Is PDE6C p.Ala592Asp (c.1775C>A) pathogenic?

PDE6C p.Ala592Asp (c.1775C>A) is classified Conflicting classifications of pathogenicity in PDE6C (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-09-04). AlphaMissense: likely pathogenic (0.9438); Absent from gnomAD v4.1; Associated with PDE6C-related disorder.

What condition is associated with PDE6C p.Ala592Asp (c.1775C>A)?

PDE6C p.Ala592Asp (c.1775C>A) is associated with PDE6C-related disorder (ClinVar).

How common is PDE6C p.Ala592Asp (c.1775C>A) in the general population?

PDE6C p.Ala592Asp (c.1775C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PDE6C p.Ala592Asp (c.1775C>A)?

AlphaMissense predicts likely pathogenic (score 0.9438) — an in-silico prediction, not a clinical call.

PDE6C p.Ala592Asp

c.1775C>A · VCV3613677

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9438 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

PDE6C-related disorder

Computational evidence

Protein change
AlphaMissense	0.9438	likely pathogenic
REVEL	0.834	moderately pathogenic-leaning
SaProt	LLR -9.74	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 5.9	GERP 2.2, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 53 kb · p 8.6e-05 · regional, not allelic
Overall
CADD	27.9	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PDE6C
Protein: p.Ala592Asp
Coding: c.1775C>A
MANE Select: NM_006204
Type: single nucleotide variant
Location: chr10:93640957 (GRCh38)
Gene constraint: LOEUF 0.976 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 88.53 · 7 PDB
Residue 592: a UniProt-annotated variant site (in achm5); the pdease domain; an α-helix

Full PDE6C gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

PDE6C-related disorder

Similar variants

PDE6C p.Ala592Gly Uncertain significance ★ ⚠ same residue
PDE6C c.1004+1G>A Pathogenic/Likely pathogenic ★★ same condition
PDE6C c.481-1G>A Likely pathogenic ★★ same condition
PDE6C c.939+2T>G Pathogenic/Likely pathogenic ★★ same condition
PDE6C c.939+5G>A Pathogenic/Likely pathogenic ★★ same condition
PDE6C p.Arg104Trp Pathogenic/Likely pathogenic ★★ same condition
PDE6C p.Arg238Ter Pathogenic/Likely pathogenic ★★ same condition
PDE6C p.Arg557Ter 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/pde6c-p-ala592asp (accessed [today's date]).

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