Is PDE4D p.Ser98Arg (c.292A>C) pathogenic?

PDE4D p.Ser98Arg (c.292A>C) is classified Uncertain significance in PDE4D (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-03). AlphaMissense: likely benign (0.2784); Very rare (popmax 8.9e-05%, nfe).

How common is PDE4D p.Ser98Arg (c.292A>C) in the general population?

PDE4D p.Ser98Arg (c.292A>C) is very rare (popmax 8.9e-05%, nfe) (gnomAD).

What do computational predictors say about PDE4D p.Ser98Arg (c.292A>C)?

AlphaMissense predicts likely benign (score 0.2784) — an in-silico prediction, not a clinical call.

PDE4D p.Ser98Arg

c.292A>C · VCV4970479

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2784 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.9e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2784	likely benign
REVEL	0.258	benign-leaning
SaProt	LLR -6.66	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 3.1	GERP 3.8, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 678 kb · p 0.77 · regional, not allelic
Overall
CADD	23.4	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 8.9e-05% European (non-Finnish) · 1/1,123,774 alleles

Overall 7.39e-05% 1/1,353,818 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: PDE4D
Protein: p.Ser98Arg
Coding: c.292A>C
MANE Select: NM_001104631
Type: single nucleotide variant
Location: chr5:59893331 (GRCh38)
Gene constraint: LOEUF 0.403 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.01 · 122 PDB
Residue 98: the 'disordered' region

Full PDE4D gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PDE4D p.Ile678Thr Pathogenic ★★ same type
PDE4D p.Pro225Leu Pathogenic ★★ same type
PDE4D c.*4886A>C Uncertain significance ★★ same type
PDE4D p.Arg133Trp Uncertain significance ★★ ⚠ same type
PDE4D p.Arg151Gly Uncertain significance ★★ ⚠ same type
PDE4D p.Arg249Gln Uncertain significance ★★ ⚠ same type
PDE4D p.Arg727Trp Uncertain significance ★★ ⚠ same type
PDE4D p.Asn264Ser 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/pde4d-p-ser98arg (accessed [today's date]).

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