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

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

71 unique Pathogenic / Likely Pathogenic· 202 VUS of 499 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 OE0.52 (0.37–0.75)

0≤0.351.4

Missense OE0.91 (0.85–0.98)

0≤0.61.4

Synonymous OE1.05

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

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 doPMID:15123990

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