Is PDE2A p.Ala461Ser (c.1381G>T) pathogenic?

PDE2A p.Ala461Ser (c.1381G>T) is classified Uncertain significance in PDE2A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-07). AlphaMissense: ambiguous (0.3834); Very rare (popmax 0.00314%, nfe); Associated with Inborn genetic diseases.

What condition is associated with PDE2A p.Ala461Ser (c.1381G>T)?

PDE2A p.Ala461Ser (c.1381G>T) is associated with Inborn genetic diseases (ClinVar).

How common is PDE2A p.Ala461Ser (c.1381G>T) in the general population?

PDE2A p.Ala461Ser (c.1381G>T) is very rare (popmax 0.00314%, nfe) (gnomAD).

What do computational predictors say about PDE2A p.Ala461Ser (c.1381G>T)?

AlphaMissense predicts ambiguous (score 0.3834) — an in-silico prediction, not a clinical call.

PDE2A p.Ala461Ser

c.1381G>T · VCV3305361

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3834 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00314%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3834	ambiguous
REVEL	0.235	benign-leaning
SaProt	LLR -7.71	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	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	27.4	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 0.00314% European (non-Finnish) · 37/1,180,010 alleles

Filtering AF 0.00231% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00202%

Overall 0.00236% 38/1,613,214 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00314%	31,892
Remaining individualsnot grpmax-eligible	0.0016%	62,482

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.Ala461Ser
Coding: c.1381G>T
MANE Select: NM_002599
Type: single nucleotide variant
Location: chr11:72584707 (GRCh38)
Gene constraint: LOEUF 0.564 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 84.17 · 44 PDB
Residue 461: a UniProt-annotated variant site (in iddpads); the gaf 3 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.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
PDE2A p.Gln41Glu 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-ala461ser (accessed [today's date]).

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