Is PDE3B p.Pro121Thr (c.361C>A) pathogenic?

PDE3B p.Pro121Thr (c.361C>A) is classified Uncertain significance in PDE3B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-24). AlphaMissense: likely pathogenic (0.6861); Very rare (popmax 0.000254%, nfe).

How common is PDE3B p.Pro121Thr (c.361C>A) in the general population?

PDE3B p.Pro121Thr (c.361C>A) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about PDE3B p.Pro121Thr (c.361C>A)?

AlphaMissense predicts likely pathogenic (score 0.6861) — an in-silico prediction, not a clinical call.

PDE3B p.Pro121Thr

c.361C>A · VCV3930038

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6861 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6861	likely pathogenic
REVEL	0.514	indeterminate
SaProt	LLR -9.63	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.6	GERP 1.1, phastCons 1
Regional constraint	o/e 1.18	unconstrained · MANE · 187 kb · p 1.5e-07 · regional, not allelic
Overall
CADD	24.9	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 0.000254% European (non-Finnish) · 3/1,179,608 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,460,656 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: PDE3B
Protein: p.Pro121Thr
Coding: c.361C>A
MANE Select: NM_000922
Type: single nucleotide variant
Location: chr11:14644436 (GRCh38)
Gene constraint: LOEUF 0.955 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.10 · 4 PDB

Full PDE3B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PDE3B p.Pro121Ser Uncertain significance ★ ⚠ same residue
CYP2R1 p.Gly450Arg Uncertain significance ★★ ⚠ same type
CYP2R1 p.Gly91Asp Uncertain significance ★★ ⚠ same type
CYP2R1 p.His381Arg Uncertain significance ★★ ⚠ same type
CYP2R1 p.Ile332Thr Uncertain significance ★★ ⚠ same type
CYP2R1 p.Met284Ile Uncertain significance ★★ ⚠ same type
CYP2R1 p.Pro36Leu Uncertain significance ★★ ⚠ same type
CYP2R1 p.Tyr431His 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/pde3b-p-pro121thr (accessed [today's date]).

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