GUCA2A

Summary

GUCA2A (guanylate cyclase activator 2A, HGNC:4682) is a protein-coding gene on chromosome 1p34.2, encoding Guanylin (Q02747). Endogenous activator of intestinal guanylate cyclase.

Predicted to enable guanylate cyclase activator activity. Predicted to be involved in signal transduction. Predicted to be located in extracellular region.

Source: NCBI Gene 2980 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 17 total
• MANE Select transcript: NM_033553

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4682
Approved symbol	GUCA2A
Name	guanylate cyclase activator 2A
Location	1p34.2
Locus type	gene with protein product
Status	Approved
Aliases	STARA
Ensembl gene	ENSG00000197273
Ensembl biotype	protein_coding
OMIM	139392
Entrez	2980

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

ENST00000357001, ENST00000888051, ENST00000949218

RefSeq mRNA: 1 — MANE Select: NM_033553 NM_033553

CCDS: CCDS465

Canonical transcript exons

ENST00000357001 — 3 exons

Exon	Start	End
ENSE00000870151	42162690	42162970
ENSE00000870152	42163403	42163610
ENSE00000870153	42164638	42164745

Expression profiles

Bgee: expression breadth ubiquitous, 130 present calls, max score 99.85.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 2.0570 / max 1893.1706, expressed in 62 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
11974	2.0516	62
11975	0.0054	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ileal mucosa	UBERON:0000331	99.85	gold quality
mucosa of transverse colon	UBERON:0004991	99.71	gold quality
rectum	UBERON:0001052	99.53	gold quality
colonic mucosa	UBERON:0000317	99.46	gold quality
mucosa of sigmoid colon	UBERON:0004993	99.33	gold quality
small intestine Peyer’s patch	UBERON:0003454	95.78	gold quality
small intestine	UBERON:0002108	93.54	gold quality
transverse colon	UBERON:0001157	91.86	gold quality
duodenum	UBERON:0002114	89.88	gold quality
jejunal mucosa	UBERON:0000399	89.60	gold quality
intestine	UBERON:0000160	84.75	gold quality
jejunum	UBERON:0002115	82.60	gold quality
large intestine	UBERON:0000059	82.28	gold quality
tongue squamous epithelium	UBERON:0006919	81.81	gold quality
triceps brachii	UBERON:0001509	81.61	gold quality
colon	UBERON:0001155	81.55	gold quality
gluteal muscle	UBERON:0002000	80.24	gold quality
colonic epithelium	UBERON:0000397	80.06	gold quality
olfactory bulb	UBERON:0002264	79.33	gold quality
type B pancreatic cell	CL:0000169	79.21	gold quality
cervix squamous epithelium	UBERON:0006922	77.03	gold quality
smooth muscle tissue	UBERON:0001135	74.93	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	74.33	gold quality
nasal cavity epithelium	UBERON:0005384	74.11	gold quality
vastus lateralis	UBERON:0001379	73.58	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	73.11	gold quality
quadriceps femoris	UBERON:0001377	73.09	gold quality
vena cava	UBERON:0004087	72.82	gold quality
caecum	UBERON:0001153	72.04	gold quality
heart right ventricle	UBERON:0002080	71.99	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-MTAB-9906	yes	50364.14
E-MTAB-8410	yes	9512.19
E-CURD-88	yes	8352.09
E-MTAB-9543	yes	2262.44
E-GEOD-125970	yes	79.58
E-ANND-3	yes	13.25

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): HNF1A

miRNA regulators (miRDB)

16 targeting GUCA2A, 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-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-10394-5P	99.65	66.83	1852
HSA-MIR-1205	99.65	66.76	1826
HSA-MIR-3616-5P	99.55	67.02	989
HSA-MIR-573	99.55	67.44	955
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-6128	99.33	67.83	1581
HSA-MIR-4795-5P	99.11	66.90	876
HSA-MIR-4763-3P	99.10	67.83	2649
HSA-MIR-29B-1-5P	98.86	68.35	1364
HSA-MIR-299-5P	98.56	71.14	1140
HSA-MIR-4722-5P	98.46	66.34	1611
HSA-MIR-558	97.50	67.16	977
HSA-MIR-6851-3P	95.73	65.11	688

Literature-anchored findings (GeneRIF, showing 14)

• guanylin as a significant marker in salivary gland tumor pathology (PMID:12163390)
• Results from circular dichroism and NMR spectroscopy validate native and recombinant proguanylin to be well-structured proteins adopting identical secondary structures and three-dimensional folds. (PMID:12463760)
• hormone prosequence interactions provide an explanation for the negligible bioactivity of the prohormone as well as the important role of the NH2-terminal residues in the disulfide-coupled folding of proguanylin (PMID:12707255)
• It is likely that gallbladder epithelial cells synthesize and release guanylin into the bile to regulate electrolyte secretion by a paracrine/luminocrine signaling pathway. (PMID:14988827)
• human cortical collecting duct cells are depolarized by guanylin. (PMID:15780094)
• Guanylin plays a role in the regulation of ion transport in the colon (PMID:15901896)
• There is differential expression of guanylin in colorectal cancer, and the differential expression is associated with tumor stage. (PMID:19742348)
• The myristoylated wild-type GCAP1 was found to have the highest Ca(2+) affinity and thermal stability. (PMID:20213926)
• In summary the structural analysis of missense SNPs is important to decrease the number of potential mutations to be in vitro evaluated for associating them with some genetic diseases (PMID:25899674)
• The specific cellular distribution of both GN and UGN differs between duodenum and colon and between human and rat intestines. (PMID:27044258)
• Both guanylin and uroguanylin trigger lipolysis in human visceral adipocytes. Given the lipolytic action of the guanylin system on visceral adipocytes, the herein reported decrease of circulating prouroguanylin concentrations in obese patients may have a role in excessive fat accumulation in obesity. (PMID:27108812)
• 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)
• Guanylin and uroguanylin, as well as their prohormones, do not seem to play a significant role in body weight regulation and glycemic control, suggesting that guanylin-family peptides do not show promise as targets for the treatment of obesity or diabetes. (PMID:29289697)
• APC-beta-catenin-TCF signaling silences the intestinal guanylin-GUCY2C tumor suppressor axis. (PMID:32037952)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Guca2a	ENSMUSG00000023247
rattus_norvegicus	Guca2a	ENSRNOG00000008849

Paralogs (1): GUCA2B (ENSG00000044012)

Protein

Protein identifiers

Guanylin — Q02747 (reviewed: Q02747)

Alternative names: Guanylate cyclase activator 2A, Guanylate cyclase-activating protein 1, Guanylate cyclase-activating protein I

All UniProt accessions (1): Q02747

UniProt curated annotations — full annotation on UniProt →

Function. Endogenous activator of intestinal guanylate cyclase. It stimulates this enzyme through the same receptor binding region as the heat-stable enterotoxins.

Subcellular location. Secreted.

Tissue specificity. Highly expressed in ileum and colon. Found in plasma.

Similarity. Belongs to the guanylin family.

RefSeq proteins (1): NP_291031* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000879	Guanylin	Family
IPR036382	Guanylin_sf	Homologous_superfamily

Pfam: PF02058

UniProt features (14 total): helix 4, disulfide bond 3, turn 2, signal peptide 1, chain 1, peptide 1, sequence variant 1, strand 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
1GNA	SOLUTION NMR
1GNB	SOLUTION NMR
1O8R	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q02747-F1	79.08	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): 69–82, 104–112, 107–115

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-8935690	Digestion

MSigDB gene sets: 74 (showing top): GATA3_01, chr1p34, GATA1_04, NADLER_HYPERGLYCEMIA_AT_OBESITY, HNF1_C, SABATES_COLORECTAL_ADENOMA_DN, GATA1_02, HNF1_01, GOMF_SIGNALING_RECEPTOR_BINDING, MCCLUNG_COCAIN_REWARD_4WK, GATA_Q6, GOMF_HORMONE_ACTIVITY, MATTHEWS_SKIN_CARCINOGENESIS_VIA_JUN, GOMF_ENZYME_ACTIVATOR_ACTIVITY, GOMF_ENZYME_REGULATOR_ACTIVITY

GO Biological Process (1): signal transduction (GO:0007165)

GO Molecular Function (3): hormone activity (GO:0005179), guanylate cyclase activator activity (GO:0030250), protein binding (GO:0005515)

GO Cellular Component (1): extracellular region (GO:0005576)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Digestion and absorption	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
receptor ligand activity	1
guanylate cyclase activity	1
cyclase activator activity	1
guanylate cyclase regulator activity	1
binding	1
cellular anatomical structure	1

Protein interactions and networks

STRING

682 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GUCA2A	GUCY2C	P25092	999
GUCA2A	NPR3	P17342	995
GUCA2A	EMD	P50402	967
GUCA2A	PRKG2	Q13237	850
GUCA2A	CFTR	P13569	797
GUCA2A	GUCA1B	Q9UMX6	738
GUCA2A	GUCY2D	Q02846	715
GUCA2A	GUCA1A	P43080	697
GUCA2A	MS4A12	Q9NXJ0	652
GUCA2A	NPPA	P01160	643
GUCA2A	TPI1	P00938	608
GUCA2A	GCDH	Q92947	593
GUCA2A	SLC9A3	P48764	579
GUCA2A	PGC	P20142	575
GUCA2A	CLCA4	Q14CN2	571

IntAct

48 interactions, top by confidence:

A	B	Type	Score
GUCA2A	SLC34A2	psi-mi:“MI:0915”(physical association)	0.560
GUCA2A	UBQLN2	psi-mi:“MI:0915”(physical association)	0.560
SGTA	GUCA2A	psi-mi:“MI:0915”(physical association)	0.560
GUCA2A	UBQLN1	psi-mi:“MI:0915”(physical association)	0.560
	GUCA2A	psi-mi:“MI:0915”(physical association)	0.560
GUCA2A	ASPH	psi-mi:“MI:0915”(physical association)	0.560
GUCA2A	TMEM237	psi-mi:“MI:0915”(physical association)	0.560
GJA8	GUCA2A	psi-mi:“MI:0915”(physical association)	0.560
GUCA2A	TMEM179B	psi-mi:“MI:0915”(physical association)	0.560
FFAR2	GUCA2A	psi-mi:“MI:0915”(physical association)	0.560
SLC34A2	GUCA2A	psi-mi:“MI:0915”(physical association)	0.560
GUCA2A	GOLM1	psi-mi:“MI:0915”(physical association)	0.560
GUCA2A	TMEM86B	psi-mi:“MI:0915”(physical association)	0.560
NEMP1	GUCA2A	psi-mi:“MI:0915”(physical association)	0.560
GUCA2A	TRAM1	psi-mi:“MI:0915”(physical association)	0.560
GUCA2A	UBQLN2	psi-mi:“MI:0915”(physical association)	0.000
GUCA2A	SGTA	psi-mi:“MI:0915”(physical association)	0.000
UBQLN1	GUCA2A	psi-mi:“MI:0915”(physical association)	0.000
GUCA2A		psi-mi:“MI:0915”(physical association)	0.000
GUCA2A	TMEM237	psi-mi:“MI:0915”(physical association)	0.000
SGTA	GUCA2A	psi-mi:“MI:0915”(physical association)	0.000
ASPH	GUCA2A	psi-mi:“MI:0915”(physical association)	0.000
GUCA2A	TMEM179B	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (15): GUCA2A (Proximity Label-MS), GUCA2A (Two-hybrid), GUCA2A (Two-hybrid), GUCA2A (Two-hybrid), GUCA2A (Two-hybrid), GUCA2A (Two-hybrid), GUCA2A (Two-hybrid), GUCA2A (Two-hybrid), GUCA2A (Two-hybrid), GUCA2A (Two-hybrid), GUCA2A (Two-hybrid), GUCA2A (Two-hybrid), GUCA2A (Two-hybrid), GUCA2A (Two-hybrid), ASPH (Two-hybrid)

ESM2 similar proteins: A0A8M9PDM1, A0JNP2, O09051, O75556, O95968, O95969, P02779, P02780, P02781, P02782, P04769, P06913, P09320, P0DMR2, P11684, P17559, P28902, P30438, P30440, P33578, P33579, P33580, P33680, P70664, P70668, P79897, Q02747, Q05702, Q06318, Q0PGP2, Q13296, Q16661, Q28358, Q2VPS3, Q4G0G5, Q6UGQ3, Q6XE38, Q7M742, Q7M747, Q8CGZ9

Diamond homologs: O09051, O13009, P70107, P70664, P70668, Q02747, Q16661, Q28358, Q8R5G8, P28902, P33680, P79897, Q8R5G9

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
GUCA2A	up-regulates	GUCY2C	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	16
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

343 predictions. Top by Δscore:

Variant	Effect	Δscore
1:42163397:GCTCA:G	donor_loss	1.0000
1:42163398:CTCAC:C	donor_loss	1.0000
1:42163399:TCA:T	donor_loss	1.0000
1:42163400:CACCC:C	donor_loss	1.0000
1:42163401:A:AC	donor_gain	1.0000
1:42163401:A:AT	donor_loss	1.0000
1:42163401:AC:A	donor_gain	1.0000
1:42163402:C:A	donor_loss	1.0000
1:42163402:C:CC	donor_gain	1.0000
1:42163402:CC:C	donor_gain	1.0000
1:42163402:CCCAG:C	donor_gain	1.0000
1:42163405:AG:A	donor_gain	1.0000
1:42163606:CCATC:C	acceptor_gain	1.0000
1:42163607:CATCC:C	acceptor_gain	1.0000
1:42163608:ATCCT:A	acceptor_loss	1.0000
1:42163609:TC:T	acceptor_gain	1.0000
1:42163610:CC:C	acceptor_gain	1.0000
1:42163611:C:CC	acceptor_gain	1.0000
1:42163611:CTG:C	acceptor_loss	1.0000
1:42163406:G:C	donor_gain	0.9900
1:42163417:ATCT:A	donor_gain	0.9900
1:42163420:T:TA	donor_gain	0.9900
1:42163607:CATC:C	acceptor_gain	0.9900
1:42163608:ATC:A	acceptor_gain	0.9900
1:42163612:T:G	acceptor_loss	0.9900
1:42164633:CTCA:C	donor_loss	0.9900
1:42164635:CA:C	donor_loss	0.9900
1:42164637:C:CA	donor_loss	0.9900
1:42162971:C:CC	acceptor_gain	0.9800
1:42163395:CTGCT:C	donor_loss	0.9800

AlphaMissense

744 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:42162943:C:T	C104Y	0.969
1:42162911:A:G	C115R	0.967
1:42162934:C:T	C107Y	0.966
1:42162934:C:G	C107S	0.964
1:42162935:A:T	C107S	0.964
1:42162935:A:G	C107R	0.963
1:42162919:C:T	C112Y	0.960
1:42163593:A:C	F31L	0.959
1:42163593:A:T	F31L	0.959
1:42163595:A:G	F31L	0.959
1:42162919:C:G	C112S	0.958
1:42162920:A:T	C112S	0.958
1:42162920:A:G	C112R	0.957
1:42163441:C:G	C82S	0.957
1:42163442:A:T	C82S	0.957
1:42163480:C:G	C69S	0.957
1:42163481:A:T	C69S	0.957
1:42162943:C:G	C104S	0.953
1:42162944:A:T	C104S	0.953
1:42162918:A:C	C112W	0.951
1:42162943:C:A	C104F	0.950
1:42162944:A:G	C104R	0.943
1:42163594:A:G	F31S	0.943
1:42162910:C:G	C115S	0.942
1:42162911:A:T	C115S	0.942
1:42163575:C:A	K37N	0.942
1:42163575:C:G	K37N	0.942
1:42162933:A:C	C107W	0.941
1:42163594:A:C	F31C	0.941
1:42162937:A:C	I106S	0.939

dbSNP variants (sampled 300 via entrez): RS1000454094 (1:42163118 C>A,T), RS1002354791 (1:42162640 G>A), RS1002714132 (1:42166705 G>A), RS1003184438 (1:42166371 C>G,T), RS1003815602 (1:42165840 G>C), RS1004187950 (1:42166620 T>C), RS1004255826 (1:42163036 C>T), RS1004492891 (1:42166215 G>A,C), RS1004586446 (1:42163234 A>C,T), RS1004591806 (1:42164259 T>A), RS1005074019 (1:42164956 C>T), RS1005704881 (1:42165186 A>G), RS1006301430 (1:42163776 C>T), RS1006805633 (1:42164887 G>A,C,T), RS1007581587 (1:42166303 G>A,T)

Disease associations

OMIM: gene MIM:139392 | 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)

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
propionaldehyde	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Atrazine	increases expression	1
Benzo(a)pyrene	affects methylation	1
Plant Extracts	affects cotreatment, decreases expression	1
Cyclosporine	decreases expression	1

Clinical trials (associated diseases)

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