GUCY2C

Summary

GUCY2C (guanylate cyclase 2C, HGNC:4688) is a protein-coding gene on chromosome 12p12.3, encoding Guanylyl cyclase C (P25092). Guanylyl cyclase that catalyzes synthesis of cyclic GMP (cGMP) from GTP.

This gene encodes a transmembrane protein that functions as a receptor for endogenous peptides guanylin and uroguanylin, and the heat-stable E. coli enterotoxin. The encoded protein activates the cystic fibrosis transmembrane conductance regulator. Mutations in this gene are associated with familial diarrhea (autosomal dominant) and meconium ileus (autosomal recessive).

Source: NCBI Gene 2984 — RefSeq curated summary.

At a glance

• Gene–disease (curated): congenital diarrhea 6 (Definitive, GenCC) — +2 more curated relationships
• Clinical variants (ClinVar): 964 total — 6 pathogenic, 5 likely-pathogenic
• Phenotypes (HPO): 12
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_004963

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4688
Approved symbol	GUCY2C
Name	guanylate cyclase 2C
Location	12p12.3
Locus type	gene with protein product
Status	Approved
Aliases	STAR, HSER, GC-C, GCC
Ensembl gene	ENSG00000070019
Ensembl biotype	protein_coding
OMIM	601330
Entrez	2984

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 4 protein_coding, 1 retained_intron

ENST00000261170, ENST00000535803, ENST00000867619, ENST00000970783, ENST00000970784

RefSeq mRNA: 1 — MANE Select: NM_004963 NM_004963

CCDS: CCDS8664

Canonical transcript exons

ENST00000261170 — 27 exons

Exon	Start	End
ENSE00000482252	14652952	14653014
ENSE00000482262	14621042	14621216
ENSE00000482263	14619211	14619309
ENSE00000541227	14651959	14652030
ENSE00000541251	14674625	14674760
ENSE00000722279	14614867	14614943
ENSE00000722283	14616633	14616727
ENSE00000722290	14622005	14622197
ENSE00000722294	14625757	14625915
ENSE00000722298	14628646	14628737
ENSE00000722341	14639862	14639950
ENSE00000722376	14641082	14641219
ENSE00000722380	14643574	14643706
ENSE00000722422	14645229	14645315
ENSE00000722431	14651407	14651511
ENSE00000722458	14656512	14656617
ENSE00000722463	14660981	14661062
ENSE00000722467	14669722	14669833
ENSE00000722501	14672873	14672958
ENSE00001159372	14612632	14613291
ENSE00001159376	14696232	14696599
ENSE00003536758	14676854	14676971
ENSE00003566380	14686161	14686225
ENSE00003566805	14687951	14688063
ENSE00003629965	14681356	14681477
ENSE00003643849	14679657	14679753
ENSE00003656926	14683042	14683257

Expression profiles

Bgee: expression breadth broad, 84 present calls, max score 97.64.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.7400 / max 556.8310, expressed in 43 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
129842	0.5942	40
129841	0.0806	13
129844	0.0233	11
129839	0.0162	3
129843	0.0110	4
129840	0.0084	1
129838	0.0063	1

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
jejunal mucosa	UBERON:0000399	97.64	gold quality
mucosa of sigmoid colon	UBERON:0004993	94.80	gold quality
colonic mucosa	UBERON:0000317	94.67	gold quality
rectum	UBERON:0001052	94.13	gold quality
duodenum	UBERON:0002114	93.33	gold quality
ileal mucosa	UBERON:0000331	91.49	gold quality
mucosa of transverse colon	UBERON:0004991	89.64	gold quality
small intestine Peyer’s patch	UBERON:0003454	83.54	gold quality
small intestine	UBERON:0002108	83.44	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.30	gold quality
transverse colon	UBERON:0001157	79.64	gold quality
jejunum	UBERON:0002115	77.41	gold quality
secondary oocyte	CL:0000655	74.98	silver quality
intestine	UBERON:0000160	74.70	gold quality
large intestine	UBERON:0000059	71.52	gold quality
colonic epithelium	UBERON:0000397	70.88	gold quality
vermiform appendix	UBERON:0001154	70.84	gold quality
colon	UBERON:0001155	70.51	gold quality
endometrium epithelium	UBERON:0004811	69.66	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	69.44	gold quality
caecum	UBERON:0001153	68.93	gold quality
oocyte	CL:0000023	64.04	silver quality
smooth muscle tissue	UBERON:0001135	60.13	gold quality
skin of hip	UBERON:0001554	58.48	silver quality
oral cavity	UBERON:0000167	58.19	gold quality
skin of leg	UBERON:0001511	57.16	gold quality
sigmoid colon	UBERON:0001159	55.70	gold quality
monocyte	CL:0000576	55.28	gold quality
mononuclear cell	CL:0000842	55.23	gold quality
leukocyte	CL:0000738	54.67	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.30
E-GEOD-125970	yes	6.14

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CDX2, CEBPA, ERF, HNF4A

miRNA regulators (miRDB)

38 targeting GUCY2C, 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-3646	100.00	73.56	5283
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-544A	99.84	68.66	1965
HSA-MIR-3180-5P	99.82	69.12	2422
HSA-MIR-548AJ-5P	99.78	71.12	3085
HSA-MIR-548F-5P	99.78	71.02	3093
HSA-MIR-548G-5P	99.78	71.12	3085
HSA-MIR-548X-5P	99.78	71.12	3085
HSA-MIR-148A-3P	99.74	73.77	1700
HSA-MIR-148B-3P	99.74	73.75	1700
HSA-MIR-152-3P	99.74	73.75	1703
HSA-MIR-208A-5P	99.42	70.83	1913
HSA-MIR-208B-5P	99.42	70.83	1952
HSA-MIR-6507-5P	99.36	70.46	2524
HSA-MIR-4777-5P	99.33	67.53	1148
HSA-MIR-3692-5P	99.29	67.04	1421
HSA-MIR-6738-3P	99.03	67.14	1326
HSA-MIR-4424	98.91	70.33	1145
HSA-MIR-4774-3P	98.90	67.82	737

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• The protein kinase-like domain in receptor guanylyl cyclase C provides a critical structural link between the extracellular domain and the catalytic domain in regulation of this family of receptors. (PMID:11478887)
• A novel PDZ protein regulates the activity of guanylyl cyclase C, the heat-stable enterotoxin receptor. (PMID:11950846)
• guanylyl cyclase c is ectopically expressed in primary and metastatis adenocarcinoma of the esophagus and stomach (PMID:12163327)
• Expression of the receptor guanylyl cyclase C and its ligands in reproductive tissues of the rat: a potential role for a novel signaling pathway in the epididymis. (PMID:12444076)
• SH3 domain -mediated protein-protein interaction with the catalytic domain of guanylyl cyclase C inhibited the cyclase activity and might be pivotal for the desensitization phenomenon of the guanylyl cyclase C receptor (PMID:12649275)
• gelatinolytic activity of GCC in colorectal tumor tissues may facilitate the hepatic metastatic process in the steps after intravasation but not during or before intravasation (PMID:14581363)
• a novel role for glycosidic modification of GC-C during its biosynthesis, in imparting subtle conformational changes in the receptor that allow for ligand-mediated activation and perhaps regulation of basal activity (PMID:14748740)
• Lack of guanylyl cyclase c expression assoeciated with significant reduction in adenomas in Apc(Min/+);Gucy2c(-/-) mice (PMID:15825168)
• Transformation associated with reflux at the gastroesophageal junction reflects activation by bile acid and acid of a transcriptional program involving NF-kappaB and Cdx2, which mediate intestinal metaplasia and ectopic expression of GC-C. (PMID:16618413)
• This validated assay is being applied to approximately 10,000 lymph nodes in a prospective trial to define the sensitivity of Guanylyl cyclase C(GCC) qRT-PCR for staging patients with colorectal cancer. (PMID:16899600)
• docking of the c-src SH2 domain to phosphorylated GC-C results in colocalization and further activation of c-src. (PMID:19620276)
• the role of the linker region in receptor guanylyl cyclases (PMID:19648115)
• GCC is a specific marker for differentiating primary and secondary metatstatic ovarian mucinous neoplasms. (PMID:19694825)
• Results suggest that GUCY2C quantitative reverse transcriptase (qRT)-PCR can be used to detect occult lymph node metastases in pN0 colorectal cancer patients. (PMID:19895223)
• Lymph nodes (range: 2-159) from 291 prospectively enrolled node-negative colorectal cancer patients were analyzed by histopathology and GUCY2C quantitative RT-PCR. (PMID:21307149)
• High guanylyl cyclase C is associated with colon cancer. (PMID:21533822)
• Longer survival was associated with hypomethylation at specific CpG sites (e.g. GREB1, TGIF and TOB1) and hypermethylation in other genes (e.g. TMCO5, PTPRN and GUCY2C). (PMID:21577013)
• Data suggest that monitoring the peripheral blood GCC expressions may allow employing different treatment options to metastatic CRC patients. (PMID:21901559)
• GUCY2C opposes systemic genotoxic tumorigenesis by regulating AKT-dependent intestinal barrier integrity (PMID:22384056)
• We identified a heterozygous missense mutation (c.2519G–>T) in GUCY2C in all family members with familial diarrhea syndrome. (PMID:22436048)
• Mutations in GUCY2C were associated with the Meconium ileus phenotype. downregulation of GUCY2C leads to a cystic fibrosis-like intestinal phenotype. (PMID:22521417)
• Data show that lower survival (OS) and disease-free survival (DFS) rates were significantly associated with guanylate cyclase C (GCC) and CK20 mRNA levels. (PMID:23150200)
• Interaction with VIP36 is dependent on glycosylation at the same sites that allow GC-C to fold and bind ligand. (PMID:23269669)
• GUCY2C signaling constitutes a direct link between the initiation of colorectal cancer and the induction of its associated desmoplastic stromal niche. (PMID:24085786)
• Intestinal cell proliferation and senescence are regulated by receptor guanylyl cyclase C and p21. (PMID:24217248)
• High guanylyl cyclase C expression is associated with colon cancer recurrence. (PMID:24919572)
• Transmission disequilibrium tests (TDT), case-control studies and quantitative analyses indicated association between GUC2C with Attention-deficit/hyperactivitydisorder and its core symptoms. (PMID:25064385)
• Data show that individuals affected with meconium ileus (MI) had either homozygous or compound heterozygous variants in enterotoxin receptor GUCY2C. (PMID:25370039)
• Mutations in GUCY2C indicate a role for this receptor in the pathogenesis of sporadic Congenital secretory diarrhea. (PMID:25994218)
• Findings show how caloric suppression of the guanylin-GUCY2C signaling axis links obesity to negation of a universal tumor suppressor pathway in colorectal cancer. (PMID:26773096)
• Results demonstrate that GC-C and its ligands, guanylin and uroguanylin are downregulated in ulcerative colitis (UC), and this downregulation is more significant with aggravation of the clinical condition. Therefore, the GC-C signaling pathway may be implicated in the progression of UC. (PMID:27125248)
• Familial GUCY2C diarrhoea syndrome is caused by an activating mutation in the GUCY2C gene, which causes impaired contractility and fluid stagnation in the small bowel (PMID:27338166)
• these data support Ad5-GUCY2C-PADRE as a safe and effective vaccination strategy in preclinical models and position Ad5-GUCY2C-PADRE for Phase I clinical testing in colorectal cancer patients. (PMID:27903079)
• High Expressions of guanylyl cyclase C is associated with rectal cancer. (PMID:28418917)
• The findings support that the activating mutation in GUCY2C creates an intestinal environment with a major influence on the microbiota, which could contribute to the increased susceptibility to inflammatory bowel disease in patients with Familial GUCY2C diarrhea syndrome. (PMID:28902124)
• To investigate gut motility and hormones before and after a meal in Familial GUCY2C diarrhea syndrome patients and compare with healthy controls (PMID:28957388)
• the expression of GCC is maintained throughout the process of tumor progression and formation of metastatic disease. (PMID:29261789)
• Human GUCY2C-targeted murine CAR-T cells promoted antigen-dependent T-cell activation quantified by activation marker upregulation, cytokine production, and killing of GUCY2C-expressing, but not GUCY2C-deficient, cancer cells in vitro GUCY2C CAR-T cells provided long-term protection against lung metastases of murine colorectal cancer cells engineered to express human GUCY2C in a syngeneic mouse model. (PMID:29615399)
• The results support a role of guanylate cyclase C signaling and disturbed electrolyte homeostasis in development of IBD. Furthermore, downregulation of metallothioneins in the ileal mucosa of familial GUCY2C diarrhea syndrome patients may contribute to inflammatory bowel disease development, possibly alongside effects from NOD2 risk variants. (PMID:30353760)
• Study reveals two discrete neuronal circuits expressing GUCY2C originating in the ventral premammillary nucleus in the hypothalamus and in the ventral tegmental area and substantia nigra in midbrain, which separately project to other sites throughout the brain. (PMID:31485718)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	gucy2ca	ENSDARG00000014320
danio_rerio	gucy2cb	ENSDARG00000056045
mus_musculus	Gucy2c	ENSMUSG00000042638
rattus_norvegicus	Gucy2c	ENSRNOG00000009031

Paralogs (17): GUCY1B1 (ENSG00000061918), ADCY2 (ENSG00000078295), GUCY2F (ENSG00000101890), 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

Guanylyl cyclase C — P25092 (reviewed: P25092)

Alternative names: Heat-stable enterotoxin receptor, Intestinal guanylate cyclase

All UniProt accessions (1): P25092

UniProt curated annotations — full annotation on UniProt →

Function. Guanylyl cyclase that catalyzes synthesis of cyclic GMP (cGMP) from GTP. Receptor for the E.coli heat-stable enterotoxin; E.coli enterotoxin markedly stimulates the accumulation of cGMP in mammalian cells expressing GUCY2C. Also activated by the endogenous peptides guanylin and uroguanylin.

Subunit / interactions. Homotrimer. Interacts via its C-terminal region with NHERF4. Interacts with the lectin chaperone VIP36.

Subcellular location. Cell membrane. Endoplasmic reticulum membrane.

Post-translational modifications. Glycosylation at Asn-75 and/or Asn-79 is required for interaction with VIP36 while glycosylation at Asn-345 and Asn-402 modulates ligand-mediated GUCY2C activation.

Disease relevance. Diarrhea 6 (DIAR6) [MIM:614616] A relatively mild, early-onset chronic diarrhea that may be associated with increased susceptibility to inflammatory bowel disease, small bowel obstruction, and esophagitis. The disease is caused by variants affecting the gene represented in this entry. Meconium ileus (MECIL) [MIM:614665] A condition characterized by intestinal obstruction due to inspissated meconium in the distal ileum and cecum, which develops in utero and presents shortly after birth as a failure to pass meconium. Meconium ileus is a known clinical manifestation of cystic fibrosis. The disease is caused by variants affecting the gene represented in this entry.

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_004954* (*=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
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR018297	A/G_cyclase_CS	Conserved_site
IPR028082	Peripla_BP_I	Homologous_superfamily
IPR029787	Nucleotide_cyclase	Homologous_superfamily
IPR042822	GC-C_PK	Domain
IPR050401	Cyclic_nucleotide_synthase	Family

Pfam: PF00211, 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 (32 total): sequence variant 11, glycosylation site 8, sequence conflict 4, topological domain 2, domain 2, signal peptide 1, chain 1, transmembrane region 1, helix 1, site 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
8GHO	X-RAY DIFFRACTION	1.6
8GHP	X-RAY DIFFRACTION	3.52
8FX4	ELECTRON MICROSCOPY	3.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P25092-F1	80.08	0.35

Antibody-complex structures (SAbDab): 2 — 8GHO, 8GHP

Functional residue map

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

Catalytic / active sites (1): 357 (not glycosylated)

Glycosylation sites (8): 79, 195, 284, 307, 345, 402, 32, 75

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-8935690	Digestion
R-HSA-8942233	Intestinal infectious diseases

MSigDB gene sets: 163 (showing top): GOBP_CGMP_BIOSYNTHETIC_PROCESS, MODULE_445, MODULE_65, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_CYCLIC_NUCLEOTIDE_METABOLIC_PROCESS, GOBP_NUCLEOSIDE_PHOSPHATE_BIOSYNTHETIC_PROCESS, ACEVEDO_LIVER_CANCER_WITH_H3K27ME3_UP, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, SHIPP_DLBCL_CURED_VS_FATAL_DN, MORF_RAD51L3, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_BIOSYNTHETIC_PROCESS, IRF1_Q6, HNF4_DR1_Q3

GO Biological Process (7): cGMP biosynthetic process (GO:0006182), receptor guanylyl cyclase signaling pathway (GO:0007168), response to toxic substance (GO:0009636), intracellular signal transduction (GO:0035556), regulation of cell population proliferation (GO:0042127), protein phosphorylation (GO:0006468), cyclic nucleotide biosynthetic process (GO:0009190)

GO Molecular Function (10): peptide receptor activity (GO:0001653), guanylate cyclase activity (GO:0004383), protein kinase activity (GO:0004672), ATP binding (GO:0005524), GTP binding (GO:0005525), toxic substance binding (GO:0015643), nucleotide binding (GO:0000166), protein binding (GO:0005515), lyase activity (GO:0016829), phosphorus-oxygen lyase activity (GO:0016849)

GO Cellular Component (4): endoplasmic reticulum membrane (GO:0005789), plasma membrane (GO:0005886), endoplasmic reticulum (GO:0005783), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Digestion and absorption	1
Uptake and actions of bacterial toxins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
purine ribonucleoside triphosphate binding	2
binding	2
purine ribonucleotide biosynthetic process	1
cyclic nucleotide biosynthetic process	1
cGMP metabolic process	1
enzyme-linked receptor protein signaling pathway	1
response to chemical	1
intracellular anatomical structure	1
signal transduction	1
cell population proliferation	1
regulation of cellular process	1
phosphorylation	1
protein modification process	1
nucleotide biosynthetic process	1
cyclic nucleotide metabolic process	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
nucleoside phosphate binding	1
heterocyclic compound binding	1
catalytic activity	1
lyase activity	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
membrane	1
cell periphery	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
cellular anatomical structure	1

Protein interactions and networks

STRING

972 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GUCY2C	GUCA2A	Q02747	999
GUCY2C	GUCA2B	Q16661	999
GUCY2C	EMD	P50402	989
GUCY2C	NHERF4	Q86UT5	914
GUCY2C	CFTR	P13569	817
GUCY2C	GGCT	O75223	816
GUCY2C	NPR3	P17342	793
GUCY2C	GLYAT	Q6IB77	673
GUCY2C	TPI1	P00938	649
GUCY2C	GTF3C6	Q969F1	635
GUCY2C	SLC26A3	P40879	631
GUCY2C	GCG	P01275	628
GUCY2C	AGA	P20933	624
GUCY2C	PRKG2	Q13237	585
GUCY2C	GGTLC3	B5MD39	574

IntAct

9 interactions, top by confidence:

A	B	Type	Score
ATP5IF1	ATP5F1B	psi-mi:“MI:0914”(association)	0.740
NHERF4	GUCY2C	psi-mi:“MI:0915”(physical association)	0.630
NHERF4	GUCY2C	psi-mi:“MI:0407”(direct interaction)	0.630
PDZK1	GUCY2C	psi-mi:“MI:0407”(direct interaction)	0.440
GPC3	PXDNL	psi-mi:“MI:0914”(association)	0.350
alsS	GUCY2C	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (5): PDZD3 (Two-hybrid), PDZD3 (Reconstituted Complex), GUCY2C (Reconstituted Complex), PDZD3 (Affinity Capture-Western), GUCY2C (Affinity Capture-MS)

ESM2 similar proteins: A0A078BQP2, A8WPG9, A8XQC7, B1Q257, E7EAU8, G5EFQ0, G5EGT9, H2L002, N1NVB7, O16544, O16715, O19064, O60674, O62026, O62179, P11528, P16065, P23897, P25092, P55204, P55205, P70106, P91550, Q07553, Q09435, Q10028, Q10029, Q18163, Q18331, Q19187, Q19768, Q23310, Q23681, Q23682, Q2HWD6, Q3UWA6, Q5RB23, Q62120, Q62689, Q6DNF3

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
GUCA2A	up-regulates	GUCY2C	binding
GUCA2B	up-regulates	GUCY2C	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	5
Uncertain significance	537
Likely benign	303
Benign	77

Top pathogenic / likely-pathogenic (11)

Variant ID	HGVS	Classification
1037779	NM_004963.4(GUCY2C):c.2381A>T (p.Asp794Val)	Pathogenic
30176	NM_004963.4(GUCY2C):c.2519G>T (p.Ser840Ile)	Pathogenic
31604	NM_004963.4(GUCY2C):c.1160A>G (p.Asp387Gly)	Pathogenic
375380	NM_004963.4(GUCY2C):c.410T>C (p.Leu137Ser)	Pathogenic
3764195	NM_004963.4(GUCY2C):c.2536G>A (p.Val846Met)	Pathogenic
931137	NM_004963.4(GUCY2C):c.2324T>C (p.Leu775Pro)	Pathogenic
3075691	NM_004963.4(GUCY2C):c.2328A>C (p.Glu776Asp)	Likely pathogenic
3393482	NM_004963.4(GUCY2C):c.2323C>G (p.Leu775Val)	Likely pathogenic
3779714	NM_004963.4(GUCY2C):c.758del (p.Glu253fs)	Likely pathogenic
932664	NM_004963.4(GUCY2C):c.245dup (p.Met83fs)	Likely pathogenic
977074	NM_004963.4(GUCY2C):c.1047del (p.Lys350fs)	Likely pathogenic

SpliceAI

3624 predictions. Top by Δscore:

Variant	Effect	Δscore
12:14614865:A:AC	donor_gain	1.0000
12:14614866:C:CC	donor_gain	1.0000
12:14614866:CA:C	donor_gain	1.0000
12:14619201:C:CA	donor_gain	1.0000
12:14622193:CTAGC:C	acceptor_gain	1.0000
12:14628653:T:C	donor_gain	1.0000
12:14639854:ATAC:A	donor_loss	1.0000
12:14639855:TACT:T	donor_loss	1.0000
12:14639856:ACTC:A	donor_loss	1.0000
12:14639858:TCACT:T	donor_loss	1.0000
12:14639859:CACT:C	donor_loss	1.0000
12:14639860:A:AC	donor_gain	1.0000
12:14639861:C:CT	donor_gain	1.0000
12:14639861:CTT:C	donor_gain	1.0000
12:14639946:CTTCT:C	acceptor_gain	1.0000
12:14639951:C:CC	acceptor_gain	1.0000
12:14639959:G:GC	acceptor_gain	1.0000
12:14639968:A:C	acceptor_gain	1.0000
12:14639975:T:TC	acceptor_gain	1.0000
12:14641048:C:CA	donor_gain	1.0000
12:14641077:TGTAC:T	donor_loss	1.0000
12:14641080:A:AT	donor_loss	1.0000
12:14641081:CCAT:C	donor_loss	1.0000
12:14641121:T:A	donor_gain	1.0000
12:14641215:CAGGT:C	acceptor_gain	1.0000
12:14641216:AGGT:A	acceptor_gain	1.0000
12:14641217:GGT:G	acceptor_gain	1.0000
12:14641218:GT:G	acceptor_gain	1.0000
12:14641219:TC:T	acceptor_loss	1.0000
12:14641220:C:CC	acceptor_gain	1.0000

AlphaMissense

7128 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:14619257:A:C	F943L	1.000
12:14619257:A:T	F943L	1.000
12:14619259:A:G	F943L	1.000
12:14619285:C:T	G934E	1.000
12:14619286:C:G	G934R	1.000
12:14619286:C:T	G934R	1.000
12:14622122:A:C	S828R	1.000
12:14622122:A:T	S828R	1.000
12:14622124:T:G	S828R	1.000
12:14625778:A:G	L796P	1.000
12:14625788:C:G	A793P	1.000
12:14625862:A:G	L768P	1.000
12:14619237:G:T	A950D	0.999
12:14619246:A:T	V947D	0.999
12:14619255:C:A	G944V	0.999
12:14619255:C:T	G944E	0.999
12:14619263:A:C	C941W	0.999
12:14619273:G:T	P938H	0.999
12:14619285:C:A	G934V	0.999
12:14619291:A:T	V932D	0.999
12:14619294:C:T	G931E	0.999
12:14619297:G:T	A930D	0.999
12:14619298:C:G	A930P	0.999
12:14619300:G:T	A929D	0.999
12:14619302:A:C	C928W	0.999
12:14621059:C:G	R920P	0.999
12:14621179:C:T	G880D	0.999
12:14621181:A:C	S879R	0.999
12:14621181:A:T	S879R	0.999
12:14621183:T:G	S879R	0.999

dbSNP variants (sampled 300 via entrez): RS1000059617 (12:14632907 C>A,T), RS1000069841 (12:14652495 T>C), RS1000100853 (12:14681220 A>G), RS1000177640 (12:14666761 A>C), RS1000268395 (12:14627654 A>G), RS1000318231 (12:14672580 G>A), RS1000321023 (12:14627265 C>T), RS1000331880 (12:14626031 A>C,G), RS1000335367 (12:14665965 C>T), RS1000394582 (12:14666506 A>G), RS1000419535 (12:14619758 G>A), RS1000425569 (12:14666147 C>A,T), RS1000429906 (12:14698424 G>A), RS1000471869 (12:14620129 G>C), RS1000557437 (12:14680908 CTT>C)

Disease associations

OMIM: gene MIM:601330 | disease phenotypes: MIM:614616, MIM:614665, MIM:214700, MIM:223400

GenCC curated gene-disease

Disease	Classification	Inheritance
congenital diarrhea 6	Definitive	Autosomal dominant
intestinal obstruction in the newborn due to guanylate cyclase 2C deficiency	Definitive	Autosomal recessive
congenital sodium diarrhea	Supportive	Autosomal dominant

Mondo (6): congenital diarrhea 6 (MONDO:0013825), intestinal obstruction in the newborn due to guanylate cyclase 2C deficiency (MONDO:0013843), meconium ileus (MONDO:0054868), congenital secretory chloride diarrhea 1 (MONDO:0008964), duodenal atresia (MONDO:0009126), congenital sodium diarrhea (MONDO:0015170)

Orphanet (4): Chronic infantile diarrhea due to guanylate cyclase 2C overactivity (Orphanet:314373), Intestinal obstruction in the newborn due to guanylate cyclase 2C deficiency (Orphanet:314376), Congenital chloride diarrhea (Orphanet:53689), Duodenal atresia (Orphanet:1203)

HPO phenotypes

12 total (13 of 12 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0002027	Abdominal pain
HP:0002028	Chronic diarrhea
HP:0003577	Congenital onset
HP:0003593	Infantile onset
HP:0004388	Microcolon
HP:0004401	Meconium ileus
HP:0040128	Abnormal sweat electrolytes
HP:0100280	Crohn’s disease
HP:0100502	Decreased circulating vitamin B12 concentration
HP:6000319	Meteorism
HP:0002247	Duodenal atresia

GWAS associations

0 associations (top):

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D000074270	Meconium Ileus	C06.405.469.531.788
C536210	Congenital chloride diarrhea (supp.)
C535720	Familial duodenal atresia (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1795197 (SINGLE PROTEIN)

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

Most potent curated ligand interactions (5 total), top 5:

Ligand	Action	Affinity	Parameter
indusatumab vedotin	Binding	9.87	pKd
linaclotide	Agonist	8.91	pKi
E. coli heat-stable enterotoxin (STa)	Agonist	8.8	pKi
PF-07062119	Binding	8.13	pKd
[125I]Sta	Agonist	7.82	pKd

CTD chemical–gene interactions

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	2
bisphenol A	increases methylation	1
trichostatin A	increases expression	1
benzo(e)pyrene	decreases methylation	1
azoxystrobin	decreases expression	1
deguelin	decreases expression	1
4-chloro-N-((4-(1,1-dimethylethyl)phenyl)methyl)-3-ethyl-1-methyl-1H-pyrazole-5-carboxamide	decreases expression	1
pyrimidifen	decreases expression	1
pyrachlostrobin	decreases expression	1
picoxystrobin	decreases expression	1
theaflavin-3,3’-digallate	affects expression	1
Arsenic	affects methylation	1
Benzo(a)pyrene	increases methylation	1
Cadmium	decreases expression, increases abundance	1
Enterotoxins	affects binding	1
Ivermectin	decreases expression	1
Methapyrilene	decreases methylation	1
Phthalic Acids	increases methylation	1
Rotenone	decreases expression	1
Tetrachlorodibenzodioxin	increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Triclosan	increases expression	1
Valproic Acid	increases expression	1
Aflatoxin B1	increases methylation	1
Antirheumatic Agents	decreases expression	1
Cadmium Chloride	increases abundance, decreases expression	1
Vitamin K 3	affects expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1838139	Binding	Inhibition of human HSER in HL60 cells lysate at 10 uM using post probe-labeling by LC-MS/MS analysis relative to control	Synthesis and structure-activity relationship of 4-quinolone-3-carboxylic acid based inhibitors of glycogen synthase kinase-3β. — Bioorg Med Chem Lett

Cellosaurus cell lines

1 cell lines: 1 spontaneously immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_E6QN	Genomeditech CHO-K1 H_GUCY2C	Spontaneously immortalized cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01515696	PHASE4	COMPLETED	Impact of Oral Application of Gastrografin on the Meconium Evacuation in Very Low Birth Weight Infants
NCT02140710	PHASE4	COMPLETED	Impact of Visceral Osteopathic Treatment on Meconium Evacuation in Preterm Infants
NCT02710383	Not specified	TERMINATED	Biomarker for Cystic Fibrosis
NCT03593252	Not specified	UNKNOWN	Bowel Preparation in Elective Pediatric Colorectal Surgery
NCT04020939	Not specified	COMPLETED	The Role of Indocyanine Green Angiography Fluorescence on Intestinal Resections in Pediatric Surgery.
NCT04713579	Not specified	COMPLETED	Timing of Stoma Closure in Neonates
NCT05293353	Not specified	UNKNOWN	Neokare Safety and Tolerability Assessment in Neonates With GI Problems
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT04114279	Not specified	UNKNOWN	Validation of a Totally Synthetic High Fidelity Laparoscopic Duodenal Atresia (DA) Surgical Simulator
NCT06115226	Not specified	UNKNOWN	Laparascopic vs. Laparotomy Management of Neonatal Duodenal Atresia
NCT06731855	Not specified	RECRUITING	An Exploratory Physiological Study of Post-operative Recovery in Surgical Neonates and Dimethylarginine:Arginine Levels