Is PDE3A p.Ala2Val (c.5C>T) pathogenic?

PDE3A p.Ala2Val (c.5C>T) is classified Uncertain significance in PDE3A (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-17). AlphaMissense: ambiguous (0.5608); Very rare (popmax 0.00828%, amr).

How common is PDE3A p.Ala2Val (c.5C>T) in the general population?

PDE3A p.Ala2Val (c.5C>T) is very rare (popmax 0.00828%, amr) (gnomAD).

What do computational predictors say about PDE3A p.Ala2Val (c.5C>T)?

AlphaMissense predicts ambiguous (score 0.5608) — an in-silico prediction, not a clinical call.

PDE3A p.Ala2Val

c.5C>T · rs986781737 · VCV1988732

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5608 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00828%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5608	ambiguous
REVEL	0.023	moderately benign-leaning
SaProt	LLR -8.00	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.3	GERP 0.41, phastCons 0.98
Regional constraint	o/e 1.14	unconstrained · MANE · 268 kb · p 2.5e-05 · regional, not allelic
Overall
CADD	20.3	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 0.00828% Admixed American · 4/48,284 alleles

Filtering AF 0.00273% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0017%

Overall 0.00099% 15/1,515,362 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00828%	12,071
Remaining individualsnot grpmax-eligible	0.00171%	58,360
European (non-Finnish)	0.000887%	112,710

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.Ala2Val
Coding: c.5C>T
MANE Select: NM_000921
dbSNP: rs986781737
Type: single nucleotide variant
Location: chr12:20369289 (GRCh38)
Gene constraint: LOEUF 0.763 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.11 · 9 PDB
Residue 2: the 'disordered' region

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

Similar variants

PDE3A p.Ala2Thr Uncertain significance ★ ⚠ same residue
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

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-ala2val (accessed [today's date]).

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