Is PDE3A p.Thr445Ser (c.1334C>G) pathogenic?

PDE3A p.Thr445Ser (c.1334C>G) is classified Pathogenic in PDE3A (ClinVar, No assertion criteria, 1 submitter; last evaluated 2015-06-01). AlphaMissense: likely pathogenic (0.8248); Absent from gnomAD v4.1; Associated with brachydactyly-arterial hypertension syndrome.

What condition is associated with PDE3A p.Thr445Ser (c.1334C>G)?

PDE3A p.Thr445Ser (c.1334C>G) is associated with brachydactyly-arterial hypertension syndrome (ClinVar).

How common is PDE3A p.Thr445Ser (c.1334C>G) in the general population?

PDE3A p.Thr445Ser (c.1334C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PDE3A p.Thr445Ser (c.1334C>G)?

AlphaMissense predicts likely pathogenic (score 0.8248) — an in-silico prediction, not a clinical call.

PDE3A p.Thr445Ser

c.1334C>G · rs794726864 · VCV193022

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8248 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

brachydactyly-arterial hypertension syndrome

Computational evidence

Protein change
AlphaMissense	0.8248	likely pathogenic ✓ concordant with ClinVar
REVEL	0.246	benign-leaning
SaProt	LLR -5.54	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.8, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 268 kb · p 2.5e-05 · regional, not allelic
Overall
CADD	23.8	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PDE3A
Protein: p.Thr445Ser
Coding: c.1334C>G
MANE Select: NM_000921
dbSNP: rs794726864
Type: single nucleotide variant
Location: chr12:20616294 (GRCh38)
Gene constraint: LOEUF 0.763 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.11 · 9 PDB
Residue 445: a UniProt-annotated variant site (in htnb; increased 3',5'-cyclic-amp phosphodiesterase activity; increased function in camp-mediated signaling); a UniProt-annotated variant site (in htnb; increased phosphorylation at s-428 and s-438; increased affinity for 3',5'-cyclic-amp; no effect on protein reaction kinetics for 3',5'-cyclic-amp phosphodiesterase activity; increased 3',5'-cyclic-amp phosphodiesterase activity; no effect on inhibition by 3',5'-cyclic-gmp; changed function in camp-mediated signaling); a UniProt-annotated variant site (in htnb; increased 3',5'-cyclic-amp phosphodiesterase activity; changed function in camp-mediated signaling); the 'disordered' region

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

Disease context

brachydactyly-arterial hypertension syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PDE3A p.Thr445Ala Pathogenic ⚠ same residue
PDE3A p.Thr445Asn Pathogenic ⚠ same residue
PDE3A p.Thr445del Likely pathogenic same residue
PDE3A p.Arg424His Uncertain significance ★★ ⚠ same condition
PDE3A p.Glu648Val Uncertain significance ★★ ⚠ same condition
PDE3A p.Pro430Leu Uncertain significance ★★ ⚠ same condition
PDE3A p.Thr383Lys Uncertain significance ★★ ⚠ same condition
PDE3A c.1760+38A>C Benign ★★ 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-thr445ser (accessed [today's date]).

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