Is PDE2A p.Arg641Gln (c.1922G>A) pathogenic?

PDE2A p.Arg641Gln (c.1922G>A) is classified Uncertain significance in PDE2A (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-11). AlphaMissense: likely benign (0.3192); Very rare (popmax 0.0022%, sas).

How common is PDE2A p.Arg641Gln (c.1922G>A) in the general population?

PDE2A p.Arg641Gln (c.1922G>A) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about PDE2A p.Arg641Gln (c.1922G>A)?

AlphaMissense predicts likely benign (score 0.3192) — an in-silico prediction, not a clinical call.

PDE2A p.Arg641Gln

c.1922G>A · rs770576443 · VCV2088213

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3192 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.3192	likely benign
REVEL	0.637	indeterminate
SaProt	LLR -10.68	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	Δ0.80	donor loss at this position · masked 0 · deltas
Pangolin	Δ0.52	loss · gain 0.02 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.7	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	34.0	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 0.0022% South Asian · 2/91,054 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000205% 3/1,461,444 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,527
European (non-Finnish)	8.48e-05%	1,179,729

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.Arg641Gln
Coding: c.1922G>A
MANE Select: NM_002599
dbSNP: rs770576443
Type: single nucleotide variant
Location: chr11:72581877 (GRCh38)
Gene constraint: LOEUF 0.564 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 84.17 · 44 PDB
Residue 641: 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

Similar variants

PDE2A p.Arg641= Likely benign ★★ same residue
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.Arg226Cys Uncertain significance ★★ ⚠ same type
PDE2A p.Arg790Gln Uncertain significance ★★ ⚠ same type
PDE2A p.Asp34Glu 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-arg641gln (accessed [today's date]).

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