Is PDE4C p.Ser404Pro (c.1210T>C) pathogenic?

PDE4C p.Ser404Pro (c.1210T>C) is classified Uncertain significance in PDE4C (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-11). AlphaMissense: likely pathogenic (0.8986); Absent from gnomAD v4.1.

How common is PDE4C p.Ser404Pro (c.1210T>C) in the general population?

PDE4C p.Ser404Pro (c.1210T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PDE4C p.Ser404Pro (c.1210T>C)?

AlphaMissense predicts likely pathogenic (score 0.8986) — an in-silico prediction, not a clinical call.

PDE4C p.Ser404Pro

c.1210T>C · VCV4133826

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8986 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.8986	likely pathogenic
REVEL	0.616	indeterminate
SaProt	LLR -12.46	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 9,339 bp · p 6.4e-05 · regional, not allelic
Overall
CADD	28.6	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S436P vs ClinVar S404P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PDE4C
Protein: p.Ser404Pro
Coding: c.1210T>C
MANE Select: NM_001098818
Type: single nucleotide variant
Location: chr19:18218173 (GRCh38)
Gene constraint: LOEUF 1.044 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.70 · 1 PDB
Residue 436 UniProt numbering: the pdease domain; an α-helix

Full PDE4C gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PDE4C p.Ala139Ser Uncertain significance ★ ⚠ same type
PDE4C p.Ala174Thr Uncertain significance ★ ⚠ same type
PDE4C p.Ala316Val Uncertain significance ★ ⚠ same type
PDE4C p.Ala351Thr Uncertain significance ★ ⚠ same type
PDE4C p.Ala354Ser Uncertain significance ★ ⚠ same type
PDE4C p.Ala354Val Uncertain significance ★ ⚠ same type
PDE4C p.Ala362Thr Uncertain significance ★ same type
PDE4C p.Ala389Val 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/pde4c-p-ser404pro (accessed [today's date]).

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