Is PDE4D p.Pro347= (c.1041T>C) pathogenic?

PDE4D p.Pro347= (c.1041T>C) is classified Benign/Likely benign in PDE4D (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-04-11). Ultra-rare (popmax 0.0174%, nfe); Associated with acrodysostosis 2 with or without hormone resistance.

What condition is associated with PDE4D p.Pro347= (c.1041T>C)?

PDE4D p.Pro347= (c.1041T>C) is associated with acrodysostosis 2 with or without hormone resistance (ClinVar).

How common is PDE4D p.Pro347= (c.1041T>C) in the general population?

PDE4D p.Pro347= (c.1041T>C) is ultra-rare (popmax 0.0174%, nfe) (gnomAD).

PDE4D p.Pro347=

c.1041T>C · rs767986152 · VCV907638

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0174%, nfe)

Conditions

acrodysostosis 2 with or without hormone resistance

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>C here scores Δ0.41 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5.2	GERP -0.16, phastCons 1
Overall
CADD	10.5	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0174% European (non-Finnish) · 203/1,166,136 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0146%

Overall 0.0134% 212/1,583,018 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0174%	5,745
Remaining individualsnot grpmax-eligible	0.00817%	12,233
African / African-American	0.00541%	18,485

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.Pro347=
Coding: c.1041T>C
MANE Select: NM_001104631
dbSNP: rs767986152
Type: single nucleotide variant
Location: chr5:58991979 (GRCh38)
Gene constraint: LOEUF 0.403 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.01 · 122 PDB
Residue 347: the 'disordered' region

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

Disease context

acrodysostosis 2 with or without hormone resistance — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PDE4D p.Ile678Thr Pathogenic ★★ same condition
PDE4D p.Pro225Leu Pathogenic ★★ same condition
PDE4D c.*4886A>C Uncertain significance ★★ same condition
PDE4D p.Arg727Trp Uncertain significance ★★ ⚠ same condition
PDE4D p.Asn526Ser Uncertain significance ★★ ⚠ same condition
PDE4D p.Ile346Met Uncertain significance ★★ ⚠ same condition
PDE4D p.Ile569= Uncertain significance ★★ same condition
PDE4D p.Lys265Thr 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/pde4d-p-pro347 (accessed [today's date]).

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