Is PDE6A p.Pro538= (c.1614A>G) pathogenic?

PDE6A p.Pro538= (c.1614A>G) is classified Conflicting classifications of pathogenicity in PDE6A (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-01-18). Rare (popmax 0.377%, sas); Associated with retinitis pigmentosa.

What condition is associated with PDE6A p.Pro538= (c.1614A>G)?

PDE6A p.Pro538= (c.1614A>G) is associated with retinitis pigmentosa (ClinVar).

How common is PDE6A p.Pro538= (c.1614A>G) in the general population?

PDE6A p.Pro538= (c.1614A>G) is rare (popmax 0.377%, sas) (gnomAD).

How is Retinitis pigmentosa inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

PDE6A p.Pro538=

c.1614A>G · rs139697733 · VCV351988

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.377%, sas)

Conditions

retinitis pigmentosa

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -8.3
Overall
CADD	0.42	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.377% South Asian · 343/91,052 alleles

Filtering AF 0.344% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.331%

Overall 0.0598% 964/1,613,038 alleles · rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.392%	255
South Asiangrpmax	0.377%	265
Middle Eastern	0.367%	273
Remaining individualsnot grpmax-eligible	0.115%	867
Admixed American	0.0833%	1,200
European (non-Finnish)	0.0296%	3,378
East Asian	0.0178%	5,611
African / African-American	0.00533%	18,754

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: PDE6A
Protein: p.Pro538=
Coding: c.1614A>G
MANE Select: NM_000440
dbSNP: rs139697733
Type: single nucleotide variant
Location: chr5:149896362 (GRCh38)
Gene constraint: LOEUF 0.888 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.80
Residue 538: the pdease domain

Full PDE6A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

retinitis pigmentosa — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Retinitis pigmentosa (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Mitochondrial inheritance
Onset: Adolescent, Adult, Childhood
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

PDE6A c.1065+2T>A Pathogenic/Likely pathogenic ★★ same condition
PDE6A c.1620+1G>A Pathogenic ★★ same condition
PDE6A c.1926+1G>A Pathogenic ★★ same condition
PDE6A c.1927-1G>C Pathogenic/Likely pathogenic ★★ same condition
PDE6A c.627+2T>G Pathogenic ★★ same condition
PDE6A c.998+1G>A Pathogenic ★★ same condition
PDE6A p.Arg102Cys Pathogenic/Likely pathogenic ★★ same condition
PDE6A p.Arg257Ter Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/pde6a-p-pro538 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown