GUCY1A2

Summary

GUCY1A2 (guanylate cyclase 1 soluble subunit alpha 2, HGNC:4684) is a protein-coding gene on chromosome 11q22.3, encoding Guanylate cyclase soluble subunit alpha-2 (P33402). Has guanylyl cyclase on binding to the beta-1 subunit.

Soluble guanylate cyclases are heterodimeric proteins that catalyze the conversion of GTP to 3’,5’-cyclic GMP and pyrophosphate. The protein encoded by this gene is an alpha subunit of this complex and it interacts with a beta subunit to form the guanylate cyclase enzyme, which is activated by nitric oxide. Two transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 2977 — RefSeq curated summary.

At a glance

• GWAS associations: 9
• Clinical variants (ClinVar): 88 total
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_000855

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4684
Approved symbol	GUCY1A2
Name	guanylate cyclase 1 soluble subunit alpha 2
Location	11q22.3
Locus type	gene with protein product
Status	Approved
Aliases	GC-SA2
Ensembl gene	ENSG00000152402
Ensembl biotype	protein_coding
OMIM	601244
Entrez	2977

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

ENST00000282249, ENST00000347596, ENST00000526355

RefSeq mRNA: 2 — MANE Select: NM_000855 NM_000855, NM_001256424

CCDS: CCDS58170, CCDS8335

Canonical transcript exons

ENST00000526355 — 8 exons

Exon	Start	End
ENSE00001005004	106809993	106810478
ENSE00001005008	106939460	106940178
ENSE00001101354	106978619	106978740
ENSE00001101362	106986070	106986131
ENSE00001132815	106776439	106776582
ENSE00001185442	106708512	106708666
ENSE00002182336	107017753	107018476
ENSE00002598075	106674019	106687756

Expression profiles

Bgee: expression breadth ubiquitous, 234 present calls, max score 96.06.

FANTOM5 (CAGE): breadth broad, TPM avg 3.1444 / max 118.0025, expressed in 592 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
122112	1.0643	359
122110	1.0477	385
122114	0.3587	172
122113	0.2382	130
122109	0.2333	143
122111	0.1071	48
122108	0.0952	48

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
Brodmann (1909) area 23	UBERON:0013554	96.06	gold quality
lateral nuclear group of thalamus	UBERON:0002736	95.90	gold quality
visceral pleura	UBERON:0002401	94.56	gold quality
saphenous vein	UBERON:0007318	94.32	gold quality
cortical plate	UBERON:0005343	93.53	gold quality
postcentral gyrus	UBERON:0002581	93.31	gold quality
parietal lobe	UBERON:0001872	93.22	gold quality
cauda epididymis	UBERON:0004360	92.98	gold quality
lower lobe of lung	UBERON:0008949	91.67	gold quality
lateral globus pallidus	UBERON:0002476	91.27	gold quality
vena cava	UBERON:0004087	91.21	gold quality
endothelial cell	CL:0000115	90.83	gold quality
seminal vesicle	UBERON:0000998	90.72	gold quality
entorhinal cortex	UBERON:0002728	90.56	gold quality
pons	UBERON:0000988	89.38	gold quality
superior frontal gyrus	UBERON:0002661	89.20	gold quality
caput epididymis	UBERON:0004358	87.91	gold quality
superior vestibular nucleus	UBERON:0007227	87.63	gold quality
middle temporal gyrus	UBERON:0002771	86.84	gold quality
substantia nigra pars compacta	UBERON:0001965	86.80	gold quality
secondary oocyte	CL:0000655	86.42	gold quality
placenta	UBERON:0001987	85.98	gold quality
globus pallidus	UBERON:0001875	85.69	gold quality
corpus epididymis	UBERON:0004359	85.63	gold quality
pleura	UBERON:0000977	85.54	gold quality
medial globus pallidus	UBERON:0002477	85.35	gold quality
ventral tegmental area	UBERON:0002691	84.59	gold quality
occipital lobe	UBERON:0002021	84.24	gold quality
adrenal tissue	UBERON:0018303	83.62	gold quality
primary visual cortex	UBERON:0002436	83.42	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-MTAB-11268	yes	2014.47
E-MTAB-6075	yes	371.82
E-HCAD-35	yes	59.05
E-CURD-119	yes	11.32
E-ANND-3	yes	7.93

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

560 targeting GUCY1A2, 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-4533	100.00	69.48	2758
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-6740-5P	100.00	65.64	932
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4747-5P	100.00	67.90	2681

Literature-anchored findings (GeneRIF, showing 6)

• Soluble guanylyl cyclase (sGC) is the major cellular receptor for the intercellular messenger nitric oxide (NO) and mediates a wide range of physiological effects through elevation of intracellular cGMP levels (PMID:11752394)
• No significant changes were found in sGC subunit mRNAs in people with schizophrenia or in controls. (PMID:15094474)
• The sGC alpha 1observed in OVCAR-3 and MDA-MB-468 cancer cells which correlated well with the sGC activity and a marked increase in cGMP levels upon exposure to the combination of a NO donor and a sGC activator. (PMID:19948239)
• The CO binding affinity of soluble guanylate cyclase alpha 2 subunit is threefold greater than that of human soluble guanylate cyclase alpha 1 subunit. (PMID:22426988)
• The data support a novel regulatory mechanism whereby sGC activity is tuned by distinct domain interactions that either promote or inhibit catalytic activity. (PMID:24669844)
• Circadian gene ARNTL initiates circGUCY1A2 transcription to suppress non-small cell lung cancer progression via miR-200c-3p/PTEN signaling. (PMID:37667322)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	GUCY1A2	ENSDARG00000093185
mus_musculus	Gucy1a2	ENSMUSG00000041624
rattus_norvegicus	Gucy1a2	ENSRNOG00000029876

Paralogs (17): GUCY1B1 (ENSG00000061918), GUCY2C (ENSG00000070019), ADCY2 (ENSG00000078295), GUCY2F (ENSG00000101890), NPR3 (ENSG00000113389), ADCY7 (ENSG00000121281), ADCY4 (ENSG00000129467), GUCY2D (ENSG00000132518), ADCY3 (ENSG00000138031), ADCY8 (ENSG00000155897), NPR2 (ENSG00000159899), ADCY9 (ENSG00000162104), GUCY1A1 (ENSG00000164116), ADCY1 (ENSG00000164742), NPR1 (ENSG00000169418), ADCY5 (ENSG00000173175), ADCY6 (ENSG00000174233)

Protein

Protein identifiers

Guanylate cyclase soluble subunit alpha-2 — P33402 (reviewed: P33402)

All UniProt accessions (1): P33402

UniProt curated annotations — full annotation on UniProt →

Function. Has guanylyl cyclase on binding to the beta-1 subunit. Isoform 2 acts as a negative regulator of guanylyl cyclase activity as it forms non-functional heterodimers with the beta subunits.

Subunit / interactions. Heterodimer of an alpha and a beta chain.

Subcellular location. Cytoplasm.

Tissue specificity. Isoform 1 is expressed in fetal brain, liver, colon, endothelium and testis. Isoform 2 is expressed only in liver, colon and endothelium.

Activity regulation. Activated by nitric oxide in the presence of magnesium or manganese ions.

Miscellaneous. There are two types of guanylate cyclases: soluble forms and membrane-associated receptor forms.

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

Isoforms (3)

UniProt ID	Names	Canonical?
P33402-1	1, Alpha-2	yes
P33402-2	2, Alpha-2-I
P33402-3	3

RefSeq proteins (2): NP_000846, NP_001243353 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001054	A/G_cyclase	Domain
IPR011644	Heme_NO-bd	Domain
IPR011645	HNOB_dom_associated	Domain
IPR018297	A/G_cyclase_CS	Conserved_site
IPR024096	NO_sig/Golgi_transp_ligand-bd	Homologous_superfamily
IPR029787	Nucleotide_cyclase	Homologous_superfamily
IPR038158	H-NOX_domain_sf	Homologous_superfamily
IPR042463	HNOB_dom_associated_sf	Homologous_superfamily

Pfam: PF00211, PF07700, PF07701

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 (8 total): splice variant 2, sequence variant 2, chain 1, domain 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P33402-F1	76.88	0.44

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-392154	Nitric oxide stimulates guanylate cyclase
R-HSA-445355	Smooth Muscle Contraction

MSigDB gene sets: 301 (showing top): BERTUCCI_MEDULLARY_VS_DUCTAL_BREAST_CANCER_DN, chr11q22, GOBP_CGMP_BIOSYNTHETIC_PROCESS, MODULE_445, MODULE_65, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_CYCLIC_NUCLEOTIDE_METABOLIC_PROCESS, GOBP_NUCLEOSIDE_PHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, GOBP_RESPONSE_TO_OXYGEN_LEVELS, GOBP_CARBOHYDRATE_DERIVATIVE_BIOSYNTHETIC_PROCESS, MODULE_99, GOBP_RESPONSE_TO_ABIOTIC_STIMULUS

GO Biological Process (8): signal transduction (GO:0007165), obsolete nitric oxide mediated signal transduction (GO:0007263), obsolete positive regulation of nitric oxide mediated signal transduction (GO:0010750), obsolete cGMP-mediated signaling (GO:0019934), response to oxygen levels (GO:0070482), cGMP biosynthetic process (GO:0006182), cyclic nucleotide biosynthetic process (GO:0009190), intracellular signal transduction (GO:0035556)

GO Molecular Function (7): guanylate cyclase activity (GO:0004383), GTP binding (GO:0005525), heme binding (GO:0020037), nucleotide binding (GO:0000166), protein binding (GO:0005515), lyase activity (GO:0016829), phosphorus-oxygen lyase activity (GO:0016849)

GO Cellular Component (3): cytosol (GO:0005829), guanylate cyclase complex, soluble (GO:0008074), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Platelet homeostasis	1
Muscle contraction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular anatomical structure	2
cellular anatomical structure	2
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
response to abiotic stimulus	1
purine ribonucleotide biosynthetic process	1
cyclic nucleotide biosynthetic process	1
cGMP metabolic process	1
nucleotide biosynthetic process	1
cyclic nucleotide metabolic process	1
signal transduction	1
cGMP biosynthetic process	1
cyclase activity	1
phosphorus-oxygen lyase activity	1
guanyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
tetrapyrrole binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
catalytic activity	1
lyase activity	1
cytoplasm	1
cytosol	1
catalytic complex	1

Protein interactions and networks

STRING

1208 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GUCY1A2	GUCY1B1	Q02153	834
GUCY1A2	GUCY1A1	Q02108	660
GUCY1A2	DLG4	P78352	578
GUCY1A2	RTBDN	Q9BSG5	503
GUCY1A2	PRKG2	Q13237	477
GUCY1A2	SCRIB	Q14160	473
GUCY1A2	TPTE2	Q6XPS3	469
GUCY1A2	SDHA	P31040	450
GUCY1A2	PRKG1	P14619	424
GUCY1A2	NDUFS6	O75380	421
GUCY1A2	NUDT21	O43809	417
GUCY1A2	ATP2B2	Q01814	414
GUCY1A2	EFHB	Q8N7U6	411
GUCY1A2	ATP2B4	P23634	408
GUCY1A2	NPTXR	O95502	407

IntAct

136 interactions, top by confidence:

A	B	Type	Score
LIN7A	CASK	psi-mi:“MI:0914”(association)	0.830
SCRIB	GUCY1A2	psi-mi:“MI:0915”(physical association)	0.770
SCRIB	GUCY1A2	psi-mi:“MI:0403”(colocalization)	0.770
SCRIB	GUCY1A2	psi-mi:“MI:0407”(direct interaction)	0.770
GUCY1A2	SCRIB	psi-mi:“MI:0407”(direct interaction)	0.770
DLG1	GUCY1A2	psi-mi:“MI:0407”(direct interaction)	0.620
DLG4	GUCY1A2	psi-mi:“MI:0407”(direct interaction)	0.620
SNTB1	GUCY1A2	psi-mi:“MI:0407”(direct interaction)	0.620
SNTA1	GUCY1A2	psi-mi:“MI:0407”(direct interaction)	0.620
GUCY1A2	SNTA1	psi-mi:“MI:0407”(direct interaction)	0.620
GUCY1A2	SNTB1	psi-mi:“MI:0407”(direct interaction)	0.620
GUCY1A2	DLG1	psi-mi:“MI:0407”(direct interaction)	0.620
GUCY1A2	DLG4	psi-mi:“MI:0407”(direct interaction)	0.620
LIN7A	GUCY1A2	psi-mi:“MI:0407”(direct interaction)	0.590
GSC2	GUCY1A2	psi-mi:“MI:0915”(physical association)	0.560
GUCY1A2	PDZRN3	psi-mi:“MI:0407”(direct interaction)	0.440
GUCY1A2	SNX27	psi-mi:“MI:0407”(direct interaction)	0.440
GUCY1A2	PDZRN4	psi-mi:“MI:0407”(direct interaction)	0.440
GUCY1A2	MAST2	psi-mi:“MI:0407”(direct interaction)	0.440
PDZK1	GUCY1A2	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (21): GUCY1A2 (Affinity Capture-MS), GUCY1A2 (Affinity Capture-Western), GUCY1A2 (Affinity Capture-MS), GUCY1A2 (Two-hybrid), GUCY1A2 (Affinity Capture-RNA), GUCY1A2 (Affinity Capture-MS), GUCY1B3 (Affinity Capture-Western), DLG1 (Affinity Capture-Western), DLG2 (Affinity Capture-Western), DLG3 (Affinity Capture-Western), DLG4 (Affinity Capture-Western), STUB1 (Affinity Capture-Western), HSPA4 (Affinity Capture-Western), HSP90AA1 (Affinity Capture-Western), GUCY1A2 (Biochemical Activity)

ESM2 similar proteins: A0A0G2JXT6, A0JMF6, A0JMK5, A2ALK8, A2BGG1, A6QLT4, A7MB43, G5ED68, O13819, O14830, P26045, P33402, P51432, Q09M05, Q13496, Q13613, Q15111, Q3USB7, Q4KWH5, Q4R6N0, Q4U2V3, Q52KU6, Q5EB32, Q5F452, Q5R6F6, Q5R9S3, Q5U581, Q62688, Q6AXQ4, Q6NU08, Q6TEL0, Q6XPS3, Q7TPM9, Q7ZXF1, Q8K394, Q8NCE2, Q8VE11, Q8VEL2, Q96EF0, Q96MI9

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

2 interactions.

A	Effect	B	Mechanism
GUCY1A2	“form complex”	GUCY1A2-B2	binding
GUCY1A2	“form complex”	GUCY1A2-B3	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 80 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Ras activation upon Ca2+ influx through NMDA receptor	5	54.9×	1e-06
Unblocking of NMDA receptors, glutamate binding and activation	5	52.3×	1e-06
Negative regulation of NMDA receptor-mediated neuronal transmission	5	52.3×	1e-06
Assembly and cell surface presentation of NMDA receptors	10	48.8×	4e-13
Dopamine Neurotransmitter Release Cycle	5	47.7×	1e-06
Long-term potentiation	5	45.8×	2e-06
Neurexins and neuroligins	11	41.6×	2e-13
Protein-protein interactions at synapses	7	35.8×	5e-08

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	9	67.9×	2e-12
protein localization to synapse	6	59.7×	8e-08
receptor clustering	7	56.7×	6e-09
regulation of postsynaptic membrane neurotransmitter receptor levels	6	38.6×	7e-07
protein-containing complex assembly	9	13.3×	2e-06
cell-cell adhesion	10	13.2×	4e-07
chemical synaptic transmission	7	7.0×	2e-03
protein transport	8	4.6×	6e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	82
Likely benign	0
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

2750 predictions. Top by Δscore:

Variant	Effect	Δscore
11:106687752:ATAAT:A	acceptor_gain	1.0000
11:106687753:TAAT:T	acceptor_gain	1.0000
11:106687754:AAT:A	acceptor_gain	1.0000
11:106687755:AT:A	acceptor_gain	1.0000
11:106687756:TCT:T	acceptor_loss	1.0000
11:106687757:C:CC	acceptor_gain	1.0000
11:106708510:A:AC	donor_gain	1.0000
11:106708511:C:CC	donor_gain	1.0000
11:106776593:C:CT	acceptor_gain	1.0000
11:106809987:CCTTA:C	donor_loss	1.0000
11:106809988:CTTA:C	donor_loss	1.0000
11:106809989:TTA:T	donor_loss	1.0000
11:106809990:TACC:T	donor_loss	1.0000
11:106809991:A:AG	donor_loss	1.0000
11:106809992:C:CA	donor_loss	1.0000
11:106939455:CTTA:C	donor_loss	1.0000
11:106939456:TTACC:T	donor_loss	1.0000
11:106939457:TACCT:T	donor_loss	1.0000
11:106940175:AAACC:A	acceptor_loss	1.0000
11:106940179:CTA:C	acceptor_loss	1.0000
11:106940180:T:C	acceptor_loss	1.0000
11:106978636:CA:C	donor_gain	1.0000
11:106978647:T:A	donor_gain	1.0000
11:106986066:TTA:T	donor_loss	1.0000
11:106986067:TA:T	donor_loss	1.0000
11:106986068:A:AC	donor_gain	1.0000
11:106986068:AC:A	donor_gain	1.0000
11:106986069:C:CC	donor_gain	1.0000
11:106986069:CC:C	donor_gain	1.0000
11:106986132:C:CC	acceptor_gain	1.0000

AlphaMissense

4817 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:106708526:G:C	S659R	1.000
11:106708526:G:T	S659R	1.000
11:106708528:T:G	S659R	1.000
11:106708530:A:T	V658D	1.000
11:106708550:A:C	S651R	1.000
11:106708550:A:T	S651R	1.000
11:106708552:T:G	S651R	1.000
11:106708559:C:A	E648D	1.000
11:106708559:C:G	E648D	1.000
11:106708572:G:T	A644E	1.000
11:106708575:A:G	L643P	1.000
11:106708581:A:T	V641D	1.000
11:106708590:C:A	G638V	1.000
11:106708590:C:T	G638E	1.000
11:106708591:C:G	G638R	1.000
11:106708591:C:T	G638R	1.000
11:106708592:A:C	F637L	1.000
11:106708592:A:T	F637L	1.000
11:106708593:A:C	F637C	1.000
11:106708593:A:G	F637S	1.000
11:106708594:A:G	F637L	1.000
11:106708594:A:T	F637I	1.000
11:106708596:A:G	L636P	1.000
11:106708598:G:C	C635W	1.000
11:106708603:A:C	Y634D	1.000
11:106708620:C:A	G628V	1.000
11:106708620:C:T	G628E	1.000
11:106708621:C:A	G628W	1.000
11:106708621:C:G	G628R	1.000
11:106708621:C:T	G628R	1.000

dbSNP variants (sampled 300 via entrez): RS1000001051 (11:106705662 C>A), RS1000007184 (11:106961634 GCTT>G), RS1000031973 (11:107007878 C>T), RS1000042538 (11:106798657 C>G), RS1000049211 (11:106966144 G>A), RS1000076656 (11:106905138 A>C), RS1000088659 (11:106962275 G>T), RS1000093246 (11:106880278 T>C), RS1000099340 (11:106776020 A>G), RS1000109222 (11:106825235 G>A,C), RS1000110336 (11:106755470 T>C), RS1000110427 (11:106751950 C>G), RS1000117796 (11:106912221 C>G,T), RS1000126245 (11:106742614 A>G,T), RS1000127309 (11:106986963 G>T)

Disease associations

OMIM: gene MIM:601244 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST001524_1	Visceral adipose tissue/subcutaneous adipose tissue ratio	8.000000e-06
GCST001762_642	Obesity-related traits	6.000000e-06
GCST002696_6	Anxiety disorder	7.000000e-06
GCST003208_8	Colorectal or endometrial cancer	1.000000e-06
GCST006107_9	Upper eyelid morphology	6.000000e-06
GCST007094_120	Diastolic blood pressure	2.000000e-07
GCST007096_57	Pulse pressure	1.000000e-06
GCST007099_15	Systolic blood pressure	4.000000e-11
GCST009200_10	Whole brain grey matter density	5.000000e-06

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004767	visceral:subcutaneous adipose tissue ratio
EFO:0004230	endometrial neoplasm
EFO:0006336	diastolic blood pressure
EFO:0005763	pulse pressure measurement
EFO:0006335	systolic blood pressure
EFO:0010306	Grey matter density measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2111348 (PROTEIN COMPLEX GROUP)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 8,193 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL12610	BENZYDAMINE	4	8,193

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: catalytic receptor — Nitric oxide (NO)-sensitive (soluble) guanylyl cyclase

ChEMBL bioactivities

477 potent at pChembl≥5 of 524 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.00	EC50	1	nM	CHEMBL3892047
9.00	EC50	1	nM	CHEMBL3925984
9.00	EC50	1	nM	CHEMBL3895428
9.00	EC50	1	nM	CHEMBL3904056
9.00	EC50	1	nM	CHEMBL3914172
9.00	EC50	1	nM	CHEMBL3940979
8.70	EC50	2	nM	CHEMBL3901016
8.70	EC50	2	nM	CHEMBL3986578
8.70	EC50	2	nM	CHEMBL3939276
8.70	EC50	2	nM	CHEMBL3934762
8.70	EC50	2	nM	CHEMBL3930782
8.70	EC50	2	nM	CHEMBL3911781
8.70	EC50	2	nM	CHEMBL3894281
8.70	EC50	2	nM	CHEMBL3977406
8.70	EC50	2	nM	CHEMBL3906766
8.70	EC50	2	nM	CHEMBL3973541
8.70	EC50	2	nM	CHEMBL3979282
8.70	EC50	2	nM	CHEMBL3931614
8.70	EC50	2	nM	CHEMBL3932128
8.70	EC50	2	nM	CHEMBL4112354
8.70	EC50	2	nM	CHEMBL3927881
8.70	EC50	2	nM	CHEMBL3905803
8.70	EC50	2	nM	CHEMBL3896300
8.70	EC50	2	nM	CHEMBL3965913
8.70	EC50	2	nM	CHEMBL4109762
8.70	EC50	2	nM	CHEMBL3986854
8.70	EC50	2	nM	CHEMBL3952024
8.52	EC50	3	nM	CHEMBL3891521
8.52	EC50	3	nM	CHEMBL3976666
8.52	EC50	3	nM	CHEMBL3928977
8.52	EC50	3	nM	CHEMBL3911781
8.52	EC50	3	nM	CHEMBL3968935
8.52	EC50	3	nM	CHEMBL3901449
8.52	EC50	3	nM	CHEMBL3916990
8.52	EC50	3	nM	CHEMBL3986729
8.52	EC50	3	nM	CHEMBL3911555
8.52	EC50	3	nM	CHEMBL3961661
8.52	EC50	3	nM	CHEMBL3915441
8.52	EC50	3	nM	CHEMBL3906941
8.52	EC50	3	nM	CHEMBL3931703
8.52	EC50	3	nM	CHEMBL4111636
8.52	EC50	3	nM	CHEMBL4112328
8.52	EC50	3	nM	CHEMBL4111581
8.52	EC50	3	nM	CHEMBL3960701
8.52	EC50	3	nM	CHEMBL3957197
8.52	EC50	3	nM	CHEMBL4110239
8.52	EC50	3	nM	CHEMBL3986811
8.52	EC50	3	nM	CHEMBL3973307
8.52	EC50	3	nM	CHEMBL3905728
8.52	EC50	3	nM	CHEMBL3901703

PubChem BioAssay actives

48 with measured affinity, of 175 total; 45 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
1-[5-fluoro-2-[1-[(2-fluorophenyl)methyl]-5-(1,2-oxazol-3-yl)pyrazol-3-yl]pyrimidin-4-yl]piperidine-4-carboxylic acid	1757088: Activation of sGC (unknown origin) in presence of DETA-NO by Glosensor cGMP assay	ec50	0.0070	uM
1-[5-fluoro-2-[1-[(2-fluorophenyl)methyl]-5-(1,2-oxazol-3-yl)pyrazol-3-yl]pyrimidin-4-yl]piperidin-4-ol	1757088: Activation of sGC (unknown origin) in presence of DETA-NO by Glosensor cGMP assay	ec50	0.0100	uM
5-fluoro-2-[1-[(2-fluorophenyl)methyl]-5-(1,2-oxazol-3-yl)pyrazol-3-yl]-N-methylpyrimidin-4-amine	1757088: Activation of sGC (unknown origin) in presence of DETA-NO by Glosensor cGMP assay	ec50	0.0200	uM
3-[1-[(2-fluorophenyl)methyl]-3-(5-fluoro-4-piperidin-1-ylpyrimidin-2-yl)pyrazol-5-yl]-1,2-oxazole	1757088: Activation of sGC (unknown origin) in presence of DETA-NO by Glosensor cGMP assay	ec50	0.0270	uM
1-[5-fluoro-2-[1-[(2-fluorophenyl)methyl]-5-(1,2-oxazol-3-yl)pyrazol-3-yl]pyrimidin-4-yl]piperidin-3-ol	1757088: Activation of sGC (unknown origin) in presence of DETA-NO by Glosensor cGMP assay	ec50	0.0330	uM
(2R,3S)-1-[5-fluoro-2-[1-[(2-fluorophenyl)methyl]-5-(1,2-oxazol-3-yl)pyrazol-3-yl]pyrimidin-4-yl]-3-methylpiperidine-2-carboxylic acid	1757088: Activation of sGC (unknown origin) in presence of DETA-NO by Glosensor cGMP assay	ec50	0.0330	uM
[1-[5-fluoro-2-[1-[(2-fluorophenyl)methyl]-5-(1,2-oxazol-3-yl)pyrazol-3-yl]pyrimidin-4-yl]piperidin-2-yl]methanol	1757088: Activation of sGC (unknown origin) in presence of DETA-NO by Glosensor cGMP assay	ec50	0.0350	uM
(2S,3R)-1-[5-fluoro-2-[1-[(2-fluorophenyl)methyl]-5-(1,2-oxazol-3-yl)pyrazol-3-yl]pyrimidin-4-yl]-3-methylpiperidine-2-carboxylic acid	1757088: Activation of sGC (unknown origin) in presence of DETA-NO by Glosensor cGMP assay	ec50	0.0400	uM
5-fluoro-2-[1-[(2-fluorophenyl)methyl]-5-(1,2-oxazol-3-yl)pyrazol-3-yl]-N-(2-morpholin-4-ylethyl)pyrimidin-4-amine	1757088: Activation of sGC (unknown origin) in presence of DETA-NO by Glosensor cGMP assay	ec50	0.0410	uM
4-[5-fluoro-2-[1-[(2-fluorophenyl)methyl]-5-(1,2-oxazol-3-yl)pyrazol-3-yl]pyrimidin-4-yl]morpholine	1757088: Activation of sGC (unknown origin) in presence of DETA-NO by Glosensor cGMP assay	ec50	0.0500	uM
1-[5-fluoro-2-[1-[(2-fluorophenyl)methyl]-5-(1,2-oxazol-3-yl)pyrazol-3-yl]pyrimidin-4-yl]piperidine-3-carboxylic acid	1757088: Activation of sGC (unknown origin) in presence of DETA-NO by Glosensor cGMP assay	ec50	0.0550	uM
3-[1-[(2-fluorophenyl)methyl]-3-(5-fluoro-4-pyrrolidin-1-ylpyrimidin-2-yl)pyrazol-5-yl]-1,2-oxazole	1757088: Activation of sGC (unknown origin) in presence of DETA-NO by Glosensor cGMP assay	ec50	0.0830	uM
5-fluoro-2-[1-[(2-fluorophenyl)methyl]-5-(1,2-oxazol-3-yl)pyrazol-3-yl]-1H-pyrimidin-6-one	1757088: Activation of sGC (unknown origin) in presence of DETA-NO by Glosensor cGMP assay	ec50	0.0970	uM
3-[1-[(2-fluorophenyl)methyl]-3-(5-fluoro-4-piperazin-1-ylpyrimidin-2-yl)pyrazol-5-yl]-1,2-oxazole	1757088: Activation of sGC (unknown origin) in presence of DETA-NO by Glosensor cGMP assay	ec50	0.1200	uM
(2R)-1-[5-fluoro-2-[1-[(2-fluorophenyl)methyl]-5-(1,2-oxazol-3-yl)pyrazol-3-yl]pyrimidin-4-yl]piperidine-2-carboxylic acid	1757088: Activation of sGC (unknown origin) in presence of DETA-NO by Glosensor cGMP assay	ec50	0.1200	uM
5-fluoro-2-[1-[(2-fluorophenyl)methyl]-5-(1,2-oxazol-3-yl)pyrazol-3-yl]pyrimidin-4-amine	1757088: Activation of sGC (unknown origin) in presence of DETA-NO by Glosensor cGMP assay	ec50	0.1300	uM
3-[3-[4-(3,3-difluoropiperidin-1-yl)-5-fluoropyrimidin-2-yl]-1-[(2-fluorophenyl)methyl]pyrazol-5-yl]-1,2-oxazole	1757088: Activation of sGC (unknown origin) in presence of DETA-NO by Glosensor cGMP assay	ec50	0.1500	uM
5-(4-chlorophenyl)sulfonyl-2-[1-[(2-fluorophenyl)methyl]-5-(1,2-oxazol-3-yl)pyrazol-3-yl]-1H-pyrimidin-6-one	1304082: Activation of SGC in HEK293 cells assessed as cGMP production after 20 mins by LC-MS/MS analysis in presence of NO-donor DETA-NONOate	ec50	0.1600	uM
5-fluoro-2-[1-[(2-fluorophenyl)methyl]-5-(1,2-thiazol-3-yl)pyrazol-3-yl]-1H-pyrimidin-6-one	1304082: Activation of SGC in HEK293 cells assessed as cGMP production after 20 mins by LC-MS/MS analysis in presence of NO-donor DETA-NONOate	ec50	0.1800	uM
(2S)-1-[5-fluoro-2-[1-[(2-fluorophenyl)methyl]-5-(1,2-oxazol-3-yl)pyrazol-3-yl]pyrimidin-4-yl]piperidine-2-carboxylic acid	1757088: Activation of sGC (unknown origin) in presence of DETA-NO by Glosensor cGMP assay	ec50	0.2000	uM
2-[1-[(2-fluorophenyl)methyl]-5-(1,2-oxazol-3-yl)pyrazol-3-yl]pyrimidin-4-amine	1304082: Activation of SGC in HEK293 cells assessed as cGMP production after 20 mins by LC-MS/MS analysis in presence of NO-donor DETA-NONOate	ec50	0.2400	uM
5-fluoro-2-[1-[(2-fluoro-3-methylphenyl)methyl]-5-(1,2-oxazol-3-yl)pyrazol-3-yl]-1H-pyrimidin-6-one	1304082: Activation of SGC in HEK293 cells assessed as cGMP production after 20 mins by LC-MS/MS analysis in presence of NO-donor DETA-NONOate	ec50	0.2400	uM
4-[5-fluoro-2-[1-[(2-fluorophenyl)methyl]-5-(1,2-oxazol-3-yl)pyrazol-3-yl]pyrimidin-4-yl]-1,4-thiazinane 1,1-dioxide	1757088: Activation of sGC (unknown origin) in presence of DETA-NO by Glosensor cGMP assay	ec50	0.2400	uM
3-[3-[4-(4,4-difluoropiperidin-1-yl)-5-fluoropyrimidin-2-yl]-1-[(2-fluorophenyl)methyl]pyrazol-5-yl]-1,2-oxazole	1757088: Activation of sGC (unknown origin) in presence of DETA-NO by Glosensor cGMP assay	ec50	0.2500	uM
5-fluoro-2-[1-[(3-fluorothiophen-2-yl)methyl]-5-(1,2-oxazol-3-yl)pyrazol-3-yl]-1H-pyrimidin-6-one	1304082: Activation of SGC in HEK293 cells assessed as cGMP production after 20 mins by LC-MS/MS analysis in presence of NO-donor DETA-NONOate	ec50	0.2800	uM
3-[3-(5-fluoro-4-methoxypyrimidin-2-yl)-1-[(2-fluorophenyl)methyl]pyrazol-5-yl]-1,2-oxazole	1304082: Activation of SGC in HEK293 cells assessed as cGMP production after 20 mins by LC-MS/MS analysis in presence of NO-donor DETA-NONOate	ec50	0.3200	uM
5-(benzenesulfonyl)-2-[1-[(2-fluorophenyl)methyl]-5-(1,2-oxazol-3-yl)pyrazol-3-yl]-1H-pyrimidin-6-one	1304082: Activation of SGC in HEK293 cells assessed as cGMP production after 20 mins by LC-MS/MS analysis in presence of NO-donor DETA-NONOate	ec50	0.3500	uM
2-[1-[(2,3-difluorophenyl)methyl]-5-(1,2-oxazol-3-yl)pyrazol-3-yl]-5-fluoro-1H-pyrimidin-6-one	1304082: Activation of SGC in HEK293 cells assessed as cGMP production after 20 mins by LC-MS/MS analysis in presence of NO-donor DETA-NONOate	ec50	0.3700	uM
2-[1-[(3-chloro-2-fluorophenyl)methyl]-5-(1,2-oxazol-3-yl)pyrazol-3-yl]-5-fluoro-1H-pyrimidin-6-one	1304082: Activation of SGC in HEK293 cells assessed as cGMP production after 20 mins by LC-MS/MS analysis in presence of NO-donor DETA-NONOate	ec50	0.3800	uM
2-[1-[(2-fluorophenyl)methyl]-5-(1,2-oxazol-3-yl)pyrazol-3-yl]-6-oxo-1H-pyrimidine-5-carbonitrile	1304082: Activation of SGC in HEK293 cells assessed as cGMP production after 20 mins by LC-MS/MS analysis in presence of NO-donor DETA-NONOate	ec50	0.5000	uM
2-[1-[(2,4-difluorophenyl)methyl]-5-(1,2-oxazol-3-yl)pyrazol-3-yl]-5-fluoro-1H-pyrimidin-6-one	1304082: Activation of SGC in HEK293 cells assessed as cGMP production after 20 mins by LC-MS/MS analysis in presence of NO-donor DETA-NONOate	ec50	0.5300	uM
5-chloro-2-[1-[(2-fluorophenyl)methyl]-5-(1,2-oxazol-3-yl)pyrazol-3-yl]-1H-pyrimidin-6-one	1304082: Activation of SGC in HEK293 cells assessed as cGMP production after 20 mins by LC-MS/MS analysis in presence of NO-donor DETA-NONOate	ec50	0.5900	uM
2-[1-[(2-fluorophenyl)methyl]-5-(1,2-oxazol-3-yl)pyrazol-3-yl]-N-methyl-6-oxo-N-phenyl-1H-pyrimidine-5-sulfonamide	1304082: Activation of SGC in HEK293 cells assessed as cGMP production after 20 mins by LC-MS/MS analysis in presence of NO-donor DETA-NONOate	ec50	0.7300	uM
2-[1-benzyl-5-(1,2-oxazol-3-yl)pyrazol-3-yl]-5-fluoro-1H-pyrimidin-6-one	1304082: Activation of SGC in HEK293 cells assessed as cGMP production after 20 mins by LC-MS/MS analysis in presence of NO-donor DETA-NONOate	ec50	0.8800	uM
2-[1-[(2-fluorophenyl)methyl]-5-(1,2-oxazol-3-yl)pyrazol-3-yl]-5-methylsulfonyl-1H-pyrimidin-6-one	1304082: Activation of SGC in HEK293 cells assessed as cGMP production after 20 mins by LC-MS/MS analysis in presence of NO-donor DETA-NONOate	ec50	0.9000	uM
(2S)-1-[5-fluoro-2-[1-[(2-fluorophenyl)methyl]-5-(1,2-oxazol-3-yl)pyrazol-3-yl]pyrimidin-4-yl]pyrrolidine-2-carboxylic acid	1757088: Activation of sGC (unknown origin) in presence of DETA-NO by Glosensor cGMP assay	ec50	0.9700	uM
6-anilinoquinoline-5,8-dione	1631031: Inhibition of soluble guanylate cyclase (unknown origin)	ic50	1.0000	uM
3-(1-benzylindazol-3-yl)oxy-N,N-dimethylpropan-1-amine	205476: The cGMP produced by compound was expressed as a ratio between the percentage of the DEA/NO response for the compound	ec50	1.0200	uM
1-[5-fluoro-2-[1-[(2-fluorophenyl)methyl]-5-(1,2-oxazol-3-yl)pyrazol-3-yl]pyrimidin-4-yl]piperidin-2-one	1757088: Activation of sGC (unknown origin) in presence of DETA-NO by Glosensor cGMP assay	ec50	1.3000	uM
1-[5-fluoro-2-[1-[(2-fluorophenyl)methyl]-5-(1,2-oxazol-3-yl)pyrazol-3-yl]pyrimidin-4-yl]-2-hydroxypiperidine-2-carboxylic acid	1757088: Activation of sGC (unknown origin) in presence of DETA-NO by Glosensor cGMP assay	ec50	1.3400	uM
5-fluoro-2-[5-(1,2-oxazol-3-yl)-1-(3,3,4,4,4-pentafluorobutyl)pyrazol-3-yl]-1H-pyrimidin-6-one	1304082: Activation of SGC in HEK293 cells assessed as cGMP production after 20 mins by LC-MS/MS analysis in presence of NO-donor DETA-NONOate	ec50	1.5000	uM
5-fluoro-2-[1-[(2-fluorophenyl)methyl]-5-(1,3-oxazol-2-yl)pyrazol-3-yl]-1H-pyrimidin-6-one	1304082: Activation of SGC in HEK293 cells assessed as cGMP production after 20 mins by LC-MS/MS analysis in presence of NO-donor DETA-NONOate	ec50	1.5000	uM
3-[3-[4-(cyclopropylmethoxy)-5-fluoropyrimidin-2-yl]-1-[(2-fluorophenyl)methyl]pyrazol-5-yl]-1,2-oxazole	1757088: Activation of sGC (unknown origin) in presence of DETA-NO by Glosensor cGMP assay	ec50	2.3000	uM
4-[5-fluoro-2-[1-[(2-fluorophenyl)methyl]-5-(1,2-oxazol-3-yl)pyrazol-3-yl]pyrimidin-4-yl]morpholine-3-carboxylic acid	1757088: Activation of sGC (unknown origin) in presence of DETA-NO by Glosensor cGMP assay	ec50	2.3000	uM
4-[2-[5-fluoro-2-[1-[(2-fluorophenyl)methyl]-5-(1,2-oxazol-3-yl)pyrazol-3-yl]pyrimidin-4-yl]oxyethyl]morpholine	1757088: Activation of sGC (unknown origin) in presence of DETA-NO by Glosensor cGMP assay	ec50	4.4000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases expression, increases methylation	2
Nickel	decreases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Valproic Acid	decreases expression, increases expression	2
Cadmium Chloride	increases abundance, increases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
aristolochic acid I	decreases expression	1
ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate	affects cotreatment, affects expression	1
methyleugenol	decreases expression	1
bisphenol A	affects cotreatment, increases methylation	1
2,5,2’,5’-tetrachlorobiphenyl	increases expression	1
decabromobiphenyl ether	decreases expression	1
kojic acid	decreases expression	1
terbufos	increases methylation	1
trichostatin A	decreases expression	1
sodium arsenite	decreases expression	1
butyraldehyde	decreases expression	1
tetrabromobisphenol A	decreases expression	1
perfluorooctanoic acid	affects cotreatment, affects expression	1
benzo(e)pyrene	increases methylation	1
S-(1,2-dichlorovinyl)cysteine	decreases reaction, increases expression	1
perfluorooctane sulfonic acid	affects cotreatment, affects expression	1
entinostat	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression, increases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
perfluorobutanesulfonic acid	affects cotreatment, affects expression	1
bisphenol S	decreases methylation	1
Resveratrol	affects cotreatment, decreases expression	1

ChEMBL screening assays

32 unique, capped per target: 27 binding, 5 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1918701	Binding	Activation of human soluble guanylate cyclase assessed as production of cGMP in presence of nitric oxide donor, SIN-1 by LC-MS enzyme assay	Acidic triazoles as soluble guanylate cyclase stimulators. — Bioorg Med Chem Lett
CHEMBL865676	Functional	Effect on cGMP production in porcine iris-ciliary body at 10 uM	Synthesis and ocular effects of imidazole nitrolic acid and amidoxime esters. — Bioorg Med Chem Lett

Clinical trials (associated diseases)

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