# NM_001083.4(PDE5A):c.2180T>C (p.Leu727Pro)

https://sugi.bio/variant/pde5a-p-leu727pro

## Summary

**PDE5A p.Leu727Pro (c.2180T>C)** is classified **Uncertain significance** in PDE5A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-01). AlphaMissense: likely pathogenic (0.9377); Very rare (popmax 0.00141%, afr).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely pathogenic · very rare (popmax 0.00141%, afr)

## For patients & families {#patients}

This is a change in the PDE5A gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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 | [PDE5A](https://sugi.bio/atlas/gene/PDE5A/) |
| Protein change (HGVS p.) | p.Leu727Pro |
| Coding change (HGVS c.) | c.2180T>C |
| MANE Select transcript | [NM_001083](https://www.ncbi.nlm.nih.gov/nuccore/NM_001083) |
| Variant type | single nucleotide variant |
| Location | chr4:119507613-119507613 (GRCh38) |
| ClinVar | [VCV3930063](https://www.ncbi.nlm.nih.gov/clinvar/variation/3930063/) |

**All HGVS expressions:** `NC_000004.11:g.120428768A>G`, `NC_000004.12:g.119507613A>G`, `NM_001083.4:c.2180T>C`, `NM_033430.3:c.2054T>C`, `NM_033437.4:c.2024T>C`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.9377)
- REVEL 0.882 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -12.187 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 11.223, GERP 2.11, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 29.2**. 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.*
- Regional missense constraint: **o/e 0.82** across the covering region of the MANE Select transcript (119,498,604–119,628,671), spanning 130,067 bp. Chi-square p 1.5e-08. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (A>C, Δ0.73 donor gain), 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 **0.00141%** (afr) · FAF95 0.000439% · FAF99 0.00032% · 1/71,090 in the highest group · 11/1,561,522 alleles overall — very rare (popmax 0.00141%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00141% | 71,090 |
| European (non-Finnish) | 0.000868% | 115,271 |

*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}

**PDE5A** population constraint: LOEUF 0.704, pLI 0.0064875, missense-Z 1.5493. *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 **727** lies in the pdease domain; an α-helix.

AlphaFold model confidence (whole protein): pLDDT 82.32, 46% of residues very-high.

**50 experimental structure(s)** (PDB): [1RKP](https://www.rcsb.org/structure/1RKP), [1T9R](https://www.rcsb.org/structure/1T9R), [1T9S](https://www.rcsb.org/structure/1T9S), [1TBF](https://www.rcsb.org/structure/1TBF), [1UDT](https://www.rcsb.org/structure/1UDT), [1UDU](https://www.rcsb.org/structure/1UDU).

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

*Describes the biological roles of PDE5A (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:** PDE5A's established molecular role includes 3',5'-cyclic-GMP phosphodiesterase activity. p.Leu727Pro falls in the pdease domain.


### Pathways affected {#pathways}

PDE5A participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [RHOBTB1 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013422) | curated |
| [Smooth Muscle Contraction](https://reactome.org/content/detail/R-HSA-445355) | curated |
| [cGMP effects](https://reactome.org/content/detail/R-HSA-418457) | curated |

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

**Molecular function:** 3',5'-cyclic-GMP phosphodiesterase activity.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-04-01.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-04-01 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related PDE5A variant pages (same residue, condition, or type): [PDE5A c.2190-4G>A](/variant/pde5a-c-2190-minus-4g-a), [PDE5A p.Arg740Lys](/variant/pde5a-p-arg740lys), [PDE5A p.Glu119Val](/variant/pde5a-p-glu119val), [PDE5A p.Glu475=](/variant/pde5a-p-glu475), [PDE5A p.Glu808=](/variant/pde5a-p-glu808), [PDE5A p.Lys480Gln](/variant/pde5a-p-lys480gln), [PDE5A p.Pro671=](/variant/pde5a-p-pro671), [PDE5A p.Ala235Val](/variant/pde5a-p-ala235val).

### 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 3930063). 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.*