# NM_000180.4(GUCY2D):c.459C>T (p.Pro153=)

https://sugi.bio/variant/gucy2d-p-pro153

## Summary

**GUCY2D p.Pro153= (c.459C>T)** is classified **Conflicting classifications of pathogenicity** in GUCY2D (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-11-15). Very rare (popmax 8.73e-05%, nfe); Associated with Leber congenital amaurosis 1.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs2151799423 · 2 submitters · 2 linked conditions · very rare (popmax 8.73e-05%, nfe)

## For patients & families {#patients}

This is a change in the GUCY2D gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 2 submitters, and is linked to Leber congenital amaurosis 1.

*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 |
| Age of onset (of this condition) | Infancy, Neonatal |
| Prevalence | 1-9 / 100 000 (Europe) |
| Clinical trials | 3 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | GUCY2D is a diagnostic-grade gene on 1 Genomics England panel |

**Commonly reported features of Leber congenital amaurosis** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Severely reduced visual acuity — Very frequent (99-80%)
- Abnormality of retinal pigmentation — Very frequent (99-80%)
- Abnormality of the optic disc — Very frequent (99-80%)
- Abnormal electroretinogram — Frequent (79-30%)
- Cataract — Frequent (79-30%)
- Hypermetropia — Frequent (79-30%)
- Keratoconus — Frequent (79-30%)
- Photophobia — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0000635/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.Pro153= |
| Coding change (HGVS c.) | c.459C>T |
| MANE Select transcript | [NM_000180](https://www.ncbi.nlm.nih.gov/nuccore/NM_000180) |
| dbSNP | [rs2151799423](https://www.ncbi.nlm.nih.gov/snp/rs2151799423/) |
| Variant type | single nucleotide variant |
| Location | chr17:8003506-8003506 (GRCh38) |
| ClinVar | [VCV1154957](https://www.ncbi.nlm.nih.gov/clinvar/variation/1154957/) |

**All HGVS expressions:** `NC_000017.10:g.7906824C>T`, `NC_000017.11:g.8003506C>T`, `NG_009092.1:g.5837C>T`, `NM_000180.4:c.459C>T`

## 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 -8.632, GERP -2.13 — fast-evolving / accelerated position
- CADD: **PHRED 1.29**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for GUCY2D (1,042 scored positions, the nearest 163 bases away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **8.73e-05%** (nfe) · 1/1,145,990 in the highest group · 1/1,532,652 alleles overall — very rare (popmax 8.73e-05%, nfe).

*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}


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.


### 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2023-11-15.

**Submitter consensus:** conflicting (1 Likely benign, 1 Uncertain significance).

**Submission history:** 2 submissions (2017–2023); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2023-11-15 |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2017-09-21 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Leber congenital amaurosis 1, Cone-rod dystrophy 6, not provided, 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, RETINAL CONE DYSTROPHY 2, Cone dystrophy progressive.

## Similar variants {#similar}

Related GUCY2D variant pages (same residue, condition, or type): [GUCY2D p.Pro153Ser](/variant/gucy2d-p-pro153ser), [GUCY2D p.Pro153Thr](/variant/gucy2d-p-pro153thr), [GUCY2D c.1956+1G>A](/variant/gucy2d-c-1956-plus-1g-a), [GUCY2D c.3224+1G>C](/variant/gucy2d-c-3224-plus-1g-c), [GUCY2D c.3224+3G>T](/variant/gucy2d-c-3224-plus-3g-t), [GUCY2D p.Ala946Thr](/variant/gucy2d-p-ala946thr), [GUCY2D p.Arg1091Ter](/variant/gucy2d-p-arg1091ter), [GUCY2D p.Arg313Cys](/variant/gucy2d-p-arg313cys).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 1154957). 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.*