# NM_001104631.2(PDE4D):c.1041T>C (p.Pro347=)

https://sugi.bio/variant/pde4d-p-pro347

## Summary

**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.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs767986152 · 3 submitters · 1 linked condition · ultra-rare (popmax 0.0174%, nfe)

## For patients & families {#patients}

This is a change in the PDE4D gene that is classified as benign/likely benign — not considered disease-causing, submitted by 3 submitters, and is linked to acrodysostosis 2 with or without hormone resistance.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015823/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PDE4D](https://sugi.bio/atlas/gene/PDE4D/) |
| Protein change (HGVS p.) | p.Pro347= |
| Coding change (HGVS c.) | c.1041T>C |
| MANE Select transcript | [NM_001104631](https://www.ncbi.nlm.nih.gov/nuccore/NM_001104631) |
| dbSNP | [rs767986152](https://www.ncbi.nlm.nih.gov/snp/rs767986152/) |
| Variant type | single nucleotide variant |
| Location | chr5:58991979-58991979 (GRCh38) |
| ClinVar | [VCV907638](https://www.ncbi.nlm.nih.gov/clinvar/variation/907638/) |

**All HGVS expressions:** `NC_000005.10:g.58991979A>G`, `NC_000005.9:g.58287806A>G`, `NG_027957.2:g.1537351T>C`, `NM_001104631.2:c.1041T>C`, `NM_001165899.2:c.858T>C`, `NM_001197218.2:c.849T>C`, `NM_001197219.2:c.675T>C`, `NM_001197220.2:c.651T>C`, `NM_001197221.2:c.135T>C`, `NM_001197222.2:c.369T>C`, `NM_001197223.2:c.168T>C`, `NM_001349241.2:c.828T>C`, `NM_001349242.2:c.711T>C`, `NM_001349243.2:c.273T>C`, `NM_001364599.1:c.858T>C`, `NM_001364603.1:c.135T>C`, `NM_001364604.1:c.273T>C`, `NM_006203.5:c.633T>C`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 5.214, GERP -0.162, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 10.5**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (A>C, Δ0.41 acceptor loss), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0174%** (nfe) · FAF95 0.0154% · FAF99 0.0146% · 203/1,166,136 in the highest group · 212/1,583,018 alleles overall — ultra-rare (popmax 0.0174%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.0174% | 5,745 |
| Remaining individuals (not grpmax-eligible) | 0.00817% | 12,233 |
| African / African-American | 0.00541% | 18,485 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**PDE4D** population constraint: LOEUF 0.403, pLI 0.9999, missense-Z 2.3461; ClinGen dosage — haploinsufficiency 0/3, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **347** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 68.01, 40% of residues very-high.

**122 experimental structure(s)** (PDB): [1E9K](https://www.rcsb.org/structure/1E9K), [1MKD](https://www.rcsb.org/structure/1MKD), [1OYN](https://www.rcsb.org/structure/1OYN), [1PTW](https://www.rcsb.org/structure/1PTW), [1Q9M](https://www.rcsb.org/structure/1Q9M), [1TB7](https://www.rcsb.org/structure/1TB7).

## What this gene does {#gene-function}

*Describes the biological roles of PDE4D (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** PDE4D's established molecular role includes 3',5'-cyclic-AMP phosphodiesterase activity. p.Pro347= falls in the disordered region.


### Pathways affected {#pathways}

PDE4D participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [DARPP-32 events](https://reactome.org/content/detail/R-HSA-180024) | curated |
| [G alpha (s) signalling events](https://reactome.org/content/detail/R-HSA-418555) | curated |
| [Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells](https://reactome.org/content/detail/R-HSA-9860927) | other |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** 3',5'-cyclic-AMP phosphodiesterase activity, cAMP binding, transmembrane transporter binding, ATPase binding, scaffold protein binding, heterocyclic compound binding.

**Biological process:** positive regulation of type II interferon production, positive regulation of interleukin-2 production, positive regulation of interleukin-5 production, T cell receptor signaling pathway, cellular response to cAMP, cellular response to epinephrine stimulus.

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-04-11.

**Submitter consensus:** conflicting (2 Likely benign, 1 Benign).

**Submission history:** 3 submissions (2018–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-01-12 |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2021-10-22 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-04-11 |

## Associated conditions {#conditions}

[acrodysostosis 2 with or without hormone resistance](https://sugi.bio/atlas/disease/acrodysostosis-2-with-or-without-hormone-resistance/).

**Reported phenotype names (ClinVar):** Acrodysostosis 2 with or without hormone resistance, not provided, PDE4D-related disorder, ACRODYSOSTOSIS 2 WITH HORMONE RESISTANCE, ACRODYSOSTOSIS 2 WITHOUT HORMONE RESISTANCE, none provided, PDE4D-related condition.

## Similar variants {#similar}

Related PDE4D variant pages (same residue, condition, or type): [PDE4D p.Ile678Thr](/variant/pde4d-p-ile678thr), [PDE4D p.Pro225Leu](/variant/pde4d-p-pro225leu), [PDE4D c.*4886A>C](/variant/pde4d-c-star-4886a-c), [PDE4D p.Arg727Trp](/variant/pde4d-p-arg727trp), [PDE4D p.Asn526Ser](/variant/pde4d-p-asn526ser), [PDE4D p.Ile346Met](/variant/pde4d-p-ile346met), [PDE4D p.Ile569=](/variant/pde4d-p-ile569), [PDE4D p.Lys265Thr](/variant/pde4d-p-lys265thr).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 907638). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*