# NM_000440.3(PDE6A):c.1097del (p.Asp366fs)

https://sugi.bio/variant/pde6a-p-asp366fs

## Summary

**PDE6A p.Asp366fs (c.1097del)** is classified **Likely pathogenic** in PDE6A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-04-08). Very rare (popmax 8.48e-05%, nfe); Associated with retinitis pigmentosa 43.

**At a glance:** Likely pathogenic · review: Multiple submitters · rsID rs1581186849 · 2 submitters · 1 linked condition · very rare (popmax 8.48e-05%, nfe)

## For patients & families {#patients}

This is a change in the PDE6A gene that is considered likely disease-causing, submitted by 2 submitters, and is linked to retinitis pigmentosa 43.

*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, Mitochondrial inheritance |
| Age of onset (of this condition) | Adolescent, Adult, Childhood |
| Prevalence | 1-5 / 10 000 (Europe) |
| Diagnostic panels | PDE6A is a diagnostic-grade gene on 1 Genomics England panel |

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

- Conductive hearing impairment — Very frequent (99-80%)
- Sensorineural hearing impairment — Very frequent (99-80%)
- Visual impairment — Very frequent (99-80%)
- Abnormal electroretinogram — Very frequent (99-80%)
- Retinal degeneration — Very frequent (99-80%)
- Photophobia — Very frequent (99-80%)
- Blindness — Very frequent (99-80%)
- Nystagmus — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015716/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PDE6A](https://sugi.bio/atlas/gene/PDE6A/) |
| Protein change (HGVS p.) | p.Asp366fs |
| Coding change (HGVS c.) | c.1097del |
| MANE Select transcript | [NM_000440](https://www.ncbi.nlm.nih.gov/nuccore/NM_000440) |
| dbSNP | [rs1581186849](https://www.ncbi.nlm.nih.gov/snp/rs1581186849/) |
| Variant type | Deletion |
| Location | chr5:149903664-149903664 (GRCh38) |
| ClinVar | [VCV817435](https://www.ncbi.nlm.nih.gov/clinvar/variation/817435/) |

**All HGVS expressions:** `NC_000005.10:g.149903664del`, `NC_000005.9:g.149283227del`, `NG_009102.1:g.46130del`, `NM_000440.2:c.1097del`, `NM_000440.3:c.1097del`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 3.321, GERP -0.313, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.888, pLI 5.867e-17. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 8 of 22**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion 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): grpmax **8.48e-05%** (nfe) · 1/1,179,618 in the highest group · 1/1,461,416 alleles overall — very rare (popmax 8.48e-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}

**PDE6A** population constraint: LOEUF 0.888, pLI 5.867e-17, missense-Z 0.89523. *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):

- **PDE6A-related retinopathy** — Definitive (AR)

## Protein context {#protein}

Residue **366** lies in the gaf 2 domain.

AlphaFold model confidence (whole protein): pLDDT 89.80, 69% of residues very-high.

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

*Describes the biological roles of PDE6A (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.*


### Pathways affected {#pathways}

PDE6A participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Inactivation, recovery and regulation of the phototransduction cascade](https://reactome.org/content/detail/R-HSA-2514859) | curated |
| [Activation of the phototransduction cascade](https://reactome.org/content/detail/R-HSA-2485179) | electronic |
| [Ca2+ pathway](https://reactome.org/content/detail/R-HSA-4086398) | electronic |

## Clinical significance {#significance}

**Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2021-04-08.

**Submitter consensus:** unanimous (2/2 Likely pathogenic).

**Submission history:** 2 submissions (2019–2021); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Likely pathogenic | criteria provided, single submitter | clinical testing | 2019-02-05 |
| Ocular Genomics Institute, Massachusetts Eye and Ear | Likely pathogenic | criteria provided, single submitter | research | 2021-04-08 |

## Associated conditions {#conditions}

[retinitis pigmentosa 43](https://sugi.bio/atlas/disease/retinitis-pigmentosa-43/).

**Reported phenotype names (ClinVar):** Retinitis pigmentosa 43, not provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM, none provided.

## Similar variants {#similar}

Related PDE6A variant pages (same residue, condition, or type): [PDE6A p.Asp778fs](/variant/pde6a-p-asp778fs), [PDE6A p.Gly844fs](/variant/pde6a-p-gly844fs), [PDE6A p.Gly850fs](/variant/pde6a-p-gly850fs), [PDE6A p.Gln699fs](/variant/pde6a-p-gln699fs), [PDE6A p.Ile453fs](/variant/pde6a-p-ile453fs), [PDE6A p.Pro512fs](/variant/pde6a-p-pro512fs), [PDE6A p.Asp366Gly](/variant/pde6a-p-asp366gly), [PDE6A p.Tyr583_Phe584del](/variant/pde6a-p-tyr583-phe584del).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2026-07-14); 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 817435). 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.*