PDE6A

Chr 5AR

phosphodiesterase 6A

Also known as: CGPR-A, PDEA, RP43

NCBI Gene: 5145ENSG00000132915UniProt: P16499

This gene encodes the cyclic-GMP (cGMP)-specific phosphodiesterase 6A alpha subunit, expressed in cells of the retinal rod outer segment. The phosphodiesterase 6 holoenzyme is a heterotrimer composed of an alpha, beta, and two gamma subunits. cGMP is an important regulator of rod cell membrane current, and its dynamic concentration is established by phosphodiesterase 6A cGMP hydrolysis and guanylate cyclase cGMP synthesis. The protein is a subunit of a key phototransduction enzyme and participates in processes of transmission and amplification of the visual signal. Mutations in this gene have been identified as one cause of autosomal recessive retinitis pigmentosa. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Retinitis pigmentosa 43MIM #613810
AR
585
ClinVar variants
78
Pathogenic / LP
0.00
pLI score
4
Active trials
Clinical Summary— PDE6A
🧬
Gene-Disease Validity (ClinGen)
PDE6A-related retinopathy · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
78 Pathogenic / Likely Pathogenic· 331 VUS of 585 total submissions
💊
Clinical Trials
4 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
1.12LOEUF
pLI 0.000
Z-score 0.87
OE 0.86 (0.67–1.12)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
-0.43Z-score
OE missense 1.05 (0.98–1.14)
504 obs / 477.8 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.86 (0.67–1.12)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.05 (0.98–1.14)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.01
0≤1.21.6
LoF obs/exp: 41 / 47.5Missense obs/exp: 504 / 477.8Syn Z: -0.10

ClinVar Variant Classifications

585 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic51
Likely Pathogenic27
VUS331
Likely Benign112
Benign19
Conflicting45
51
Pathogenic
27
Likely Pathogenic
331
VUS
112
Likely Benign
19
Benign
45
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
22
2
27
0
51
Likely Pathogenic
16
5
6
0
27
VUS
2
247
76
6
331
Likely Benign
0
1
56
55
112
Benign
0
0
13
6
19
Conflicting
—45
Total4025517867585

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

PDE6A · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

PDE6A-related retinitis pigmentosa

definitive
ARLoss Of FunctionAbsent Gene Product
Eye
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Retinitis pigmentosa 43

MIM #613810

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — PDE6A
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Central Visual Function and Genotype-Phenotype Correlations in PDE6A-Associated Retinitis Pigmentosa.
Kuehlewein L et al.·Invest Ophthalmol Vis Sci
2022
PDE6A-Associated Retinitis Pigmentosa, Clinical Characteristics, Genetics, and Natural History.
Hashem SA et al.·Ophthalmol Retina
2025
Clinical Phenotype and Course of PDE6A-Associated Retinitis Pigmentosa Disease, Characterized in Preparation for a Gene Supplementation Trial.
Kuehlewein L et al.·JAMA Ophthalmol
2020
Phenotypic and Genetic Spectrum in 309 Consecutive Pediatric Patients with Inherited Retinal Disease.
Priglinger CS et al.·Int J Mol Sci
2024Cohort
Novel variants in PDE6A and PDE6B genes and its phenotypes in patients with retinitis pigmentosa in Chinese families.
Li Y et al.·BMC Ophthalmol
2022Cohort
Monogenic Retinal Diseases Associated With Genes Encoding Phototransduction Proteins: A Review.
Wong WM et al.·Clin Exp Ophthalmol
2025Review
A hypoxia-glycolysis-lactate-related gene signature for prognosis prediction in hepatocellular carcinoma.
Qin X et al.·BMC Med Genomics
2024
A combination treatment based on drug repurposing demonstrates mutation-agnostic efficacy in pre-clinical retinopathy models.
Leinonen H et al.·Nat Commun
2024Functional
Longitudinal Clinical Follow-up and Genetic Spectrum of Patients With Rod-Cone Dystrophy Associated With Mutations in PDE6A and PDE6B.
Khateb S et al.·JAMA Ophthalmol
2019Cohort
A new PDE6A missense variant p.Arg544Gln in rod-cone dystrophy.
Hayashi T et al.·Doc Ophthalmol
2021Case report
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Retinitis Pigmentosa

Promising ROd-cone DYstrophy Gene therapY

RECRUITING
NCT05748873Phase PHASE1, PHASE2SparingVisionStarted 2023-04-12
SPVN06
Retinitis Pigmentosa

Natural History Study in Patients with PDE6A-, PDE6B- and RHO-linked Retinitis Pigmentosa

RECRUITING
NCT06323772University Hospital TuebingenStarted 2023-11-17
Retinitis Pigmentosa

Prospective Natural History Study of Retinitis Pigmentosa

ACTIVE NOT RECRUITING
NCT04285398Phase NASparingVisionStarted 2020-02-12
Ophthalmic examinationsMobility Test
Retinitis Pigmentosa

PDE6A Gene Therapy for Retinitis Pigmentosa

ACTIVE NOT RECRUITING
NCT04611503Phase PHASE1, PHASE2STZ eyetrialStarted 2019-09-24
subretinal injection of rAAV.hPDE6A

External Resources

Links to major genomics databases and tools