Is PDE8A p.Arg524Pro (c.1571G>C) pathogenic?

PDE8A p.Arg524Pro (c.1571G>C) is classified Uncertain significance in PDE8A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-22). AlphaMissense: likely pathogenic (0.8831); Absent from gnomAD v4.1.

How common is PDE8A p.Arg524Pro (c.1571G>C) in the general population?

PDE8A p.Arg524Pro (c.1571G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PDE8A p.Arg524Pro (c.1571G>C)?

AlphaMissense predicts likely pathogenic (score 0.8831) — an in-silico prediction, not a clinical call.

PDE8A p.Arg524Pro

c.1571G>C · VCV4133911

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8831 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8831	likely pathogenic
REVEL	0.74	pathogenic-leaning
SaProt	LLR -12.75	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.4	GERP -0.84, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 156 kb · p 0.32 · regional, not allelic
Overall
CADD	23.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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: PDE8A
Protein: p.Arg524Pro
Coding: c.1571G>C
MANE Select: NM_002605
Type: single nucleotide variant
Location: chr15:85117676 (GRCh38)
Gene constraint: LOEUF 0.631 · pLI 0.03 (gnomAD)
Structure: AlphaFold pLDDT 78.51 · 10 PDB
Residue 524: the pdease domain; an α-helix

Full PDE8A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PDE8A p.Arg524Cys Uncertain significance ★ ⚠ same residue
PDE8A p.Ala366Val Uncertain significance ★ ⚠ same type
PDE8A p.Ala41Ser Uncertain significance ★ ⚠ same type
PDE8A p.Ala4Val Uncertain significance ★ ⚠ same type
PDE8A p.Ala630Val Uncertain significance ★ ⚠ same type
PDE8A p.Ala633Val Uncertain significance ★ ⚠ same type
PDE8A p.Ala667Thr Uncertain significance ★ ⚠ same type
PDE8A p.Ala792Gly Uncertain significance ★ same type

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/pde8a-p-arg524pro (accessed [today's date]).

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