GUCY2F

Summary

GUCY2F (guanylate cyclase 2F, retinal, HGNC:4691) is a protein-coding gene on chromosome Xq22.3-q23, encoding Retinal guanylyl cyclase 2 (P51841). Responsible for the synthesis of cyclic GMP (cGMP) in rods and cones of photoreceptors.

The protein encoded by this gene is a guanylyl cyclase found predominantly in photoreceptors in the retina. The encoded protein is thought to be involved in resynthesis of cGMP after light activation of the visual signal transduction cascade, allowing a return to the dark state. This protein is a single-pass type I membrane protein. Defects in this gene may be a cause of X-linked retinitis pigmentosa.

Source: NCBI Gene 2986 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 149 total
• MANE Select transcript: NM_001522

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4691
Approved symbol	GUCY2F
Name	guanylate cyclase 2F, retinal
Location	Xq22.3-q23
Locus type	gene with protein product
Status	Approved
Aliases	GUC2DL, GC-F, RetGC-2, ROS-GC2, CYGF
Ensembl gene	ENSG00000101890
Ensembl biotype	protein_coding
OMIM	300041
Entrez	2986

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000218006

RefSeq mRNA: 1 — MANE Select: NM_001522 NM_001522

CCDS: CCDS14545

Canonical transcript exons

ENST00000218006 — 20 exons

Exon	Start	End
ENSE00000674541	109465142	109465443
ENSE00000674542	109453505	109453859
ENSE00000674543	109452023	109452107
ENSE00000674544	109448069	109448165
ENSE00000674545	109441351	109441482
ENSE00000674547	109430307	109430396
ENSE00000674548	109408992	109409168
ENSE00000674550	109404328	109404484
ENSE00000674551	109398549	109398698
ENSE00000674552	109395341	109395489
ENSE00000674556	109391911	109392103
ENSE00000674557	109388489	109388663
ENSE00000674558	109385184	109385282
ENSE00000674559	109382118	109382212
ENSE00000674560	109376079	109376167
ENSE00000674561	109375898	109375986
ENSE00000866653	109475207	109476021
ENSE00000866654	109392892	109393055
ENSE00001362733	109372906	109372999
ENSE00001362754	109481866	109482086

Expression profiles

Bgee: expression breadth broad, 13 present calls, max score 78.82.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0113 / max 16.7985, expressed in 2 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
200116	0.0083	2
200115	0.0030	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	78.82	silver quality
frontal pole	UBERON:0002795	68.68	gold quality
paraflocculus	UBERON:0005351	68.31	gold quality
middle frontal gyrus	UBERON:0002702	68.21	gold quality
endometrium epithelium	UBERON:0004811	59.38	gold quality
nasal cavity epithelium	UBERON:0005384	56.13	gold quality
metanephric glomerulus	UBERON:0004736	55.97	gold quality
right uterine tube	UBERON:0001302	54.42	gold quality
thymus	UBERON:0002370	52.03	gold quality
Brodmann (1909) area 10	UBERON:0013541	50.18	gold quality
cerebellar vermis	UBERON:0004720	49.25	gold quality
trachea	UBERON:0003126	48.33	gold quality
quadriceps femoris	UBERON:0001377	46.11	gold quality
layer of synovial tissue	UBERON:0007616	45.73	gold quality
vastus lateralis	UBERON:0001379	45.25	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	43.71	silver quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	43.37	gold quality
pigmented layer of retina	UBERON:0001782	43.07	gold quality
secondary oocyte	CL:0000655	42.57	gold quality
oviduct epithelium	UBERON:0004804	41.87	gold quality
fallopian tube	UBERON:0003889	41.85	gold quality
epithelium of bronchus	UBERON:0002031	41.73	gold quality
bronchus	UBERON:0002185	41.62	gold quality
dorsal root ganglion	UBERON:0000044	41.42	gold quality
bronchial epithelial cell	CL:0002328	41.34	gold quality
superficial temporal artery	UBERON:0001614	41.33	gold quality
biceps brachii	UBERON:0001507	41.18	gold quality
palpebral conjunctiva	UBERON:0001812	41.10	gold quality
endometrium	UBERON:0001295	41.02	silver quality
mucosa of paranasal sinus	UBERON:0005030	40.98	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.24

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 3)

• Results show GUCY2F gene was implicated in the pathogenesis of breast, lung, and pancreatic cancers and it may be useful targets for diagnostic and therapeutic intervention in selected patients. (PMID:16941478)
• Mutants of GC-activating protein 2 modulated ROS-GC2 in a manner different from their action on ROS-GC1 indicating that the Ca2+ sensitivity of the Ca2+ sensor is controlled by the mode of target-sensor interaction. (PMID:17868328)
• Retinal degeneration-3 protein attenuates photoreceptor degeneration in transgenic mice expressing dominant mutation of human retinal guanylyl cyclase. (PMID:34537244)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Gucy2f	ENSMUSG00000042282
rattus_norvegicus	Gucy2f	ENSRNOG00000019086

Paralogs (17): GUCY1B1 (ENSG00000061918), GUCY2C (ENSG00000070019), ADCY2 (ENSG00000078295), NPR3 (ENSG00000113389), ADCY7 (ENSG00000121281), ADCY4 (ENSG00000129467), GUCY2D (ENSG00000132518), 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 2 — P51841 (reviewed: P51841)

Alternative names: Guanylate cyclase 2F, retinal, Guanylate cyclase F, Rod outer segment membrane guanylate cyclase 2

All UniProt accessions (1): P51841

UniProt curated annotations — full annotation on UniProt →

Function. Responsible for 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. Interacts with RD3; promotes the exit of GUCY2F from the endoplasmic reticulum and its trafficking to the photoreceptor outer segments.

Subcellular location. Photoreceptor outer segment membrane.

Tissue specificity. Retina. Localized exclusively in the outer nuclear layer and inner segments of the rod and cone photoreceptor cells.

Post-translational modifications. There are 9 conserved cysteine residues in sensory guanylate cyclases, 6 in the extracellular domain, which may be involved in intra- or interchain disulfide bonds.

Activity regulation. Activated by GUCA1B when free calcium ions concentration is low, and inhibited by GUCA1B when free calcium ions concentration is high. Inhibited by RD3.

Domain organisation. The protein kinase domain is predicted to be catalytically inactive.

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

RefSeq proteins (1): NP_001513* (*=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 (28 total): sequence variant 18, disulfide bond 3, topological domain 2, domain 2, signal peptide 1, chain 1, transmembrane region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P51841-F1	82.16	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 (3): 104–132, 452, 460

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: 137 (showing top): MORF_ITGA2, GOBP_CELLULAR_RESPONSE_TO_LIGHT_STIMULUS, GOBP_CGMP_BIOSYNTHETIC_PROCESS, MODULE_64, 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, MORF_RAD51L3, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS

GO Biological Process (9): 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), detection of light stimulus involved in visual perception (GO:0050908), protein phosphorylation (GO:0006468), cyclic nucleotide biosynthetic process (GO:0009190), intracellular signal transduction (GO:0035556)

GO Molecular Function (11): 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), identical protein binding (GO:0042802), protein-containing complex binding (GO:0044877), nucleotide binding (GO:0000166), lyase activity (GO:0016829), phosphorus-oxygen lyase activity (GO:0016849)

GO Cellular Component (6): nuclear outer membrane (GO:0005640), plasma membrane (GO:0005886), photoreceptor disc membrane (GO:0097381), rod photoreceptor outer segment (GO:0120200), 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
purine ribonucleoside triphosphate binding	2
photoreceptor outer segment	2
cellular anatomical structure	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
visual perception	1
detection of light stimulus involved in sensory perception	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
protein binding	1
binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
catalytic activity	1
lyase activity	1
nuclear membrane	1
organelle outer membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
membrane	1

Protein interactions and networks

STRING

1081 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GUCY2F	GUCA1A	P43080	816
GUCY2F	GUCA1B	Q9UMX6	789
GUCY2F	KCNE5	Q9UJ90	784
GUCY2F	AMMECR1	Q9Y4X0	765
GUCY2F	PDIK1L	Q8N165	744
GUCY2F	PTPRK	Q15262	716
GUCY2F	NXT2	Q9NPJ8	684
GUCY2F	MYLK2	Q9H1R3	664
GUCY2F	GNGT1	P63211	619
GUCY2F	ACSL4	O60488	609
GUCY2F	OMP	P47874	607
GUCY2F	GUCA1C	O95843	592
GUCY2F	GCDH	Q92947	591
GUCY2F	MAP3K21	Q5TCX8	562
GUCY2F	GRK1	Q15835	530

IntAct

4 interactions, top by confidence:

A	B	Type	Score
Dlg4	GUCY2F	psi-mi:“MI:0407”(direct interaction)	0.440
GABARAPL2		psi-mi:“MI:0914”(association)	0.350
GUCY2F	ACTA2	psi-mi:“MI:0914”(association)	0.350

BioGRID (6): GUCY2F (Affinity Capture-Western), GUCY2F (Affinity Capture-Western), ACTA2 (Affinity Capture-MS), GUCY2D (Affinity Capture-MS), PLS1 (Affinity Capture-MS), MICAL1 (Affinity Capture-MS)

ESM2 similar proteins: A0A0U1RPR8, O02740, O08644, O09127, O15197, O19179, O73875, O73878, P0C0K6, P0C0K7, P14616, P16067, P20594, P21709, P26770, P29317, P29322, P35590, P46197, P51839, P51840, P51841, P51842, P52333, P52785, P54753, P54754, P54760, P54761, P55203, P55205, Q02846, Q03146, Q06805, Q06806, Q08345, Q1KL86, Q5JZY3, Q5SDA5, Q60750

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

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	95
Likely benign	9
Benign	5

Top pathogenic / likely-pathogenic (0)

SpliceAI

3535 predictions. Top by Δscore:

Variant	Effect	Δscore
X:109382213:C:CC	acceptor_gain	1.0000
X:109385182:A:AC	donor_gain	1.0000
X:109385183:C:CC	donor_gain	1.0000
X:109388485:TTACC:T	donor_loss	1.0000
X:109388486:TACC:T	donor_loss	1.0000
X:109388660:CTAC:C	acceptor_gain	1.0000
X:109391906:CCTA:C	donor_loss	1.0000
X:109391907:CTA:C	donor_loss	1.0000
X:109391908:TACCT:T	donor_loss	1.0000
X:109391909:A:T	donor_loss	1.0000
X:109391910:C:CT	donor_loss	1.0000
X:109392099:CTGAT:C	acceptor_gain	1.0000
X:109392851:A:AC	donor_gain	1.0000
X:109392852:C:CC	donor_gain	1.0000
X:109392871:T:A	donor_gain	1.0000
X:109392887:CATA:C	donor_gain	1.0000
X:109392890:A:AC	donor_gain	1.0000
X:109392891:C:CC	donor_gain	1.0000
X:109392919:T:A	donor_gain	1.0000
X:109393056:C:CC	acceptor_gain	1.0000
X:109395495:C:CT	acceptor_gain	1.0000
X:109395495:C:T	acceptor_gain	1.0000
X:109395513:CGTT:C	acceptor_gain	1.0000
X:109408983:C:A	donor_gain	1.0000
X:109430302:CATA:C	donor_loss	1.0000
X:109430305:ACCA:A	donor_loss	1.0000
X:109430393:CACC:C	acceptor_gain	1.0000
X:109430395:CC:C	acceptor_gain	1.0000
X:109430396:CC:C	acceptor_gain	1.0000
X:109441479:CTCT:C	acceptor_gain	1.0000

AlphaMissense

7298 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:109385228:C:A	G1004V	1.000
X:109385228:C:T	G1004E	1.000
X:109385230:A:C	F1003L	1.000
X:109385230:A:T	F1003L	1.000
X:109385232:A:G	F1003L	1.000
X:109385236:G:C	C1001W	1.000
X:109385259:C:G	G994R	1.000
X:109388647:T:A	D933V	1.000
X:109388647:T:C	D933G	1.000
X:109388647:T:G	D933A	1.000
X:109388650:C:T	G932E	1.000
X:109391911:C:A	K927N	1.000
X:109391911:C:G	K927N	1.000
X:109391942:T:A	D917V	1.000
X:109392013:G:C	F893L	1.000
X:109392013:G:T	F893L	1.000
X:109392015:A:G	F893L	1.000
X:109392026:T:A	D889V	1.000
X:109392026:T:G	D889A	1.000
X:109392031:G:C	F887L	1.000
X:109392031:G:T	F887L	1.000
X:109392033:A:G	F887L	1.000
X:109392086:A:T	L869H	1.000
X:109392913:A:G	L856P	1.000
X:109392943:A:G	L846P	1.000
X:109392976:A:G	L835S	1.000
X:109404407:A:C	F682L	1.000
X:109404407:A:T	F682L	1.000
X:109404409:A:G	F682L	1.000
X:109409022:A:C	F646L	1.000

dbSNP variants (sampled 300 via entrez): RS1000020826 (X:109433825 C>T), RS1000072988 (X:109446180 A>G), RS1000126509 (X:109447739 C>T), RS1000192779 (X:109381726 A>C), RS1000200268 (X:109407858 A>C,T), RS1000201584 (X:109397139 G>C), RS1000268555 (X:109482660 A>G,T), RS1000289656 (X:109464373 A>G), RS1000343203 (X:109436954 A>C,T), RS1000355224 (X:109417048 C>G), RS1000402342 (X:109434030 G>A), RS1000404224 (X:109426956 T>C), RS1000507505 (X:109410204 A>G), RS1000531650 (X:109388881 A>G), RS1000542501 (X:109399196 G>A)

Disease associations

OMIM: gene MIM:300041 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

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

6 total (human), top 6 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases methylation	1
Diethylhexyl Phthalate	decreases expression	1
Silicon Dioxide	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Aflatoxin B1	decreases expression	1
Copper Sulfate	decreases expression	1

Clinical trials (associated diseases)

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