Is PDE2A p.Arg226Cys (c.676C>T) pathogenic?

PDE2A p.Arg226Cys (c.676C>T) is classified Uncertain significance in PDE2A (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-07-07). AlphaMissense: likely benign (0.1319); Rare (popmax 0.103%, mid).

How common is PDE2A p.Arg226Cys (c.676C>T) in the general population?

PDE2A p.Arg226Cys (c.676C>T) is rare (popmax 0.103%, mid) (gnomAD).

What do computational predictors say about PDE2A p.Arg226Cys (c.676C>T)?

AlphaMissense predicts likely benign (score 0.1319) — an in-silico prediction, not a clinical call.

PDE2A p.Arg226Cys

c.676C>T · rs371714314 · VCV1175802

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1319 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.103%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1319	likely benign
REVEL	0.183	benign-leaning
SaProt	LLR -10.62	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.5	GERP 0.38, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 88 kb · p 0.0075 · regional, not allelic
Overall
CADD	25.1	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 0.103% Middle Eastern · 6/5,816 alleles

Filtering AF 0.0449% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0306%

Overall 0.0275% 426/1,551,330 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.103%	969
European (non-Finnish)	0.0333%	3,001
Finnishnot grpmax-eligible	0.0239%	4,184
Remaining individualsnot grpmax-eligible	0.0235%	4,253
Admixed American	0.00957%	10,453
African / African-American	0.00274%	36,554
South Asian	0.00244%	41,042

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.Arg226Cys
Coding: c.676C>T
MANE Select: NM_002599
dbSNP: rs371714314
Type: single nucleotide variant
Location: chr11:72590454 (GRCh38)
Gene constraint: LOEUF 0.564 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 84.17 · 44 PDB
Residue 226: the gaf 2 domain; an α-helix

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.Arg790Gln Uncertain significance ★★ ⚠ same type
PDE2A p.Asp34Glu Uncertain significance ★★ ⚠ same type
PDE2A p.Asp59Asn Uncertain significance ★★ ⚠ same type
PDE2A p.Cys263Gly 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-arg226cys (accessed [today's date]).

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