Is PDE8B p.Ala83Pro (c.247G>C) pathogenic?

PDE8B p.Ala83Pro (c.247G>C) is classified Conflicting classifications of pathogenicity in PDE8B (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-09-11). AlphaMissense: likely benign (0.0819); Rare (popmax 0.105%, afr); Associated with Inborn genetic diseases.

What condition is associated with PDE8B p.Ala83Pro (c.247G>C)?

PDE8B p.Ala83Pro (c.247G>C) is associated with Inborn genetic diseases (ClinVar).

How common is PDE8B p.Ala83Pro (c.247G>C) in the general population?

PDE8B p.Ala83Pro (c.247G>C) is rare (popmax 0.105%, afr) (gnomAD).

What do computational predictors say about PDE8B p.Ala83Pro (c.247G>C)?

AlphaMissense predicts likely benign (score 0.0819) — an in-silico prediction, not a clinical call.

PDE8B p.Ala83Pro

c.247G>C · rs561890042 · VCV2712997

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0819 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.105%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0819	likely benign
REVEL	0.252	benign-leaning
SaProt	LLR -7.04	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 3.2	GERP -1.1, phastCons 0.99
Regional constraint	o/e 1.08	unconstrained · MANE · 279 bp · p 0.3 · regional, not allelic
Overall
CADD	16.87	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 0.105% African / African-American · 76/72,370 alleles

Filtering AF 0.0859% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.079%

Overall 0.00593% 91/1,534,792 alleles · rare exomes 50/1,382,606 · genomes 41/152,186 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.105%	952
Admixed American	0.0136%	7,367
Remaining individualsnot grpmax-eligible	0.0117%	8,546
European (non-Finnish)	8.72e-05%	1,147,353

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: PDE8B
Protein: p.Ala83Pro
Coding: c.247G>C
MANE Select: NM_003719
dbSNP: rs561890042
Type: single nucleotide variant
Location: chr5:77211172 (GRCh38)
Gene constraint: LOEUF 0.351 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 74.88
Residue 83: the 'disordered' region

Full PDE8B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PDE8B p.Ala232Ser Uncertain significance ★★ ⚠ same condition
PDE8B p.Ala4Val Uncertain significance ★★ ⚠ same condition
PDE8B p.Ala65Pro Uncertain significance ★★ ⚠ same condition
PDE8B p.Ala86Thr Uncertain significance ★★ ⚠ same condition
PDE8B p.Arg237Lys Uncertain significance ★★ ⚠ same condition
PDE8B p.Arg483Trp Uncertain significance ★★ ⚠ same condition
PDE8B p.Arg57Gly Uncertain significance ★★ ⚠ same condition
PDE8B p.Asp191Asn Uncertain significance ★★ ⚠ same condition

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/pde8b-p-ala83pro (accessed [today's date]).

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