Is PDE2A p.His741= (c.2223C>T) pathogenic?

PDE2A p.His741= (c.2223C>T) is classified Likely benign in PDE2A (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-23). Ultra-rare (popmax 0.0169%, mid).

How common is PDE2A p.His741= (c.2223C>T) in the general population?

PDE2A p.His741= (c.2223C>T) is ultra-rare (popmax 0.0169%, mid) (gnomAD).

PDE2A p.His741=

c.2223C>T · rs372366765 · VCV2902981

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0169%, mid)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -13	GERP -2.9
Overall
CADD	0.072	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0169% Middle Eastern · 1/5,914 alleles

Filtering AF 0.00677% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00494%

Overall 0.00399% 63/1,579,570 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0169%	5,914
Admixed American	0.0137%	7,303
South Asian	0.00556%	17,974
Remaining individualsnot grpmax-eligible	0.00496%	20,174
East Asian	0.00476%	21,027
African / African-American	0.00413%	24,202
European (non-Finnish)	0.00353%	28,304

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.His741=
Coding: c.2223C>T
MANE Select: NM_002599
dbSNP: rs372366765
Type: single nucleotide variant
Location: chr11:72579567 (GRCh38)
Gene constraint: LOEUF 0.564 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 84.17 · 44 PDB
Residue 741: a UniProt-annotated variant site (in iddpads); the pdease domain; a turn

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.Arg226Cys 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

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-his741 (accessed [today's date]).

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