Is PDE3A p.Leu206Pro (c.617T>C) pathogenic?

PDE3A p.Leu206Pro (c.617T>C) is classified Likely benign in PDE3A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-22). AlphaMissense: ambiguous (0.467); Rare (popmax 0.166%, mid).

How common is PDE3A p.Leu206Pro (c.617T>C) in the general population?

PDE3A p.Leu206Pro (c.617T>C) is rare (popmax 0.166%, mid) (gnomAD).

What do computational predictors say about PDE3A p.Leu206Pro (c.617T>C)?

AlphaMissense predicts ambiguous (score 0.467) — an in-silico prediction, not a clinical call.

PDE3A p.Leu206Pro

c.617T>C · rs138393409 · VCV2060477

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.467 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.166%, mid)

Computational evidence

Protein change
AlphaMissense	0.467	ambiguous
REVEL	0.393	indeterminate
SaProt	LLR -6.20	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.2	GERP 1.4, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 268 kb · p 2.5e-05 · regional, not allelic
Overall
CADD	25.2	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 0.166% Middle Eastern · 10/6,030 alleles

Filtering AF 0.0899% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0756%

Overall 0.068% 1,097/1,613,364 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.166%	603
Remaining individualsnot grpmax-eligible	0.0928%	1,077
European (non-Finnish)	0.0817%	1,224
South Asian	0.0351%	2,846
Admixed American	0.0283%	3,531
African / African-American	0.016%	6,254
Finnishnot grpmax-eligible	0.00473%	21,149
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,604

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: PDE3A
Protein: p.Leu206Pro
Coding: c.617T>C
MANE Select: NM_000921
dbSNP: rs138393409
Type: single nucleotide variant
Location: chr12:20369901 (GRCh38)
Gene constraint: LOEUF 0.763 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.11 · 9 PDB

Full PDE3A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PDE3A p.Arg268Lys Uncertain significance ★★ ⚠ same type
PDE3A p.Arg424His Uncertain significance ★★ ⚠ same type
PDE3A p.Glu648Val Uncertain significance ★★ ⚠ same type
PDE3A p.Pro430Leu Uncertain significance ★★ ⚠ same type
PDE3A p.Ser325Pro Uncertain significance ★★ ⚠ same type
PDE3A p.Ser633Ile Uncertain significance ★★ ⚠ same type
PDE3A p.Thr383Lys Uncertain significance ★★ ⚠ same type
PDE3A p.Thr609Ser 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/pde3a-p-leu206pro (accessed [today's date]).

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