Is PDE2A p.Arg338Trp (c.1012C>T) pathogenic?

PDE2A p.Arg338Trp (c.1012C>T) is classified Uncertain significance in PDE2A (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-20). AlphaMissense: likely benign (0.2522); Ultra-rare (popmax 0.0167%, amr); Associated with Inborn genetic diseases.

What condition is associated with PDE2A p.Arg338Trp (c.1012C>T)?

PDE2A p.Arg338Trp (c.1012C>T) is associated with Inborn genetic diseases (ClinVar).

How common is PDE2A p.Arg338Trp (c.1012C>T) in the general population?

PDE2A p.Arg338Trp (c.1012C>T) is ultra-rare (popmax 0.0167%, amr) (gnomAD).

What do computational predictors say about PDE2A p.Arg338Trp (c.1012C>T)?

AlphaMissense predicts likely benign (score 0.2522) — an in-silico prediction, not a clinical call.

PDE2A p.Arg338Trp

c.1012C>T · rs746253555 · VCV2360871

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2522 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2522	likely benign
REVEL	0.567	indeterminate
SaProt	LLR -10.30	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP 0.38, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 88 kb · p 0.0075 · regional, not allelic
Overall
CADD	28.7	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 0.0167% Admixed American · 10/59,944 alleles

Filtering AF 0.009% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00682%

Overall 0.00441% 71/1,611,476 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0167%	5,994
South Asian	0.011%	9,098
European (non-Finnish)	0.0039%	25,614
Remaining individualsnot grpmax-eligible	0.00321%	31,186
African / African-American	0.00267%	37,454
East Asian	0.00223%	44,838

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.Arg338Trp
Coding: c.1012C>T
MANE Select: NM_002599
dbSNP: rs746253555
Type: single nucleotide variant
Location: chr11:72588842 (GRCh38)
Gene constraint: LOEUF 0.564 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 84.17 · 44 PDB
Residue 338: the gaf 2 domain; a β-strand

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.Arg338Gln 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-arg338trp (accessed [today's date]).

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