GUCA1A

Chr 6AD

guanylate cyclase activator 1A

ENSG00000048545UniProt: P43080

Stimulates retinal guanylyl cyclase when free calcium ions concentration is low and inhibits guanylyl cyclase when free calcium ions concentration is elevated (PubMed:18706439, PubMed:19459154, PubMed:30184081, PubMed:30622141). 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 (By similarity). May be involved in cone photoreceptor light response and recovery of response in bright light (By similarity)

Primary Disease Associations & Inheritance

Cone dystrophy-3MIM #602093
AD
Cone-rod dystrophy 14MIM #602093
AD
UniProtCone dystrophy 3
0
ClinVar variants
0
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— GUCA1A
🧬
Gene-Disease Validity (ClinGen)
cone dystrophy 3 · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
Some data sources returned errors (1)

ncbi: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
1.42LOEUF
pLI 0.000
Z-score 0.74
OE 0.72 (0.40–1.42)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.37Z-score
OE missense 0.91 (0.78–1.06)
111 obs / 122.5 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.72 (0.40–1.42)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.91 (0.78–1.06)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.02
0≤1.21.6
LoF obs/exp: 6 / 8.3Missense obs/exp: 111 / 122.5Syn Z: -0.14

ClinVar Variant Classifications

0 submitted variants in ClinVar

ClinVar

Protein Context — Lollipop Plot

GUCA1A · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

GUCA1A-related macular dystrophy

strong
ADGain Of FunctionAltered Gene Product Structure
Eye
G2P ↗

GUCA1A-related cone-rod dystrophy

definitive
ADUndeterminedAltered Gene Product Structure
Eye
G2P ↗
missense variantinframe deletioninframe insertion

GUCA1A-related cone dystrophy

definitive
ADUndeterminedAltered Gene Product Structure
Eye
G2P ↗
missense variantinframe deletioninframe insertion

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Cone dystrophy-3

MIM #602093

Molecular basis of disorder known

Autosomal dominant

Cone-rod dystrophy 14

MIM #602093

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Clinical and genetic characteristics of 251 consecutive patients with macular and cone/cone-rod dystrophy.
Birtel J et al.·Sci Rep
2018Cohort
Phenotyping and genotyping inherited retinal diseases: Molecular genetics, clinical and imaging features, and therapeutics of macular dystrophies, cone and cone-rod dystrophies, rod-cone dystrophies, Leber congenital amaurosis, and cone dysfunction syndromes.
Georgiou M et al.·Prog Retin Eye Res
2024Review
Clinical, Genetic, Imaging and Electrophysiological Findings in a Cohort of Patients With GUCA1A-Associated Retinopathy.
Allon G et al.·Invest Ophthalmol Vis Sci
2025Cohort
Monogenic Retinal Diseases Associated With Genes Encoding Phototransduction Proteins: A Review.
Wong WM et al.·Clin Exp Ophthalmol
2025Review
Cone dystrophy or macular dystrophy associated with novel autosomal dominant GUCA1A mutations.
Manes G et al.·Mol Vis
2017
GUCY2D- or GUCA1A-related autosomal dominant cone-rod dystrophy: is there a phenotypic difference?
Zobor D et al.·Retina
2014
Functional characterization of a novel GUCA1A missense mutation (D144G) in autosomal dominant cone dystrophy: A novel pathogenic GUCA1A variant in COD.
Tang S et al.·Mol Vis
2019Functional
GUCA1A mutation causes maculopathy in a five-generation family with a wide spectrum of severity.
Chen X et al.·Genet Med
2017
Characterization of GUCA1A-associated dominant cone/cone-rod dystrophy: low prevalence among Japanese patients with inherited retinal dystrophies.
Mizobuchi K et al.·Sci Rep
2019Cohort
Neuronal Calcium Sensor GCAP1 Encoded by GUCA1A Exhibits Heterogeneous Functional Properties in Two Cases of Retinitis Pigmentosa.
Abbas S et al.·ACS Chem Neurosci
2020Cohort
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools