# NM_002599.5(PDE2A):c.447G>A (p.Pro149=)

https://sugi.bio/variant/pde2a-p-pro149

## Summary

**PDE2A p.Pro149= (c.447G>A)** is classified **Likely benign** in PDE2A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-01-01). Ultra-rare (popmax 0.0154%, afr).

**At a glance:** Likely benign · review: Multiple submitters · rsID rs956348156 · 2 submitters · ultra-rare (popmax 0.0154%, afr)

## For patients & families {#patients}

This is a change in the PDE2A gene that is classified as likely benign — not considered disease-causing, submitted by 2 submitters.

*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:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PDE2A](https://sugi.bio/atlas/gene/PDE2A/) |
| Protein change (HGVS p.) | p.Pro149= |
| Coding change (HGVS c.) | c.447G>A |
| MANE Select transcript | [NM_002599](https://www.ncbi.nlm.nih.gov/nuccore/NM_002599) |
| dbSNP | [rs956348156](https://www.ncbi.nlm.nih.gov/snp/rs956348156/) |
| Variant type | single nucleotide variant |
| Location | chr11:72596635-72596635 (GRCh38) |
| ClinVar | [VCV1653974](https://www.ncbi.nlm.nih.gov/clinvar/variation/1653974/) |

**All HGVS expressions:** `NC_000011.10:g.72596635C>T`, `NC_000011.9:g.72307679C>T`, `NM_001143839.4:c.426G>A`, `NM_001146209.3:c.420G>A`, `NM_001243784.2:c.384G>A`, `NM_002599.5:c.447G>A`

## 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 -0.406, GERP -3.51, phastCons 0.057 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 7.357**. 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 (C>G, Δ0.25 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 **0.0154%** (afr) · FAF95 0.00853% · FAF99 0.00661% · 11/71,460 in the highest group · 20/1,512,384 alleles overall — ultra-rare (popmax 0.0154%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.0154% | 6,496 |
| South Asian | 0.00263% | 38,074 |
| European (non-Finnish) | 0.000624% | 160,365 |

*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}

**PDE2A** population constraint: LOEUF 0.564, pLI 0.015822, missense-Z 3.8751. *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 **149** lies in the gaf 1 domain; a UniProt-annotated variant site (in iddpads; uncertain significance).

AlphaFold model confidence (whole protein): pLDDT 84.17, 53% of residues very-high.

**44 experimental structure(s)** (PDB): [1Z1L](https://www.rcsb.org/structure/1Z1L), [3IBJ](https://www.rcsb.org/structure/3IBJ), [3ITM](https://www.rcsb.org/structure/3ITM), [3ITU](https://www.rcsb.org/structure/3ITU), [4C1I](https://www.rcsb.org/structure/4C1I), [4D08](https://www.rcsb.org/structure/4D08).

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

*Describes the biological roles of PDE2A (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:** PDE2A's established molecular role includes magnesium ion binding. p.Pro149= falls in the gaf 1 domain.


### Pathways affected {#pathways}

PDE2A participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [G alpha (s) signalling events](https://reactome.org/content/detail/R-HSA-418555) | curated |
| [cGMP effects](https://reactome.org/content/detail/R-HSA-418457) | curated |

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

**Molecular function:** magnesium ion binding, 3',5'-cyclic-AMP phosphodiesterase activity, 3',5'-cGMP-stimulated cyclic-nucleotide phosphodiesterase activity, zinc ion binding, cAMP binding, cGMP binding.

**Biological process:** negative regulation of transcription by RNA polymerase II, adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway, monocyte differentiation, cellular response to macrophage colony-stimulating factor stimulus, negative regulation of vascular permeability, positive regulation of vascular permeability.

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-01-01.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2020–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2020-11-20 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2024-01-01 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Same-residue context {#hotspot}

Residue **149** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [PDE2A p.Pro149Leu](/variant/pde2a-p-pro149leu). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related PDE2A variant pages (same residue, condition, or type): [PDE2A p.Pro149Leu](/variant/pde2a-p-pro149leu), [PDE2A c.1922+4C>T](/variant/pde2a-c-1922-plus-4c-t), [PDE2A p.Ala157Val](/variant/pde2a-p-ala157val), [PDE2A p.Ala205Val](/variant/pde2a-p-ala205val), [PDE2A p.Ala349Thr](/variant/pde2a-p-ala349thr), [PDE2A p.Arg226Cys](/variant/pde2a-p-arg226cys), [PDE2A p.Arg790Gln](/variant/pde2a-p-arg790gln), [PDE2A p.Asp34Glu](/variant/pde2a-p-asp34glu).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2026-07-14); 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 1653974). 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.*