# NM_000180.4(GUCY2D):c.2291dup (p.Pro765fs)

https://sugi.bio/variant/gucy2d-p-pro765fs

## Summary

**GUCY2D p.Pro765fs (c.2291dup)** is classified **Pathogenic** in GUCY2D (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-01). Ultra-rare (gnomAD MAF 5.711e-06); Associated with cone-rod dystrophy 6.

**At a glance:** Pathogenic · review: Single submitter · rsID rs772242251 · 1 submitter · 2 linked conditions · ultra-rare (gnomAD MAF 5.711e-06)

## For patients & families {#patients}

This is a change in the GUCY2D gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to cone-rod dystrophy 6.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant, Autosomal recessive, X-linked recessive |
| Age of onset (of this condition) | Adolescent, Adult, Childhood |
| Prevalence | 1-9 / 100 000 (Europe) |
| Diagnostic panels | GUCY2D is a diagnostic-grade gene on 1 Genomics England panel |

**Commonly reported features of Cone rod dystrophy** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Photophobia — Very frequent (99-80%)
- Nyctalopia — Very frequent (99-80%)
- Abnormality of retinal pigmentation — Very frequent (99-80%)
- Progressive visual loss — Frequent (79-30%)
- Optic disc pallor — Frequent (79-30%)
- Color vision defect — Frequent (79-30%)
- Central scotoma — Frequent (79-30%)
- Retinal atrophy — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0010656/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [GUCY2D](https://sugi.bio/atlas/gene/GUCY2D/) |
| Protein change (HGVS p.) | p.Pro765fs |
| Coding change (HGVS c.) | c.2291dup |
| MANE Select transcript | [NM_000180](https://www.ncbi.nlm.nih.gov/nuccore/NM_000180) |
| dbSNP | [rs772242251](https://www.ncbi.nlm.nih.gov/snp/rs772242251/) |
| Variant type | Duplication |
| Location | chr17:8013901-8013902 (GRCh38) |
| ClinVar | [VCV2954361](https://www.ncbi.nlm.nih.gov/clinvar/variation/2954361/) |

**All HGVS expressions:** `NC_000017.10:g.7917225dup`, `NC_000017.11:g.8013907dup`, `NG_009092.1:g.16238dup`, `NM_000180.4:c.2291dup`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 0.345, GERP -0.452 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.911, pLI 1.1666e-16. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 12 of 20**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): global (via dbSNP) **0.000571%** — ultra-rare (gnomAD MAF 5.711e-06).

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**GUCY2D** population constraint: LOEUF 0.911, pLI 1.1666e-16, missense-Z 0.020837. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **GUCY2D-related dominant retinopathy** — Definitive (AD)
- **GUCY2D-related recessive retinopathy** — Definitive (AR)

## Protein context {#protein}

Residue **765** lies in the protein kinase domain.

AlphaFold model confidence (whole protein): pLDDT 82.37, 44% of residues very-high.

## What this gene does {#gene-function}

*Describes the biological roles of GUCY2D (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** GUCY2D's established molecular role includes guanylate cyclase activity. p.Pro765fs falls in the protein kinase domain.


### Pathways affected {#pathways}

GUCY2D participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Inactivation, recovery and regulation of the phototransduction cascade](https://reactome.org/content/detail/R-HSA-2514859) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** guanylate cyclase activity.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-12-01.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2023-12-01 |

## Associated conditions {#conditions}

[cone-rod dystrophy 6](https://sugi.bio/atlas/disease/cone-rod-dystrophy-6/), [Leber congenital amaurosis 1](https://sugi.bio/atlas/disease/leber-congenital-amaurosis-1/).

**Reported phenotype names (ClinVar):** Cone-rod dystrophy 6, Leber congenital amaurosis 1, RETINAL CONE DYSTROPHY 2, Cone dystrophy progressive, RETINAL BLINDNESS, CONGENITAL, Congenital absence of the rods and cones, Leber's congenital tapetoretinal degeneration, Leber's congenital tapetoretinal dysplasia, AMAUROSIS CONGENITA OF LEBER I.

## Similar variants {#similar}

Related GUCY2D variant pages (same residue, condition, or type): [GUCY2D p.Arg31fs](/variant/gucy2d-p-arg31fs), [GUCY2D p.Arg78_Ala81dup](/variant/gucy2d-p-arg78-ala81dup), [GUCY2D p.Ala117fs](/variant/gucy2d-p-ala117fs), [GUCY2D p.Ala162fs](/variant/gucy2d-p-ala162fs), [GUCY2D p.Ala49fs](/variant/gucy2d-p-ala49fs), [GUCY2D p.Ala609fs](/variant/gucy2d-p-ala609fs), [GUCY2D p.Gln191fs](/variant/gucy2d-p-gln191fs), [GUCY2D p.His314fs](/variant/gucy2d-p-his314fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 2954361). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*