# NM_000283.4(PDE6B):c.1635C>T (p.Phe545=)

https://sugi.bio/variant/pde6b-p-phe545

## Summary

**PDE6B p.Phe545= (c.1635C>T)** is classified **Conflicting classifications of pathogenicity** in PDE6B (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-01-26). Low-frequency (popmax 1.46%, afr); Associated with retinitis pigmentosa.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs141813304 · 3 submitters · 2 linked conditions · low-frequency (popmax 1.46%, afr)

## For patients & families {#patients}

This is a change in the PDE6B gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 3 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 | PDE6B 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 | [PDE6B](https://sugi.bio/atlas/gene/PDE6B/) |
| Protein change (HGVS p.) | p.Phe545= |
| Coding change (HGVS c.) | c.1635C>T |
| MANE Select transcript | [NM_000283](https://www.ncbi.nlm.nih.gov/nuccore/NM_000283) |
| dbSNP | [rs141813304](https://www.ncbi.nlm.nih.gov/snp/rs141813304/) |
| Variant type | single nucleotide variant |
| Location | chr4:662154-662154 (GRCh38) |
| ClinVar | [VCV349382](https://www.ncbi.nlm.nih.gov/clinvar/variation/349382/) |

**All HGVS expressions:** `NC_000004.11:g.655943C>T`, `NC_000004.12:g.662154C>T`, `NG_009839.1:g.41581C>T`, `NM_000283.4:c.1635C>T`, `NM_001145291.2:c.1635C>T`, `NM_001145292.2:c.798C>T`, `NM_001350154.3:c.798C>T`, `NM_001350155.3:c.480C>T`, `NM_001379246.1:c.798C>T`, `NM_001379247.1:c.798C>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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor gain** (Δ 0.25) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 0.679, GERP 0.167, phastCons 0.999 — weakly conserved position
- CADD: **PHRED 16.99**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.25**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.25**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **1.46%** (afr) · FAF95 1.38% · FAF99 1.35% · 1,077/74,014 in the highest group · 1,268/1,569,064 alleles overall — low-frequency (popmax 1.46%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 1.46% | 69 |
| Remaining individuals (not grpmax-eligible) | 0.139% | 717 |
| Middle Eastern | 0.133% | 752 |
| Admixed American | 0.115% | 867 |
| South Asian | 0.0151% | 6,608 |
| European (non-Finnish) | 0.00199% | 50,234 |

*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 **545** lies in the pdease 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-01-26.

**Submitter consensus:** conflicting (2 Benign, 1 Likely benign, 1 Uncertain significance).

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-26 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-09-09 |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-13 |

## Associated conditions {#conditions}

[retinitis pigmentosa](https://sugi.bio/atlas/disease/retinitis-pigmentosa/), [congenital stationary night blindness autosomal dominant 2](https://sugi.bio/atlas/disease/congenital-stationary-night-blindness-autosomal-dominant-2/).

**Reported phenotype names (ClinVar):** Retinitis pigmentosa, Congenital stationary night blindness autosomal dominant 2, not provided, not specified, AllHighlyPenetrant, none provided, NIGHT BLINDNESS, CONGENITAL STATIONARY, RAMBUSCH TYPE.

## Similar variants {#similar}

Related PDE6B variant pages (same residue, condition, or type): [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.1832+1G>T](/variant/pde6b-c-1832-plus-1g-t), [PDE6B c.1921-9C>G](/variant/pde6b-c-1921-minus-9c-g), [PDE6B c.2021+2T>G](/variant/pde6b-c-2021-plus-2t-g), [PDE6B c.2193+1G>A](/variant/pde6b-c-2193-plus-1g-a), [PDE6B p.Arg560Cys](/variant/pde6b-p-arg560cys), [PDE6B p.Asp600Asn](/variant/pde6b-p-asp600asn).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 349382). 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.*