# NM_000283.4(PDE6B):c.222dup (p.Val75fs)

https://sugi.bio/variant/pde6b-p-val75fs

## Summary

**PDE6B p.Val75fs (c.222dup)** is classified **Pathogenic** in PDE6B (ClinVar, Single submitter, 2 submitters; last evaluated 2020-01-09). Very rare (popmax 0.0011%, sas); Associated with cone-rod dystrophy.

**At a glance:** Pathogenic · review: Single submitter · rsID rs1734066547 · 2 submitters · 2 linked conditions · very rare (popmax 0.0011%, sas)

## For patients & families {#patients}

This is a change in the PDE6B gene that is reported as disease-causing, but on limited review, submitted by 2 submitters, and is linked to cone-rod dystrophy.

*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) |
| Clinical trials | 11 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | PDE6B 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/0010790/index) · [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.Val75fs |
| Coding change (HGVS c.) | c.222dup |
| MANE Select transcript | [NM_000283](https://www.ncbi.nlm.nih.gov/nuccore/NM_000283) |
| dbSNP | [rs1734066547](https://www.ncbi.nlm.nih.gov/snp/rs1734066547/) |
| Variant type | Duplication |
| Location | chr4:625847-625848 (GRCh38) |
| ClinVar | [VCV813067](https://www.ncbi.nlm.nih.gov/clinvar/variation/813067/) |

**All HGVS expressions:** `NC_000004.11:g.619637dup`, `NC_000004.12:g.625848dup`, `NG_009839.1:g.5275dup`, `NM_000283.4:c.222dup`, `NM_001145291.2:c.222dup`

## 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 1.238, GERP -2.61, phastCons 0.246 — weakly conserved 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 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): grpmax **0.0011%** (sas) · FAF95 2.8e-05% · FAF99 1.1e-05% · 1/90,986 in the highest group · 3/1,460,146 alleles overall — very rare (popmax 0.0011%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.0011% | 90,986 |
| European (non-Finnish) | 0.00017% | 589,838 |

*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}

Residue **75** lies in the gaf 1 domain.

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 Single submitter *(criteria provided, single submitter)*, last evaluated 2020-01-09.

**Submitter consensus:** conflicting (1 Pathogenic, 1 Likely pathogenic).

**Submission history:** 2 submissions (2020); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Molecular Genetics Laboratory, Institute for Ophthalmic Research | Pathogenic | criteria provided, single submitter | research | 2020-01-09 |
| Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg | Likely pathogenic | no assertion criteria provided | clinical testing | 2020-01-01 |

## Associated conditions {#conditions}

[cone-rod dystrophy](https://sugi.bio/atlas/disease/cone-rod-dystrophy/), [inherited retinal dystrophy](https://sugi.bio/atlas/disease/inherited-retinal-dystrophy/).

**Reported phenotype names (ClinVar):** Cone-rod dystrophy, Retinal dystrophy, Cone-rod degeneration, Cone/cone-rod dystrophy, Inherited retinal dystrophy.

## Similar variants {#similar}

Related PDE6B variant pages (same residue, condition, or type): [PDE6B c.928-9_940dup](/variant/pde6b-c-928-minus-9-940dup), [PDE6B p.Lys674fs](/variant/pde6b-p-lys674fs), [PDE6B p.Val75Met](/variant/pde6b-p-val75met), [PDE6B c.1060-1G>T](/variant/pde6b-c-1060-minus-1g-t), [PDE6B c.1107+3A>G](/variant/pde6b-c-1107-plus-3a-g), [PDE6B c.1468-2A>G](/variant/pde6b-c-1468-minus-2a-g), [PDE6B c.1921-9C>G](/variant/pde6b-c-1921-minus-9c-g), [PDE6B p.Ala143fs](/variant/pde6b-p-ala143fs).

### 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 813067). 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.*