Is PDE3A p.Ala655Val (c.1964C>T) pathogenic?

PDE3A p.Ala655Val (c.1964C>T) is classified Conflicting classifications of pathogenicity in PDE3A (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-03-27). AlphaMissense: likely benign (0.0741); Very rare (popmax 0.00246%, nfe).

How common is PDE3A p.Ala655Val (c.1964C>T) in the general population?

PDE3A p.Ala655Val (c.1964C>T) is very rare (popmax 0.00246%, nfe) (gnomAD).

What do computational predictors say about PDE3A p.Ala655Val (c.1964C>T)?

AlphaMissense predicts likely benign (score 0.0741) — an in-silico prediction, not a clinical call.

PDE3A p.Ala655Val

c.1964C>T · rs1418650299 · VCV3020614

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0741 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00246%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0741	likely benign
REVEL	0.07	moderately benign-leaning
SaProt	LLR -4.55	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.22	donor gain · deltas
Constraint at this position
Conservation	phyloP 3.3	GERP 1.6, phastCons 0.46
Regional constraint	o/e 1.14	unconstrained · MANE · 268 kb · p 2.5e-05 · regional, not allelic
Overall
CADD	16.89	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 0.00246% European (non-Finnish) · 29/1,179,704 alleles

Filtering AF 0.00172% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00149%

Overall 0.00192% 31/1,613,618 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,237
European (non-Finnish)grpmax	0.00246%	40,680

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala655Val
Coding: c.1964C>T
MANE Select: NM_000921
dbSNP: rs1418650299
Type: single nucleotide variant
Location: chr12:20635019 (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

Similar variants

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
PDE3A p.Thr609Ser 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-ala655val (accessed [today's date]).

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