895:T:TA	donor_gain	1.0000
17:6426915:T:TA	donor_gain	1.0000
17:6433913:A:AC	donor_gain	1.0000
17:6433914:C:CC	donor_gain	1.0000
17:6433915:T:TC	donor_loss	1.0000
17:6433916:T:TC	donor_loss	1.0000
17:6433917:A:AC	donor_gain	1.0000

AlphaMissense

2511 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:6425768:C:G	A283P	0.999
17:6433942:C:G	A85P	0.999
17:6425755:A:G	L287P	0.998
17:6425797:G:T	A273D	0.998
17:6425804:C:G	A271P	0.998
17:6426969:C:T	G185E	0.998
17:6426970:C:G	G185R	0.998
17:6426970:C:T	G185R	0.998
17:6425798:C:G	A273P	0.997
17:6425803:G:T	A271D	0.997
17:6425806:C:G	R270P	0.997
17:6426913:C:G	A204P	0.997
17:6428468:C:A	R105S	0.997
17:6428468:C:G	R105S	0.997
17:6428469:C:G	R105T	0.997
17:6428494:A:C	Y97D	0.997
17:6433930:A:G	C89R	0.997
17:6433934:G:C	F87L	0.997
17:6433934:G:T	F87L	0.997
17:6433935:A:G	F87S	0.997
17:6433936:A:G	F87L	0.997
17:6433981:A:G	W72R	0.997
17:6433981:A:T	W72R	0.997
17:6426682:G:C	C239W	0.996
17:6426684:A:G	C239R	0.996
17:6426688:G:C	C237W	0.996
17:6426921:T:G	Y201S	0.996
17:6426922:A:C	Y201D	0.996
17:6426922:A:G	Y201H	0.996
17:6428343:A:G	L147P	0.996

dbSNP variants (sampled 300 via entrez): RS1000841300 (17:6428870 C>T), RS1001191592 (17:6435180 G>A,C), RS1001510819 (17:6425029 A>G), RS1001669891 (17:6432915 A>C), RS1001735627 (17:6430088 C>A,G,T), RS1001816113 (17:6436570 G>T), RS1002015299 (17:6431012 C>A,T), RS1002035835 (17:6432643 T>TC), RS1002073318 (17:6429848 A>C,G), RS1002084036 (17:6431944 C>A,T), RS1002108268 (17:6426176 G>A,T), RS1002470734 (17:6431262 C>T), RS1002814277 (17:6435968 G>C,T), RS1002851248 (17:6426505 G>A,T), RS1003188440 (17:6425311 T>G)

Disease associations

OMIM: gene MIM:604392 | disease phenotypes: MIM:604393, MIM:268000, MIM:615905, MIM:204000, MIM:120970, MIM:617238, MIM:617667, MIM:611603

GenCC curated gene-disease

Disease	Classification	Inheritance
Leber congenital amaurosis 4	Definitive	Autosomal recessive
AIPL1-related retinopathy	Strong	Semidominant
Leber congenital amaurosis	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (2)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
AIPL1-related retinopathy	Definitive	AR
inherited retinal dystrophy	Disputed	AD

Mondo (13): Leber congenital amaurosis 4 (MONDO:0011458), AIPL1-related retinopathy (MONDO:0100438), inherited retinal dystrophy (MONDO:0019118), retinitis pigmentosa (MONDO:0019200), developmental and epileptic encephalopathy, 25 (MONDO:0014392), Leber congenital amaurosis 1 (MONDO:0008764), Leber congenital amaurosis (MONDO:0018998), retinal disorder (MONDO:0005283), cone-rod dystrophy 2 (MONDO:0007362), pathologic nystagmus (MONDO:0004843), myopia 25, autosomal dominant (MONDO:0014982), Fraser syndrome 3 (MONDO:0054739), lissencephaly due to TUBA1A mutation (MONDO:0012703)

Orphanet (6): OBSOLETE: Inherited retinal disorder (Orphanet:71862), Retinitis pigmentosa (Orphanet:791), Non-specific early-onset epileptic encephalopathy (Orphanet:442835), Leber congenital amaurosis (Orphanet:65), Cone rod dystrophy (Orphanet:1872), Lissencephaly due to TUBA1A mutation (Orphanet:171680)

HPO phenotypes

47 total (30 of 47 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000365	Hearing impairment
HP:0000505	Visual impairment
HP:0000510	Rod-cone dystrophy
HP:0000512	Abnormal electroretinogram
HP:0000518	Cataract
HP:0000529	Progressive visual loss
HP:0000540	Hypermetropia
HP:0000543	Optic disc pallor
HP:0000548	Cone/cone-rod dystrophy
HP:0000551	Color vision defect
HP:0000563	Keratoconus
HP:0000603	Central scotoma
HP:0000613	Photophobia
HP:0000618	Blindness
HP:0000639	Nystagmus
HP:0000662	Nyctalopia
HP:0000729	Autistic behavior
HP:0001105	Retinal atrophy
HP:0001133	Constriction of peripheral visual field
HP:0001141	Severely reduced visual acuity
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001270	Motor delay
HP:0001419	X-linked recessive inheritance
HP:0001483	Eye poking
HP:0002084	Encephalocele

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST002924_3	Paclitaxel-induced cytotoxicity	9.000000e-07
GCST002932_2	Manganese levels	5.000000e-06
GCST003075_57	Cognitive decline rate in late mild cognitive impairment	8.000000e-07
GCST003075_76	Cognitive decline rate in late mild cognitive impairment	1.000000e-06
GCST006012_1	C-reactive protein levels	2.000000e-09
GCST009163_3	Hormone measurements	6.000000e-09
GCST009897_6	Reading disability	7.000000e-06
GCST011350_5	C-reactive protein levels	3.000000e-08

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0006952	cytotoxicity measurement
EFO:0007710	cognitive decline measurement
EFO:0004458	C-reactive protein measurement
EFO:0004730	hormone measurement

MeSH disease descriptors (7)

Descriptor	Name	Tree numbers
D057130	Leber Congenital Amaurosis	C11.270.516; C11.768.364
D009759	Nystagmus, Pathologic	C10.292.562.675; C11.590.400
D012164	Retinal Diseases	C11.768
D058499	Retinal Dystrophies	C11.768.585.658
D012174	Retinitis Pigmentosa	C11.270.684; C11.768.585.658.500; C16.320.290.684
C565778	Leber Congenital Amaurosis 4 (supp.)
C566908	Lissencephaly 3 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067455 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

1 potent at pChembl≥5 of 1 total, top 1 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.70	IC50	2000	nM	CHEMBL5558181

PubChem BioAssay actives

1 with measured affinity, of 3 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
N,N’-bis(3-carbamoyl-4,5-dimethylthiophen-2-yl)pentanediamide	2084028: Inhibition of GST-tagged human AIPL1 expressed in Escherichia coli BL21 (DE3) using NH2-EDASRMEEVD-COOH peptide as substrate preincubated for 15 mins followed by substrate addition measured after 15 mins by Alpha Screen assay	ic50	2.0000	uM

CTD chemical–gene interactions

13 total (human), top 13 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
cobaltous chloride	increases expression	1
benzo(e)pyrene	decreases methylation	1
aflatoxin B2	decreases methylation	1
theaflavin-3,3’-digallate	affects expression	1
Decitabine	affects expression	1
Benzo(a)pyrene	affects methylation	1
Cisplatin	affects expression	1
Methapyrilene	decreases methylation	1
Tamoxifen	decreases expression	1
Testosterone	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Aflatoxin B1	decreases methylation	1
Lactic Acid	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5524501	Binding	Inhibition of GST-tagged human AIPL1 expressed in Escherichia coli BL21 (DE3) using NH2-EDASRMEEVD-COOH peptide as substrate preincubated for 15 mins followed by substrate addition measured after 15 mins by Alpha Screen assay	Structure-based discovery of small molecule inhibitors of FKBP51-Hsp90 protein-protein interaction. — Eur J Med Chem

Cellosaurus cell lines

1 cell lines: 1 induced pluripotent stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_UF40	RCPFi007-A	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

280 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00717080	PHASE4	COMPLETED	The Role of Capsular Tension Ring (CTR) in Anterior Capsular Contraction
NCT00999609	PHASE3	ACTIVE_NOT_RECRUITING	Safety and Efficacy Study in Subjects With Leber Congenital Amaurosis
NCT06891443	PHASE3	RECRUITING	Study to Evaluate Sepofarsen in Subjects With Leber Congenital Amaurosis (LCA) Type 10 (HYPERION)
NCT04224207	PHASE3	COMPLETED	Management of Retinitis Pigmentosa by Mesenchymal Stem Cells by Wharton’s Jelly Derived Mesenchymal Stem Cells
NCT07082855	PHASE3	NOT_YET_RECRUITING	A Multicenter, Randomized, Double-Blind, Controlled Clinical Study of Minocycline for the Treatment of Retinitis Pigmentosa
NCT00000114	PHASE3	COMPLETED	Randomized Trial of Vitamin A and Vitamin E Supplementation for Retinitis Pigmentosa
NCT00000116	PHASE3	COMPLETED	Randomized Trial of DHA for Retinitis Pigmentosa Patients Receiving Vitamin A
NCT00346333	PHASE3	COMPLETED	Clinical Trial of Lutein for Patients With Retinitis Pigmentosa Receiving Vitamin A
NCT01786395	PHASE3	TERMINATED	Phase III Efficacy and Safety Clinical Study of UF-021 for Treatment of Retinitis Pigmentosa
NCT04636853	PHASE3	COMPLETED	CB-PRP in Retinitis Pigmentosa and Dry Age-related Macular Degeneration
NCT05537220	PHASE3	ACTIVE_NOT_RECRUITING	Oral N-acetylcysteine for Retinitis Pigmentosa
NCT05800301	PHASE3	COMPLETED	Management of Retinitis Pigmentosa Via Combination of Wharton’s Jelly-derived Mesenchymal Stem Cells and Magnovision
NCT05926583	PHASE3	ACTIVE_NOT_RECRUITING	A Study of AAV5-hRKp.RPGR for the Treatment of Japanese Participants With X-linked Retinitis Pigmentosa
NCT06388200	PHASE3	ACTIVE_NOT_RECRUITING	A Phase 3 Study Of OCU400 Gene Therapy for the Treatment Of Retinitis Pigmentosa
NCT07290530	PHASE3	NOT_YET_RECRUITING	24-Month Trial of NPI-001 for the Preservation of Photoreceptors in Retinitis Pigmentosa Associated With Usher Syndrome
NCT01773278	PHASE2	RECRUITING	Cholesterol and Antioxidant Treatment in Patients With Smith-Lemli-Opitz Syndrome (SLOS)
NCT03763227	PHASE2	COMPLETED	Intravitreal Ranibizumab (Lucentis®) in the Treatment of Non-leaking Macular Cysts in Retinal Dystrophy
NCT04068207	PHASE2	COMPLETED	Minocycline Treatment in Retinitis Pigmentosa
NCT04945772	PHASE2	COMPLETED	Efficacy and Safety of MCO-010 Optogenetic Therapy in Adults With Retinitis Pigmentosa [RESTORE]
NCT00100230	PHASE2	COMPLETED	DHA and X-Linked Retinitis Pigmentosa
NCT00447980	PHASE2	COMPLETED	A Study of Encapsulated Cell Technology (ECT) Implant for Participants With Early Stage Retinitis Pigmentosa
NCT00447993	PHASE2	COMPLETED	A Study of Encapsulated Cell Technology (ECT) Implant for Patients With Late Stage Retinitis Pigmentosa
NCT01233609	PHASE2	COMPLETED	Trial of Oral Valproic Acid for Retinitis Pigmentosa
NCT01399515	PHASE2	COMPLETED	Efficacy and Safety of Oral Valproic Acid for Retinitis Pigmentosa
NCT01530659	PHASE2	COMPLETED	Retinal Imaging in CNTF -Releasing Encapsulated Cell Implant Treated Patients for Early-stage Retinitis Pigmentosa
NCT01560715	PHASE2	COMPLETED	Autologous Bone Marrow-Derived Stem Cells Transplantation For Retinitis Pigmentosa
NCT02609165	PHASE2	COMPLETED	Nerve Growth Factor Eye Drops Treatment in Patients With Retinitis Pigmentosa and Cystoid Macular Edema
NCT02661711	PHASE2	COMPLETED	Aflibercept for Macular Oedema With Underlying Retinitis Pigmentosa (AMOUR) Study
NCT02804360	PHASE2	UNKNOWN	Intravitreal Dexamethasone Implant in Retinitis Pigmentosa-related Macular Edema- a Retrospective Study
NCT02837640	PHASE2	UNKNOWN	Studying a Potential Protective Effect of L-Dopa on Retinitis Pigmentosa
NCT03073733	PHASE2	COMPLETED	Safety and Efficacy of Intravitreal Injection of Human Retinal Progenitor Cells in Adults With Retinitis Pigmentosa
NCT04356716	PHASE2	COMPLETED	Sildenafil for Treatment of Choroidal Ischemia
NCT04604899	PHASE2	COMPLETED	Safety of Repeat Intravitreal Injection of Human Retinal Progenitor Cells (jCell) in Adult Subjects With Retinitis Pigmentosa
NCT04763369	PHASE2	UNKNOWN	Investigation of Therapeutic Efficacy and Safety of UMSCs for the Management of Retinitis Pigmentosa (RP)
NCT04864496	PHASE2	UNKNOWN	Effects of Treatment With N- Acetylcysteine on Visual Outcomes in Patients With Retinitis Pigmentosa
NCT05085964	PHASE2	TERMINATED	An Open-Label Extension Study to Evaluate Safety & Tolerability of QR-421a in Subjects With Retinitis Pigmentosa
NCT05392179	PHASE2	COMPLETED	A Study in Subjects With Retinitis Pigmentosa
NCT06627179	PHASE2	RECRUITING	Study to Evaluate Ultevursen in Subjects With Retinitis Pigmentosa (RP) Due to Mutations in Exon 13 of the USH2A Gene
NCT06628947	PHASE2	RECRUITING	A Phase II Study of Intravitreal KIO-301 in Patients With Late-stage Retinitis Pigmentosa
NCT06912633	PHASE2	RECRUITING	Safety of a Single, Intravitreal Injection of 6.0M jCell (Famzeretcel) in Retinitis Pigmentosa (RP)