GUCY2D

Summary

GUCY2D (guanylate cyclase 2D, retinal, HGNC:4689) is a protein-coding gene on chromosome 17p13.1, encoding Retinal guanylyl cyclase 1 (Q02846). Catalyzes the synthesis of cyclic GMP (cGMP) in rods and cones of photoreceptors.

This gene encodes a retina-specific guanylate cyclase, which is a member of the membrane guanylyl cyclase family. Like other membrane guanylyl cyclases, this enzyme has a hydrophobic amino-terminal signal sequence followed by a large extracellular domain, a single membrane spanning domain, a kinase homology domain, and a guanylyl cyclase catalytic domain. In contrast to other membrane guanylyl cyclases, this enzyme is not activated by natriuretic peptides. Mutations in this gene result in Leber congenital amaurosis and cone-rod dystrophy-6 diseases.

Source: NCBI Gene 3000 — RefSeq curated summary.

At a glance

• Gene–disease (curated): GUCY2D-related dominant retinopathy (Definitive, ClinGen) — +7 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 1,697 total — 153 pathogenic, 92 likely-pathogenic
• Phenotypes (HPO): 68
• MANE Select transcript: NM_000180

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4689
Approved symbol	GUCY2D
Name	guanylate cyclase 2D, retinal
Location	17p13.1
Locus type	gene with protein product
Status	Approved
Aliases	retGC, RETGC-1, ROS-GC1, CYGD, LCA1, ROS-GC
Ensembl gene	ENSG00000132518
Ensembl biotype	protein_coding
OMIM	600179
Entrez	3000

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 1 protein_coding, 1 retained_intron

ENST00000254854, ENST00000574510

RefSeq mRNA: 1 — MANE Select: NM_000180 NM_000180

CCDS: CCDS11127

Canonical transcript exons

ENST00000254854 — 20 exons

Exon	Start	End
ENSE00000905467	8003852	8004156
ENSE00000905480	8015743	8015841
ENSE00001293688	8007931	8008032
ENSE00001293922	8014859	8015051
ENSE00001300099	8012144	8012350
ENSE00001300811	8003039	8003768
ENSE00001305434	8007426	8007528
ENSE00001306526	8013103	8013252
ENSE00001308194	8006363	8006714
ENSE00001310706	8015328	8015502
ENSE00001311387	8014601	8014764
ENSE00001311972	8009506	8009586
ENSE00001312940	8016205	8016290
ENSE00001317612	8016443	8016554
ENSE00001321424	8012450	8012606
ENSE00001328414	8013880	8014028
ENSE00001329972	8015927	8016021
ENSE00001330137	8007060	8007144
ENSE00001365187	8002615	8002734
ENSE00001390086	8020128	8020342

Expression profiles

Bgee: expression breadth ubiquitous, 121 present calls, max score 72.09.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.3056 / max 39.1722, expressed in 98 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
159451	0.1565	84
159447	0.0664	6
159449	0.0564	8
159448	0.0263	8

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	72.09	gold quality
esophagus mucosa	UBERON:0002469	66.43	gold quality
lower esophagus mucosa	UBERON:0035834	64.02	gold quality
leukocyte	CL:0000738	59.38	gold quality
monocyte	CL:0000576	59.07	gold quality
oviduct epithelium	UBERON:0004804	58.85	gold quality
bone marrow cell	CL:0002092	56.53	gold quality
minor salivary gland	UBERON:0001830	56.05	gold quality
granulocyte	CL:0000094	55.99	gold quality
esophagus squamous epithelium	UBERON:0006920	55.92	gold quality
saliva-secreting gland	UBERON:0001044	55.44	gold quality
middle temporal gyrus	UBERON:0002771	55.24	gold quality
vagina	UBERON:0000996	54.99	gold quality
parietal pleura	UBERON:0002400	54.21	gold quality
upper leg skin	UBERON:0004262	54.05	silver quality
mouth mucosa	UBERON:0003729	53.99	gold quality
visceral pleura	UBERON:0002401	53.81	gold quality
right lung	UBERON:0002167	53.62	gold quality
lymph node	UBERON:0000029	53.28	gold quality
Brodmann (1909) area 23	UBERON:0013554	52.77	gold quality
prostate gland	UBERON:0002367	52.70	gold quality
primary visual cortex	UBERON:0002436	51.63	silver quality
upper lobe of left lung	UBERON:0008952	51.33	gold quality
parotid gland	UBERON:0001831	51.25	gold quality
blood	UBERON:0000178	50.69	gold quality
esophagus	UBERON:0001043	50.48	gold quality
body of stomach	UBERON:0001161	50.39	gold quality
prefrontal cortex	UBERON:0000451	50.27	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	50.18	gold quality
left lobe of thyroid gland	UBERON:0001120	49.95	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.40

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CRX

miRNA regulators (miRDB)

8 targeting GUCY2D, 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-5193	100.00	67.26	1744
HSA-MIR-6752-3P	99.72	66.71	1587
HSA-MIR-324-3P	99.26	66.31	1034
HSA-MIR-615-5P	98.10	63.76	591
HSA-MIR-4690-3P	97.02	64.72	981
HSA-MIR-5685	97.02	64.34	1004
HSA-MIR-711	96.60	65.75	528
HSA-MIR-5092	93.86	62.63	151

Literature-anchored findings (GeneRIF, showing 40)

• clustering and frequency of mutations in patients with dominant cone-rod dystrophies (PMID:11565546)
• Some carrier parents of patients with Leber congenital amaurosis and a GUCY2D mutation develop measurable cone and possibly rod abnormalities most consistent with a mild cone-rod dysfunction. (PMID:12365911)
• Two amino acid substitution missense mutations at R838C and R838H have been identified as well as 11 new polymorphic markers. (PMID:12552567)
• Leber congenital amaurosis (LCA) caused by mutant GUCY2D had only light perception but retained substantial numbers of cones and rods in the macula and far periphery. (PMID:12623820)
• A heterozygous complex mutation of I915T and G917R in the GUCY2D gene caused autosomal dominant CORD (cone-rod dystrophy) (PMID:15111605)
• LCA (leber congenital amaurosis) is caused by the modifying effect of a heterozygous GUCY2D mutation observed against the disease background of a homozygous RPE65 mutation. (PMID:15512997)
• AIPL1, CRB1, GUCY2D, RPE65, and RPGRIP1 mutations may have roles in juvenile retinitis pigmentosa (PMID:16272259)
• Microarray-based mutation detection allowed the identification of 32% of LCA sequence variants and represents an efficient first-pass screening tool. Mutations in CRB1, and to a lesser extent, in GUCY2D, underlie most LCA cases in this cohort (PMID:16505055)
• There is a phenotype-genotype correlation of autosomal dominant cone-rod dystrophy due to the R838C mutation of the GUCY2D gene encoding retinal guanylate cyclase-1 (PMID:17041576)
• Testing confirms the diagnosis at the molecular level and allows for a more precise prognosis of the possible future clinical evolution (PMID:17651254)
• illustrate the use of haplotype information about allele-sharing decay around a mutation as a genetic clock, using data for two GUCY2D mutations in Mediterranean populations (PMID:17684531)
• RPE65 gene mutations represented a significant cause of LCA in the Italian population, whereas GUCY2D and CEP290 mutations had a lower frequency than that found in other reports. (PMID:17724218)
• a novel mutation, P575L, was found in exon 8 of the GUCY2D gene in 12 members of a family with autosomal dominant progressive cone degeneration (PMID:18332321)
• GUCY2D is a major gene responsible for progressive autosomal dominant cone degeneration. All identified mutations localize to codon 838. (PMID:18487367)
• Studies show that a fold recognition based model of the catalytic domain of ROS-GC1 was built, and neurocalcin delta docking simulations were carried out to define the three-dimensional features of the interacting domains of the two molecules. (PMID:18500817)
• metal binding in EF-hand 2 is crucial for GCAP1 attachment to RetGC1, and in EF-hand 3 it is less critical, although it enhances the efficiency of the GCAP1 docking on the target enzyme (PMID:18541533)
• The coexpression of ROS-GC1 and its activators in spermatozoa suggests that the Ca(2+)-modulated ROS-GC1 transduction system may be a part of the fertilization machinery (PMID:19111294)
• Variations of macular microstructures were observed among LCA (Leber congenital amaurosis) patients with different genotypes. (PMID:19959640)
• This study hence establishes GUCY2D, which is a common cause for both recessive Leber’s congenital amaurosis and dominant cone-rod dystrophy, as a good candidate for autosomal recessive cone-rod dystrophy. (PMID:20517349)
• Two macular dystrophy-associated disease mutations at codon 838 of the GUCY2D gene were found among the 22 unrelated Spanish families, one of which had not been previously described (p.R838P). This novel mutation exhibited phenotypic variability. (PMID:21552474)
• Following subretinal delivery of a vector containing GUCY2D in Gucy2e(-/-) mice, GC1 protein was detected in the rod and cone outer segments, transducin was appropriately localized to cone outer segments, and an improvement in visual behavior. (PMID:21671801)
• A recurrent heterozygous (p.Arg838His) mutation in GUCY2D is associated with autosomal dominant cone dystrophy in a Chinese family. (PMID:22194653)
• This is the first report of a GUCY2D mutation causing central areolar choroidal dystrophy and adds to our understanding of genotype-phenotype correlation in this heterogeneous group of choroidoretinal dystrophies. (PMID:22695961)
• postulate a relationship between the level of RetGC1 activity and the degree of cone vision abnormality, and argue for cone function being the efficacy outcome in clinical trials of gene augmentation therapy in LCA1 (PMID:23035049)
• Expression of mutant human RETGC-1 leads to a retinal phenotype that includes aberrant photoreceptor morphology and a reduced number of photoreceptors. (PMID:23328348)
• A missense mutation in the GUCY2D gene caused ADCRD in this family. Clinical follow-up of this family with a typical CRD phenotype revealed disease progression during the time period. (PMID:23686677)
• A novel missense mutation of the GUCY2D gene was identified in this study. (PMID:23734073)
• Data suggest that dimerization domain of GUCY2D operates as a calcium-sensitive regulatory module; GUCY2D requires correct conformation of monomer-monomer interface for interaction with guanylate cyclase activating proteins (GCAP1; GCAP2). (PMID:23815670)
• Screening of the GUCY2D gene revealed the mutation p.R838H in all the affected individuals with autosomal dominant cone dystrophy and was absent in the asymptomatic patients. (PMID:24480840)
• GUCA1A and GUCY2D mutations are both accompanied by similar pattern of generalized cone dysfunction with a tendency to less involvement of the rod photoreceptors and a less severe phenotype in patients with GUCA1A. (PMID:24875811)
• 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)
• Cardiac fibrosis and the endogenous natriuretic peptide system were evaluated in end-stage heart failure to assess the anti-fibrotic actions of the dual GC-A/-B activator. (PMID:25117468)
• A deletion mutation in the GUCY2D gene is associated with Leber congenital amaurosis in a consanguineous Pakistani family. (PMID:25189253)
• GUCY2D is a major cause of autosomal dominant cone and cone-rod dystrophies in Israel (PMID:25515582)
• The GCAP1 and GCAP2 binding site(s) overlaps within the kinase homology and/or dimerization domains of retinal GC1. (PMID:25616661)
• Guanylate cyclase signaling pathway is down regulated in the pathogenesis of inflammatory bowel diseases. (PMID:25979109)
• Dimerization domain of RETGC1 is an essential part of GCAP1 and GCAP2 binding interface. (PMID:26100624)
• The GUCY2D mutations were frequent in Chinese families with autosomal dominant cone or cone-rod dystrophies. All mutations were found in exon 13. (PMID:26298565)
• Studies indicate that mutations in retinal guanylate cylase-1 (GUCY2D) are associated with a leading cause of recessive Leber congenital amaurosis (LCA1). (PMID:26427419)
• Data suggest that GCAP1 (guanylate cyclase activator 1A; Mg2+ vs. Ca2+) exhibits conformational changes in Ca2+ switch helix that are important in activation of RetGC1; myristoylation of GCAP1 is important as well in attaining activator conformation. (PMID:26703466)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Gucy2e	ENSMUSG00000020890
rattus_norvegicus	Gucy2e	ENSRNOG00000007931

Paralogs (17): GUCY1B1 (ENSG00000061918), GUCY2C (ENSG00000070019), ADCY2 (ENSG00000078295), GUCY2F (ENSG00000101890), NPR3 (ENSG00000113389), ADCY7 (ENSG00000121281), ADCY4 (ENSG00000129467), ADCY3 (ENSG00000138031), GUCY1A2 (ENSG00000152402), ADCY8 (ENSG00000155897), NPR2 (ENSG00000159899), ADCY9 (ENSG00000162104), GUCY1A1 (ENSG00000164116), ADCY1 (ENSG00000164742), NPR1 (ENSG00000169418), ADCY5 (ENSG00000173175), ADCY6 (ENSG00000174233)

Protein

Protein identifiers

Retinal guanylyl cyclase 1 — Q02846 (reviewed: Q02846)

Alternative names: CG-E, Guanylate cyclase 2D, retinal, Rod outer segment membrane guanylate cyclase

All UniProt accessions (1): Q02846

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the synthesis of cyclic GMP (cGMP) in rods and cones of photoreceptors. Plays an essential role in phototransduction, by mediating cGMP replenishment. May also participate in the trafficking of membrane-associated proteins to the photoreceptor outer segment membrane.

Subunit / interactions. Homodimer; requires homodimerization for guanylyl cyclase activity. Interacts with RD3; promotes the exit of GUCY2D from the endoplasmic reticulum and its trafficking to the photoreceptor outer segments. Interaction with RD3 negatively regulates guanylate cyclase activity.

Subcellular location. Photoreceptor outer segment membrane. Endoplasmic reticulum membrane.

Tissue specificity. Retina.

Disease relevance. Leber congenital amaurosis 1 (LCA1) [MIM:204000] 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 6 (CORD6) [MIM:601777] 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. Choroidal dystrophy, central areolar, 1 (CACD1) [MIM:215500] A form of central areolar choroidal dystrophy, a retinal disease that affects the macula and results in a well-demarcated circumscribed area of atrophy of the pigment epithelium and choriocapillaris. CACD1 inheritance is autosomal recessive. The disease may be caused by variants affecting the gene represented in this entry. Night blindness, congenital stationary, 1I (CSNB1I) [MIM:618555] A form of congenital stationary night blindness, a non-progressive retinal disorder characterized by impaired night vision or in dim light, with good vision only on bright days. CSNB1I patients present with night blindness from infancy or early childhood. Visual acuity is preserved, but some patients have color vision and/or visual field defects. Progression to mild retinitis pigmentosa may occur. CSNB1I inheritance is autosomal recessive. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Activated by GUCA1A when free calcium ions concentration is low, and inhibited by GUCA1A when free calcium ions concentration is high. Negatively regulated by RD3; inhibits the basal and GUCA1A-stimulated guanylate cyclase activity.

Miscellaneous. The gene names for receptor guanylyl cyclases are inconsistent between mouse and human. The ortholog of the mouse Gucy2d gene is a pseudogene in humans.

Similarity. Belongs to the adenylyl cyclase class-4/guanylyl cyclase family.

RefSeq proteins (1): NP_000171* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR001054	A/G_cyclase	Domain
IPR001245	Ser-Thr/Tyr_kinase_cat_dom	Domain
IPR001828	ANF_lig-bd_rcpt	Domain
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR011645	HNOB_dom_associated	Domain
IPR018297	A/G_cyclase_CS	Conserved_site
IPR028082	Peripla_BP_I	Homologous_superfamily
IPR029787	Nucleotide_cyclase	Homologous_superfamily
IPR050401	Cyclic_nucleotide_synthase	Family

Pfam: PF00211, PF01094, PF07701, PF07714

Enzyme classification (BRENDA):

• EC 4.6.1.2 — guanylate cyclase (BRENDA: 58 organisms, 213 substrates, 212 inhibitors, 100 Km, 16 kcat entries)

Substrate kinetics (BRENDA)

5 substrates with measured Km, best-characterized 5. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
GTP	0.01–6.09	90
2’-O-(N-METHYLANTHRANILOYL) GUANOSINE 5’-TRIPHOS	0.0357	1
GUANYL-(BETA,GAMMA-METHYLENE)-DIPHOSPHONATE	0.37	1
GUANYL-IMIDODIPHOSPHATE	0.07	1
MN2+	2.7	1

Catalyzed reactions (Rhea), 1 shown:

• GTP = 3’,5’-cyclic GMP + diphosphate (RHEA:13665)

UniProt features (62 total): sequence variant 47, mutagenesis site 4, disulfide bond 2, topological domain 2, domain 2, signal peptide 1, chain 1, transmembrane region 1, region of interest 1, glycosylation site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q02846-F1	82.37	0.44

Functional residue map

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

Disulfide bonds (2): 457, 449

Glycosylation sites (1): 297

Mutagenesis-validated functional residues (4):

Position	Phenotype
822	fails to become activated by guca1a and by guca1b. does not affect the binding to rp3.
823	fails to become activated by guca1a and by guca1b. does not affect the binding to rp3.
925	changes the substrate specificity from gtp to atp.
997	changes the substrate specificity from gtp to atp.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-2514859	Inactivation, recovery and regulation of the phototransduction cascade

MSigDB gene sets: 249 (showing top): BENPORATH_ES_WITH_H3K27ME3, GOBP_CELLULAR_RESPONSE_TO_LIGHT_STIMULUS, GOBP_CGMP_BIOSYNTHETIC_PROCESS, MODULE_445, MODULE_65, GOBP_PHOTOTRANSDUCTION, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_CYCLIC_NUCLEOTIDE_METABOLIC_PROCESS, GOBP_NUCLEOSIDE_PHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, PID_CONE_PATHWAY, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, GOBP_PHOTOTRANSDUCTION_VISIBLE_LIGHT, GOBP_CARBOHYDRATE_DERIVATIVE_BIOSYNTHETIC_PROCESS

GO Biological Process (8): cGMP biosynthetic process (GO:0006182), receptor guanylyl cyclase signaling pathway (GO:0007168), visual perception (GO:0007601), obsolete cGMP-mediated signaling (GO:0019934), regulation of opsin-mediated signaling pathway (GO:0022400), protein phosphorylation (GO:0006468), cyclic nucleotide biosynthetic process (GO:0009190), intracellular signal transduction (GO:0035556)

GO Molecular Function (13): peptide receptor activity (GO:0001653), guanylate cyclase activity (GO:0004383), protein kinase activity (GO:0004672), ATP binding (GO:0005524), GTP binding (GO:0005525), signaling receptor activity (GO:0038023), protein homodimerization activity (GO:0042803), protein-containing complex binding (GO:0044877), nucleotide binding (GO:0000166), protein binding (GO:0005515), lyase activity (GO:0016829), phosphorus-oxygen lyase activity (GO:0016849), identical protein binding (GO:0042802)

GO Cellular Component (9): photoreceptor outer segment (GO:0001750), nuclear outer membrane (GO:0005640), endoplasmic reticulum membrane (GO:0005789), plasma membrane (GO:0005886), photoreceptor outer segment membrane (GO:0042622), photoreceptor disc membrane (GO:0097381), endoplasmic reticulum (GO:0005783), membrane (GO:0016020), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
The phototransduction cascade	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
purine ribonucleoside triphosphate binding	2
binding	2
nuclear outer membrane-endoplasmic reticulum membrane network	2
organelle membrane	2
photoreceptor outer segment	2
purine ribonucleotide biosynthetic process	1
cyclic nucleotide biosynthetic process	1
cGMP metabolic process	1
enzyme-linked receptor protein signaling pathway	1
sensory perception of light stimulus	1
regulation of G protein-coupled receptor signaling pathway	1
G protein-coupled opsin signaling pathway	1
regulation of response to external stimulus	1
phosphorylation	1
protein modification process	1
nucleotide biosynthetic process	1
cyclic nucleotide metabolic process	1
intracellular anatomical structure	1
signal transduction	1
signaling receptor activity	1
peptide binding	1
cGMP biosynthetic process	1
cyclase activity	1
phosphorus-oxygen lyase activity	1
kinase activity	1
phosphotransferase activity, alcohol group as acceptor	1
catalytic activity, acting on a protein	1
adenyl ribonucleotide binding	1
guanyl ribonucleotide binding	1
molecular transducer activity	1
identical protein binding	1
protein dimerization activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
catalytic activity	1
lyase activity	1
protein binding	1
photoreceptor cell cilium	1
nuclear membrane	1

Protein interactions and networks

STRING

1063 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GUCY2D	GUCA1A	P43080	991
GUCY2D	AIPL1	Q9NZN9	971
GUCY2D	GUCA1B	Q9UMX6	967
GUCY2D	RPGRIP1	Q96KN7	940
GUCY2D	RD3	Q7Z3Z2	903
GUCY2D	PRPH2	P23942	887
GUCY2D	RPE65	Q16518	882
GUCY2D	CRX	O43186	875
GUCY2D	LCA5	Q86VQ0	868
GUCY2D	TULP1	O00294	861
GUCY2D	RCVRN	P35243	850
GUCY2D	LRAT	O95237	823
GUCY2D	ABCA4	P78363	820
GUCY2D	PITPNM3	Q9BZ71	817
GUCY2D	GUCA1C	O95843	808

IntAct

8 interactions, top by confidence:

A	B	Type	Score
RD3	GUCY2D	psi-mi:“MI:0915”(physical association)	0.460
GUCY2D	RD3	psi-mi:“MI:0915”(physical association)	0.460
GUCY2D	RD3	psi-mi:“MI:0403”(colocalization)	0.460
GUCY2D	FYN	psi-mi:“MI:0915”(physical association)	0.400
Ankmy2	GUCY2D	psi-mi:“MI:0915”(physical association)	0.400
GUCY2D	HSP90AA1	psi-mi:“MI:0914”(association)	0.350
GUCY2F	ACTA2	psi-mi:“MI:0914”(association)	0.350

BioGRID (12): GUCY2D (Proximity Label-MS), MOCS1 (Affinity Capture-MS), HSP90AB4P (Affinity Capture-MS), HSP90AA1 (Affinity Capture-MS), HSP90AB3P (Affinity Capture-MS), GUCY2D (Affinity Capture-MS), MXRA7 (Affinity Capture-MS), HSPA1A (Affinity Capture-MS), HSP90AA5P (Affinity Capture-MS), TUFT1 (Affinity Capture-MS), GUCY2D (Affinity Capture-MS), GUCY2D (Affinity Capture-Western)

ESM2 similar proteins: A0A061IR73, A0A7N9VSG0, A7YSY2, D3KCC4, D3ZU57, D4A2B7, O08644, O15197, O19179, O43542, O75064, O95382, P0C0K6, P0C0K7, P51840, P52785, P52824, P54777, Q02846, Q05932, Q13470, Q13608, Q1HG60, Q3ZBE0, Q4KM32, Q5JZY3, Q643R3, Q6MG64, Q6NVG1, Q6ZPS2, Q76MJ5, Q7TNJ2, Q80SX8, Q8BYG9, Q8IZY2, Q8NFF5, Q8R5G7, Q8TDZ2, Q8WWN8, Q91V24

Diamond homologs: A0A078BQP2, A0A0U1RPR8, E7EAU8, H2L002, O02298, O02740, O16715, O19179, O54865, O62179, O75343, P0A4Y1, P16065, P16066, P16068, P18293, P18910, P19686, P19687, P20594, P20595, P22717, P23897, P25092, P26770, P33402, P51840, P51841, P51842, P52785, P55202, P55203, P55204, P70106, P90895, P91550, P92006, P9WQ34, P9WQ35, Q02108

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

1697 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	153
Likely pathogenic	92
Uncertain significance	662
Likely benign	660
Benign	38

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1066142	NM_000180.4(GUCY2D):c.-2_3del (p.Met1fs)	Pathogenic
1069546	NM_000180.4(GUCY2D):c.1361_1367del (p.Asn454fs)	Pathogenic
1070768	NM_000180.4(GUCY2D):c.2383C>T (p.Arg795Trp)	Pathogenic
1070769	NM_000180.4(GUCY2D):c.2476C>T (p.Gln826Ter)	Pathogenic
1072504	NM_000180.4(GUCY2D):c.484dup (p.Ala162fs)	Pathogenic
1074833	NM_000180.4(GUCY2D):c.2646C>G (p.Tyr882Ter)	Pathogenic
1075556	NM_000180.4(GUCY2D):c.3105C>G (p.Tyr1035Ter)	Pathogenic
1076325	NM_000180.4(GUCY2D):c.564del (p.Ala189fs)	Pathogenic
1213844	NM_000180.4(GUCY2D):c.690_693del (p.Lys232fs)	Pathogenic
1333159	NM_000180.4(GUCY2D):c.3026T>A (p.Met1009Lys)	Pathogenic
1413732	NM_000180.4(GUCY2D):c.2871del (p.Ser958fs)	Pathogenic
1454622	NM_000180.4(GUCY2D):c.175del (p.Leu59fs)	Pathogenic
1456503	NM_000180.4(GUCY2D):c.2209C>T (p.Gln737Ter)	Pathogenic
1685872	NM_000180.4(GUCY2D):c.1A>G (p.Met1Val)	Pathogenic
1685873	NM_000180.4(GUCY2D):c.2512C>G (p.Arg838Gly)	Pathogenic
1687499	NM_000180.4(GUCY2D):c.315C>A (p.Cys105Ter)	Pathogenic
1915862	NM_000180.4(GUCY2D):c.2678_2679del (p.Ser893fs)	Pathogenic
198995	NM_000180.4(GUCY2D):c.1773del (p.Asn591fs)	Pathogenic
2021991	NM_000180.4(GUCY2D):c.860del (p.Pro287fs)	Pathogenic
2046697	NM_000180.4(GUCY2D):c.2323C>T (p.Gln775Ter)	Pathogenic
2060321	NM_000180.4(GUCY2D):c.781_782insT (p.Glu261fs)	Pathogenic
2069382	NM_000180.4(GUCY2D):c.3118_3125delinsAAGGTGAGGTAC (p.Arg1040fs)	Pathogenic
2086516	NM_000180.4(GUCY2D):c.1150del (p.Asp384fs)	Pathogenic
2108666	NM_000180.4(GUCY2D):c.1821_1824dup (p.Ala609fs)	Pathogenic
2137915	NM_000180.4(GUCY2D):c.1762C>T (p.Arg588Trp)	Pathogenic
2422545	NC_000017.10:g.(?7906366)(7912924_?)del	Pathogenic
280359	NM_000180.4(GUCY2D):c.3139-1G>C	Pathogenic
2923457	NM_000180.4(GUCY2D):c.185G>A (p.Trp62Ter)	Pathogenic
2925598	NM_000180.4(GUCY2D):c.186G>A (p.Trp62Ter)	Pathogenic
2925599	NM_000180.4(GUCY2D):c.308A>T (p.Glu103Val)	Pathogenic

SpliceAI

3110 predictions. Top by Δscore:

Variant	Effect	Δscore
17:8007369:T:A	acceptor_gain	1.0000
17:8007912:ATT:A	acceptor_gain	1.0000
17:8009501:T:A	acceptor_gain	1.0000
17:8009502:GCA:G	acceptor_loss	1.0000
17:8009503:CAG:C	acceptor_loss	1.0000
17:8009504:AG:A	acceptor_gain	1.0000
17:8009505:GG:G	acceptor_gain	1.0000
17:8009505:GGGA:G	acceptor_gain	1.0000
17:8009582:CCAAG:C	donor_loss	1.0000
17:8009583:CAAGG:C	donor_loss	1.0000
17:8009584:AAGGT:A	donor_loss	1.0000
17:8009585:AGG:A	donor_loss	1.0000
17:8009587:GT:G	donor_loss	1.0000
17:8009588:T:A	donor_loss	1.0000
17:8012352:T:A	donor_loss	1.0000
17:8012442:A:AG	acceptor_gain	1.0000
17:8012443:T:G	acceptor_gain	1.0000
17:8012447:A:AG	acceptor_gain	1.0000
17:8012447:AAG:A	acceptor_gain	1.0000
17:8012447:AAGG:A	acceptor_gain	1.0000
17:8012448:A:G	acceptor_gain	1.0000
17:8012449:G:A	acceptor_gain	1.0000
17:8012602:GGAGG:G	donor_gain	1.0000
17:8012603:GAGG:G	donor_gain	1.0000
17:8012603:GAGGG:G	donor_gain	1.0000
17:8012605:GG:G	donor_gain	1.0000
17:8012606:GG:G	donor_gain	1.0000
17:8012607:G:GG	donor_gain	1.0000
17:8013097:CCCCA:C	acceptor_loss	1.0000
17:8013098:CCCA:C	acceptor_loss	1.0000

AlphaMissense

7038 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:8014921:C:A	T880K	1.000
17:8014929:T:C	F883L	1.000
17:8014931:T:A	F883L	1.000
17:8014931:T:G	F883L	1.000
17:8014932:A:C	S884R	1.000
17:8014934:T:A	S884R	1.000
17:8014934:T:G	S884R	1.000
17:8014935:G:C	D885H	1.000
17:8014936:A:C	D885A	1.000
17:8014936:A:G	D885G	1.000
17:8014936:A:T	D885V	1.000
17:8014937:C:A	D885E	1.000
17:8014937:C:G	D885E	1.000
17:8014947:T:C	F889L	1.000
17:8014948:T:C	F889S	1.000
17:8014949:C:A	F889L	1.000
17:8014949:C:G	F889L	1.000
17:8014993:T:C	L904P	1.000
17:8014996:T:A	L905H	1.000
17:8014996:T:C	L905P	1.000
17:8015005:T:C	L908P	1.000
17:8015020:A:C	D913A	1.000
17:8015020:A:T	D913V	1.000
17:8015051:G:C	K923N	1.000
17:8015051:G:T	K923N	1.000
17:8015332:A:T	E925V	1.000
17:8015338:T:A	I927K	1.000
17:8015340:G:A	G928R	1.000
17:8015340:G:C	G928R	1.000
17:8015340:G:T	G928W	1.000

dbSNP variants (sampled 300 via entrez): RS1000135302 (17:8016302 G>A), RS1000246114 (17:8010585 T>C), RS1000299743 (17:8010757 C>T), RS1000501472 (17:8004158 T>C), RS1001056697 (17:8004918 A>G), RS1001190305 (17:8015170 C>G,T), RS1001240787 (17:8009095 C>G,T), RS1001458682 (17:8002489 C>T), RS1001538483 (17:8014902 G>A,C), RS1001737567 (17:8000829 T>A,C), RS1001909837 (17:8002822 G>A,C,T), RS1002232336 (17:8012999 G>A,C), RS1002502608 (17:8001363 A>G), RS1002687581 (17:8009693 G>A), RS1002745311 (17:8002441 G>T)

Disease associations

OMIM: gene MIM:600179 | disease phenotypes: MIM:204000, MIM:601777, MIM:215500, MIM:618555, MIM:268000, MIM:120970, MIM:116200

GenCC curated gene-disease

Disease	Classification	Inheritance
Leber congenital amaurosis 1	Definitive	Autosomal recessive
cone-rod dystrophy	Definitive	Autosomal dominant
cone-rod dystrophy 6	Strong	Autosomal dominant
night blindness, congenital stationary, type1i	Strong	Autosomal recessive
GUCY2D-related dominant retinopathy	Strong	Autosomal dominant
GUCY2D-related recessive retinopathy	Strong	Autosomal recessive
Leber congenital amaurosis	Supportive	Autosomal dominant
central areolar choroidal dystrophy	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
GUCY2D-related dominant retinopathy	Definitive	AD
GUCY2D-related recessive retinopathy	Definitive	AR

Mondo (18): Leber congenital amaurosis 1 (MONDO:0008764), cone-rod dystrophy 6 (MONDO:0011143), inherited retinal dystrophy (MONDO:0019118), choroidal dystrophy, central areolar, 1 (MONDO:0024539), night blindness, congenital stationary, type1i (MONDO:0032811), GUCY2D-related recessive retinopathy (MONDO:0100453), optic atrophy (MONDO:0003608), Leber congenital amaurosis (MONDO:0018998), retinitis pigmentosa (MONDO:0019200), pathologic nystagmus (MONDO:0004843), cone dystrophy (MONDO:0000455), POLR-related leukodystrophy (MONDO:0100605), cone-rod dystrophy (MONDO:0015993), retinal disorder (MONDO:0005283), cataract (MONDO:0005129)

Orphanet (8): Cone rod dystrophy (Orphanet:1872), Leber congenital amaurosis (Orphanet:65), OBSOLETE: Inherited retinal disorder (Orphanet:71862), Central areolar choroidal dystrophy (Orphanet:75377), Retinitis pigmentosa (Orphanet:791), Autosomal recessive isolated optic atrophy (Orphanet:98676), Progressive cone dystrophy (Orphanet:1871), 4H leukodystrophy (Orphanet:289494)

HPO phenotypes

68 total (30 of 68 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000365	Hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000505	Visual impairment
HP:0000512	Abnormal electroretinogram
HP:0000518	Cataract
HP:0000529	Progressive visual loss
HP:0000533	Chorioretinal atrophy
HP:0000540	Hypermetropia
HP:0000543	Optic disc pallor
HP:0000548	Cone/cone-rod dystrophy
HP:0000551	Color vision defect
HP:0000552	Tritanomaly
HP:0000563	Keratoconus
HP:0000572	Visual loss
HP:0000580	Pigmentary retinopathy
HP:0000603	Central scotoma
HP:0000613	Photophobia
HP:0000618	Blindness
HP:0000639	Nystagmus
HP:0000654	Decreased light- and dark-adapted electroretinogram amplitude
HP:0000662	Nyctalopia
HP:0000729	Autistic behavior
HP:0001099	Atrophic fundus lesion
HP:0001105	Retinal atrophy
HP:0001141	Severely reduced visual acuity
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST010002_119	Refractive error	3.000000e-22

MeSH disease descriptors (10)

Descriptor	Name	Tree numbers
D002386	Cataract	C11.510.245
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
D009759	Nystagmus, Pathologic	C10.292.562.675; C11.590.400
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
C538363	Retinal cone dystrophy 2 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: catalytic receptor — Transmembrane guanylyl cyclases

CTD chemical–gene interactions

16 total (human), top 16 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression, decreases methylation, increases methylation, affects methylation	2
lasiocarpine	decreases expression	1
methyleugenol	decreases expression	1
pirinixic acid	affects binding, increases activity, increases expression	1
terbufos	increases methylation	1
16 alpha-ethyl-21-hydroxy-19-nor-4-pregnene-3,20-dione	increases expression	1
benzo(e)pyrene	increases methylation	1
Gefitinib	decreases expression	1
Acetaminophen	decreases expression	1
Drugs, Chinese Herbal	increases expression	1
Fonofos	increases methylation	1
Ivermectin	increases expression	1
Methapyrilene	increases methylation	1
Naphthoquinones	increases expression	1
Parathion	increases methylation	1
Okadaic Acid	decreases expression	1

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)
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)