# NM_000283.4(PDE6B):c.121_125del (p.Pro41fs)

https://sugi.bio/variant/pde6b-p-pro41fs

## Summary

**PDE6B p.Pro41fs (c.121_125del)** is classified **Pathogenic** in PDE6B (ClinVar, No assertion criteria, 1 submitter; last evaluated 2014-03-13). No gnomAD frequency available for this variant; Associated with Autosomal recessive retinitis pigmentosa.

**At a glance:** Pathogenic · review: No assertion criteria · rsID rs1734056711 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the PDE6B gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to Autosomal recessive 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.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PDE6B](https://sugi.bio/atlas/gene/PDE6B/) |
| Protein change (HGVS p.) | p.Pro41fs |
| Coding change (HGVS c.) | c.121_125del |
| MANE Select transcript | [NM_000283](https://www.ncbi.nlm.nih.gov/nuccore/NM_000283) |
| dbSNP | [rs1734056711](https://www.ncbi.nlm.nih.gov/snp/rs1734056711/) |
| Variant type | Deletion |
| Location | chr4:625746-625750 (GRCh38) |
| ClinVar | [VCV978977](https://www.ncbi.nlm.nih.gov/clinvar/variation/978977/) |

**All HGVS expressions:** `NC_000004.11:g.619536_619540del`, `NC_000004.12:g.625747_625751del`, `NG_009839.1:g.5174_5178del`, `NM_000283.4:c.121_125del`, `NM_001145291.2:c.121_125del`

## 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 -2.805, GERP -3.73 — fast-evolving / accelerated position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.238, pLI 7.3529e-27. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 1 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: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**PDE6B** population constraint: LOEUF 1.238, pLI 7.3529e-27, missense-Z -0.08566. *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):

- **inherited retinal dystrophy** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 89.72, 73% of residues very-high.

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

*Describes the biological roles of PDE6B (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}

PDE6B 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}

**Pathogenic** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2014-03-13.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Faculty of Health Sciences, Beirut Arab University | Pathogenic | no assertion criteria provided | literature only | 2014-03-13 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Autosomal recessive retinitis pigmentosa.

## Similar variants {#similar}

Related PDE6B variant pages (same residue, condition, or type): [PDE6B p.Pro41Arg](/variant/pde6b-p-pro41arg), [PDE6B p.Pro41=](/variant/pde6b-p-pro41), [PDE6B p.Pro41Leu](/variant/pde6b-p-pro41leu), [PDE6B c.2353-18_2354del](/variant/pde6b-c-2353-minus-18-2354del), [PDE6B p.Ala143fs](/variant/pde6b-p-ala143fs), [PDE6B p.Arg82fs](/variant/pde6b-p-arg82fs), [PDE6B p.Asn643fs](/variant/pde6b-p-asn643fs), [PDE6B p.Asp252fs](/variant/pde6b-p-asp252fs).

### 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 978977). 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.*