# NM_006204.4(PDE6C):c.306G>A (p.Arg102=)

https://sugi.bio/variant/pde6c-p-arg102

## Summary

**PDE6C p.Arg102= (c.306G>A)** is classified **Conflicting classifications of pathogenicity** in PDE6C (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-07-03). Ultra-rare (popmax 0.0178%, eas); Associated with achromatopsia.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs545034158 · 3 submitters · 2 linked conditions · ultra-rare (popmax 0.0178%, eas)

## For patients & families {#patients}

This is a change in the PDE6C gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 3 submitters, and is linked to achromatopsia.

*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 recessive |
| Age of onset (of this condition) | Infancy, Neonatal |
| Prevalence | 1-9 / 100 000 (Worldwide) |
| Clinical trials | 12 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | PDE6C is a diagnostic-grade gene on 1 Genomics England panel |

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

- Abnormality of refraction — Very frequent (99-80%)
- Color vision defect — Very frequent (99-80%)
- Photophobia — Very frequent (99-80%)
- Monochromacy — Very frequent (99-80%)
- Pendular nystagmus — Very frequent (99-80%)
- Undetectable light-adapted electroretinogram — Very frequent (99-80%)
- Color vision test abnormality — Very frequent (99-80%)
- Inner retinal layer loss on macular OCT — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015015/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PDE6C](https://sugi.bio/atlas/gene/PDE6C/) |
| Protein change (HGVS p.) | p.Arg102= |
| Coding change (HGVS c.) | c.306G>A |
| MANE Select transcript | [NM_006204](https://www.ncbi.nlm.nih.gov/nuccore/NM_006204) |
| dbSNP | [rs545034158](https://www.ncbi.nlm.nih.gov/snp/rs545034158/) |
| Variant type | single nucleotide variant |
| Location | chr10:93613031-93613031 (GRCh38) |
| ClinVar | [VCV878956](https://www.ncbi.nlm.nih.gov/clinvar/variation/878956/) |

**All HGVS expressions:** `NC_000010.10:g.95372788G>A`, `NC_000010.11:g.93613031G>A`, `NG_016752.1:g.5444G>A`, `NM_006204.4:c.306G>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 -0.323, GERP -1.83, phastCons 0.009 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 5.095**. 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 **0.0178%** (eas) · FAF95 0.00884% · FAF99 0.00641% · 8/44,870 in the highest group · 11/1,614,166 alleles overall — ultra-rare (popmax 0.0178%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.0178% | 5,609 |
| Remaining individuals (not grpmax-eligible) | 0.0048% | 20,837 |

*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}

**PDE6C** population constraint: LOEUF 0.976, pLI 3.3177e-14, missense-Z 1.3389; ClinGen dosage — haploinsufficiency 30, triplosensitivity 0 (0–3 scale). *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):

- **PDE6C-related retinopathy** — Definitive (AR)

## Protein context {#protein}

Residue **102** lies in the gaf 1 domain; a β-strand.

AlphaFold model confidence (whole protein): pLDDT 88.53, 63% of residues very-high.

**7 experimental structure(s)** (PDB): [3JWQ](https://www.rcsb.org/structure/3JWQ), [3JWR](https://www.rcsb.org/structure/3JWR), [5E8F](https://www.rcsb.org/structure/5E8F), [9CXG](https://www.rcsb.org/structure/9CXG), [9CXH](https://www.rcsb.org/structure/9CXH), [9CXI](https://www.rcsb.org/structure/9CXI).

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-07-03.

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

**Submission history:** 4 submissions (2017–2025); 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 | 2017-04-27 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-07-03 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2025-02-01 |

## Associated conditions {#conditions}

[achromatopsia](https://sugi.bio/atlas/disease/achromatopsia/), [cone dystrophy 4](https://sugi.bio/atlas/disease/cone-dystrophy-4/).

**Reported phenotype names (ClinVar):** Achromatopsia, Cone dystrophy 4, not provided, none provided, Rod monochromatism.

## Same-residue context {#hotspot}

Residue **102** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [PDE6C p.Arg102Gln](/variant/pde6c-p-arg102gln). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related PDE6C variant pages (same residue, condition, or type): [PDE6C p.Arg102Trp](/variant/pde6c-p-arg102trp), [PDE6C p.Arg102Gln](/variant/pde6c-p-arg102gln), [PDE6C p.Arg102Gly](/variant/pde6c-p-arg102gly), [PDE6C c.1004+1G>A](/variant/pde6c-c-1004-plus-1g-a), [PDE6C c.1269+1G>A](/variant/pde6c-c-1269-plus-1g-a), [PDE6C c.2283+1G>T](/variant/pde6c-c-2283-plus-1g-t), [PDE6C c.939+5G>A](/variant/pde6c-c-939-plus-5g-a), [PDE6C p.Arg238Ter](/variant/pde6c-p-arg238ter).

### 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 878956). 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.*