Is PDE2A p.Cys43Phe (c.128G>T) pathogenic?

PDE2A p.Cys43Phe (c.128G>T) is classified Uncertain significance in PDE2A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-28). AlphaMissense: likely benign (0.0727); Very rare (popmax 8.7e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with PDE2A p.Cys43Phe (c.128G>T)?

PDE2A p.Cys43Phe (c.128G>T) is associated with Inborn genetic diseases (ClinVar).

How common is PDE2A p.Cys43Phe (c.128G>T) in the general population?

PDE2A p.Cys43Phe (c.128G>T) is very rare (popmax 8.7e-05%, nfe) (gnomAD).

What do computational predictors say about PDE2A p.Cys43Phe (c.128G>T)?

AlphaMissense predicts likely benign (score 0.0727) — an in-silico prediction, not a clinical call.

PDE2A p.Cys43Phe

c.128G>T · VCV4133752

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0727 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.7e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0727	likely benign
REVEL	0.342	indeterminate
SaProt	LLR -6.39	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.2	GERP 1.7, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 88 kb · p 0.0075 · regional, not allelic
Overall
CADD	23.0	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 8.7e-05% European (non-Finnish) · 1/1,149,156 alleles

Overall 7.17e-05% 1/1,393,904 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.Cys43Phe
Coding: c.128G>T
MANE Select: NM_002599
Type: single nucleotide variant
Location: chr11:72642270 (GRCh38)
Gene constraint: LOEUF 0.564 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 84.17 · 44 PDB
Residue 43: 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.Cys43Trp Uncertain significance ★ ⚠ same residue
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

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-cys43phe (accessed [today's date]).

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