Is PDE3A p.Cys46Phe (c.137G>T) pathogenic?

PDE3A p.Cys46Phe (c.137G>T) is classified Uncertain significance in PDE3A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-20). AlphaMissense: likely benign (0.0747); Very rare (popmax 0.000174%, nfe); Associated with Inborn genetic diseases.

What condition is associated with PDE3A p.Cys46Phe (c.137G>T)?

PDE3A p.Cys46Phe (c.137G>T) is associated with Inborn genetic diseases (ClinVar).

How common is PDE3A p.Cys46Phe (c.137G>T) in the general population?

PDE3A p.Cys46Phe (c.137G>T) is very rare (popmax 0.000174%, nfe) (gnomAD).

What do computational predictors say about PDE3A p.Cys46Phe (c.137G>T)?

AlphaMissense predicts likely benign (score 0.0747) — an in-silico prediction, not a clinical call.

PDE3A p.Cys46Phe

c.137G>T · VCV3416221

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0747 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000174%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0747	likely benign
REVEL	0.149	moderately benign-leaning
SaProt	LLR -6.46	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 3.4	GERP 0.37, phastCons 0.99
Regional constraint	o/e 1.14	unconstrained · MANE · 268 kb · p 2.5e-05 · regional, not allelic
Overall
CADD	19.46	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 0.000174% European (non-Finnish) · 2/1,150,424 alleles

Filtering AF 2.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000129% 2/1,555,214 alleles · very rare

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.Cys46Phe
Coding: c.137G>T
MANE Select: NM_000921
Type: single nucleotide variant
Location: chr12:20369421 (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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

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PDE3A p.Ser633Ile Uncertain significance ★★ ⚠ same condition
PDE3A p.Thr383Lys Uncertain significance ★★ ⚠ same condition
PDE3A p.Thr609Ser Uncertain significance ★★ ⚠ same condition
PDE3A p.Ala447Thr Pathogenic ★ ⚠ same condition
PDE3A p.Ala1097Glu 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/pde3a-p-cys46phe (accessed [today's date]).

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