Is PDE2A p.Asp59Asn (c.175G>A) pathogenic?

PDE2A p.Asp59Asn (c.175G>A) is classified Uncertain significance in PDE2A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-08). AlphaMissense: likely benign (0.1272); Very rare (popmax 0.00967%, nfe); Associated with Inborn genetic diseases.

What condition is associated with PDE2A p.Asp59Asn (c.175G>A)?

PDE2A p.Asp59Asn (c.175G>A) is associated with Inborn genetic diseases (ClinVar).

How common is PDE2A p.Asp59Asn (c.175G>A) in the general population?

PDE2A p.Asp59Asn (c.175G>A) is very rare (popmax 0.00967%, nfe) (gnomAD).

What do computational predictors say about PDE2A p.Asp59Asn (c.175G>A)?

AlphaMissense predicts likely benign (score 0.1272) — an in-silico prediction, not a clinical call.

PDE2A p.Asp59Asn

c.175G>A · rs376352935 · VCV2885554

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1272 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00967%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1272	likely benign
REVEL	0.143	moderately benign-leaning
SaProt	LLR -7.61	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2	GERP 0.76, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 88 kb · p 0.0075 · regional, not allelic
Overall
CADD	21.9	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 0.00967% European (non-Finnish) · 112/1,157,908 alleles

Filtering AF 0.00819% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00766%

Overall 0.00738% 116/1,572,050 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00967%	10,338
South Asian	0.00234%	42,745
Remaining individualsnot grpmax-eligible	0.00164%	61,106
African / African-American	0.00134%	74,582

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.Asp59Asn
Coding: c.175G>A
MANE Select: NM_002599
dbSNP: rs376352935
Type: single nucleotide variant
Location: chr11:72608721 (GRCh38)
Gene constraint: LOEUF 0.564 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 84.17 · 44 PDB
Residue 59: the gaf 1 domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PDE2A p.Ala157Val Uncertain significance ★★ ⚠ same condition
PDE2A p.Ala205Val Uncertain significance ★★ ⚠ same condition
PDE2A p.Ala349Thr Uncertain significance ★★ ⚠ same condition
PDE2A p.Arg790Gln Uncertain significance ★★ ⚠ same condition
PDE2A p.Asp34Glu Uncertain significance ★★ ⚠ same condition
PDE2A p.Cys263Gly Uncertain significance ★★ ⚠ same condition
PDE2A p.Gln41Glu Uncertain significance ★★ ⚠ same condition
PDE2A p.Glu211Gly Uncertain significance ★★ ⚠ same condition

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-asp59asn (accessed [today's date]).

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