Is PDE3B p.Pro213Arg (c.638C>G) pathogenic?

PDE3B p.Pro213Arg (c.638C>G) is classified Uncertain significance in PDE3B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-12). AlphaMissense: likely benign (0.0705); Ultra-rare (popmax 0.0173%, mid).

How common is PDE3B p.Pro213Arg (c.638C>G) in the general population?

PDE3B p.Pro213Arg (c.638C>G) is ultra-rare (popmax 0.0173%, mid) (gnomAD).

What do computational predictors say about PDE3B p.Pro213Arg (c.638C>G)?

AlphaMissense predicts likely benign (score 0.0705) — an in-silico prediction, not a clinical call.

PDE3B p.Pro213Arg

c.638C>G · rs756035375 · VCV2374182

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0705 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0173%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0705	likely benign
REVEL	0.082	moderately benign-leaning
SaProt	LLR -6.67	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2	GERP -0.39, phastCons 0.56
Regional constraint	o/e 1.18	unconstrained · MANE · 187 kb · p 1.5e-07 · regional, not allelic
Overall
CADD	14.61	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0173% Middle Eastern · 1/5,776 alleles

Filtering AF 0.00534% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00361%

Overall 0.00208% 32/1,535,126 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0173%	5,776
Remaining individualsnot grpmax-eligible	0.0135%	7,434
Admixed American	0.0124%	8,067
European (non-Finnish)	0.00149%	67,253

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: PDE3B
Protein: p.Pro213Arg
Coding: c.638C>G
MANE Select: NM_000922
dbSNP: rs756035375
Type: single nucleotide variant
Location: chr11:14644713 (GRCh38)
Gene constraint: LOEUF 0.955 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.10 · 4 PDB

Full PDE3B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CYP2R1 p.Gly450Arg Uncertain significance ★★ ⚠ same type
CYP2R1 p.Gly91Asp Uncertain significance ★★ ⚠ same type
CYP2R1 p.His381Arg Uncertain significance ★★ ⚠ same type
CYP2R1 p.Ile332Thr Uncertain significance ★★ ⚠ same type
CYP2R1 p.Met284Ile Uncertain significance ★★ ⚠ same type
CYP2R1 p.Pro36Leu Uncertain significance ★★ ⚠ same type
CYP2R1 p.Tyr431His Uncertain significance ★★ ⚠ same type
PDE3B p.Thr137Ala 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/pde3b-p-pro213arg (accessed [today's date]).

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