# NM_000440.3(PDE6A):c.879G>A (p.Pro293=)

https://sugi.bio/variant/pde6a-p-pro293

## Summary

**PDE6A p.Pro293= (c.879G>A)** is classified **Conflicting classifications of pathogenicity** in PDE6A (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-09). Ultra-rare (popmax 0.0174%, afr); Associated with retinitis pigmentosa.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs137853899 · 4 submitters · 1 linked condition · ultra-rare (popmax 0.0174%, afr)

## For patients & families {#patients}

This is a change in the PDE6A gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 4 submitters, and is linked to retinitis pigmentosa.

*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) |
| Clinical trials | 238 registered for this condition — see ClinicalTrials.gov |
| 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/0005694/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.Pro293= |
| Coding change (HGVS c.) | c.879G>A |
| MANE Select transcript | [NM_000440](https://www.ncbi.nlm.nih.gov/nuccore/NM_000440) |
| dbSNP | [rs137853899](https://www.ncbi.nlm.nih.gov/snp/rs137853899/) |
| Variant type | single nucleotide variant |
| Location | chr5:149921689-149921689 (GRCh38) |
| ClinVar | [VCV100557](https://www.ncbi.nlm.nih.gov/clinvar/variation/100557/) |

**All HGVS expressions:** `NC_000005.10:g.149921689C>T`, `NC_000005.9:g.149301252C>T`, `NG_009102.1:g.28105G>A`, `NM_000440.3:c.879G>A`

## 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 -0.113, GERP -2.24, phastCons 0.764 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 8.724**. 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: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0174%** (afr) · FAF95 0.0103% · FAF99 0.00813% · 13/74,836 in the highest group · 247/1,613,486 alleles overall — ultra-rare (popmax 0.0174%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Ashkenazi Jewish (not grpmax-eligible) | 0.48% | 208 |
| Remaining individuals (not grpmax-eligible) | 0.0448% | 2,231 |
| African / African-American (grpmax) | 0.0174% | 5,757 |
| European (non-Finnish) | 0.005% | 19,994 |
| Admixed American | 0.005% | 19,995 |
| East Asian | 0.00223% | 44,884 |
| South Asian | 0.0011% | 91,056 |

Ashkenazi Jewish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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 **293** lies in a UniProt-annotated variant site (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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-01-09.

**Submitter consensus:** conflicting (1 Uncertain significance, 1 not provided, 1 Benign, 1 Likely benign).

**Submission history:** 4 submissions (2018–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-13 |
| NEI Ophthalmic Genomics Laboratory, National Institutes of Health | not provided | no classification provided | not provided |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-09 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2023-08-31 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Retinitis pigmentosa, not provided, not specified, none provided, AllHighlyPenetrant.

## Similar variants {#similar}

Related PDE6A variant pages (same residue, condition, or type): [PDE6A p.Pro293Leu](/variant/pde6a-p-pro293leu), [PDE6A c.1065+2T>A](/variant/pde6a-c-1065-plus-2t-a), [PDE6A c.1620+1G>A](/variant/pde6a-c-1620-plus-1g-a), [PDE6A c.1926+1G>A](/variant/pde6a-c-1926-plus-1g-a), [PDE6A c.1927-1G>C](/variant/pde6a-c-1927-minus-1g-c), [PDE6A c.627+2T>G](/variant/pde6a-c-627-plus-2t-g), [PDE6A c.998+1G>A](/variant/pde6a-c-998-plus-1g-a), [PDE6A p.Arg102Cys](/variant/pde6a-p-arg102cys).

### 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 100557). 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.*