Is PDE2A p.Val376Met (c.1126G>A) pathogenic?

PDE2A p.Val376Met (c.1126G>A) is classified Uncertain significance in PDE2A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-11). AlphaMissense: likely pathogenic (0.6906); Very rare (popmax 0.00223%, eas); Associated with Inborn genetic diseases.

What condition is associated with PDE2A p.Val376Met (c.1126G>A)?

PDE2A p.Val376Met (c.1126G>A) is associated with Inborn genetic diseases (ClinVar).

How common is PDE2A p.Val376Met (c.1126G>A) in the general population?

PDE2A p.Val376Met (c.1126G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about PDE2A p.Val376Met (c.1126G>A)?

AlphaMissense predicts likely pathogenic (score 0.6906) — an in-silico prediction, not a clinical call.

PDE2A p.Val376Met

c.1126G>A · VCV3659977

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6906 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6906	likely pathogenic
REVEL	0.347	indeterminate
SaProt	LLR -5.77	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL 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 0.44	unconstrained · MANE · 770 bp · p 2.9e-06 · regional, not allelic
Overall
CADD	26.6	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 0.00223% East Asian · 1/44,866 alleles

Overall 0.000205% 3/1,460,874 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,866
Remaining individualsnot grpmax-eligible	0.0016%	62,468
European (non-Finnish)	8.48e-05%	1,179,558

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.Val376Met
Coding: c.1126G>A
MANE Select: NM_002599
Type: single nucleotide variant
Location: chr11:72586126 (GRCh38)
Gene constraint: LOEUF 0.564 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 84.17 · 44 PDB
Residue 376: the gaf 2 domain; an α-helix

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-val376met (accessed [today's date]).

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