GUCY2D

Chr 17ADAR

guanylate cyclase 2D, retinal

NCBI Gene: 3000ENSG00000132518UniProt: Q02846

Catalyzes the synthesis of cyclic GMP (cGMP) in rods and cones of photoreceptors. Plays an essential role in phototransduction, by mediating cGMP replenishment (PubMed:15123990, PubMed:21928830, PubMed:26100624, PubMed:30319355, PubMed:9600905). May also participate in the trafficking of membrane-associated proteins to the photoreceptor outer segment membrane (By similarity)

Primary Disease Associations & Inheritance

?Choroidal dystrophy, central areolar 1MIM #215500
AD
Cone-rod dystrophy 6MIM #601777
ADAR
Leber congenital amaurosis 1MIM #204000
AR
Night blindness, congenital stationary, type 1IMIM #618555
AR
599
ClinVar variants
57
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— GUCY2D
🧬
Gene-Disease Validity (ClinGen)
GUCY2D-related dominant retinopathy · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
57 Pathogenic / Likely Pathogenic· 172 VUS of 599 total submissions

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.
0.75LOEUF
pLI 0.000
Z-score 2.86
OE 0.52 (0.37–0.75)
Tolerant

Typical tolerance to LoF variation

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.
0.78Z-score
OE missense 0.91 (0.85–0.98)
598 obs / 654.2 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.0.52 (0.37–0.75)
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 (0.85–0.98)
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.1.05
0≤1.21.6
LoF obs/exp: 22 / 42.0Missense obs/exp: 598 / 654.2Syn Z: -0.62

ClinVar Variant Classifications

599 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic34
Likely Pathogenic23
VUS172
Likely Benign353
Benign16
Conflicting1
34
Pathogenic
23
Likely Pathogenic
172
VUS
353
Likely Benign
16
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
19
3
12
0
34
Likely Pathogenic
11
6
6
0
23
VUS
0
161
10
1
172
Likely Benign
0
2
126
225
353
Benign
0
0
14
2
16
Conflicting
—1
Total30172168228599

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

GUCY2D · protein map & ClinVar variants

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

Gene2Phenotype Curations

GUCY2D-related central areolar choroidal dystrophy

limited
ARUndeterminedAltered Gene Product Structure
Eye
G2P ↗
missense variantinframe deletioninframe insertion

GUCY2D-related cone-rod dystrophy

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

GUCY2D-related Leber congenital amaurosis

definitive
ARLoss Of FunctionAbsent Gene Product
Eye
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

?Choroidal dystrophy, central areolar 1

MIM #215500

Molecular basis of disorder known

Autosomal dominant

Cone-rod dystrophy 6

MIM #601777

Molecular basis of disorder known

Autosomal dominantAutosomal recessive

Leber congenital amaurosis 1

MIM #204000

Molecular basis of disorder known

Autosomal recessive

Night blindness, congenital stationary, type 1I

MIM #618555

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — GUCY2D
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Genetic epidemiology of inherited retinal diseases in a large patient cohort followed at a single center in Italy.
Karali M et al.·Sci Rep
2022Cohort
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
Genetic and clinical findings in a Chinese cohort with Leber congenital amaurosis and early onset severe retinal dystrophy.
Xu K et al.·Br J Ophthalmol
2020Cohort
Leber's Congenital Amaurosis: Current Concepts of Genotype-Phenotype Correlations.
Huang CH et al.·Genes (Basel)
2021Review
Cone rod dystrophies.
Hamel CP·Orphanet J Rare Dis
2007Review
Leber Congenital Amaurosis.
Tsang SH et al.·Adv Exp Med Biol
2018Review
Genotype-functional-phenotype correlations in photoreceptor guanylate cyclase (GC-E) encoded by GUCY2D.
Sharon D et al.·Prog Retin Eye Res
2018Review
Comprehensive Genotyping and Phenotyping Analysis of GUCY2D-Associated Rod- and Cone-Dominated Dystrophies.
Rodilla C et al.·Am J Ophthalmol
2023
Leber congenital amaurosis caused by mutations in GUCY2D.
Boye SE·Cold Spring Harb Perspect Med
2014Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
GUCY2D-Associated Retinopathy: A Comparative Study Between Humans and German Spitz Dogs.
Guareschi BLV et al.·Vet Sci
2025🔓 Open Access
De novo variant in GUCY2D gene causing atypical cone-rod dystrophy in a consanguineous family and literature review.
Fang XH et al.·Int J Ophthalmol
2025Review
Clinical and Biochemical Characterization of Specific GUCY2D Alleles Associated With a Rare Form of Night Blindness.
Ba-Abbad R et al.·Invest Ophthalmol Vis Sci
2025🔓 Open Access
A Novel GUCY2D Frameshift Deletion Identified in a Patient with Leber Congenital Amaurosis 1: A Case Report.
Zheng X et al.·Case Rep Ophthalmol
2025🔓 Open AccessCase report
Erratum: Safety and improved efficacy signals following gene therapy in childhood blindness caused by GUCY2D mutations.
Jacobson SG et al.·iScience
2024🔓 Open Access
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