Is PDE4C p.Phe331Cys (c.992T>G) pathogenic?

PDE4C p.Phe331Cys (c.992T>G) is classified Uncertain significance in PDE4C (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-26). AlphaMissense: likely pathogenic (0.7116); Very rare (popmax 0.00127%, nfe).

How common is PDE4C p.Phe331Cys (c.992T>G) in the general population?

PDE4C p.Phe331Cys (c.992T>G) is very rare (popmax 0.00127%, nfe) (gnomAD).

What do computational predictors say about PDE4C p.Phe331Cys (c.992T>G)?

AlphaMissense predicts likely pathogenic (score 0.7116) — an in-silico prediction, not a clinical call.

PDE4C p.Phe331Cys

c.992T>G · rs1428272715 · VCV2319831

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7116 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00127%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7116	likely pathogenic
REVEL	0.741	pathogenic-leaning
SaProt	LLR -14.42	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 0.84, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 9,339 bp · p 6.4e-05 · regional, not allelic
Overall
CADD	28.3	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 F363C vs ClinVar F331C) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00127% European (non-Finnish) · 15/1,180,020 alleles

Filtering AF 0.000763% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000605%

Overall 0.000929% 15/1,614,004 alleles · very rare exomes 13/1,461,882 · genomes 2/152,122 · 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: PDE4C
Protein: p.Phe331Cys
Coding: c.992T>G
MANE Select: NM_001098818
dbSNP: rs1428272715
Type: single nucleotide variant
Location: chr19:18218476 (GRCh38)
Gene constraint: LOEUF 1.044 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.70 · 1 PDB
Residue 363 UniProt numbering: the pdease domain

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-phe331cys (accessed [today's date]).

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