Is PDE8A p.Ala633Val (c.1898C>T) pathogenic?

PDE8A p.Ala633Val (c.1898C>T) is classified Uncertain significance in PDE8A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-30). AlphaMissense: likely pathogenic (0.918); Ultra-rare (popmax 0.0115%, nfe).

How common is PDE8A p.Ala633Val (c.1898C>T) in the general population?

PDE8A p.Ala633Val (c.1898C>T) is ultra-rare (popmax 0.0115%, nfe) (gnomAD).

What do computational predictors say about PDE8A p.Ala633Val (c.1898C>T)?

AlphaMissense predicts likely pathogenic (score 0.918) — an in-silico prediction, not a clinical call.

PDE8A p.Ala633Val

c.1898C>T · VCV3930122

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.918 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0115%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.918	likely pathogenic
REVEL	0.664	pathogenic-leaning
SaProt	LLR -10.55	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.4	GERP -0.002, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 156 kb · p 0.32 · regional, not allelic
Overall
CADD	24.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0115% European (non-Finnish) · 136/1,179,936 alleles

Filtering AF 0.00994% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00931%

Overall 0.00917% 148/1,613,880 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0115%	8,676
African / African-American	0.00934%	10,703
Remaining individualsnot grpmax-eligible	0.0048%	20,825
Admixed American	0.00167%	59,992
South Asian	0.0011%	91,068

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.Ala633Val
Coding: c.1898C>T
MANE Select: NM_002605
Type: single nucleotide variant
Location: chr15:85120960 (GRCh38)
Gene constraint: LOEUF 0.631 · pLI 0.03 (gnomAD)
Structure: AlphaFold pLDDT 78.51 · 10 PDB
Residue 633: the pdease domain; an α-helix

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.Ala4Val Uncertain significance ★ ⚠ same type
PDE8A p.Ala630Val 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-ala633val (accessed [today's date]).

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