Is PDE8A p.Pro43Ser (c.127C>T) pathogenic?

PDE8A p.Pro43Ser (c.127C>T) is classified Likely benign in PDE8A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-27). AlphaMissense: likely benign (0.0678); Very rare (popmax 0.00305%, afr).

How common is PDE8A p.Pro43Ser (c.127C>T) in the general population?

PDE8A p.Pro43Ser (c.127C>T) is very rare (popmax 0.00305%, afr) (gnomAD).

What do computational predictors say about PDE8A p.Pro43Ser (c.127C>T)?

AlphaMissense predicts likely benign (score 0.0678) — an in-silico prediction, not a clinical call.

PDE8A p.Pro43Ser

c.127C>T · VCV4133906

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0678 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00305%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0678	likely benign
REVEL	0.098	moderately benign-leaning
SaProt	LLR -5.85	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 -2.7
Regional constraint	o/e 0.97	unconstrained · MANE · 156 kb · p 0.32 · regional, not allelic
Overall
CADD	0.269	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 0.00305% African / African-American · 2/65,624 alleles

Filtering AF 0.0015% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00126%

Overall 0.00188% 26/1,385,122 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00305%	32,812
European (non-Finnish)	0.00222%	44,995

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: PDE8A
Protein: p.Pro43Ser
Coding: c.127C>T
MANE Select: NM_002605
Type: single nucleotide variant
Location: chr15:84982289 (GRCh38)
Gene constraint: LOEUF 0.631 · pLI 0.03 (gnomAD)
Structure: AlphaFold pLDDT 78.51 · 10 PDB
Residue 43: the 'disordered' region

Full PDE8A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PDE8A p.Pro43Leu Uncertain significance ★ ⚠ same residue
PDE8A p.Ala366Val Uncertain significance ★ ⚠ same type
PDE8A p.Ala41Ser Uncertain significance ★ ⚠ same type
PDE8A p.Ala4Val Uncertain significance ★ ⚠ same type
PDE8A p.Ala630Val Uncertain significance ★ ⚠ same type
PDE8A p.Ala633Val Uncertain significance ★ ⚠ same type
PDE8A p.Ala667Thr Uncertain significance ★ ⚠ same type
PDE8A p.Ala792Gly 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/pde8a-p-pro43ser (accessed [today's date]).

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