Is PDE2A p.Phe642Leu (c.1926C>A) pathogenic?

PDE2A p.Phe642Leu (c.1926C>A) is classified Uncertain significance in PDE2A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-22). AlphaMissense: likely pathogenic (0.9986); Very rare (popmax 0.00114%, sas); Associated with intellectual developmental disorder with paroxysmal dyskinesia or seizures.

What condition is associated with PDE2A p.Phe642Leu (c.1926C>A)?

PDE2A p.Phe642Leu (c.1926C>A) is associated with intellectual developmental disorder with paroxysmal dyskinesia or seizures (ClinVar).

How common is PDE2A p.Phe642Leu (c.1926C>A) in the general population?

PDE2A p.Phe642Leu (c.1926C>A) is very rare (popmax 0.00114%, sas) (gnomAD).

What do computational predictors say about PDE2A p.Phe642Leu (c.1926C>A)?

AlphaMissense predicts likely pathogenic (score 0.9986) — an in-silico prediction, not a clinical call.

PDE2A p.Phe642Leu

c.1926C>A · VCV3362652

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9986 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00114%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intellectual developmental disorder with paroxysmal dyskinesia or seizures

Computational evidence

Protein change
AlphaMissense	0.9986	likely pathogenic · top 9% in PDE2A
REVEL	0.778	moderately pathogenic-leaning
SaProt	LLR -9.15	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.47	unconstrained · MANE · 5,892 bp · p 1.6e-30 · regional, not allelic
Overall
CADD	26.8	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 0.00114% South Asian · 1/87,394 alleles

Overall 6.94e-05% 1/1,440,736 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.Phe642Leu
Coding: c.1926C>A
MANE Select: NM_002599
Type: single nucleotide variant
Location: chr11:72581476 (GRCh38)
Gene constraint: LOEUF 0.564 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 84.17 · 44 PDB
Residue 642: a UniProt-annotated variant site (in iddpads); the pdease domain; an α-helix

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

Disease context

intellectual developmental disorder with paroxysmal dyskinesia or seizures — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PDE2A p.Ala205Val Uncertain significance ★★ ⚠ same condition
PDE2A p.Arg790Gln Uncertain significance ★★ ⚠ same condition
PDE2A p.Met617Val Uncertain significance ★★ ⚠ same condition
PDE2A p.Val81Ile Uncertain significance ★★ ⚠ same condition
PDE2A c.2134-2A>G Likely pathogenic ★ same condition
PDE2A p.Gln394Ter Pathogenic ★ same condition
PDE2A c.144+11147C>T Uncertain significance ★ same condition
PDE2A c.2469+90G>A 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-phe642leu (accessed [today's date]).

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