Is PDE3A p.Arg459Gln (c.1376G>A) pathogenic?

PDE3A p.Arg459Gln (c.1376G>A) is classified Benign/Likely benign in PDE3A (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-15). AlphaMissense: likely benign (0.1769); Rare (popmax 0.309%, nfe); Associated with brachydactyly-arterial hypertension syndrome.

What condition is associated with PDE3A p.Arg459Gln (c.1376G>A)?

PDE3A p.Arg459Gln (c.1376G>A) is associated with brachydactyly-arterial hypertension syndrome (ClinVar).

How common is PDE3A p.Arg459Gln (c.1376G>A) in the general population?

PDE3A p.Arg459Gln (c.1376G>A) is rare (popmax 0.309%, nfe) (gnomAD).

What do computational predictors say about PDE3A p.Arg459Gln (c.1376G>A)?

AlphaMissense predicts likely benign (score 0.1769) — an in-silico prediction, not a clinical call.

PDE3A p.Arg459Gln

c.1376G>A · rs141325069 · VCV725921

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1769 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.309%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

brachydactyly-arterial hypertension syndrome

Computational evidence

Protein change
AlphaMissense	0.1769	likely benign
REVEL	0.275	benign-leaning
SaProt	LLR -7.99	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 12	GERP 1.8, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 268 kb · p 2.5e-05 · regional, not allelic
Overall
CADD	29.3	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 0.309% European (non-Finnish) · 3,646/1,179,880 alleles

Filtering AF 0.301% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.297%

Overall 0.243% 3,924/1,613,874 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.309%	324
Remaining individualsnot grpmax-eligible	0.2%	500
Admixed American	0.183%	546
Middle Eastern	0.0826%	1,211
African / African-American	0.044%	2,273
East Asian	0.00669%	14,948
Finnishnot grpmax-eligible	0.00312%	32,004

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.Arg459Gln
Coding: c.1376G>A
MANE Select: NM_000921
dbSNP: rs141325069
Type: single nucleotide variant
Location: chr12:20616336 (GRCh38)
Gene constraint: LOEUF 0.763 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.11 · 9 PDB
Residue 459: 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.Arg459Trp Uncertain significance ★ ⚠ 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
PDE3A c.2769+30C>T Benign ★★ same condition
PDE3A c.2925+15T>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-arg459gln (accessed [today's date]).

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