Is PDE2A p.Tyr680Asp (c.2038T>G) pathogenic?

PDE2A p.Tyr680Asp (c.2038T>G) is classified Uncertain significance in PDE2A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-12-05). AlphaMissense: ambiguous (0.4778); Ultra-rare (popmax 0.015%, amr); Associated with Inborn genetic diseases.

What condition is associated with PDE2A p.Tyr680Asp (c.2038T>G)?

PDE2A p.Tyr680Asp (c.2038T>G) is associated with Inborn genetic diseases (ClinVar).

How common is PDE2A p.Tyr680Asp (c.2038T>G) in the general population?

PDE2A p.Tyr680Asp (c.2038T>G) is ultra-rare (popmax 0.015%, amr) (gnomAD).

What do computational predictors say about PDE2A p.Tyr680Asp (c.2038T>G)?

AlphaMissense predicts ambiguous (score 0.4778) — an in-silico prediction, not a clinical call.

PDE2A p.Tyr680Asp

c.2038T>G · rs770031228 · VCV1917367

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4778 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.015%, amr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4778	ambiguous
REVEL	0.874	moderately pathogenic-leaning
SaProt	LLR -7.88	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.6, phastCons 1
Regional constraint	o/e 0.47	unconstrained · MANE · 5,892 bp · p 1.6e-30 · regional, not allelic
Overall
CADD	29.1	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 0.015% Admixed American · 9/59,968 alleles

Filtering AF 0.00774% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00579%

Overall 0.00062% 10/1,612,910 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.015%	6,663
Remaining individualsnot grpmax-eligible	0.0016%	62,432

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.Tyr680Asp
Coding: c.2038T>G
MANE Select: NM_002599
dbSNP: rs770031228
Type: single nucleotide variant
Location: chr11:72581364 (GRCh38)
Gene constraint: LOEUF 0.564 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 84.17 · 44 PDB
Residue 680: a UniProt-annotated variant site (in iddpads); the pdease 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.Asp59Asn Uncertain significance ★★ ⚠ same condition
PDE2A p.Cys263Gly Uncertain significance ★★ ⚠ same condition
PDE2A p.Gln41Glu 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-tyr680asp (accessed [today's date]).

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