RPGRIP1

Summary

RPGRIP1 (RPGR interacting protein 1, HGNC:13436) is a protein-coding gene on chromosome 14q11.2, encoding X-linked retinitis pigmentosa GTPase regulator-interacting protein 1 (Q96KN7). May function as scaffolding protein.

This gene encodes a photoreceptor protein that interacts with retinitis pigmentosa GTPase regulator protein and is a key component of cone and rod photoreceptor cells. Mutations in this gene lead to autosomal recessive congenital blindness.

Source: NCBI Gene 57096 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cone-rod dystrophy 13 (Definitive, GenCC) — +3 more curated relationships
• GWAS associations: 7
• Clinical variants (ClinVar): 1,198 total — 125 pathogenic, 56 likely-pathogenic
• Phenotypes (HPO): 117
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_020366

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13436
Approved symbol	RPGRIP1
Name	RPGR interacting protein 1
Location	14q11.2
Locus type	gene with protein product
Status	Approved
Aliases	RGI1, LCA6, CORD13
Ensembl gene	ENSG00000092200
Ensembl biotype	protein_coding
OMIM	605446
Entrez	57096

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 8 protein_coding, 2 retained_intron, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000382933, ENST00000400017, ENST00000553500, ENST00000553927, ENST00000554303, ENST00000554750, ENST00000555322, ENST00000555489, ENST00000555587, ENST00000556336, ENST00000557351, ENST00000557606, ENST00000557771

RefSeq mRNA: 6 — MANE Select: NM_020366 NM_001377523, NM_001377948, NM_001377949, NM_001377950, NM_001377951, NM_020366

CCDS: CCDS45080, CCDS91848

Canonical transcript exons

ENST00000400017 — 25 exons

Exon	Start	End
ENSE00001235411	21324618	21325070
ENSE00001604657	21310584	21310607
ENSE00001609577	21317696	21317850
ENSE00001629871	21302488	21302584
ENSE00001695472	21312433	21312506
ENSE00001707762	21320017	21320177
ENSE00001714357	21307731	21307836
ENSE00001723260	21303331	21303543
ENSE00001736531	21321259	21321402
ENSE00001742649	21311824	21311970
ENSE00001770254	21294677	21294809
ENSE00001782143	21300966	21301237
ENSE00002491902	21287939	21288061
ENSE00003499462	21327623	21327807
ENSE00003504248	21325831	21326173
ENSE00003523426	21325232	21325383
ENSE00003539066	21334605	21334705
ENSE00003539162	21345113	21345197
ENSE00003543509	21343036	21343228
ENSE00003556192	21321854	21322004
ENSE00003561781	21328424	21328627
ENSE00003563426	21330249	21330387
ENSE00003653386	21351104	21351301
ENSE00003678241	21348172	21348302
ENSE00003913716	21280083	21280159

Expression profiles

Bgee: expression breadth ubiquitous, 168 present calls, max score 92.11.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.5122 / max 67.9735, expressed in 176 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
138530	0.3801	164
138525	0.0690	8
138528	0.0322	3
138527	0.0183	5
138526	0.0095	5
138529	0.0032	1

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left testis	UBERON:0004533	92.11	gold quality
sperm	CL:0000019	91.97	gold quality
right testis	UBERON:0004534	91.39	gold quality
male germ cell	CL:0000015	90.00	gold quality
testis	UBERON:0000473	89.09	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	83.62	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.21	gold quality
monocyte	CL:0000576	80.77	gold quality
mononuclear cell	CL:0000842	80.50	gold quality
leukocyte	CL:0000738	80.26	gold quality
granulocyte	CL:0000094	77.17	gold quality
adult organism	UBERON:0007023	74.33	gold quality
blood	UBERON:0000178	70.77	gold quality
triceps brachii	UBERON:0001509	67.03	gold quality
gluteal muscle	UBERON:0002000	66.82	gold quality
right lobe of liver	UBERON:0001114	65.76	gold quality
calcaneal tendon	UBERON:0003701	63.83	gold quality
spleen	UBERON:0002106	63.43	gold quality
pancreatic ductal cell	CL:0002079	62.72	silver quality
placenta	UBERON:0001987	62.46	gold quality
germinal epithelium of ovary	UBERON:0001304	62.20	gold quality
deltoid	UBERON:0001476	61.53	gold quality
liver	UBERON:0002107	61.38	gold quality
bone marrow	UBERON:0002371	61.16	gold quality
pigmented layer of retina	UBERON:0001782	60.76	silver quality
vermiform appendix	UBERON:0001154	60.63	gold quality
caecum	UBERON:0001153	60.51	gold quality
ileal mucosa	UBERON:0000331	59.88	gold quality
epithelial cell of pancreas	CL:0000083	59.83	gold quality
tibialis anterior	UBERON:0001385	59.83	silver quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.93

Regulation

Is transcription factor: no

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 26)

• RPGR and RPGRIP isoforms are distributed and co-localized at restricted foci throughout the outer segments of human and bovine, but not mice rod photoreceptors. (PMID:12140192)
• RPGR ORF15 isoform co-localizes with RPGRIP1 at cenrioles and basal bodies and interacts with nucleophosmin. (PMID:15772089)
• RPGRIP1-mediated nucleocytoplasmic crosstalk emerges with implications in the molecular pathogenesis of retinopathies (PMID:15800011)
• AIPL1, CRB1, GUCY2D, RPE65, and RPGRIP1 mutations may have roles in juvenile retinitis pigmentosa (PMID:16272259)
• RPGRIP1 and nephrocystin-4 interact strongly in vitro and in vivo, and that they colocalize in the retina (PMID:16339905)
• The RPGRIP1-Lebers congenital amaurosis patient has treatment potential for a gene replacement strategy if targeted to central, but not pericentral or peripheral, retina. (PMID:17306875)
• Studies highlight the recent developments in understanding the mechanism of cilia-dependent photoreceptor degeneration due to mutations in RPGR and PGR-interacting proteins in severe genetic diseases. (PMID:20090203)
• heterozygous non-synonymous variants of RPGRIP1 may cause or increase the susceptibility to various forms of glaucoma (PMID:21224891)
• Nek4 interaction with both RPGRIP1 and the RPGRIP1L is involved in cilium assembly. (PMID:21685204)
• RPGRIP1 in human and in canine model involves protein network and photoreceptor cilia. (PMID:22183349)
• We report a novel RPGRIP1 mutation causing LCA in a consanguineous Emirati family. To the best of our knowledge, this alteration has not been described in the literature so far. (PMID:23278760)
• Recessive RPGRIP1 mutations cause a severe cone-rod Leber congenital amaurosis phenotype, often with poor or no fixation and an oculodigital sign. In the first decade of life retinal changes are clinically most evident in the periphery. (PMID:23505306)
• Neurodevelopmental delay is a potential feature of strictly defined LCA, documented in our series for some children with homozygous RPGRIP1 and GUCY2D mutations. (PMID:24997176)
• Although the present patients did not show sufficient clinical findings as Leber congenital amaurosis (LCA), PCR findings and direct sequencing following microarray analysis confirmed that they were LCA. (PMID:25096270)
• SPATA7 plays a role in RPGRIP1-mediated protein trafficking across the connecting cilium of photoreceptor cells. Apoptotic degeneration of these cells triggered by protein mislocalization is a mechanism of disease progression in LCA3/juvenile RP patients (PMID:25398945)
• RPGRIP1 has an essential role in the photoreceptor connecting cilia, and photoreceptors lacking RPGRIP1 are unable to maintain the light sensing outer segments. [review] (PMID:25414380)
• Neurodevelopmental delay and brain atrophy in the CT scan were reported. Genomic sequencing identified a novel homozygous deletion, c.[420delG], in RPGRIP1. This mutation was not detected in 80 ethnically matched controls and has not been reported elsewhere. CONCLUSIONS: Identifying new mutations in Leber congenital amaurosis-related genes and their clinical manifestations can improve our understanding of the disease and. (PMID:27116508)
• Gene capture sequencing results found three probands carrying mutations of RPGRIP1, which was known to be associated with pathogenesis of LCA (Leber’s congenital amaurosis). By further clinical analysis, two probands were confirmed to be retinitis pigmentosa (RP) patients and one was confirmed to be LCA patient. These novel mutations were co-segregated with the disease phenotype in their families. (PMID:28456785)
• Data indicate that the c. 2889delT (p.P963 fs) mutation in the retinitis pigmentosa GTPase regulator interacting protein 1 (RPGRIP1) gene works as a pathogenic mutation that contributes to the progression of Leber congenital amaurosis (LCA). (PMID:29193763)
• Loss of Rpgrip1 expression is associated with Ciliopathy. (PMID:29650680)
• Although the patients had 2 mutated genes in common (RPGRIP1 and TMEM216), they only shared one common mutation in RPGRIP1 gene. Thus, it seems that this common RPGRIP1 mutation is associated with radial polydactyly but probably does not play a significant role in the Wassel type differentiation. (PMID:30498907)
• Clinical and molecular findings in a cohort of 152 Brazilian severe early onset inherited retinal dystrophy patients. (PMID:32865313)
• Whole Locus Sequencing Identifies a Prevalent Founder Deep Intronic RPGRIP1 Pathologic Variant in the French Leber Congenital Amaurosis Cohort. (PMID:33670832)
• Noncoding mutation in RPGRIP1 contributes to inherited retinal degenerations. (PMID:33907365)
• Molecular genetics with clinical characteristics of Leber congenital amaurosis in the Han population of western China. (PMID:33970760)
• RPGRIP1-related retinal disease presenting as isolated cone dysfunction. (PMID:36762997)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	rpgrip1	ENSDARG00000076055
mus_musculus	Rpgrip1	ENSMUSG00000057132
rattus_norvegicus	Rpgrip1	ENSRNOG00000011809
caenorhabditis_elegans		WBGENE00007490
caenorhabditis_elegans		WBGENE00206538

Paralogs (1): RPGRIP1L (ENSG00000103494)

Protein

Protein identifiers

X-linked retinitis pigmentosa GTPase regulator-interacting protein 1 — Q96KN7 (reviewed: Q96KN7)

All UniProt accessions (10): Q96KN7, G3V236, G3V3F7, G3V3I7, G3V577, H0YIY1, H0YJ18, H0YJ99, H0YJK6, Q5D221

UniProt curated annotations — full annotation on UniProt →

Function. May function as scaffolding protein. Required for normal location of RPGR at the connecting cilium of photoreceptor cells. Required for normal disk morphogenesis and disk organization in the outer segment of photoreceptor cells and for survival of photoreceptor cells.

Subunit / interactions. Forms homodimers and elongated homopolymers. Interacts with RPGR. Interacts with NPHP4. Interacts with NEK4. Interacts with SPATA7. Interacts with CEP290/NPHP6; mediating the association between RPGR and CEP290/NPHP6.

Subcellular location. Cell projection. Cilium.

Tissue specificity. Strong expression in retina, with weaker expression in testis. Expressed in other neurons such as amacrine cells. Colocalizes with RGPR in the outer segment of rod photoreceptors and cone outer segments.

Disease relevance. Leber congenital amaurosis 6 (LCA6) [MIM:613826] 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. Cone-rod dystrophy 13 (CORD13) [MIM:608194] An inherited retinal dystrophy characterized by retinal pigment deposits visible on fundus examination, predominantly in the macular region, and initial loss of cone photoreceptors followed by rod degeneration. This leads to decreased visual acuity and sensitivity in the central visual field, followed by loss of peripheral vision. Severe loss of vision occurs earlier than in retinitis pigmentosa, due to cone photoreceptors degenerating at a higher rate than rod photoreceptors. The disease is caused by variants affecting the gene represented in this entry. Heterozygous non-synonymous variants of RPGRIP1 may cause or increase the susceptibility to various forms of glaucoma, a genetically heterogeneous disorder. It is the second cause of blindness worldwide owing to the progressive degeneration of retinal ganglion neurons.

Domain organisation. The C2 domain does not bind calcium ions, and does not bind phosphoinositides.

Similarity. Belongs to the RPGRIP1 family.

Isoforms (6)

UniProt ID	Names	Canonical?
Q96KN7-1	1	yes
Q96KN7-2	2, a
Q96KN7-3	3, b
Q96KN7-4	4
Q96KN7-5	5
Q96KN7-6	6

RefSeq proteins (6): NP_001364452, NP_001364877, NP_001364878, NP_001364879, NP_001364880, NP_065099* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000008	C2_dom	Domain
IPR021656	C2-C2_1	Domain
IPR031139	RPGRIP1_fam	Family
IPR035892	C2_domain_sf	Homologous_superfamily
IPR041091	RPGRIP1_C	Domain

Pfam: PF00168, PF11618, PF18111

UniProt features (83 total): sequence variant 36, splice variant 9, strand 7, compositionally biased region 6, mutagenesis site 6, helix 6, region of interest 4, sequence conflict 4, turn 2, chain 1, domain 1, coiled-coil region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
4QAM	X-RAY DIFFRACTION	1.83

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96KN7-F1	67.60	0.29

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
1121	nearly abolishes interaction with rpgr; when associated with a-1174 and a-1245.
1121	decreases interaction with rpgr.
1174	nearly abolishes interaction with rpgr; when associated with a-1121 and a-1245.
1174	abolishes interaction with rpgr.
1245	nearly abolishes interaction with rpgr; when associated with a-1121 and a-1174.
1245	no effect on interaction with rpgr.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 358 (showing top): GOBP_NEUROGENESIS, GOBP_NEURAL_RETINA_DEVELOPMENT, BOYLAN_MULTIPLE_MYELOMA_D_DN, MODULE_59, GOBP_NEURAL_PRECURSOR_CELL_PROLIFERATION, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, GOBP_EYE_PHOTORECEPTOR_CELL_DIFFERENTIATION, MORF_ZNF10, BOYLAN_MULTIPLE_MYELOMA_D_CLUSTER_DN, MARTINEZ_RB1_TARGETS_DN, BLALOCK_ALZHEIMERS_DISEASE_UP, GOBP_SENSORY_PERCEPTION_OF_LIGHT_STIMULUS, GOBP_CILIUM_ORGANIZATION, GOBP_PHOTORECEPTOR_CELL_DEVELOPMENT, GOBP_ORGANELLE_ASSEMBLY

GO Biological Process (6): visual perception (GO:0007601), retinal rod cell development (GO:0046548), neural precursor cell proliferation (GO:0061351), non-motile cilium assembly (GO:1905515), eye photoreceptor cell development (GO:0042462), retina development in camera-type eye (GO:0060041)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (13): cytosol (GO:0005829), cilium (GO:0005929), axoneme (GO:0005930), microtubule cytoskeleton (GO:0015630), photoreceptor connecting cilium (GO:0032391), intercellular bridge (GO:0045171), ciliary tip (GO:0097542), photoreceptor distal connecting cilium (GO:0120206), cytoplasm (GO:0005737), cytoskeleton (GO:0005856), cell projection (GO:0042995), neuron projection (GO:0043005), non-motile cilium (GO:0097730)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	7
plasma membrane bounded cell projection	2
cytoskeleton	2
cilium	2
sensory perception of light stimulus	1
eye photoreceptor cell development	1
retinal rod cell differentiation	1
cell population proliferation	1
cilium assembly	1
eye photoreceptor cell differentiation	1
photoreceptor cell development	1
camera-type eye development	1
anatomical structure development	1
binding	1
cytoplasm	1
intraciliary transport particle	1
membrane-bounded organelle	1
microtubule	1
ciliary plasm	1
ciliary transition zone	1
photoreceptor cell cilium	1
photoreceptor connecting cilium	1
intracellular anatomical structure	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

1260 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RPGRIP1	RPGR	Q92834	999
RPGRIP1	NPHP4	O75161	992
RPGRIP1	CEP290	O15078	949
RPGRIP1	AIPL1	Q9NZN9	943
RPGRIP1	GUCY2D	Q02846	940
RPGRIP1	SPATA7	Q9P0W8	935
RPGRIP1	NPHP1	O15259	906
RPGRIP1	LCA5	Q86VQ0	895
RPGRIP1	TULP1	O00294	868
RPGRIP1	RDH12	Q96NR8	862
RPGRIP1	RPE65	Q16518	861
RPGRIP1	RD3	Q7Z3Z2	860
RPGRIP1	CRX	O43186	858
RPGRIP1	IQCB1	Q15051	853
RPGRIP1	LRAT	O95237	806

IntAct

80 interactions, top by confidence:

A	B	Type	Score
RPGRIP1	RPGR	psi-mi:“MI:0915”(physical association)	0.840
RPGR	RPGRIP1	psi-mi:“MI:0915”(physical association)	0.840
RPGRIP1	NEK4	psi-mi:“MI:0914”(association)	0.620
RPGRIP1	NPHP4	psi-mi:“MI:0915”(physical association)	0.620
NPHP4	RPGRIP1	psi-mi:“MI:0915”(physical association)	0.620
TFPT	RPGRIP1	psi-mi:“MI:0915”(physical association)	0.560
MAGEB2	RPGRIP1	psi-mi:“MI:0915”(physical association)	0.560
CSPP1	RPGRIP1	psi-mi:“MI:0915”(physical association)	0.560
RPGRIP1	FAM74A4	psi-mi:“MI:0915”(physical association)	0.560
RPGRIP1	DPPA4	psi-mi:“MI:0915”(physical association)	0.560
CCDC146	RPGRIP1	psi-mi:“MI:0915”(physical association)	0.560
RPGRIP1	RPP25L	psi-mi:“MI:0915”(physical association)	0.560
RPGRIP1	ZNF417	psi-mi:“MI:0915”(physical association)	0.560
RPGRIP1	ZNF564	psi-mi:“MI:0915”(physical association)	0.560
RPGRIP1	AEN	psi-mi:“MI:0915”(physical association)	0.560
RPGRIP1	GATAD2B	psi-mi:“MI:0915”(physical association)	0.560
FEM1C	RPGRIP1	psi-mi:“MI:0915”(physical association)	0.560
RPGRIP1	TRIB3	psi-mi:“MI:0915”(physical association)	0.560
SCNM1	RPGRIP1	psi-mi:“MI:0915”(physical association)	0.560
CBX8	RPGRIP1	psi-mi:“MI:0915”(physical association)	0.560
HEYL	RPGRIP1	psi-mi:“MI:0915”(physical association)	0.560
RPGRIP1	CHCHD3	psi-mi:“MI:0915”(physical association)	0.560
RPGRIP1	TBC1D7	psi-mi:“MI:0915”(physical association)	0.560
RPGRIP1	ZNF337	psi-mi:“MI:0915”(physical association)	0.560
RPGRIP1	TFPT	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (82): RPGRIP1 (Two-hybrid), RPGRIP1 (Two-hybrid), RPGRIP1 (Two-hybrid), RPGRIP1 (Two-hybrid), RPGRIP1 (Two-hybrid), RPGRIP1 (Two-hybrid), RPGRIP1 (Two-hybrid), RPGRIP1 (Two-hybrid), RPGRIP1 (Two-hybrid), CBX8 (Two-hybrid), GATAD2B (Two-hybrid), CCDC146 (Two-hybrid), TRIB3 (Two-hybrid), AEN (Two-hybrid), SCNM1 (Two-hybrid)

ESM2 similar proteins: A0JM13, A1A4L4, A2RRS8, B0DOB4, D4A039, O00750, O70167, O70173, Q08EC4, Q1LXR6, Q3ULW6, Q3UQI9, Q3V0L5, Q3ZAV8, Q4AC94, Q4G0A6, Q52KB6, Q5DTU0, Q5F479, Q5JV73, Q5SUS0, Q5T0N1, Q5XIR4, Q5XIZ9, Q6IFT4, Q6IRN0, Q6IRU7, Q6P1H6, Q6P4K6, Q6PF55, Q6REY9, Q6ZPF3, Q7TP65, Q7Z2Z1, Q80TQ5, Q80VH0, Q8C008, Q8IWE5, Q8N4X5, Q8N5R6

Diamond homologs: A0A096LPI5, P51957, P78312, Q09FC8, Q5H9K5, Q68CZ1, Q8CG73, Q8N9N2, Q8TDM0, Q92918, Q96J02, Q96KN7, Q96MD7, Q9EPQ2, Q9GLM3

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
RPGRIP1	“down-regulates activity”	RPGR	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

1198 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	125
Likely pathogenic	56
Uncertain significance	527
Likely benign	333
Benign	54

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1069706	NM_020366.4(RPGRIP1):c.711del (p.Lys239fs)	Pathogenic
1073081	NC_000014.8:g.(?21795782)(21795966_?)del	Pathogenic
1073082	NC_000014.8:g.(?21798388)(21798566_?)del	Pathogenic
1074385	NM_020366.4(RPGRIP1):c.1363del (p.Glu455fs)	Pathogenic
1074924	NM_020366.4(RPGRIP1):c.313C>T (p.Gln105Ter)	Pathogenic
1357904	NM_020366.4(RPGRIP1):c.663dup (p.Asn222Ter)	Pathogenic
1369938	NM_020366.4(RPGRIP1):c.2024del (p.Leu675fs)	Pathogenic
1375717	NM_020366.4(RPGRIP1):c.1111C>T (p.Arg371Ter)	Pathogenic
1382627	NM_020366.4(RPGRIP1):c.1145T>A (p.Leu382Ter)	Pathogenic
1387428	NM_020366.4(RPGRIP1):c.1867C>T (p.Gln623Ter)	Pathogenic
1395639	NM_020366.4(RPGRIP1):c.2308_2311del (p.Lys770fs)	Pathogenic
1415268	NM_020366.4(RPGRIP1):c.931-2_935delinsT	Pathogenic
1436742	NM_020366.4(RPGRIP1):c.3617+1G>T	Pathogenic
1437865	NM_020366.4(RPGRIP1):c.3275_3276dup (p.Ala1093fs)	Pathogenic
1451134	NM_020366.4(RPGRIP1):c.898del (p.Val300fs)	Pathogenic
1451517	NM_020366.4(RPGRIP1):c.808_826del (p.Ser269_Ile270insTer)	Pathogenic
1452635	NM_020366.4(RPGRIP1):c.1995T>A (p.Cys665Ter)	Pathogenic
1452857	NM_020366.4(RPGRIP1):c.3610C>T (p.Gln1204Ter)	Pathogenic
1455333	NM_020366.4(RPGRIP1):c.767C>G (p.Ser256Ter)	Pathogenic
1455614	NM_020366.4(RPGRIP1):c.1930C>T (p.Gln644Ter)	Pathogenic
1456668	NC_000014.8:g.(?21785835)(21788356_?)del	Pathogenic
1458554	NM_020366.4(RPGRIP1):c.1089_1090dup (p.Val364fs)	Pathogenic
1459285	NM_020366.4(RPGRIP1):c.282_283dup (p.Ala95fs)	Pathogenic
1459438	NC_000014.8:g.(?21756136)(21756240_?)del	Pathogenic
156380	NM_020366.4(RPGRIP1):c.1892A>T (p.His631Leu)	Pathogenic
156381	NM_020366.4(RPGRIP1):c.3565_3571del (p.Arg1189fs)	Pathogenic
156387	NM_020366.4(RPGRIP1):c.832C>T (p.Arg278Ter)	Pathogenic
156388	NM_020366.4(RPGRIP1):c.2356C>T (p.Gln786Ter)	Pathogenic
1687212	NM_020366.4(RPGRIP1):c.1151+1G>A	Pathogenic
1929443	NM_020366.4(RPGRIP1):c.442A>T (p.Arg148Ter)	Pathogenic

SpliceAI

4169 predictions. Top by Δscore:

Variant	Effect	Δscore
14:21294796:G:GT	donor_gain	1.0000
14:21294805:AAAAG:A	donor_loss	1.0000
14:21294807:AAGG:A	donor_loss	1.0000
14:21294808:AGGT:A	donor_loss	1.0000
14:21294809:GGTA:G	donor_loss	1.0000
14:21294810:G:A	donor_loss	1.0000
14:21294811:T:G	donor_loss	1.0000
14:21301233:GAGGG:G	donor_gain	1.0000
14:21307728:CAG:C	acceptor_gain	1.0000
14:21307729:A:AG	acceptor_gain	1.0000
14:21307729:AGA:A	acceptor_gain	1.0000
14:21307730:G:GG	acceptor_gain	1.0000
14:21307730:GA:G	acceptor_gain	1.0000
14:21307730:GAG:G	acceptor_gain	1.0000
14:21307832:AAGAG:A	donor_loss	1.0000
14:21307833:AGAGG:A	donor_loss	1.0000
14:21307834:GAG:G	donor_gain	1.0000
14:21307835:AGGT:A	donor_loss	1.0000
14:21307836:GGTG:G	donor_loss	1.0000
14:21307837:GTG:G	donor_loss	1.0000
14:21307838:T:A	donor_loss	1.0000
14:21317694:A:AG	acceptor_gain	1.0000
14:21317695:G:GG	acceptor_gain	1.0000
14:21317695:GC:G	acceptor_gain	1.0000
14:21320014:CAGCC:C	acceptor_loss	1.0000
14:21320015:A:AG	acceptor_gain	1.0000
14:21320015:A:AT	acceptor_loss	1.0000
14:21320016:G:GA	acceptor_gain	1.0000
14:21320016:GC:G	acceptor_gain	1.0000
14:21320016:GCC:G	acceptor_gain	1.0000

AlphaMissense

8483 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:21348180:T:C	F1209S	0.996
14:21321347:T:C	L519P	0.993
14:21326057:T:C	L865P	0.993
14:21327685:T:A	W925R	0.992
14:21327685:T:C	W925R	0.992
14:21351143:T:C	L1263P	0.992
14:21321368:T:C	L526P	0.991
14:21325939:T:G	Y826D	0.991
14:21324812:T:C	F653L	0.990
14:21324814:C:A	F653L	0.990
14:21324814:C:G	F653L	0.990
14:21327687:G:C	W925C	0.990
14:21327687:G:T	W925C	0.990
14:21321374:T:C	L528P	0.989
14:21326084:T:A	V874D	0.989
14:21321377:A:C	Q529P	0.988
14:21321954:G:C	R571P	0.987
14:21326078:T:A	I872K	0.987
14:21343070:T:C	L1125P	0.987
14:21325946:T:C	F828S	0.986
14:21343219:T:C	F1175L	0.986
14:21343221:T:A	F1175L	0.986
14:21343221:T:G	F1175L	0.986
14:21326003:T:C	F847S	0.984
14:21327680:T:C	L923P	0.984
14:21326141:T:C	L893S	0.983
14:21327635:T:C	L908P	0.983
14:21348186:T:A	V1211E	0.983
14:21348234:G:A	G1227E	0.983
14:21326072:T:C	L870S	0.982

dbSNP variants (sampled 300 via entrez): RS1000012269 (14:21347463 A>G), RS1000031000 (14:21333866 C>G), RS1000123165 (14:21339213 C>T), RS1000126550 (14:21347787 G>A,T), RS1000126762 (14:21306061 A>G), RS1000142616 (14:21281062 G>A), RS1000194407 (14:21285216 A>G), RS1000196714 (14:21281297 C>G,T), RS1000250149 (14:21310658 C>G), RS1000468148 (14:21344484 C>T), RS1000515164 (14:21297579 G>A), RS1000557159 (14:21288513 T>A,C,G), RS1000636441 (14:21335171 C>A,T), RS1000657040 (14:21337778 T>A), RS1000730329 (14:21328973 G>A,C)

Disease associations

OMIM: gene MIM:605446 | disease phenotypes: MIM:608194, MIM:613826, MIM:268000, MIM:204000, MIM:209900, MIM:120970, MIM:611560

GenCC curated gene-disease

Disease	Classification	Inheritance
Leber congenital amaurosis 6	Definitive	Autosomal recessive
cone-rod dystrophy 13	Definitive	Autosomal recessive
cone-rod dystrophy	Supportive	Autosomal dominant
Leber congenital amaurosis	Supportive	Autosomal dominant

Mondo (13): cone-rod dystrophy 13 (MONDO:0011987), Leber congenital amaurosis 6 (MONDO:0013446), inherited retinal dystrophy (MONDO:0019118), retinitis pigmentosa (MONDO:0019200), Leber congenital amaurosis (MONDO:0018998), Leber congenital amaurosis 1 (MONDO:0008764), Bardet-Biedl syndrome (MONDO:0015229), optic atrophy (MONDO:0003608), retinal disorder (MONDO:0005283), cone dystrophy (MONDO:0000455), cone-rod dystrophy (MONDO:0015993), microcephaly (MONDO:0001149), Joubert syndrome 7 (MONDO:0012694)

Orphanet (8): Cone rod dystrophy (Orphanet:1872), Leber congenital amaurosis (Orphanet:65), OBSOLETE: Inherited retinal disorder (Orphanet:71862), Retinitis pigmentosa (Orphanet:791), Microphthalmia-anophthalmia-coloboma (Orphanet:98555), Bardet-Biedl syndrome (Orphanet:110), Progressive cone dystrophy (Orphanet:1871), Joubert syndrome with renal defect (Orphanet:220497)

HPO phenotypes

117 total (30 of 117 shown, HPO-id order):

HPO	Term
HP:0000003	Multicystic kidney dysplasia
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000037	Male pseudohermaphroditism
HP:0000062	Ambiguous genitalia
HP:0000068	Urethral atresia
HP:0000073	Ureteral duplication
HP:0000175	Cleft palate
HP:0000221	Furrowed tongue
HP:0000238	Hydrocephalus
HP:0000252	Microcephaly
HP:0000293	Full cheeks
HP:0000316	Hypertelorism
HP:0000340	Sloping forehead
HP:0000347	Micrognathia
HP:0000358	Posteriorly rotated ears
HP:0000365	Hearing impairment
HP:0000457	Depressed nasal ridge
HP:0000482	Microcornea
HP:0000486	Strabismus
HP:0000505	Visual impairment
HP:0000512	Abnormal electroretinogram
HP:0000518	Cataract
HP:0000528	Anophthalmia
HP:0000529	Progressive visual loss
HP:0000532	Abnormal chorioretinal morphology
HP:0000533	Chorioretinal atrophy
HP:0000540	Hypermetropia
HP:0000543	Optic disc pallor
HP:0000545	Myopia

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST005950_1	Body mass index x sex x age interaction (4df test)	2.000000e-187
GCST005951_192	Body mass index	4.000000e-188
GCST005952_1	Body mass index (age>50)	1.000000e-97
GCST008839_563	Height	2.000000e-12
GCST009256_11	Superior temporal sulcus banks volume	1.000000e-06
GCST010002_196	Refractive error	6.000000e-09
GCST010796_1841	Electrocardiogram morphology (amplitude at temporal datapoints)	5.000000e-08

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0004327	electrocardiography

MeSH disease descriptors (12)

Descriptor	Name	Tree numbers
D020788	Bardet-Biedl Syndrome	C10.228.140.617.200; C11.270.684.624; C16.131.077.245.125; C16.320.184.125
D000077765	Cone Dystrophy	C11.270.151; C11.768.216
D000071700	Cone-Rod Dystrophies	C11.270.152; C11.768.585.658.250; C16.320.290.152
D057130	Leber Congenital Amaurosis	C11.270.516; C11.768.364
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
D009896	Optic Atrophy	C10.292.700.225; C11.640.451
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
C567698	Cone-Rod Dystrophy 13 (supp.)
C566916	Joubert Syndrome 7 (supp.)
C565327	Leber Congenital Amaurosis 6 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

17 total (human), top 17 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
triphenyl phosphate	affects expression	1
2,4,5,2’,4’,5’-hexachlorobiphenyl	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine	increases expression	1
di-n-butylphosphoric acid	affects expression	1
abrine	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
Air Pollutants	increases abundance, affects expression	1
Benzo(a)pyrene	decreases methylation	1
Cadmium	decreases expression, increases abundance	1
Camptothecin	increases expression	1
Lipopolysaccharides	affects response to substance, increases expression, decreases expression	1
Ozone	affects expression, increases abundance	1
Silicon Dioxide	decreases expression	1
Tretinoin	increases expression	1
Antirheumatic Agents	decreases expression	1
Cadmium Chloride	decreases expression, increases abundance	1

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)