Is PDE3A p.Ala955Pro (c.2863G>C) pathogenic?

PDE3A p.Ala955Pro (c.2863G>C) is classified Uncertain significance in PDE3A (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-14). AlphaMissense: likely pathogenic (0.9876); Very rare (popmax 0.0011%, sas); Associated with brachydactyly-arterial hypertension syndrome.

What condition is associated with PDE3A p.Ala955Pro (c.2863G>C)?

PDE3A p.Ala955Pro (c.2863G>C) is associated with brachydactyly-arterial hypertension syndrome (ClinVar).

How common is PDE3A p.Ala955Pro (c.2863G>C) in the general population?

PDE3A p.Ala955Pro (c.2863G>C) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about PDE3A p.Ala955Pro (c.2863G>C)?

AlphaMissense predicts likely pathogenic (score 0.9876) — an in-silico prediction, not a clinical call.

PDE3A p.Ala955Pro

c.2863G>C · VCV3891924

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9876 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

brachydactyly-arterial hypertension syndrome

Computational evidence

Protein change
AlphaMissense	0.9876	likely pathogenic · top 8% in PDE3A
REVEL	0.771	pathogenic-leaning
SaProt	LLR -12.88	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.65	unconstrained · MANE · 17 kb · p 6.8e-13 · regional, not allelic
Overall
CADD	26.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0011% South Asian · 1/91,002 alleles

Overall 6.85e-05% 1/1,459,672 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.Ala955Pro
Coding: c.2863G>C
MANE Select: NM_000921
Type: single nucleotide variant
Location: chr12:20650538 (GRCh38)
Gene constraint: LOEUF 0.763 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.11 · 9 PDB
Residue 955: the 'interaction with slfn12' region; the pdease domain; an α-helix

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.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
PDE3A p.Arg459Gln Benign/Likely 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-ala955pro (accessed [today's date]).

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