RTN4IP1

Summary

RTN4IP1 (reticulon 4 interacting protein 1, HGNC:18647) is a protein-coding gene on chromosome 6q21, encoding NAD(P)H oxidoreductase RTN4IP1, mitochondrial (Q8WWV3). NAD(P)H oxidoreductase involved in the ubiquinone biosynthetic pathway. It is a selective cancer dependency (DepMap: 11.1% of cell lines).

This gene encodes a mitochondrial protein that interacts with reticulon 4, which is a potent inhibitor of regeneration following spinal cord injury. This interaction may be important for reticulon-induced inhibition of neurite growth. Mutations in this gene can cause optic atrophy 10, with or without ataxia, cognitive disability, and seizures. There is a pseudogene for this gene on chromosome 12. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 84816 — RefSeq curated summary.

At a glance

• Gene–disease (curated): optic atrophy 10 with or without ataxia, intellectual disability, and seizures (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 2
• Clinical variants (ClinVar): 351 total — 27 pathogenic, 9 likely-pathogenic
• Phenotypes (HPO): 13
• Cancer dependency (DepMap): dependent in 11.1% of screened cell lines
• MANE Select transcript: NM_032730

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18647
Approved symbol	RTN4IP1
Name	reticulon 4 interacting protein 1
Location	6q21
Locus type	gene with protein product
Status	Approved
Aliases	Yim1, NIMP
Ensembl gene	ENSG00000130347
Ensembl biotype	protein_coding
OMIM	610502
Entrez	84816

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 8 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000369063, ENST00000493619, ENST00000498091, ENST00000539449, ENST00000865781, ENST00000865782, ENST00000865783, ENST00000865784, ENST00000913981, ENST00000947236

RefSeq mRNA: 2 — MANE Select: NM_032730 NM_001318746, NM_032730

CCDS: CCDS5056

Canonical transcript exons

ENST00000369063 — 9 exons

Exon	Start	End
ENSE00000895078	106622818	106622969
ENSE00000895086	106621425	106621493
ENSE00000895094	106619202	106619326
ENSE00000895101	106602874	106602922
ENSE00000895107	106592164	106592300
ENSE00000895114	106587679	106587862
ENSE00001448731	106628748	106629498
ENSE00001859100	106570771	106572103
ENSE00003587712	106583328	106583420

Expression profiles

Bgee: expression breadth ubiquitous, 223 present calls, max score 96.37.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 4.3109 / max 44.3196, expressed in 1569 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
74907	2.9544	1455
74906	1.1244	612
74905	0.1760	82
74908	0.0561	19

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	96.37	gold quality
oocyte	CL:0000023	95.02	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	86.92	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.38	gold quality
mucosa of transverse colon	UBERON:0004991	83.48	gold quality
hindlimb stylopod muscle	UBERON:0004252	82.92	gold quality
apex of heart	UBERON:0002098	82.37	gold quality
biceps brachii	UBERON:0001507	82.26	gold quality
heart left ventricle	UBERON:0002084	82.07	gold quality
vastus lateralis	UBERON:0001379	82.05	gold quality
middle temporal gyrus	UBERON:0002771	81.88	gold quality
muscle of leg	UBERON:0001383	81.82	gold quality
gastrocnemius	UBERON:0001388	81.81	gold quality
cardiac ventricle	UBERON:0002082	81.74	gold quality
quadriceps femoris	UBERON:0001377	80.89	gold quality
adrenal tissue	UBERON:0018303	79.99	gold quality
skeletal muscle tissue	UBERON:0001134	79.67	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	78.95	gold quality
right atrium auricular region	UBERON:0006631	78.91	gold quality
heart	UBERON:0000948	78.79	gold quality
heart right ventricle	UBERON:0002080	78.42	gold quality
islet of Langerhans	UBERON:0000006	78.13	gold quality
right adrenal gland cortex	UBERON:0035827	77.84	gold quality
right adrenal gland	UBERON:0001233	77.62	gold quality
adult mammalian kidney	UBERON:0000082	77.56	gold quality
prefrontal cortex	UBERON:0000451	77.52	gold quality
cardiac atrium	UBERON:0002081	77.48	gold quality
metanephros cortex	UBERON:0010533	77.46	gold quality
rectum	UBERON:0001052	77.43	gold quality
muscle tissue	UBERON:0002385	77.36	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.52

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GATA3

miRNA regulators (miRDB)

67 targeting RTN4IP1, 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-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4650-5P	99.98	64.69	999
HSA-MIR-512-3P	99.97	67.35	1049
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-3605-5P	99.96	67.12	932
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-1-3P	99.93	72.35	1914
HSA-MIR-206	99.93	72.50	1893
HSA-MIR-613	99.91	71.50	1710
HSA-MIR-489-3P	99.80	66.46	839
HSA-MIR-1299	99.77	71.24	2389
HSA-MIR-3913-3P	99.74	66.53	938
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-548AU-3P	99.70	68.22	1373
HSA-MIR-3934-5P	99.67	64.04	846
HSA-MIR-1303	99.65	69.77	1662
HSA-MIR-875-3P	99.63	69.47	2548
HSA-MIR-488-3P	99.61	68.79	1731

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 11.1% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 7)

• RTN4IP1 has a tumor-suppressive function and may regulate thyroid cancer progression. (PMID:23393170)
• Recessive Mutations in RTN4IP1 Cause Isolated and Syndromic Optic Neuropathies. (PMID:26593267)
• This study showed that large spectrum of neurologic features, ranging from isolated optic atrophy to severe early-onset encephalopathy, can be associated with biallelic mutations in RTN4IP1. (PMID:29181510)
• Exome sequencing identifies novel missense and deletion variants in RTN4IP1 associated with optic atrophy, global developmental delay, epilepsy, ataxia, and choreoathetosis. (PMID:33037779)
• Combined Optic Atrophy and Rod-Cone Dystrophy Expands the RTN4IP1 (Optic Atrophy 10) Phenotype. (PMID:33136666)
• A ROD-CONE DYSTROPHY IS SYSTEMATICALLY ASSOCIATED TO THE RTN4IP1 RECESSIVE OPTIC ATROPHY. (PMID:33315831)
• A Novel Homozygous Founder Variant of RTN4IP1 in Two Consanguineous Saudi Families. (PMID:36231115)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	rtn4ip1	ENSDARG00000031366
mus_musculus	Rtn4ip1	ENSMUSG00000019864
rattus_norvegicus	Rtn4ip1	ENSRNOG00000000279
drosophila_melanogaster	CG17221	FBGN0031500
caenorhabditis_elegans	rad-8	WBGENE00044305

Paralogs (17): PTGR1 (ENSG00000106853), VAT1 (ENSG00000108828), TP53I3 (ENSG00000115129), MECR (ENSG00000116353), CRYZ (ENSG00000116791), PTGR2 (ENSG00000140043), SORD (ENSG00000140263), VAT1L (ENSG00000171724), ADH6 (ENSG00000172955), PTGR3 (ENSG00000180011), ADH1A (ENSG00000187758), ADH7 (ENSG00000196344), ADH1B (ENSG00000196616), ADH5 (ENSG00000197894), ADH4 (ENSG00000198099), CRYZL1 (ENSG00000205758), ADH1C (ENSG00000248144)

Protein

Protein identifiers

NAD(P)H oxidoreductase RTN4IP1, mitochondrial — Q8WWV3 (reviewed: Q8WWV3)

Alternative names: NOGO-interacting mitochondrial protein, Reticulon-4-interacting protein 1

All UniProt accessions (2): Q8WWV3, G3V1R2

UniProt curated annotations — full annotation on UniProt →

Function. NAD(P)H oxidoreductase involved in the ubiquinone biosynthetic pathway. Required for the O-methyltransferase activity of COQ3. Able to catalyze the oxidoreduction of 3-demethylubiquinone into 3-demethylubiquinol in vitro. However, it is unclear if 3-demethylubiquinone constitutes a substrate in vivo. May also play a role in the regulation of retinal ganglion cell (RGC) neurite outgrowth, and hence in the development of the inner retina and optic nerve. Appears to be a potent inhibitor of regeneration following spinal cord injury.

Subunit / interactions. Interacts with RTN4, UQCRC1 and UQCRC2.

Subcellular location. Mitochondrion matrix. Mitochondrion outer membrane.

Tissue specificity. Widely expressed in mitochondria-enriched tissues. Found in heart, muscle, kidney, liver, brain and placenta.

Disease relevance. Optic atrophy 10 with or without ataxia, impaired intellectual development, and seizures (OPA10) [MIM:616732] An autosomal recessive disease characterized by progressive visual loss in association with optic atrophy. Atrophy of the optic disk indicates a deficiency in the number of nerve fibers which arise in the retina and converge to form the optic disk, optic nerve, optic chiasm and optic tracts. OPA10 patients may also manifest mild ataxia, mild intellectual disability and, rarely, generalized seizures. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Cofactor biosynthesis; ubiquinone biosynthesis.

Similarity. Belongs to the zinc-containing alcohol dehydrogenase family. Quinone oxidoreductase subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
Q8WWV3-1	1	yes
Q8WWV3-2	2
Q8WWV3-3	3, Short

RefSeq proteins (2): NP_001305675, NP_116119* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002364	Quin_OxRdtase/zeta-crystal_CS	Conserved_site
IPR011032	GroES-like_sf	Homologous_superfamily
IPR013154	ADH-like_N	Domain
IPR020843	ER	Domain
IPR036291	NAD(P)-bd_dom_sf	Homologous_superfamily
IPR037397	RTN4IP1	Family
IPR050700	YIM1/Zinc_Alcohol_DH_Fams	Family

Pfam: PF08240, PF13602

Catalyzed reactions (Rhea), 4 shown:

• a 3-demethylubiquinone + NADH + 2 H(+) = a 3-demethylubiquinol + NAD(+) (RHEA:83235)
• a 3-demethylubiquinone + NADPH + 2 H(+) = a 3-demethylubiquinol + NADP(+) (RHEA:83239)
• 3-demethylubiquinone-10 + NADH + 2 H(+) = 3-demethylubiquinol-10 + NAD(+) (RHEA:83243)
• 3-demethylubiquinone-10 + NADPH + 2 H(+) = 3-demethylubiquinol-10 + NADP(+) (RHEA:83247)

UniProt features (76 total): helix 17, strand 16, sequence variant 15, binding site 12, sequence conflict 5, turn 4, splice variant 3, transit peptide 1, chain 1, domain 1, mutagenesis site 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2VN8	X-RAY DIFFRACTION	2.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8WWV3-F1	91.54	0.86

Functional residue map

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

Ligand- & substrate-binding residues (12): 341; 343; 386; 387; 388; 214; 216; 217; 237; 255; 276; 300

Mutagenesis-validated functional residues (1):

Position	Phenotype
215	abolished nad(p)h oxidoreductase activity.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 122 (showing top): GOBP_DENDRITE_DEVELOPMENT, GOBP_NEUROGENESIS, GOBP_KETONE_METABOLIC_PROCESS, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, GOBP_REGULATION_OF_CELL_PROJECTION_ORGANIZATION, GOCC_MITOCHONDRIAL_ENVELOPE, GOBP_KETONE_BIOSYNTHETIC_PROCESS, GOBP_REGULATION_OF_NEURON_PROJECTION_DEVELOPMENT, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_NAD_P_H, GOBP_CELL_PROJECTION_ORGANIZATION, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_CH_OH_GROUP_OF_DONORS, GOBP_REGULATION_OF_DENDRITE_DEVELOPMENT, GOBP_QUINONE_METABOLIC_PROCESS, GOCC_MITOCHONDRIAL_MATRIX, MARSON_BOUND_BY_FOXP3_UNSTIMULATED

GO Biological Process (3): ubiquinone biosynthetic process (GO:0006744), nervous system development (GO:0007399), regulation of dendrite development (GO:0050773)

GO Molecular Function (6): nucleotide binding (GO:0000166), zinc ion binding (GO:0008270), NADPH dehydrogenase (quinone) activity (GO:0008753), NADH dehydrogenase (quinone) (non-electrogenic) activity (GO:0050136), protein binding (GO:0005515), oxidoreductase activity (GO:0016491)

GO Cellular Component (4): mitochondrion (GO:0005739), mitochondrial outer membrane (GO:0005741), mitochondrial matrix (GO:0005759), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
NAD(P)H dehydrogenase (quinone) activity	2
ubiquinone metabolic process	1
quinone biosynthetic process	1
system development	1
regulation of neuron projection development	1
dendrite development	1
regulation of developmental process	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
transition metal ion binding	1
NADPH dehydrogenase activity	1
NADH dehydrogenase activity	1
binding	1
catalytic activity	1
cytoplasm	1
intracellular membrane-bounded organelle	1
mitochondrial membrane	1
organelle outer membrane	1
mitochondrion	1
intracellular organelle lumen	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1764 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RTN4IP1	RTN4	Q9NQC3	985
RTN4IP1	TMEM126A	Q9H061	700
RTN4IP1	MTRES1	Q9P0P8	498
RTN4IP1	VWA8	A3KMH1	486
RTN4IP1	WFS1	O76024	464
RTN4IP1	SPG7	Q9UQ90	460
RTN4IP1	QRSL1	Q9H0R6	433
RTN4IP1	AFG3L2	Q9Y4W6	432
RTN4IP1	BEND3	Q5T5X7	425
RTN4IP1	HCCS	P53701	408
RTN4IP1	SCML4	Q8N228	404
RTN4IP1	NDUFC1	O43677	399
RTN4IP1	NDUFS2	O75306	397
RTN4IP1	PRDM1	O75626	378
RTN4IP1	ITGAM	P11215	373

IntAct

93 interactions, top by confidence:

A	B	Type	Score
RTN4IP1	ZYX	psi-mi:“MI:0915”(physical association)	0.740
ZYX	RTN4IP1	psi-mi:“MI:0915”(physical association)	0.740
LETMD1	RTN4IP1	psi-mi:“MI:0914”(association)	0.640
RTN4IP1	PYM1	psi-mi:“MI:0915”(physical association)	0.560
CTAG1A	RTN4IP1	psi-mi:“MI:0915”(physical association)	0.560
RTN4IP1	CENPK	psi-mi:“MI:0915”(physical association)	0.560
RTN4IP1	SMURF2	psi-mi:“MI:0915”(physical association)	0.560
HDX	RTN4IP1	psi-mi:“MI:0915”(physical association)	0.560
RTN4IP1	WWTR1	psi-mi:“MI:0915”(physical association)	0.560
RTN4IP1	GGA2	psi-mi:“MI:0915”(physical association)	0.560
	RTN4IP1	psi-mi:“MI:0915”(physical association)	0.560
RTN4IP1	RELA	psi-mi:“MI:0915”(physical association)	0.560
RTN4IP1	ARFGAP3	psi-mi:“MI:0915”(physical association)	0.560
PPP1R8	RTN4IP1	psi-mi:“MI:0915”(physical association)	0.560
RUNX1T1	RTN4IP1	psi-mi:“MI:0915”(physical association)	0.560
RTN4IP1	SCAF1	psi-mi:“MI:0915”(physical association)	0.560
ERMN	RTN4IP1	psi-mi:“MI:0915”(physical association)	0.560
RTN4IP1	MARCHF5	psi-mi:“MI:0915”(physical association)	0.560
RTN4IP1	SORBS1	psi-mi:“MI:0915”(physical association)	0.560
BLVRA	DDHD2	psi-mi:“MI:0914”(association)	0.530
RTN4IP1	HEXIM1	psi-mi:“MI:0914”(association)	0.530
ATP5F1D	NDUFB5	psi-mi:“MI:0914”(association)	0.530
PPTC7	UBB	psi-mi:“MI:0914”(association)	0.530
WBP11	RTN4IP1	psi-mi:“MI:0915”(physical association)	0.370
EXOC7	RTN4IP1	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (112): RTN4IP1 (Two-hybrid), RTN4IP1 (Two-hybrid), RTN4IP1 (Two-hybrid), RTN4IP1 (Affinity Capture-MS), CDC42EP4 (Affinity Capture-MS), HEXIM1 (Affinity Capture-MS), RTN4IP1 (Affinity Capture-MS), RTN4IP1 (Two-hybrid), RTN4IP1 (Two-hybrid), RTN4IP1 (Two-hybrid), RTN4IP1 (Two-hybrid), RTN4IP1 (Affinity Capture-MS), RTN4IP1 (Affinity Capture-MS), RTN4IP1 (Affinity Capture-MS), RTN4IP1 (Affinity Capture-MS)

ESM2 similar proteins: A0A1W5SKT4, A0A7L9EZZ4, A0A8F4NVX8, A1CFL1, A1L1K7, A1L4Y2, A2TIL1, A5JYX5, A6QLU1, A7DZP8, A7RK30, B1GVX6, E5AE42, O42909, O74822, P00390, P0DO83, P0DXF9, P19333, P34055, P39714, P42865, P43304, Q0CJC5, Q0VC50, Q16881, Q24K16, Q28719, Q2HEW4, Q2XU92, Q32L99, Q4R755, Q4W4Z2, Q5FVE4, Q5R806, Q5ZKR7, Q63151, Q7T3C7, Q7ZYC4, Q86VQ6

Diamond homologs: A0A089FS99, A0A089QRB9, A0A0E0RXA7, A0A0E4FKF7, A0A0F9XJT1, A0A0L1JEX1, A0A0U4ZX08, A0A179H0J7, A0A179H2I8, A0A1L7TY28, A0A1L7U3D7, A0A1P8VF85, A0A1V6PAP3, A0A1W5T1Y4, A0A2L0P0L5, A0A2Z5TIQ0, A0A2Z5XAK4, A0A3G1DJF3, A0A3Q9U4Z5, A0A411KZZ8, A0A481WQL4, A0A482N9T9, A0A4P8W733, A0A5C1RDA3, A0A6F8RQ72, A0A7L8UWS6, A0A7L9EZZ4, A0A8F4NUY3, A0A8K1AWG4, A0R1E8, A1CLZ2, A1KQG0, A2QQU5, A2QTF1, A5U9F4, A7RK30, B1GVX6, B2HIL7, B4ER96, B8NJH1

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	27
Likely pathogenic	9
Uncertain significance	159
Likely benign	98
Benign	35

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1071096	NM_032730.5(RTN4IP1):c.340G>T (p.Glu114Ter)	Pathogenic
1213927	NM_032730.5(RTN4IP1):c.2T>C (p.Met1Thr)	Pathogenic
1401751	NM_032730.5(RTN4IP1):c.355_356del (p.Leu119fs)	Pathogenic
1451258	NM_032730.5(RTN4IP1):c.804dup (p.Pro269fs)	Pathogenic
1454192	NM_032730.5(RTN4IP1):c.878C>G (p.Ser293Ter)	Pathogenic
1489361	NM_032730.5(RTN4IP1):c.646G>A (p.Gly216Arg)	Pathogenic
1686986	NM_032730.5(RTN4IP1):c.500C>T (p.Ser167Phe)	Pathogenic
1686987	NM_032730.5(RTN4IP1):c.432G>A (p.Trp144Ter)	Pathogenic
1686988	NM_032730.5(RTN4IP1):c.962G>A (p.Gly321Glu)	Pathogenic
1968090	NM_032730.5(RTN4IP1):c.712C>T (p.Gln238Ter)	Pathogenic
2002548	NM_032730.5(RTN4IP1):c.679del (p.Ala227fs)	Pathogenic
2014205	NM_032730.5(RTN4IP1):c.968_972dup (p.Gly325delinsLeuTer)	Pathogenic
218932	NM_032730.5(RTN4IP1):c.308G>A (p.Arg103His)	Pathogenic
218933	NM_032730.5(RTN4IP1):c.601A>T (p.Lys201Ter)	Pathogenic
2427061	NC_000006.11:g.(?107067057)(107067221_?)del	Pathogenic
2427062	NC_000006.11:g.(?107040019)(107040195_?)del	Pathogenic
2427063	NC_000006.11:g.(?107069280)(107070864_?)del	Pathogenic
2804911	NM_032730.5(RTN4IP1):c.1063G>T (p.Glu355Ter)	Pathogenic
2811530	NM_032730.5(RTN4IP1):c.986T>G (p.Leu329Ter)	Pathogenic
2980753	NM_032730.5(RTN4IP1):c.928C>T (p.Arg310Ter)	Pathogenic
3249630	NM_032730.5(RTN4IP1):c.620+1del	Pathogenic
3630338	NM_032730.5(RTN4IP1):c.960_961del (p.Gly321fs)	Pathogenic
840561	NM_032730.5(RTN4IP1):c.1083+2T>C	Pathogenic
844298	NM_032730.5(RTN4IP1):c.587del (p.Gly196fs)	Pathogenic
943679	NM_032730.5(RTN4IP1):c.138G>A (p.Trp46Ter)	Pathogenic
954709	NM_032730.5(RTN4IP1):c.52del (p.Cys18fs)	Pathogenic
997855	NM_032730.5(RTN4IP1):c.806+1G>A	Pathogenic
1067145	NM_032730.5(RTN4IP1):c.620+1G>C	Likely pathogenic
1067963	NC_000006.11:g.(?107067077)(107069368_?)dup	Likely pathogenic
1486837	NM_032730.5(RTN4IP1):c.991-2A>G	Likely pathogenic

SpliceAI

1492 predictions. Top by Δscore:

Variant	Effect	Δscore
6:106583419:TG:T	acceptor_gain	1.0000
6:106592162:A:AC	donor_gain	1.0000
6:106592163:C:CC	donor_gain	1.0000
6:106592312:C:CT	acceptor_gain	1.0000
6:106592312:C:T	acceptor_gain	1.0000
6:106592313:A:T	acceptor_gain	1.0000
6:106622814:TCAC:T	donor_loss	1.0000
6:106622815:CAC:C	donor_loss	1.0000
6:106622816:ACC:A	donor_loss	1.0000
6:106622817:C:CG	donor_loss	1.0000
6:106622966:CCAC:C	acceptor_gain	1.0000
6:106622967:CAC:C	acceptor_gain	1.0000
6:106622967:CACC:C	acceptor_gain	1.0000
6:106622968:ACC:A	acceptor_loss	1.0000
6:106622971:T:A	acceptor_loss	1.0000
6:106583421:C:CC	acceptor_gain	0.9900
6:106592158:ACAT:A	donor_loss	0.9900
6:106592159:CA:C	donor_loss	0.9900
6:106592160:AT:A	donor_loss	0.9900
6:106592161:T:TG	donor_loss	0.9900
6:106592162:ACGGT:A	donor_loss	0.9900
6:106592163:C:CG	donor_loss	0.9900
6:106592163:CG:C	donor_gain	0.9900
6:106592163:CGG:C	donor_gain	0.9900
6:106592163:CGGT:C	donor_gain	0.9900
6:106592196:T:TA	donor_gain	0.9900
6:106592297:TTAC:T	acceptor_gain	0.9900
6:106592300:CCTGC:C	acceptor_loss	0.9900
6:106592301:CTGC:C	acceptor_loss	0.9900
6:106592309:C:CT	acceptor_gain	0.9900

AlphaMissense

2588 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:106619290:C:G	A178P	0.998
6:106622882:C:G	R121P	0.998
6:106621490:A:G	W144R	0.997
6:106621490:A:T	W144R	0.997
6:106622874:A:G	S124P	0.997
6:106628770:A:C	N84K	0.997
6:106628770:A:T	N84K	0.997
6:106628776:A:C	S82R	0.997
6:106628776:A:T	S82R	0.997
6:106628778:T:G	S82R	0.997
6:106583393:A:G	W340R	0.996
6:106583393:A:T	W340R	0.996
6:106619286:G:T	A179D	0.996
6:106621492:A:T	V143D	0.996
6:106622873:G:A	S124F	0.996
6:106622880:C:G	D122H	0.996
6:106628784:C:G	A80P	0.996
6:106628795:A:T	V76D	0.996
6:106621487:C:G	A145P	0.995
6:106628763:C:G	D87H	0.995
6:106628801:A:T	V74D	0.995
6:106628886:A:G	W46R	0.995
6:106628886:A:T	W46R	0.995
6:106619250:G:T	A191D	0.994
6:106621462:C:A	G153V	0.994
6:106621462:C:T	G153D	0.994
6:106622870:C:T	G125D	0.994
6:106622879:T:G	D122A	0.994
6:106602917:A:G	L209P	0.993
6:106621463:C:G	G153R	0.993

dbSNP variants (sampled 300 via entrez): RS1000034558 (6:106615306 T>C), RS1000192478 (6:106626361 A>C), RS1000239147 (6:106619768 C>A,T), RS1000320485 (6:106601306 T>C,G), RS1000327489 (6:106632391 T>A), RS1000364966 (6:106581911 T>C), RS1000375810 (6:106588668 T>C), RS1000380593 (6:106588901 A>G), RS1000407232 (6:106614993 T>C), RS1000510146 (6:106606860 T>C), RS1000690257 (6:106631578 C>T), RS1000703283 (6:106589379 A>G), RS1000743114 (6:106596923 A>G), RS1000784425 (6:106620757 G>A), RS1000790063 (6:106613693 C>T)

Disease associations

OMIM: gene MIM:610502 | disease phenotypes: MIM:616732

GenCC curated gene-disease

Disease	Classification	Inheritance
optic atrophy 10 with or without ataxia, intellectual disability, and seizures	Definitive	Autosomal recessive
autosomal recessive optic atrophy	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
optic atrophy 10 with or without ataxia, intellectual disability, and seizures	Definitive	AR

Mondo (5): optic atrophy 10 with or without ataxia, intellectual disability, and seizures (MONDO:0020737), inherited retinal dystrophy (MONDO:0019118), optic atrophy (MONDO:0003608), choreatic disease (MONDO:0001595), (MONDO:0014753)

Orphanet (2): OBSOLETE: Inherited retinal disorder (Orphanet:71862), Benign hereditary chorea (Orphanet:1429)

HPO phenotypes

13 total (15 of 13 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000543	Optic disc pallor
HP:0000551	Color vision defect
HP:0000603	Central scotoma
HP:0000613	Photophobia
HP:0000639	Nystagmus
HP:0001251	Ataxia
HP:0001256	Mild intellectual disability
HP:0007663	Reduced visual acuity
HP:0007976	Cerulean cataract
HP:0011463	Childhood onset
HP:0030644	Blind-spot enlargement
HP:0032794	Myoclonic seizure
HP:0000556	Retinal dystrophy
HP:0002072	Chorea

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST003518_17	Daytime sleep phenotypes	8.000000e-06
GCST009391_697	Metabolite levels	3.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0007828	daytime rest measurement
EFO:0007745	lactate measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D002819	Chorea	C10.228.662.262.249; C10.597.350.250; C23.888.592.350.250
D009896	Optic Atrophy	C10.292.700.225; C11.640.451
D058499	Retinal Dystrophies	C11.768.585.658

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

51 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	5
sodium arsenite	decreases expression, increases expression	2
entinostat	increases expression, affects cotreatment	2
Acetaminophen	decreases expression, increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
Cyclosporine	decreases expression	2
Cadmium Chloride	decreases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	decreases expression	1
dicrotophos	decreases expression	1
urushiol	decreases expression	1
triphenyl phosphate	affects expression	1
arsenite	increases reaction, affects binding	1
methylparaben	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
deguelin	decreases expression	1
corosolic acid	decreases expression	1
K 7174	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, decreases expression, affects cotreatment	1
erucylphospho-N,N,N-trimethylpropylammonium	decreases expression	1
ICG 001	decreases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, increases expression, decreases expression	1
picoxystrobin	decreases expression	1
NSC 689534	affects binding, decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
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
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]
NCT05902962	PHASE1	COMPLETED	SAD of IVT VP-001 in PRPF31 Mutation-Associated Retinal Dystrophy Subjects
NCT06319872	PHASE1	RECRUITING	The Effects of Disulfiram (Antabuse®) on Visual Acuity in Patients With Retinal Degeneration
NCT06455826	PHASE1	COMPLETED	MAD of IVT VP-001 in PRPF31 Mutation-Associated Retinal Dystrophy Subjects (Wallaby)
NCT01064505	PHASE1	COMPLETED	Safety Study of a Single IVT Injection of QPI-1007 in Chronic Optic Nerve Atrophy and Recent Onset NAION Patients
NCT05147701	PHASE1	RECRUITING	Safety of Cultured Allogeneic Adult Umbilical Cord Derived Mesenchymal Stem Cells for NAION
NCT04855045	PHASE2/PHASE3	UNKNOWN	An Open-label, Dose Escalation and Double-masked, Randomized, Controlled Trial Evaluating Safety and Tolerability of Sepofarsen in Children (<8 Years of Age) With LCA10 Caused by Mutations in the CEP290 Gene.
NCT03872479	PHASE1/PHASE2	UNKNOWN	Single Ascending Dose Study in Participants With LCA10
NCT04123626	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	A Study to Evaluate the Safety and Tolerability of QR-1123 in Subjects With Autosomal Dominant Retinitis Pigmentosa Due to the P23H Mutation in the RHO Gene
NCT04545736	PHASE1/PHASE2	RECRUITING	Oral Metformin for Treatment of ABCA4 Retinopathy
NCT06212297	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Fellow-eye Study (FE) of LX101 in Subjects With Inherited Retinal Dystrophy
NCT06852963	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	A Repeat-Dose, Open-Label, Two Arm Safety and Efficacy Study of Two Doses of VP-001 Administered Intravitreally in Participants With Confirmed PRPF31 Mutation-Associated Retinal Dystrophy, Including Participants Previously Treated With VP001
NCT07177196	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Personalized Antisense Oligonucleotide Therapy for a Single Participant With PRPH2 Mutation Associated With Retinal Dystrophy
NCT07063030	EARLY_PHASE1	RECRUITING	A Study of LX107 Gene Therapy in AIPL1-IRD Patients
NCT01546181	Not specified	COMPLETED	Retinal Imaging by Adaptive Optics in Healthy Eyes and During Retinal and General Diseases
NCT01876147	Not specified	COMPLETED	Visual and Functional Assessment in Low Vision Patients
NCT01920867	Not specified	UNKNOWN	Stem Cell Ophthalmology Treatment Study
NCT02014389	Not specified	RECRUITING	Evaluation of Objective Perimetry Using Chromatic Multifocal Pupillometer
NCT02983305	Not specified	COMPLETED	Optical Head-Mounted Display Technology for Low Vision Rehabilitation
NCT03592017	Not specified	COMPLETED	Performance of Long-wavelength Autofluorescence Imaging
NCT03662386	Not specified	TERMINATED	Prospective Analysis of Genotype-phenotype Correlations Observed in a Large Cohort of Patients With Hereditary Retinal Dystrophies - GEPHIRD
NCT03691168	Not specified	UNKNOWN	Multi-center Observation of the Natural Course of Inherited Retinal Dystrophies
NCT03843840	Not specified	COMPLETED	Dual Wavelength OCT
NCT03853252	Not specified	COMPLETED	iPS Cells of Patients for Models of Retinal Dystrophies
NCT05130385	Not specified	UNKNOWN	High Resolution Optical Coherence Tomography
NCT05294978	Not specified	RECRUITING	EyeConic: Qualification for Cone-Optogenetics
NCT05573984	Not specified	ACTIVE_NOT_RECRUITING	Natural History of PRPF31 Mutation-Associated Retinal Dystrophy
NCT05793515	Not specified	COMPLETED	Mechanisms of Inherited Retinal Dystrophies Using Whole Genome Sequencing and in Vitro and in Vivo Models
NCT05820100	Not specified	COMPLETED	Observational Study to Assess the Reliability and Validity of the MLYMT and MLSDT
NCT05976139	Not specified	RECRUITING	Micropulsed Laser in Patients With Macular Oedema in Retinal Dystrophies
NCT06162585	Not specified	ACTIVE_NOT_RECRUITING	Non-Interventional Long Term Follow-up Study of Participants Previously Enrolled in the RESTORE Study
NCT06177977	Not specified	RECRUITING	SS-HH-OCT as a Novel Diagnostic Modality for Early-Onset Retinal Dystrophies (EORDs)
NCT06375239	Not specified	RECRUITING	Observational Study to Assess Endpoint Operational Feasibility & Measurement Properties in Patients with Retinal Degeneration
NCT06908161	Not specified	NOT_YET_RECRUITING	Functional Assessments in Vision Impairment
NCT07085533	Not specified	RECRUITING	Natural History Study of Inherited Retinal Diseases
NCT07502664	Not specified	RECRUITING	Development and Evaluation of Functional Visual Field and Navigation Endpoints in Moderate to Profound Inherited Retinal Disease (DEFINE-IRD)