GUCA1C

Summary

GUCA1C (guanylate cyclase activator 1C, HGNC:4680) is a protein-coding gene on chromosome 3q13.13, encoding Guanylyl cyclase-activating protein 3 (O95843). Stimulates guanylyl cyclase 1 (GC1) and GC2 when free calcium ions concentration is low and inhibits guanylyl cyclases when free calcium ions concentration is elevated.

Predicted to enable calcium ion binding activity and calcium sensitive guanylate cyclase activator activity. Predicted to be involved in regulation of signal transduction. Predicted to be located in photoreceptor disc membrane.

Source: NCBI Gene 9626 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 45 total
• Dosage sensitivity (ClinGen): haploinsufficiency dosage sensitivity unlikely, triplosensitivity no evidence
• MANE Select transcript: NM_005459

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4680
Approved symbol	GUCA1C
Name	guanylate cyclase activator 1C
Location	3q13.13
Locus type	gene with protein product
Status	Approved
Aliases	GCAP3
Ensembl gene	ENSG00000138472
Ensembl biotype	protein_coding
OMIM	605128
Entrez	9626

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

ENST00000261047, ENST00000393963, ENST00000471108

RefSeq mRNA: 2 — MANE Select: NM_005459 NM_001363884, NM_005459

CCDS: CCDS2954, CCDS87118

Canonical transcript exons

ENST00000261047 — 4 exons

Exon	Start	End
ENSE00000934149	108916127	108916214
ENSE00000967379	108953559	108953879
ENSE00000967380	108920436	108920585
ENSE00001814555	108907792	108908209

Expression profiles

Bgee: expression breadth broad, 73 present calls, max score 92.46.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.9475 / max 1098.5541, expressed in 16 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
43679	0.3446	7
43678	0.2071	6
43680	0.1640	10
43677	0.1557	6
43681	0.0762	9

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
body of pancreas	UBERON:0001150	92.46	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.94	gold quality
pancreas	UBERON:0001264	76.38	gold quality
left ventricle myocardium	UBERON:0006566	74.87	gold quality
heart left ventricle	UBERON:0002084	73.20	gold quality
cardiac ventricle	UBERON:0002082	72.78	gold quality
heart right ventricle	UBERON:0002080	64.01	gold quality
buccal mucosa cell	CL:0002336	62.05	gold quality
myocardium	UBERON:0002349	61.48	silver quality
apex of heart	UBERON:0002098	61.34	gold quality
sperm	CL:0000019	56.94	gold quality
pineal body	UBERON:0001905	56.80	silver quality
lower lobe of lung	UBERON:0008949	55.87	silver quality
body of stomach	UBERON:0001161	55.10	gold quality
epithelial cell of pancreas	CL:0000083	55.08	gold quality
retina	UBERON:0000966	55.05	gold quality
pigmented layer of retina	UBERON:0001782	55.05	gold quality
cardiac muscle of right atrium	UBERON:0003379	54.34	gold quality
kidney epithelium	UBERON:0004819	53.93	gold quality
upper arm skin	UBERON:0004263	53.52	gold quality
stomach	UBERON:0000945	52.01	gold quality
tibialis anterior	UBERON:0001385	51.21	silver quality
heart	UBERON:0000948	51.18	gold quality
islet of Langerhans	UBERON:0000006	50.40	gold quality
left testis	UBERON:0004533	50.11	gold quality
pancreatic ductal cell	CL:0002079	49.91	silver quality
testis	UBERON:0000473	49.85	gold quality
right testis	UBERON:0004534	49.36	gold quality
oocyte	CL:0000023	48.99	gold quality
anterior cingulate cortex	UBERON:0009835	48.77	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-7316	yes	1809.30
E-MTAB-11121	yes	706.03
E-ANND-3	yes	12.21

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

30 targeting GUCA1C, 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-302E	99.96	70.74	2669
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-302A-3P	99.89	71.23	1777
HSA-MIR-302B-3P	99.89	71.23	1777
HSA-MIR-302C-3P	99.89	71.20	1778
HSA-MIR-302D-3P	99.89	71.25	1777
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-373-3P	99.84	70.68	1668
HSA-MIR-520E-3P	99.84	70.55	1698
HSA-MIR-372-3P	99.83	70.58	1691
HSA-MIR-520A-3P	99.83	70.59	1687
HSA-MIR-520B-3P	99.83	70.56	1699
HSA-MIR-520C-3P	99.83	70.56	1699
HSA-MIR-520D-3P	99.83	70.78	1676
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-651-5P	99.64	68.49	1104
HSA-MIR-942-5P	99.41	68.40	1977
HSA-MIR-183-3P	99.41	69.41	1598
HSA-MIR-138-2-3P	98.91	68.33	1643
HSA-MIR-421	98.90	67.04	1883
HSA-MIR-6074	98.89	69.64	2187
HSA-MIR-491-3P	98.88	68.86	1224
HSA-MIR-4684-5P	98.29	67.99	1650
HSA-MIR-1243	97.07	65.44	719
HSA-MIR-6839-5P	96.74	68.29	1088
HSA-MIR-378J	96.44	66.20	1020

Functional genomics

ClinGen dosage: haploinsufficiency 40 (dosage sensitivity unlikely), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 3)

• Results report the crystal structure of unmyristoylated human guanylate cyclase-activating protein 3 (GCAP3) with calcium bound. (PMID:16626734)
• Role of GUCA1C in Primary Congenital Glaucoma and in the Retina: Functional Evaluation in Zebrafish. (PMID:32422965)
• Molecular Properties of Human Guanylate Cyclase-Activating Protein 3 (GCAP3) and Its Possible Association with Retinitis Pigmentosa. (PMID:35328663)

Cross-species orthologs

15 orthologs

Organism	Symbol	Gene ID
danio_rerio	guca1c	ENSDARG00000030758
danio_rerio	guca1d	ENSDARG00000044629
danio_rerio	guca1g	ENSDARG00000045737
danio_rerio	rcvrna	ENSDARG00000052223
danio_rerio	rcvrnb	ENSDARG00000111827
drosophila_melanogaster	CG2256	FBGN0029995
drosophila_melanogaster	CG3565	FBGN0035034
drosophila_melanogaster	CG7646	FBGN0036926
drosophila_melanogaster	sowi	FBGN0037460
drosophila_melanogaster	CG15177	FBGN0037461
drosophila_melanogaster	sunz	FBGN0037462
drosophila_melanogaster	d-cup	FBGN0038089
drosophila_melanogaster	CG5890	FBGN0039380
caenorhabditis_elegans	ncs-2	WBGENE00003564
caenorhabditis_elegans		WBGENE00015867

Paralogs (14): CLXN (ENSG00000034239), GUCA1A (ENSG00000048545), NCALD (ENSG00000104490), NCS1 (ENSG00000107130), RCVRN (ENSG00000109047), GUCA1B (ENSG00000112599), KCNIP3 (ENSG00000115041), HPCAL1 (ENSG00000115756), HPCAL4 (ENSG00000116983), KCNIP2 (ENSG00000120049), HPCA (ENSG00000121905), VSNL1 (ENSG00000163032), KCNIP1 (ENSG00000182132), KCNIP4 (ENSG00000185774)

Protein

Protein identifiers

Guanylyl cyclase-activating protein 3 — O95843 (reviewed: O95843)

Alternative names: Guanylate cyclase activator 1C

All UniProt accessions (3): O95843, C9J7M7, C9JNI2

UniProt curated annotations — full annotation on UniProt →

Function. Stimulates guanylyl cyclase 1 (GC1) and GC2 when free calcium ions concentration is low and inhibits guanylyl cyclases when free calcium ions concentration is elevated. This Ca(2+)-sensitive regulation of guanylyl cyclase (GC) is a key event in recovery of the dark state of rod photoreceptors following light exposure.

Tissue specificity. Retina.

Domain organisation. Binds three calcium ions (via EF-hand 2, 3 and 4).

Isoforms (2)

UniProt ID	Names	Canonical?
O95843-1	1	yes
O95843-2	2

RefSeq proteins (2): NP_001350813, NP_005450* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002048	EF_hand_dom	Domain
IPR011992	EF-hand-dom_pair	Homologous_superfamily
IPR018247	EF_Hand_1_Ca_BS	Binding_site
IPR028846	Recoverin	Family

Pfam: PF13202, PF13499

UniProt features (43 total): binding site 14, helix 10, domain 4, sequence variant 4, strand 4, initiator methionine 1, chain 1, modified residue 1, lipid moiety-binding region 1, splice variant 1, turn 1, region of interest 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2GGZ	X-RAY DIFFRACTION	3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O95843-F1	83.33	0.68

Functional residue map

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

Ligand- & substrate-binding residues (14): 76; 101; 103; 105; 107; 112; 143; 145; 147; 149; 154; 65 …

Post-translational modifications (2): 3, 2

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: 46 (showing top): PID_CONE_PATHWAY, GOBP_SENSORY_PERCEPTION_OF_LIGHT_STIMULUS, TGACATY_UNKNOWN, KEGG_OLFACTORY_TRANSDUCTION, GOBP_SENSORY_PERCEPTION, GOCC_NEURON_PROJECTION, WGTTNNNNNAAA_UNKNOWN, GOCC_CILIUM, GOCC_PHOTORECEPTOR_DISC_MEMBRANE, GOCC_PHOTORECEPTOR_OUTER_SEGMENT, YKACATTT_UNKNOWN, GOMF_ENZYME_ACTIVATOR_ACTIVITY, GOMF_ENZYME_REGULATOR_ACTIVITY, TGATTTRY_GFI1_01, PID_RHODOPSIN_PATHWAY

GO Biological Process (3): signal transduction (GO:0007165), visual perception (GO:0007601), regulation of signal transduction (GO:0009966)

GO Molecular Function (4): calcium ion binding (GO:0005509), calcium sensitive guanylate cyclase activator activity (GO:0008048), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (1): photoreceptor disc membrane (GO:0097381)

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
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
sensory perception of light stimulus	1
signal transduction	1
regulation of cell communication	1
regulation of signaling	1
regulation of response to stimulus	1
metal ion binding	1
guanylate cyclase activator activity	1
binding	1
cation binding	1
photoreceptor outer segment	1
organelle membrane	1

Protein interactions and networks

STRING

1266 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GUCA1C	GUCY2D	Q02846	808
GUCA1C	SLC25A18	Q9H1K4	760
GUCA1C	GUCY2F	P51841	592
GUCA1C	RPGRIP1L	Q68CZ1	588
GUCA1C	CNGB1	Q14028	576
GUCA1C	OPN1LW	P04000	557
GUCA1C	AIPL1	Q9NZN9	557
GUCA1C	RPGRIP1	Q96KN7	552
GUCA1C	LRAT	O95237	549
GUCA1C	TULP1	O00294	542
GUCA1C	RD3	Q7Z3Z2	542
GUCA1C	PDE6H	Q13956	538
GUCA1C	PDE6B	P35913	535
GUCA1C	CRX	O43186	532
GUCA1C	PDE6C	P51160	531

IntAct

8 interactions, top by confidence:

A	B	Type	Score
HGS	GUCA1C	psi-mi:“MI:0915”(physical association)	0.560
PSORS1C2	GUCA1C	psi-mi:“MI:0915”(physical association)	0.560
GUCA1C	PSORS1C2	psi-mi:“MI:0915”(physical association)	0.560
GUCA1C	SERPINA10	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (3): HGS (Two-hybrid), PSORS1C2 (Two-hybrid), SERPINA10 (Affinity Capture-MS)

ESM2 similar proteins: B5FZ84, G5EDN6, O73761, O73762, O95843, P21457, P22728, P28470, P29104, P31227, P34057, P35243, P42322, P42324, P43080, P43081, P46065, P48451, P51177, P61022, P61023, P63098, P63099, P63100, P79880, P79881, P84074, P84075, P84076, P87072, Q06AT1, Q24214, Q2TBI5, Q4PL64, Q55G87, Q5R632, Q5R6S5, Q63810, Q63811, Q6AXL4

Diamond homologs: A9JTH1, B3DLU1, B3VSB7, B5FZ84, O73761, O73762, O73763, O95843, P21457, P22728, P25296, P29104, P29105, P31227, P34057, P35243, P35332, P36608, P36609, P37235, P37236, P42322, P42324, P42325, P43080, P43081, P46065, P51177, P61601, P61602, P62166, P62167, P62168, P62748, P62749, P62758, P62759, P62760, P62761, P62762

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	34
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

647 predictions. Top by Δscore:

Variant	Effect	Δscore
3:108908205:TTCCC:T	acceptor_gain	1.0000
3:108908207:CCC:C	acceptor_gain	1.0000
3:108908208:CC:C	acceptor_gain	1.0000
3:108908208:CCC:C	acceptor_gain	1.0000
3:108908209:CC:C	acceptor_gain	1.0000
3:108908209:CCTG:C	acceptor_loss	1.0000
3:108908210:C:CA	acceptor_loss	1.0000
3:108908210:C:CC	acceptor_gain	1.0000
3:108916085:A:AC	donor_gain	1.0000
3:108916086:C:CC	donor_gain	1.0000
3:108920432:TTACC:T	donor_loss	1.0000
3:108920433:T:TG	donor_loss	1.0000
3:108920434:A:AC	donor_gain	1.0000
3:108920435:C:CC	donor_gain	1.0000
3:108920435:C:CT	donor_loss	1.0000
3:108920584:TC:T	acceptor_gain	1.0000
3:108920585:CC:C	acceptor_gain	1.0000
3:108920587:T:A	acceptor_loss	1.0000
3:108920588:A:C	acceptor_gain	1.0000
3:108920595:G:C	acceptor_gain	1.0000
3:108947272:CTATT:C	donor_gain	1.0000
3:108908206:TCCC:T	acceptor_gain	0.9900
3:108908207:CCCC:C	acceptor_gain	0.9900
3:108908211:T:C	acceptor_loss	0.9900
3:108916073:C:CT	donor_gain	0.9900
3:108916211:CCGC:C	acceptor_gain	0.9900
3:108916212:CGCC:C	acceptor_gain	0.9900
3:108916213:GCC:G	acceptor_loss	0.9900
3:108916215:C:CA	acceptor_loss	0.9900
3:108916216:T:G	acceptor_loss	0.9900

AlphaMissense

1422 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:108920499:A:C	F97L	0.928
3:108920499:A:T	F97L	0.928
3:108920501:A:G	F97L	0.928
3:108953685:A:C	F26L	0.905
3:108953685:A:T	F26L	0.905
3:108953687:A:G	F26L	0.905
3:108908203:A:G	L150S	0.898
3:108908187:A:C	F155L	0.895
3:108908187:A:T	F155L	0.895
3:108908189:A:G	F155L	0.895
3:108920559:A:C	F77L	0.863
3:108920559:A:T	F77L	0.863
3:108920561:A:G	F77L	0.863
3:108953640:C:A	K41N	0.857
3:108953640:C:G	K41N	0.857
3:108920577:A:C	F71L	0.829
3:108920577:A:T	F71L	0.829
3:108920579:A:G	F71L	0.829
3:108920568:A:C	F74L	0.823
3:108920568:A:T	F74L	0.823
3:108920570:A:G	F74L	0.823
3:108920575:A:T	V72D	0.815
3:108953571:A:C	F64L	0.798
3:108953571:A:T	F64L	0.798
3:108953573:A:G	F64L	0.798
3:108908188:A:G	F155S	0.797
3:108916140:A:C	D143E	0.785
3:108916140:A:T	D143E	0.785
3:108916152:G:C	F139L	0.785
3:108916152:G:T	F139L	0.785

dbSNP variants (sampled 300 via entrez): RS1000053057 (3:108923634 CT>C,CTT), RS1000088125 (3:108944674 T>C), RS1000100956 (3:108939776 C>A,T), RS1000113463 (3:108918668 G>A), RS1000144566 (3:108918903 T>C), RS1000224254 (3:108942825 C>T), RS1000245947 (3:108948367 T>C), RS1000255407 (3:108943155 C>T), RS1000343116 (3:108929910 A>G,T), RS1000403660 (3:108924760 C>G), RS1000408059 (3:108936223 C>T), RS1000417445 (3:108930780 C>G,T), RS1000495009 (3:108919123 A>G), RS1000497207 (3:108955565 G>T), RS1000582525 (3:108914346 T>A,G)

Disease associations

OMIM: gene MIM:605128 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): megacolon (MONDO:0001273)

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST003225_27	Pelvic organ prolapse (moderate/severe)	6.000000e-07

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008531	Megacolon	C06.405.469.158.701

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
CGP 52608	affects binding, increases reaction	1
Zoledronic Acid	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Lead	increases expression	1
Rotenone	increases expression	1
Aflatoxin B1	decreases methylation	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04340856	Not specified	COMPLETED	Retrospective, Uncontrolled Cohort Study on the Therapy of Chronic Megalon
NCT07470892	Not specified	NOT_YET_RECRUITING	Preoperative Fish Oil PN and Prognosis After Constipation Surgery