Is PDE8A p.Arg487Trp (c.1459C>T) pathogenic?

PDE8A p.Arg487Trp (c.1459C>T) is classified Uncertain significance in PDE8A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-04). AlphaMissense: likely benign (0.1132); Ultra-rare (popmax 0.0133%, amr).

How common is PDE8A p.Arg487Trp (c.1459C>T) in the general population?

PDE8A p.Arg487Trp (c.1459C>T) is ultra-rare (popmax 0.0133%, amr) (gnomAD).

What do computational predictors say about PDE8A p.Arg487Trp (c.1459C>T)?

AlphaMissense predicts likely benign (score 0.1132) — an in-silico prediction, not a clinical call.

PDE8A p.Arg487Trp

c.1459C>T · VCV4566328

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1132 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1132	likely benign
REVEL	0.451	indeterminate
SaProt	LLR -9.38	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.64 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1	GERP 0.027
Regional constraint	o/e 0.97	unconstrained · MANE · 156 kb · p 0.32 · regional, not allelic
Overall
CADD	26.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.0133% Admixed American · 8/60,002 alleles

Filtering AF 0.00661% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00482%

Overall 0.00167% 27/1,613,136 alleles · ultra-rare exomes 21/1,460,952 · genomes 6/152,184 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0133%	7,500
East Asian	0.00445%	22,447
African / African-American	0.004%	24,971
South Asian	0.0022%	45,533
Remaining individualsnot grpmax-eligible	0.0016%	62,470
European (non-Finnish)	0.000933%	107,198

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: PDE8A
Protein: p.Arg487Trp
Coding: c.1459C>T
MANE Select: NM_002605
Type: single nucleotide variant
Location: chr15:85116043 (GRCh38)
Gene constraint: LOEUF 0.631 · pLI 0.03 (gnomAD)
Structure: AlphaFold pLDDT 78.51 · 10 PDB
Residue 487: the pdease domain; an α-helix

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

Similar variants

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
PDE8A p.Arg163Cys 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-arg487trp (accessed [today's date]).

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