Is PDE2A p.Asp409Glu (c.1227C>G) pathogenic?

PDE2A p.Asp409Glu (c.1227C>G) is classified Uncertain significance in PDE2A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-18). AlphaMissense: likely pathogenic (0.9779); Very rare (popmax 8.47e-05%, nfe).

How common is PDE2A p.Asp409Glu (c.1227C>G) in the general population?

PDE2A p.Asp409Glu (c.1227C>G) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about PDE2A p.Asp409Glu (c.1227C>G)?

AlphaMissense predicts likely pathogenic (score 0.9779) — an in-silico prediction, not a clinical call.

PDE2A p.Asp409Glu

c.1227C>G · rs1249687173 · VCV2109711

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9779 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9779	likely pathogenic
REVEL	0.498	indeterminate
SaProt	LLR -8.33	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -10	GERP -3.5
Regional constraint	o/e 0.44	unconstrained · MANE · 770 bp · p 2.9e-06 · regional, not allelic
Overall
CADD	17.28	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 8.47e-05% European (non-Finnish) · 1/1,179,968 alleles

Overall 0.000186% 3/1,613,956 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,242
European (non-Finnish)grpmax	8.47e-05%	1,179,967

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Asp409Glu
Coding: c.1227C>G
MANE Select: NM_002599
dbSNP: rs1249687173
Type: single nucleotide variant
Location: chr11:72585430 (GRCh38)
Gene constraint: LOEUF 0.564 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 84.17 · 44 PDB
Residue 409: a UniProt-annotated variant site (in iddpads); the gaf 3 domain

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-asp409glu (accessed [today's date]).

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