RDH12

Summary

RDH12 (retinol dehydrogenase 12, HGNC:19977) is a protein-coding gene on chromosome 14q24.1, encoding Retinol dehydrogenase 12 (Q96NR8). Retinoids dehydrogenase/reductase with a clear preference for NADP.

The protein encoded by this gene is an NADPH-dependent retinal reductase whose highest activity is toward 9-cis and all-trans-retinol. The encoded enzyme also plays a role in the metabolism of short-chain aldehydes but does not exhibit steroid dehydrogenase activity. Defects in this gene are a cause of Leber congenital amaurosis type 13 and Retinitis Pigmentosa 53.

Source: NCBI Gene 145226 — RefSeq curated summary.

At a glance

• Gene–disease (curated): RDH12-related recessive retinopathy (Definitive, ClinGen) — +4 more curated relationships
• Clinical variants (ClinVar): 263 total — 22 pathogenic, 24 likely-pathogenic
• Phenotypes (HPO): 52
• MANE Select transcript: NM_152443

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19977
Approved symbol	RDH12
Name	retinol dehydrogenase 12
Location	14q24.1
Locus type	gene with protein product
Status	Approved
Aliases	FLJ30273, SDR7C2, LCA13, RP53
Ensembl gene	ENSG00000139988
Ensembl biotype	protein_coding
OMIM	608830
Entrez	145226

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 2 protein_coding, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000267502, ENST00000547463, ENST00000551171, ENST00000552873

RefSeq mRNA: 1 — MANE Select: NM_152443 NM_152443

CCDS: CCDS9787

Canonical transcript exons

ENST00000551171 — 9 exons

Exon	Start	End
ENSE00000658669	67725099	67725254
ENSE00000940928	67724473	67724591
ENSE00000940935	67726981	67727190
ENSE00000940936	67729191	67729380
ENSE00001168191	67722424	67722710
ENSE00001764854	67726051	67726155
ENSE00002341500	67733746	67734451
ENSE00002347634	67720848	67720902
ENSE00002356906	67701886	67701935

Expression profiles

Bgee: expression breadth ubiquitous, 180 present calls, max score 94.47.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.3888 / max 84.6600, expressed in 82 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
140244	0.3432	76
140246	0.0295	8
140245	0.0161	9

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
upper arm skin	UBERON:0004263	94.47	gold quality
skin of leg	UBERON:0001511	93.46	gold quality
mammalian vulva	UBERON:0000997	93.24	gold quality
skin of abdomen	UBERON:0001416	93.10	gold quality
lower esophagus mucosa	UBERON:0035834	92.77	gold quality
zone of skin	UBERON:0000014	92.59	gold quality
upper leg skin	UBERON:0004262	89.46	gold quality
gingiva	UBERON:0001828	89.06	gold quality
gingival epithelium	UBERON:0001949	89.00	gold quality
gall bladder	UBERON:0002110	87.74	gold quality
penis	UBERON:0000989	87.58	gold quality
esophagus squamous epithelium	UBERON:0006920	84.11	gold quality
esophagus mucosa	UBERON:0002469	83.75	gold quality
kidney epithelium	UBERON:0004819	83.02	gold quality
skin of hip	UBERON:0001554	78.97	gold quality
corpus epididymis	UBERON:0004359	78.24	gold quality
vagina	UBERON:0000996	77.81	gold quality
nipple	UBERON:0002030	76.51	gold quality
right adrenal gland	UBERON:0001233	74.78	gold quality
right adrenal gland cortex	UBERON:0035827	74.65	gold quality
adrenal tissue	UBERON:0018303	74.26	gold quality
body of stomach	UBERON:0001161	73.60	gold quality
left adrenal gland	UBERON:0001234	72.16	gold quality
mucosa of stomach	UBERON:0001199	70.84	gold quality
oral cavity	UBERON:0000167	70.64	gold quality
left adrenal gland cortex	UBERON:0035825	70.37	gold quality
adrenal cortex	UBERON:0001235	70.18	gold quality
adrenal gland	UBERON:0002369	69.72	gold quality
cardiac muscle of right atrium	UBERON:0003379	69.18	gold quality
stomach	UBERON:0000945	69.05	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-7316	yes	1727.51
E-GEOD-137537	yes	16.30
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NPAS2

miRNA regulators (miRDB)

36 targeting RDH12, 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-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-9718	99.94	68.91	918
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-3180-5P	99.82	69.12	2422
HSA-MIR-34B-5P	99.78	67.56	1175
HSA-MIR-449C-5P	99.78	67.63	1168
HSA-MIR-2682-5P	99.73	67.38	1055
HSA-MIR-5004-5P	99.68	66.63	1294
HSA-MIR-488-3P	99.61	68.79	1731
HSA-MIR-203A-3P	99.49	70.56	2806
HSA-MIR-6853-3P	99.36	70.79	1558
HSA-MIR-520F-5P	99.34	70.40	1632
HSA-MIR-320A-5P	98.88	66.75	1248
HSA-MIR-3190-5P	98.87	64.89	1345
HSA-MIR-500A-5P	98.76	69.13	1241
HSA-MIR-548Q	98.71	65.35	563
HSA-MIR-4684-5P	98.29	67.99	1650
HSA-MIR-6529-5P	97.85	66.47	673
HSA-MIR-4676-5P	97.54	65.29	715
HSA-MIR-575	97.54	65.18	718
HSA-MIR-122-5P	97.23	64.92	1024
HSA-MIR-1295B-3P	96.68	66.11	276
HSA-MIR-601	95.98	67.59	421
HSA-MIR-3943	95.87	64.57	523
HSA-MIR-1178-5P	95.83	64.12	504

Literature-anchored findings (GeneRIF, showing 38)

• Our studies show that RDH12 is associated with retinal dystrophy and encodes an enzyme with a unique, nonredundant role in the photoreceptor cells. (PMID:15258582)
• All patients harboring RDH12 mutations had a severe yet progressive rod-cone dystrophy with severe macular atrophy but no or mild hyperopia. (PMID:15322982)
• In most tissues RDH12 primarily contributes to the reduction of all-trans-retinaldehyde; however, in cells undergoing oxidative stress, such as photoreceptors, RDH12 might also play a role in detoxification of lipid peroxidation products. (PMID:15865448)
• The results demand critical consideration of the human disease mechanism and the therapeutic approach in patients with mutations in the putative visual cycle gene RDH12. (PMID:17197551)
• Ophthalmic findings in persons with RDH12 mutations suggest that RDH12 loss-of-function results in a characteristic form of early and progressive rod-cone degeneration (PMID:17389517)
• Human type 12 RDH reduces dihydrotestosterone to androstanediol, and is thus involved in steroid metabolism. (PMID:17512723)
• in patients with Leber congenital amaurosis, autosomal recessive retinitis pigmentosa, and autosomal dominant/recessive cone-rod dystrophies six different variants of RDH12 were observed of which three variants were novel (PMID:17512964)
• The demonstration that mutations in a gene previously associated with recessive Leber congenital amaurosis can also cause dominant RP illustrates the wide phenotypic variability of retinal degeneration genes. (PMID:18779497)
• The RDH12-associated phenotype is not homogeneous, the position and nature of the mutations clearly influence the pathologic expression of this disease. (PMID:19011012)
• The retina RDH12 reduces 4-HNE to a nontoxic alcohol, protecting cellular macromolecules against oxidative modification and protecting photoreceptors from light-induced apoptosis. (PMID:19686838)
• Results suggest that the accelerated degradation of RDH12 mutants by the ubiquitin-proteasome system contributes to the pathophysiology and phenotypic variability associated with mutations in the RDH12 gene. (PMID:20006610)
• LCA has been associated with sequence variations of 14 different genes; in approximately 30% of all cases pathogenic mutations remain to be determined. (PMID:20736127)
• Seventeen novel mutations in the RDH12 gene were identified that accounted for approximately 7% of disease in a cohort of patients diagnosed with Leber congenital amaurosis and early-onset retinal dystrophy. (PMID:22065924)
• Here we demonstrate that microtubule-associated protein 1 light chain 3A (LC3A), a marker of autophagy, is related to hypoxia and poor prognosis in clear cell ovarian cancer. (PMID:22926683)
• Two novel missense mutations in the RDH12 gene are associated with retinitis pigmentosa. (PMID:23900199)
• The three patients with Leber congenital amaurosis/early-onset retinal dystrophy had a progressive decrease of their vision with the formation of a posterior staphyloma. (PMID:24752437)
• Mutations in the AIPL1 and RDH12 genes associated with leber congenital amaurosis in two Turkish families. (PMID:25148430)
• We report 4 children from 3 consanguineous families with bilateral elevation deficiency in the context of retinal dystrophy. All were found to harbor recessive mutations in retinal dehydrogenase 12 (RDH12). (PMID:26691045)
• The mutation detection of RDH12 in this study also implies that whole exome sequencing is a useful method for detection of potential mutations in small families with atypical clinical manifestations of genetic disease. (PMID:26848971)
• The RDH12 compound heterozygous variants might be the cause of the LCA family. Our study adds to the molecular spectrum of RDH12-related retinopathy and offers an effective example of the power of phenotype-genotype correlations in molecular diagnosis of LCA. (PMID:28471114)
• Peripapillary sparing is a novel phenotypic feature of RDH12-associated Leber congenital amaurosis. (PMID:28513254)
• PHENOTYPIC VARIABILITY OF RECESSIVE RDH12-ASSOCIATED RETINAL DYSTROPHY. (PMID:30134391)
• RDH12-IRD causes an early-onset, retina-wide disease with particularly severe central retinal abnormalities associated with relatively less severe rod photoreceptor dysfunction, a pattern consistent with an early-onset cone-rod dystrophy. (PMID:30372751)
• This study includes the largest collection of phenotypic data from children with RDH12-associated early-onset severe retinal dystrophy (EOSRD) and provides a comprehensive description of the timeline of vision loss in this severe, early-onset condition. (PMID:30979730)
• study of genotype-phenotype correlations in RDH12-associated retinal degeneration [review] (PMID:31884613)
• Expanding the phenotypic spectrum in RDH12-associated retinal disease. (PMID:32014858)
• Macula-predominant retinopathy associated with biallelic variants in RDH12. (PMID:32790509)
• A Novel RNA-Seq-Based Model for Preoperative Prediction of Lymph Node Metastasis in Oral Squamous Cell Carcinoma. (PMID:32934959)
• Molecular genetics with clinical characteristics of Leber congenital amaurosis in the Han population of western China. (PMID:33970760)
• ISOLATED MACULOPATHY AND MODERATE ROD-CONE DYSTROPHY REPRESENT THE MILDER END OF THE RDH12-RELATED RETINAL DYSTROPHY SPECTRUM. (PMID:34001834)
• Generation of two human iPSC lines from patients with autosomal dominant retinitis pigmentosa (UCLi014-A) and autosomal recessive Leber congenital amaurosis (UCLi015-A), associated with RDH12 variants. (PMID:34216980)
• Investigation of genotype-phenotype relationship in Turkish patients with inherited retinal disease by next generation sequencing. (PMID:34315337)
• Involvement of Oxidative and Endoplasmic Reticulum Stress in RDH12-Related Retinopathies. (PMID:34445569)
• Associations Between Fundus Types and Clinical Manifestations in Patients with RDH12 Gene Mutations. (PMID:35006499)
• Clinical and Genetic Analysis of RDH12-Associated Retinopathy in 27 Chinese Families: A Hypomorphic Allele Leads to Cone-Rod Dystrophy. (PMID:35994252)
• Pseudocoloboma-like maculopathy with biallelic RDH12 missense mutations. (PMID:36690427)
• Clinical and Genetic Characterization of RDH12-Retinal Dystrophy in a South American Cohort. (PMID:37714431)
• RDH12 allows cone photoreceptors to regenerate opsin visual pigments from a chromophore precursor to escape competition with rods. (PMID:38981477)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Rdh12	ENSMUSG00000021123
rattus_norvegicus	Rdh12	ENSRNOG00000056553

Paralogs (25): HSD17B6 (ENSG00000025423), RDH11 (ENSG00000072042), HSD17B10 (ENSG00000072506), DHRS9 (ENSG00000073737), HSD17B2 (ENSG00000086696), HSD17B14 (ENSG00000087076), DHRS12 (ENSG00000102796), HSDL1 (ENSG00000103160), HSD17B1 (ENSG00000108786), RDH10 (ENSG00000121039), HSD17B3 (ENSG00000130948), HSD17B7 (ENSG00000132196), HSD17B4 (ENSG00000133835), RDH5 (ENSG00000135437), RDH16 (ENSG00000139547), HSD17B12 (ENSG00000149084), BDH1 (ENSG00000161267), DHRS3 (ENSG00000162496), SDR9C7 (ENSG00000170426), HSD17B13 (ENSG00000170509), SDR16C5 (ENSG00000170786), HSD11B2 (ENSG00000176387), WWOX (ENSG00000186153), HSD17B11 (ENSG00000198189), HSD17B8 (ENSG00000204228)

Protein

Protein identifiers

Retinol dehydrogenase 12 — Q96NR8 (reviewed: Q96NR8)

Alternative names: All-trans and 9-cis retinol dehydrogenase, Short chain dehydrogenase/reductase family 7C member 2

All UniProt accessions (2): Q96NR8, A0A0S2Z613

UniProt curated annotations — full annotation on UniProt →

Function. Retinoids dehydrogenase/reductase with a clear preference for NADP. Displays high activity towards 9-cis, 11-cis and all-trans-retinal. Shows very weak activity towards 13-cis-retinol. Also exhibits activity, albeit with lower affinity than for retinaldehydes, towards lipid peroxidation products (C9 aldehydes) such as 4-hydroxynonenal and trans-2-nonenal. May play an important function in photoreceptor cells to detoxify 4-hydroxynonenal and potentially other toxic aldehyde products resulting from lipid peroxidation. Has no dehydrogenase activity towards steroids.

Subcellular location. Endoplasmic reticulum membrane.

Tissue specificity. Widely expressed, mostly in retina, kidney, brain, skeletal muscle, pancreas and stomach.

Disease relevance. Leber congenital amaurosis 13 (LCA13) [MIM:612712] 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. Retinitis pigmentosa 53 (RP53) [MIM:612712] A retinal dystrophy belonging to the group of pigmentary retinopathies. Retinitis pigmentosa is characterized by retinal pigment deposits visible on fundus examination and primary loss of rod photoreceptor cells followed by secondary loss of cone photoreceptors. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well. RP53 inheritance is autosomal dominant or autosomal recessive. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Cofactor metabolism; retinol metabolism.

Miscellaneous. Shows clear specificity for the pro-S hydrogen on C4 of NADPH and the pro-R hydrogen on C15 of retinols.

Similarity. Belongs to the short-chain dehydrogenases/reductases (SDR) family.

RefSeq proteins (1): NP_689656* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002347	SDR_fam	Family
IPR036291	NAD(P)-bd_dom_sf	Homologous_superfamily

Pfam: PF00106

Enzyme classification (BRENDA):

• EC 1.1.1.105 — all-trans-retinol dehydrogenase (NAD+) (BRENDA: 12 organisms, 80 substrates, 15 inhibitors, 31 Km, 2 kcat entries)
• EC 1.1.1.300 — NADP-retinol dehydrogenase (BRENDA: 11 organisms, 101 substrates, 7 inhibitors, 67 Km, 12 kcat entries)

Substrate kinetics (BRENDA)

27 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ALL-TRANS-RETINAL	0.0001–0.5	19
NADPH	0.0005–0.23	10
NADP+	0.0004–0.8	9
ALL-TRANS-RETINOL	—	6
NADH	0.011–0.224	6
ALL-TRANS-RETINOL	0.0006–1.3	6
ALL-TRANS-RETINAL	0.0018–0.57	5
NADH	2.22–1300	4
NAD+	0.0002–0.46	3
ALL-TRANS-3-HYDROXYRETINAL	0.0032–0.0044	3
ESTRONE	0.0096–0.0307	3
NAD+	0.004–680	3
11-CIS-RETINOL	0.0001–0.086	2
9-CIS-RETINAL	0.0001–0.19	2
RETINAL	0.007–0.13	2

Catalyzed reactions (Rhea), 7 shown:

• all-trans-retinol + NADP(+) = all-trans-retinal + NADPH + H(+) (RHEA:25033)
• 11-cis-retinol + NADP(+) = 11-cis-retinal + NADPH + H(+) (RHEA:54912)
• 9-cis-retinol + NADP(+) = 9-cis-retinal + NADPH + H(+) (RHEA:54916)
• (Z)-non-6-en-1-ol + NADP(+) = (Z)-non-6-enal + NADPH + H(+) (RHEA:58328)
• (E)-non-2-en-1-ol + NADP(+) = (E)-non-2-enal + NADPH + H(+) (RHEA:58332)
• a 4-hydroxynonen-1-ol + NADP(+) = a 4-hydroxynonenal + NADPH + H(+) (RHEA:58336)
• nonan-1-ol + NADP(+) = nonanal + NADPH + H(+) (RHEA:58380)

UniProt features (32 total): sequence variant 28, binding site 2, chain 1, active site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96NR8-F1	92.21	0.80

Functional residue map

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

Catalytic / active sites (1): 200 (proton acceptor)

Ligand- & substrate-binding residues (2): 46–52; 175

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-2453902	The canonical retinoid cycle in rods (twilight vision)
R-HSA-9918440	Defective visual phototransduction due to RDH12 loss of function

MSigDB gene sets: 231 (showing top): GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_DN, GOBP_REGULATION_OF_HORMONE_LEVELS, GOBP_RETINOL_METABOLIC_PROCESS, GGAMTNNNNNTCCY_UNKNOWN, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, PID_CONE_PATHWAY, chr14q24, GOBP_CELLULAR_RESPONSE_TO_TOXIC_SUBSTANCE, GOBP_PHOTORECEPTOR_CELL_MAINTENANCE, GOBP_SENSORY_PERCEPTION_OF_LIGHT_STIMULUS, GOBP_DETOXIFICATION, GOBP_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_LIPID_METABOLIC_PROCESS, GOBP_MULTICELLULAR_ORGANISMAL_LEVEL_HOMEOSTASIS, GOBP_SENSORY_PERCEPTION

GO Biological Process (6): retinoid metabolic process (GO:0001523), visual perception (GO:0007601), retinol metabolic process (GO:0042572), photoreceptor cell maintenance (GO:0045494), cellular detoxification of aldehyde (GO:0110095), lipid metabolic process (GO:0006629)

GO Molecular Function (5): all-trans-retinol dehydrogenase (NAD+) activity (GO:0004745), all-trans-retinol dehydrogenase (NADP+) activity (GO:0052650), 11-cis-retinol dehydrogenase (NADP+) activity (GO:0102354), protein binding (GO:0005515), oxidoreductase activity (GO:0016491)

GO Cellular Component (5): photoreceptor inner segment (GO:0001917), endoplasmic reticulum membrane (GO:0005789), photoreceptor inner segment membrane (GO:0060342), endoplasmic reticulum (GO:0005783), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Visual phototransduction	1
Retinoid cycle disease events	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
alcohol dehydrogenase (NADP+) activity	2
cellular anatomical structure	2
diterpenoid metabolic process	1
sensory perception of light stimulus	1
retinoid metabolic process	1
primary alcohol metabolic process	1
hormone metabolic process	1
olefinic compound metabolic process	1
retina homeostasis	1
multicellular organismal process	1
cellular response to aldehyde	1
cellular detoxification	1
primary metabolic process	1
alcohol dehydrogenase (NAD+) activity	1
retinol metabolic process	1
binding	1
catalytic activity	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
photoreceptor inner segment	1
plasma membrane region	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

3419 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RDH12	RPE65	Q16518	932
RDH12	SPATA7	Q9P0W8	917
RDH12	TULP1	O00294	892
RDH12	IMPDH1	P20839	890
RDH12	AIPL1	Q9NZN9	889
RDH12	LRAT	O95237	883
RDH12	RPGRIP1	Q96KN7	862
RDH12	RLBP1	P12271	857
RDH12	CRX	O43186	856
RDH12	RD3	Q7Z3Z2	852
RDH12	ALDH1A3	P47895	847
RDH12	LCA5	Q86VQ0	845
RDH12	CERKL	Q49MI3	827
RDH12	ABCA4	P78363	824
RDH12	CEP290	O15078	807

IntAct

37 interactions, top by confidence:

A	B	Type	Score
RBPMS	RDH12	psi-mi:“MI:0915”(physical association)	0.560
RDH12	RBPMS	psi-mi:“MI:0915”(physical association)	0.560
PLEKHA7	RDH12	psi-mi:“MI:0915”(physical association)	0.560
RDH12	NME2P1	psi-mi:“MI:0914”(association)	0.530
PEX19	FAM20B	psi-mi:“MI:0914”(association)	0.530
TSPAN5	SC5D	psi-mi:“MI:0914”(association)	0.530
UBC	RDH12	psi-mi:“MI:0915”(physical association)	0.400
RDH12	UBC	psi-mi:“MI:0915”(physical association)	0.400
RDH12	ANXA8	psi-mi:“MI:0915”(physical association)	0.370
BUB1	RDH12	psi-mi:“MI:0915”(physical association)	0.370
MAP1LC3A	RDH12	psi-mi:“MI:0915”(physical association)	0.370
CFTR	RDH12	psi-mi:“MI:0915”(physical association)	0.370
TSPAN5	KLHL2	psi-mi:“MI:0914”(association)	0.350
rep	B4GALT3	psi-mi:“MI:0914”(association)	0.350
ITM2B	ILVBL	psi-mi:“MI:0914”(association)	0.350
TTYH1	TMEM223	psi-mi:“MI:0914”(association)	0.350
TSPAN15	TMEM223	psi-mi:“MI:0914”(association)	0.350
STX17	A2ML1	psi-mi:“MI:0914”(association)	0.350
OR2A4	A2ML1	psi-mi:“MI:0914”(association)	0.350
PPP2R2B	A2ML1	psi-mi:“MI:0914”(association)	0.350
CCR1	UBA6	psi-mi:“MI:0914”(association)	0.350
SSUH2	IGLC7	psi-mi:“MI:0914”(association)	0.350

BioGRID (70): RDH12 (Two-hybrid), RDH12 (Affinity Capture-MS), RDH12 (Affinity Capture-MS), AGFG1 (Affinity Capture-MS), UBE2T (Affinity Capture-MS), RNF123 (Affinity Capture-MS), CCDC25 (Affinity Capture-MS), NME2P1 (Affinity Capture-MS), UBE2D2 (Affinity Capture-MS), ZBTB8OS (Affinity Capture-MS), UBE2E3 (Affinity Capture-MS), LASP1 (Affinity Capture-MS), ARPIN (Affinity Capture-MS), ARFGAP1 (Affinity Capture-MS), DAK (Affinity Capture-MS)

ESM2 similar proteins: A0A078IS66, A0A078ISJ6, A0A0B6VQ48, A0A1V0QS34, A0A2H3CZZ2, A0AAW1NHX6, A2RVM0, A4UHT7, A5PJJ7, B2X050, B8A5W4, G9N4A9, O17795, O74959, P16232, P40579, P40580, P59837, P70385, Q05A13, Q071N0, Q08651, Q17703, Q17704, Q4JK73, Q5F389, Q5NVG2, Q5R9W5, Q5ZJG8, Q6AYS8, Q6P3L6, Q6QA32, Q6RVV4, Q7SHI2, Q7TQA3, Q7Z5P4, Q8BYK4, Q8CEE7, Q8N3Y7, Q8NBN7

Diamond homologs: A0A017SEY2, A0A023I4F1, A0A078IS66, A0A078ISJ6, A0A0U1LQE2, A0A0U5CNP2, A0A1B7YCL6, A0A1V0QS34, A0A1V6PAN1, A0A223HDI5, A0A2H3CNT9, A0A2H3D905, A0A443HJZ3, A0A482ND39, A0A823A767, A0PJE2, A2RVM0, A6QP05, B2X050, B6H062, B8A5W4, C8VI80, D7UTD0, G1XTZ5, I1RL15, O32291, O74959, P0DXW2, P16152, P19871, P21218, P35320, P40747, P47727, P50163, P51657, P59837, Q01289, Q03326, Q08651

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	22
Likely pathogenic	24
Uncertain significance	86
Likely benign	94
Benign	5

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1072734	NM_152443.3(RDH12):c.823G>T (p.Glu275Ter)	Pathogenic
1076205	NM_152443.3(RDH12):c.524C>A (p.Ser175Ter)	Pathogenic
1419341	NM_152443.3(RDH12):c.68+1G>A	Pathogenic
1988417	NM_152443.3(RDH12):c.272dup (p.Val92fs)	Pathogenic
2053	NM_152443.3(RDH12):c.688C>G (p.Pro230Ala)	Pathogenic
2097799	NM_152443.3(RDH12):c.344-43_421del	Pathogenic
2122502	NM_152443.3(RDH12):c.867_884del (p.Trp289_Arg295delinsTer)	Pathogenic
2122910	NM_152443.3(RDH12):c.314_318del (p.Ile105fs)	Pathogenic
2137598	NM_152443.3(RDH12):c.697_698dup (p.Arg234fs)	Pathogenic
2743303	NM_152443.3(RDH12):c.98del (p.Thr33fs)	Pathogenic
2856969	NM_152443.3(RDH12):c.189del (p.Ala64fs)	Pathogenic
2910355	NM_152443.3(RDH12):c.343+1G>A	Pathogenic
2978945	NM_152443.3(RDH12):c.106C>T (p.Gln36Ter)	Pathogenic
3776098	NM_152443.3(RDH12):c.659-2A>G	Pathogenic
4750851	NM_152443.3(RDH12):c.448+2T>A	Pathogenic
662998	NM_152443.3(RDH12):c.157_187+178del	Pathogenic
813085	NM_152443.3(RDH12):c.599A>C (p.Tyr200Ser)	Pathogenic
836859	NM_152443.3(RDH12):c.680_683del (p.Ala227fs)	Pathogenic
934121	NM_152443.3(RDH12):c.582C>G (p.Tyr194Ter)	Pathogenic
936624	NM_152443.3(RDH12):c.869dup (p.Ser291fs)	Pathogenic
977808	NM_152443.3(RDH12):c.429_432delinsGGT (p.His143fs)	Pathogenic
977809	NM_152443.3(RDH12):c.448+1G>A	Pathogenic
1066021	NC_000014.8:g.(?68195898)(68200575_?)del	Likely pathogenic
1066530	NM_152443.3(RDH12):c.188-1G>A	Likely pathogenic
1213888	NM_152443.3(RDH12):c.148G>A (p.Gly50Ser)	Likely pathogenic
1213892	NM_152443.3(RDH12):c.607A>G (p.Ser203Gly)	Likely pathogenic
1523328	NM_152443.3(RDH12):c.659-2A>C	Likely pathogenic
2678297	NM_152443.3(RDH12):c.164C>A (p.Thr55Lys)	Likely pathogenic
2678301	NM_152443.3(RDH12):c.51_52dup (p.Val18fs)	Likely pathogenic
2678303	NM_152443.3(RDH12):c.69del	Likely pathogenic

SpliceAI

1715 predictions. Top by Δscore:

Variant	Effect	Δscore
14:67720900:AAGGT:A	donor_loss	1.0000
14:67720902:GGTG:G	donor_loss	1.0000
14:67720903:GTGA:G	donor_loss	1.0000
14:67724467:C:CA	acceptor_gain	1.0000
14:67724472:GGAA:G	acceptor_gain	1.0000
14:67724588:CGAGG:C	donor_loss	1.0000
14:67724589:GAG:G	donor_gain	1.0000
14:67724590:AG:A	donor_gain	1.0000
14:67724590:AGGT:A	donor_loss	1.0000
14:67724591:GG:G	donor_gain	1.0000
14:67724592:G:GG	donor_gain	1.0000
14:67724593:T:A	donor_loss	1.0000
14:67725085:T:TA	acceptor_gain	1.0000
14:67725090:T:TA	acceptor_gain	1.0000
14:67725091:G:A	acceptor_gain	1.0000
14:67725094:CCCAG:C	acceptor_loss	1.0000
14:67725096:CAG:C	acceptor_loss	1.0000
14:67725097:A:AG	acceptor_gain	1.0000
14:67725097:AGG:A	acceptor_loss	1.0000
14:67725098:G:GT	acceptor_gain	1.0000
14:67725098:GGA:G	acceptor_gain	1.0000
14:67726041:T:TA	acceptor_gain	1.0000
14:67726046:TATA:T	acceptor_loss	1.0000
14:67726048:T:G	acceptor_gain	1.0000
14:67726048:TAGA:T	acceptor_loss	1.0000
14:67726049:A:AG	acceptor_gain	1.0000
14:67726049:AGAG:A	acceptor_gain	1.0000
14:67726050:G:GT	acceptor_gain	1.0000
14:67726050:GA:G	acceptor_gain	1.0000
14:67726050:GAGG:G	acceptor_gain	1.0000

AlphaMissense

2026 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:67729336:C:G	C268W	0.993
14:67733816:A:C	S307R	0.993
14:67733818:C:A	S307R	0.993
14:67733818:C:G	S307R	0.993
14:67726079:C:A	N124K	0.992
14:67726079:C:G	N124K	0.992
14:67727139:A:C	S203R	0.992
14:67727140:G:T	S203I	0.992
14:67727141:C:A	S203R	0.992
14:67727141:C:G	S203R	0.992
14:67729313:G:T	G261W	0.992
14:67724570:G:C	A56P	0.991
14:67724571:C:A	A56D	0.990
14:67725137:G:T	G76W	0.989
14:67727130:T:C	Y200H	0.989
14:67725233:T:C	F108L	0.988
14:67725235:T:A	F108L	0.988
14:67725235:T:G	F108L	0.988
14:67727038:G:C	R169P	0.987
14:67727044:T:A	V171D	0.987
14:67724559:G:A	G52D	0.986
14:67729334:T:C	C268R	0.986
14:67727144:G:C	K204N	0.985
14:67727144:G:T	K204N	0.985
14:67725117:C:A	A69D	0.984
14:67726072:T:C	L122P	0.984
14:67726083:G:C	A126P	0.984
14:67726148:C:A	N147K	0.984
14:67726148:C:G	N147K	0.984
14:67729335:G:A	C268Y	0.984

dbSNP variants (sampled 300 via entrez): RS1000009876 (14:67719329 T>C), RS1000219795 (14:67726420 A>G), RS1000338333 (14:67725866 T>C), RS1000415132 (14:67719266 T>A,C,G), RS1000417141 (14:67712493 C>A), RS1000444901 (14:67719711 C>T), RS1000503664 (14:67714494 G>A), RS1000621590 (14:67713275 A>C,G), RS1000756147 (14:67701345 C>T), RS1000777121 (14:67731503 C>G), RS1000787149 (14:67731913 G>A), RS1000860650 (14:67733452 T>G), RS1001063457 (14:67706923 A>G), RS1001090137 (14:67732616 G>A), RS1001229397 (14:67711797 G>C)

Disease associations

OMIM: gene MIM:608830 | disease phenotypes: MIM:612712, MIM:204000, MIM:120970, MIM:268000, MIM:248200, MIM:620762

GenCC curated gene-disease

Disease	Classification	Inheritance
Leber congenital amaurosis 13	Definitive	Autosomal recessive
RDH12-related recessive retinopathy	Strong	Autosomal recessive
RDH12-related dominant retinopathy	Strong	Autosomal dominant
Leber congenital amaurosis	Supportive	Autosomal dominant
retinitis pigmentosa	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
RDH12-related dominant retinopathy	Moderate	AD
RDH12-related recessive retinopathy	Definitive	AR

Mondo (10): Leber congenital amaurosis 13 (MONDO:0012990), Leber congenital amaurosis (MONDO:0018998), cone-rod dystrophy (MONDO:0015993), retinitis pigmentosa (MONDO:0019200), Stargardt disease (MONDO:0019353), inherited retinal dystrophy (MONDO:0019118), retinitis pigmentosa 53 (MONDO:0800348), macular dystrophy with or without cone dysfunction (MONDO:0958326), RDH12-related recessive retinopathy (MONDO:0800099), RDH12-related dominant retinopathy (MONDO:0800100)

Orphanet (5): Leber congenital amaurosis (Orphanet:65), Cone rod dystrophy (Orphanet:1872), Retinitis pigmentosa (Orphanet:791), Stargardt disease (Orphanet:827), OBSOLETE: Inherited retinal disorder (Orphanet:71862)

HPO phenotypes

52 total (30 of 52 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000365	Hearing impairment
HP:0000405	Conductive hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000501	Glaucoma
HP:0000505	Visual impairment
HP:0000512	Abnormal electroretinogram
HP:0000518	Cataract
HP:0000540	Hypermetropia
HP:0000543	Optic disc pallor
HP:0000546	Retinal degeneration
HP:0000551	Color vision defect
HP:0000556	Retinal dystrophy
HP:0000563	Keratoconus
HP:0000602	Ophthalmoplegia
HP:0000613	Photophobia
HP:0000618	Blindness
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000662	Nyctalopia
HP:0000729	Autistic behavior
HP:0000842	Hyperinsulinemia
HP:0001105	Retinal atrophy
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

GWAS associations

0 associations (top):

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
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
D058499	Retinal Dystrophies	C11.768.585.658
D012174	Retinitis Pigmentosa	C11.270.684; C11.768.585.658.500; C16.320.290.684
D000080362	Stargardt Disease	C11.270.872; C11.768.585.439.339; C16.320.290.724
C567197	Leber Congenital Amaurosis 13 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression	2
Cyclosporine	decreases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, increases expression	2
dicrotophos	decreases expression	1
propionaldehyde	increases expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
bisphenol A	decreases methylation	1
sodium arsenate	decreases expression, increases abundance	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	decreases expression	1
hydroquinone	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
bisphenol S	increases methylation	1
Fulvestrant	increases methylation	1
Arsenic	decreases expression, increases abundance	1
Benzo(a)pyrene	affects methylation	1
Diethylhexyl Phthalate	decreases expression	1
Lipopolysaccharides	affects response to substance, increases expression, affects cotreatment	1
N-Nitrosopyrrolidine	increases expression	1
NADP	affects binding, increases activity	1
Quercetin	decreases expression	1
Retinaldehyde	increases metabolic processing	1
Sodium Dodecyl Sulfate	decreases expression	1
Thiram	increases expression	1
Vitamin A	increases chemical synthesis	1
Cadmium Chloride	decreases expression	1
Copper Sulfate	increases expression	1

Cellosaurus cell lines

5 cell lines: 5 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A0KB	UCLi014-A	Induced pluripotent stem cell	Male
CVCL_A0KC	UCLi015-A	Induced pluripotent stem cell	Female
CVCL_B5S6	PUMCHi018-A	Induced pluripotent stem cell	Male
CVCL_D0KY	SCAUi001-A-1	Induced pluripotent stem cell	Male
CVCL_YT21	ERPLi002-A	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

287 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)
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
NCT04224207	PHASE3	COMPLETED	Management of Retinitis Pigmentosa by Mesenchymal Stem Cells by Wharton’s Jelly Derived Mesenchymal Stem Cells
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
NCT07082855	PHASE3	NOT_YET_RECRUITING	A Multicenter, Randomized, Double-Blind, Controlled Clinical Study of Minocycline 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
NCT03772665	PHASE3	COMPLETED	Safety and Efficacy of Emixustat in Stargardt Disease
NCT05244304	PHASE3	COMPLETED	Phase 3, Randomized, Placebo-Controlled Study of Tinlarebant to Explore Safety and Efficacy in Adolescent Stargardt Disease
NCT07419334	PHASE3	RECRUITING	Study of ALK-001 on the Progression of Stargardt Disease
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
NCT04068207	PHASE2	COMPLETED	Minocycline Treatment in 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
NCT04945772	PHASE2	COMPLETED	Efficacy and Safety of MCO-010 Optogenetic Therapy in Adults With Retinitis Pigmentosa [RESTORE]
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