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…

Primary Disease Associations & Inheritance

?Choroidal dystrophy, central areolar 1MIM #215500

Cone-rod dystrophy 6MIM #601777

ADAR

Leber congenital amaurosis 1MIM #204000

Night blindness, congenital stationary, type 1IMIM #618555

Clinical highlights

Gene–disease validity (ClinGen)

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.75

LOEUF

LOF*

Mechanism· G2P

📖

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

Background carrier burden — how many people carry a rare variant somewhere in GUCY2D?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 36

1,570 rare PASS variants

Rare truncating (LoF)

1 in 670

204 rare PASS variants

Rare synonymous (reference)

1 in 80

721 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for GUCY2D. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 41	1 in 840
South Asian	~43k	1 in 36	1 in 660
Remaining (unassigned)	~30k	1 in 29	1 in 310
European (Finnish)	~27k	1 in 120	1 in 3,300
Admixed American	~22k	1 in 40	1 in 940
African / African American	~21k	1 in 40	1 in 770
East Asian	~20k	1 in 42	1 in 520
Ashkenazi Jewish	~13k	1 in 190	≈ 1 in 6,500
Middle Eastern	~2,884	1 in 42	≈ 1 in 720

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.