Is PDE2A p.Asp227Glu (c.681C>A) pathogenic?

PDE2A p.Asp227Glu (c.681C>A) is classified Uncertain significance in PDE2A (ClinVar, Single submitter, 1 submitter; last evaluated 2021-05-18). AlphaMissense: likely pathogenic (0.6666); Very rare (popmax 0.000261%, nfe).

How common is PDE2A p.Asp227Glu (c.681C>A) in the general population?

PDE2A p.Asp227Glu (c.681C>A) is very rare (popmax 0.000261%, nfe) (gnomAD).

What do computational predictors say about PDE2A p.Asp227Glu (c.681C>A)?

AlphaMissense predicts likely pathogenic (score 0.6666) — an in-silico prediction, not a clinical call.

PDE2A p.Asp227Glu

c.681C>A · rs1397646566 · VCV1428234

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6666 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000261%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6666	likely pathogenic
REVEL	0.221	benign-leaning
SaProt	LLR -2.77	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP 0.4, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 88 kb · p 0.0075 · regional, not allelic
Overall
CADD	19.83	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 0.000261% European (non-Finnish) · 3/1,149,812 alleles

Filtering AF 7e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000214% 3/1,400,390 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: PDE2A
Protein: p.Asp227Glu
Coding: c.681C>A
MANE Select: NM_002599
dbSNP: rs1397646566
Type: single nucleotide variant
Location: chr11:72590449 (GRCh38)
Gene constraint: LOEUF 0.564 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 84.17 · 44 PDB
Residue 227: the gaf 2 domain; an α-helix

Full PDE2A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PDE2A c.1922+4C>T Uncertain significance ★★ same type
PDE2A p.Ala157Val Uncertain significance ★★ ⚠ same type
PDE2A p.Ala205Val Uncertain significance ★★ ⚠ same type
PDE2A p.Ala349Thr Uncertain significance ★★ ⚠ same type
PDE2A p.Arg226Cys Uncertain significance ★★ ⚠ same type
PDE2A p.Arg790Gln Uncertain significance ★★ ⚠ same type
PDE2A p.Asp34Glu Uncertain significance ★★ ⚠ same type
PDE2A p.Asp59Asn 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/pde2a-p-asp227glu (accessed [today's date]).

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