GUCA1A

protein-coding

guanylate cyclase activator 1A, the group of EF-hand domain containing

Gene summary

This gene encodes an enzyme that plays a role in the recovery of retinal photoreceptors from photobleaching. This enzyme promotes the activity of retinal guanylyl cyclase-1 (GC1) at low calcium concentrations and inhibits GC1 at high calcium concentrations. Mutations in this gene can cause cone dystrophy 3 and code-rod dystrophy 14. provided by RefSeq, Jul 2020]

Previous symbols:

GUCA
GUCA1
C6orf131

MANE transcript

NM_001384910.1

Inheritance

ClinVar variants

P:35U:123B:57

Top phenotype

Cone dystrophy 3

gnomAD constraint

pLI —, LoF o/e 0.72

Max pathogenic AF

—

Genomic locus

chr6:42,173,364-42,181,338

External References & Databases

Ensembl (ENSG00000048545)

Transcript & Mutation Effects

hg38 • Region Span ~8.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

cone dystrophy 3DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011193

Submitter: G2P

cone dystrophy 3STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011193

Submitter: Labcorp Genetics (formerly Invitae)

cone-rod dystrophy 14DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0800326

Submitter: G2P

cone dystrophySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0000455

Submitter: Orphanet

cone-rod dystrophySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015993

Submitter: Orphanet

cone dystrophy 3STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011193

Submitter: PanelApp Australia

central areolar choroidal dystrophySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008982

Submitter: Orphanet

hereditary macular dystrophySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0020242

Submitter: G2P

cone dystrophy 3DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011193

Submitter: ClinGen

GUCA1A was first reported in relation to autosomal dominant cone dystrophy in 1998 (Payne et al., PMID: 9425234). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern or phenotypic variability between cone dystrophy and cone-rod dystrophy patients who carry pathogenic GUCA1A mutations. Therefore, the following disease entities have been lumped into a single disease entity: [cone dystrophy] (OMIM: 602093) and [cone-rod dystrophy] (OMIM: 602093). The resulting lumped disease entity has been named GUCA1A-related retinopathy. Twelve missense variants that have been reported in twelve probands in eight publications (PMIDs: 28125083, 24024198, 15953638, 9425234, 19459154, 18706439, 15790869 and 30622141) are included in this curation. Six families were scored for segregation evidence (PMIDs: 28125083, 24024198, 15953638, 9425234, 19459154). The mechanism of pathogenicity appears to be gain-of-function. This gene-disease association is also supported by RNA and protein expression data from ProteinAtlas showing that GUCA1A is highly and specifically expressed only in the retina, supporting the role of altered GUCA1A function in the development of retinal dystrophy (PMID: 25613900). Co-expression of RetGCI and GUCA1A in HEK293 cells show that GUCA1A functions biochemically as an activator of GUCY2D / RetGC1 and collaborates with it to produce cGMP (PMID: 18541533). Immunoprecipitation assays also show an association between GUCA1A and RD3, a gene that was found by the Retina GCEP to be Definitely associated with a similar retinopathy. A knock-in mouse model introducing the E155G mutation, suspected to be pathogenic in human cone dystrophy patients, was also scored. The authors were able to demonstrate that mice heterozygous for this mutation recapitulate many of the features seen in human patients carrying pathogenic GUCA1A mutations including decreased cone and rod ERG responses, and photoreceptor degeneration (PMID: 21464903). Another mouse model, using mice heterozygous for the L151F mutation in GUCA1A, demonstrates that mutant mice exhibit a reduction in ONL thickness, decreased ERG response, and diminished visual acuity compared to wild-type mice (PMID: 23472098). In summary, GUCA1A is Definitively associated with autosomal dominant GUCA1A-related retinopathy. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Retina GCEP on May 1, 2025 (SOP Version 9).

Clinical Genomic Database (CGD)

Cone dystrophy 3AD

Manifestation: Ophthalmologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 9425234; 15735604; 15953638; 15790869; 19459154; 24024198; 28125083

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GUCA1A variants in ClinVar

16 Conditions Cataloged

not providedTotal: 242

not specifiedTotal: 42

Cone dystrophy 3Total: 40

GUCA1A-related disordersTotal: 16

Inborn genetic diseasesTotal: 14

Retinal dystrophyTotal: 11

Cone-rod dystrophy 14Total: 3

Cone-rod dystrophyTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001384910.1. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous				43 clinvar		43
missense	6 clinvar	29 clinvar	105 clinvar	14 clinvar		154
nonsense			6 clinvar			6
start loss						0
frameshift			9 clinvar			9
splice donor/acceptor (+/-2bp)			3 clinvar			3
Total	6	29	123	57	0	215

Highest pathogenic variant AF is 0.000006572116

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 4 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001384910.1	RefSeq	NP_001371839.1	4	MANE Select
ENST00000372958.2	Ensembl	ENSP00000362049.1	4	MANE Select
ENST00000679182.1	Ensembl	ENSP00000504837.1	3	Standard
ENST00001138806.1	Ensembl	ENSP00000810134.1	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Phototransduction - Homo sapiens (human)
Cardiac Hypertrophic Response
Signaling by GPCR
Signal Transduction
visual signal transduction

Biological Process

signal transduction
visual perception
phototransduction
positive regulation of cGMP-mediated signaling
regulation of rhodopsin mediated signaling pathway

Molecular Function

calcium ion binding
calcium sensitive guanylate cyclase activator activity
guanylate cyclase regulator activity

Cellular Component

photoreceptor inner segment
photoreceptor disc membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000394237
Coding exons: 4
Length: 24651
Individuals with no LoFs: 125731
Homozygous LoFs: 0
Heterozygous LoFs: 17
Defined: 125748
p: 0.0000676

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.369	111	123	0.906	0.00000777	1345
Missense (PolyPhen)		48	48.659	0.98646		595
Synonymous	-0.135	50	48.8	1.02	0.00000348	359
Loss of Function	0.739	6	8.30	0.723	3.65e-7	99

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.00014	0.00014	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000079	0.000079	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Stimulates retinal guanylyl cyclase when free calcium ions concentration is low and inhibits guanylyl cyclase when free calcium ions concentration is elevated (PubMed:19459154). This Ca(2+)-sensitive regulation of retinal guanylyl cyclase is a key event in recovery of the dark state of rod photoreceptors following light exposure. {ECO:0000269|PubMed:19459154, ECO:0000305}.;
Disease: DISEASE: Cone dystrophy 3 (COD3) [MIM:602093]: An autosomal dominant cone dystrophy. Cone dystrophies are retinal dystrophies characterized by progressive degeneration of the cone photoreceptors with preservation of rod function, as indicated by electroretinogram. However, some rod involvement may be present in some cone dystrophies, particularly at late stage. Affected individuals suffer from photophobia, loss of visual acuity, color vision and central visual field. Another sign is the absence of macular lesions for many years. Cone dystrophies are distinguished from the cone-rod dystrophies in which some loss of peripheral vision also occurs. {ECO:0000269|PubMed:11108966, ECO:0000269|PubMed:11146732, ECO:0000269|PubMed:11484154, ECO:0000269|PubMed:15505030, ECO:0000269|PubMed:15735604, ECO:0000269|PubMed:15790869, ECO:0000269|PubMed:19459154, ECO:0000269|PubMed:9425234}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.183

Intolerance Scores

LoFtool: 0.549
RVIS EVS: -0.05
RVIS percentile EVS: 49.76

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.414

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium