Is PDE4B p.Asp528Asn (c.1582G>A) pathogenic?

PDE4B p.Asp528Asn (c.1582G>A) is classified Uncertain significance in PDE4B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-27). AlphaMissense: ambiguous (0.3682); Very rare (popmax 0.00161%, nfe).

How common is PDE4B p.Asp528Asn (c.1582G>A) in the general population?

PDE4B p.Asp528Asn (c.1582G>A) is very rare (popmax 0.00161%, nfe) (gnomAD).

What do computational predictors say about PDE4B p.Asp528Asn (c.1582G>A)?

AlphaMissense predicts ambiguous (score 0.3682) — an in-silico prediction, not a clinical call.

PDE4B p.Asp528Asn

c.1582G>A · VCV4133819

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3682 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00161%, nfe)

Computational evidence

Protein change
AlphaMissense	0.3682	ambiguous
REVEL	0.306	indeterminate
SaProt	LLR -13.63	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 6.8, phastCons 1
Regional constraint	o/e 0.55	unconstrained · MANE · 40 kb · p 9.4e-25 · regional, not allelic
Overall
CADD	26.2	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 0.00161% European (non-Finnish) · 19/1,179,828 alleles

Filtering AF 0.00103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00083%

Overall 0.00118% 19/1,613,734 alleles · very rare

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: PDE4B
Protein: p.Asp528Asn
Coding: c.1582G>A
MANE Select: NM_002600
Type: single nucleotide variant
Location: chr1:66367985 (GRCh38)
Gene constraint: LOEUF 0.374 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 71.22 · 43 PDB
Residue 528: the pdease domain; an α-helix

Full PDE4B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PDE4B p.Arg596= Benign ★★ same type
PDE4B p.Leu642= Benign ★★ same type
PDE4B p.Ser703Cys Benign ★★ ⚠ same type
PDE4B p.Ala148Val Uncertain significance ★ ⚠ same type
PDE4B p.Arg130Cys Uncertain significance ★ ⚠ same type
PDE4B p.Arg503Cys Uncertain significance ★ ⚠ same type
PDE4B p.Arg552His Uncertain significance ★ ⚠ same type
PDE4B p.Arg576Pro 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/pde4b-p-asp528asn (accessed [today's date]).

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