Is PDE8A p.Ala4Val (c.11C>T) pathogenic?

PDE8A p.Ala4Val (c.11C>T) is classified Uncertain significance in PDE8A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-07). AlphaMissense: ambiguous (0.5229); Very rare (popmax 0.00258%, sas).

How common is PDE8A p.Ala4Val (c.11C>T) in the general population?

PDE8A p.Ala4Val (c.11C>T) is very rare (popmax 0.00258%, sas) (gnomAD).

What do computational predictors say about PDE8A p.Ala4Val (c.11C>T)?

AlphaMissense predicts ambiguous (score 0.5229) — an in-silico prediction, not a clinical call.

PDE8A p.Ala4Val

c.11C>T · VCV3930130

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5229 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00258%, sas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5229	ambiguous
REVEL	0.288	benign-leaning
SaProt	LLR -7.53	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 4	phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 156 kb · p 0.32 · regional, not allelic
Overall
CADD	24.4	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 0.00258% South Asian · 2/77,578 alleles

Filtering AF 0.000428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00016%

Overall 0.000151% 2/1,323,816 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: PDE8A
Protein: p.Ala4Val
Coding: c.11C>T
MANE Select: NM_002605
Type: single nucleotide variant
Location: chr15:84982173 (GRCh38)
Gene constraint: LOEUF 0.631 · pLI 0.03 (gnomAD)
Structure: AlphaFold pLDDT 78.51 · 10 PDB

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

Similar variants

PDE8A p.Ala366Val Uncertain significance ★ ⚠ same type
PDE8A p.Ala41Ser 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
PDE8A p.Arg163Cys Uncertain significance ★ ⚠ same type
PDE8A p.Arg235Leu 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-ala4val (accessed [today's date]).

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