Is PDE6A p.Leu609Pro (c.1826T>C) pathogenic?

PDE6A p.Leu609Pro (c.1826T>C) is classified Uncertain significance in PDE6A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-07-19). AlphaMissense: likely pathogenic (0.999); Ultra-rare (popmax 0.0187%, sas); Associated with Inborn genetic diseases.

What condition is associated with PDE6A p.Leu609Pro (c.1826T>C)?

PDE6A p.Leu609Pro (c.1826T>C) is associated with Inborn genetic diseases (ClinVar).

How common is PDE6A p.Leu609Pro (c.1826T>C) in the general population?

PDE6A p.Leu609Pro (c.1826T>C) is ultra-rare (popmax 0.0187%, sas) (gnomAD).

What do computational predictors say about PDE6A p.Leu609Pro (c.1826T>C)?

AlphaMissense predicts likely pathogenic (score 0.999) — an in-silico prediction, not a clinical call.

PDE6A p.Leu609Pro

c.1826T>C · rs770246880 · VCV1972537

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.999 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0187%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.999	likely pathogenic · top 4% in PDE6A
REVEL	0.836	moderately pathogenic-leaning
SaProt	LLR -7.25	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 77 kb · p 0.94 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0187% South Asian · 17/91,016 alleles

Filtering AF 0.0118% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00976%

Overall 0.00123% 18/1,459,768 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0187%	5,354
European (non-Finnish)	8.49e-05%	1,178,114

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.Leu609Pro
Coding: c.1826T>C
MANE Select: NM_000440
dbSNP: rs770246880
Type: single nucleotide variant
Location: chr5:149886277 (GRCh38)
Gene constraint: LOEUF 0.888 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.80
Residue 609: the pdease domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PDE6A p.Ala766Gly Uncertain significance ★★ ⚠ same condition
PDE6A p.Arg236Leu Uncertain significance ★★ ⚠ same condition
PDE6A p.Arg237Cys Uncertain significance ★★ ⚠ same condition
PDE6A p.Arg237His Uncertain significance ★★ ⚠ same condition
PDE6A p.Arg257Gln Uncertain significance ★★ ⚠ same condition
PDE6A p.Arg267Cys Uncertain significance ★★ ⚠ same condition
PDE6A p.Arg306Gly Uncertain significance ★★ ⚠ same condition
PDE6A p.Arg554Cys Uncertain significance ★★ ⚠ 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-leu609pro (accessed [today's date]).

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