GUCY2D

Chr 17ADAR

guanylate cyclase 2D, retinal

Also known as: CACD, CACD1, CG-E, CORD5, CORD6, CSNB1I, CYGD, GUC1A4

NCBI Gene: 3000 ENSG00000132518 UniProt: Q02846 OMIM: 600179

This protein catalyzes the synthesis of cyclic GMP in photoreceptor rods and cones, playing an essential role in phototransduction by mediating cGMP replenishment. Mutations cause a spectrum of retinal dystrophies including Leber congenital amaurosis (with onset in infancy), cone-rod dystrophy, congenital stationary night blindness, and central areolar choroidal dystrophy. The gene shows both autosomal dominant and autosomal recessive inheritance patterns depending on the specific variant and associated phenotype.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a retina-specific guanylate cyclase, which is a member of the membrane guanylyl cyclase family. Like other membrane guanylyl cyclases, this enzyme has a hydrophobic amino-terminal signal sequence followed by a large extracellular domain, a single membrane spanning domain, a kinase homology domain, and a guanylyl cyclase catalytic domain. In contrast to other membrane guanylyl cyclases, this enzyme is not activated by natriuretic peptides. Mutations in this gene result in Leber congenital amaurosis and cone-rod dystrophy-6 diseases. [provided by RefSeq, Dec 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismAD/ARLOEUF 0.754 OMIM phenotypes

Clinical Summary— GUCY2D

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Gene-Disease Validity (ClinGen)

GUCY2D-related dominant retinopathy · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

262 unique Pathogenic / Likely Pathogenic· 663 VUS of 1699 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — GUCY2D

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.75LOEUF

pLI 0.000

Z-score 2.86

OE 0.52 (0.37–0.75)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.78Z-score

OE missense 0.91 (0.85–0.98)

598 obs / 654.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.52 (0.37–0.75)

0≤0.351.4

Missense OE?0.91 (0.85–0.98)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 22 / 42.0Missense obs/exp: 598 / 654.2Syn Z: -0.62

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedGUCY2D-related central areolar choroidal dystrophyOTHERAR

definitiveGUCY2D-related cone-rod dystrophyOTHERAD

definitiveGUCY2D-related Leber congenital amaurosisLOFAR

This gene — mechanism propensity

0.75top 25%

GOF

0.83top 5%

LOF

0.2582th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports dominant-negative. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median · 1 literature citation

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNGUCY2D mutations from LCA patients have distinct functional consequences on RetGC-1 catalytic activity in vitro. Our analyses showed that the catalytic domain mutations cause a marked reduction in cyclase activity, while the extracellular domain mutations moderately reduce activity. The catalytic do1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References

1.PMID 15123990 ↗

ClinVar Variant Classifications

1699 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic155

Likely Pathogenic107

VUS663

Likely Benign665

Benign38

Conflicting40

155

Pathogenic

107

Likely Pathogenic

663

VUS

665

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	120	30	5	0	155
Likely Pathogenic	48	57	2	0	107
VUS	6	623	25	9	663
Likely Benign	0	15	220	430	665
Benign	0	9	20	9	38
Conflicting	—				40
Total	174	734	272	448	1,668

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

View in ClinVar →

22 pathogenic / likely-pathogenic (of 35) ClinVar copy-number / structural variants overlap GUCY2D — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →