Is PDE8B p.Val574Phe (c.1720G>T) pathogenic?

PDE8B p.Val574Phe (c.1720G>T) is classified Uncertain significance in PDE8B (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-06-04). AlphaMissense: likely benign (0.2426); Very rare (popmax 0.000848%, nfe); Associated with PDE8B-related disorder.

What condition is associated with PDE8B p.Val574Phe (c.1720G>T)?

PDE8B p.Val574Phe (c.1720G>T) is associated with PDE8B-related disorder (ClinVar).

How common is PDE8B p.Val574Phe (c.1720G>T) in the general population?

PDE8B p.Val574Phe (c.1720G>T) is very rare (popmax 0.000848%, nfe) (gnomAD).

What do computational predictors say about PDE8B p.Val574Phe (c.1720G>T)?

AlphaMissense predicts likely benign (score 0.2426) — an in-silico prediction, not a clinical call.

PDE8B p.Val574Phe

c.1720G>T · VCV3348305

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2426 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000848%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

PDE8B-related disorder

Computational evidence

Protein change
AlphaMissense	0.2426	likely benign
REVEL	0.468	indeterminate
SaProt	LLR -9.32	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	Δ0.21	acceptor gain · deltas
Pangolin	Δ0.20	loss · gain 0.16 · SpliceAI calls gain · independent
Constraint at this position
Conservation	phyloP 9.9	GERP 2.2, phastCons 1
Regional constraint	o/e 0.58	unconstrained · MANE · 19 kb · p 2.3e-23 · regional, not allelic
Overall
CADD	25.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.000848% European (non-Finnish) · 10/1,179,852 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000313%

Overall 0.00062% 10/1,613,780 alleles · very rare exomes 9/1,461,682 · genomes 1/152,098 · joint denominator

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.Val574Phe
Coding: c.1720G>T
MANE Select: NM_003719
Type: single nucleotide variant
Location: chr5:77413118 (GRCh38)
Gene constraint: LOEUF 0.351 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 74.88
Residue 574: the pdease domain

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

Disease context

PDE8B-related disorder

Similar variants

PDE8B p.Glu299Ter Pathogenic ★ same condition
PDE8B p.Lys706Arg Uncertain significance ⚠ same condition
PDE8B c.1577-5C>T Likely benign same condition
PDE8B c.*498C>A Uncertain significance ★★ same type
PDE8B p.Ala232Ser Uncertain significance ★★ ⚠ same type
PDE8B p.Ala4Val Uncertain significance ★★ ⚠ same type
PDE8B p.Ala65Pro Uncertain significance ★★ ⚠ same type
PDE8B p.Ala70Ser 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/pde8b-p-val574phe (accessed [today's date]).

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