Is PDE5A p.Leu727Pro (c.2180T>C) pathogenic?

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).

How common is PDE5A p.Leu727Pro (c.2180T>C) in the general population?

PDE5A p.Leu727Pro (c.2180T>C) is very rare (popmax 0.00141%, afr) (gnomAD).

What do computational predictors say about PDE5A p.Leu727Pro (c.2180T>C)?

AlphaMissense predicts likely pathogenic (score 0.9377) — an in-silico prediction, not a clinical call.

PDE5A p.Leu727Pro

c.2180T>C · VCV3930063

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9377 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00141%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9377	likely pathogenic
REVEL	0.882	moderately pathogenic-leaning
SaProt	LLR -12.19	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>C here scores Δ0.73 · evaluated, not missing
Constraint at this position
Conservation	phyloP 11	GERP 2.1, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 130 kb · p 1.5e-08 · regional, not allelic
Overall
CADD	29.2	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00141% African / African-American · 1/71,090 alleles

Filtering AF 0.000439% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00032%

Overall 0.000704% 11/1,561,522 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00141%	71,090
European (non-Finnish)	0.000868%	115,271

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: PDE5A
Protein: p.Leu727Pro
Coding: c.2180T>C
MANE Select: NM_001083
Type: single nucleotide variant
Location: chr4:119507613 (GRCh38)
Gene constraint: LOEUF 0.704 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.32 · 50 PDB
Residue 727: the pdease domain; an α-helix

Full PDE5A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PDE5A c.2190-4G>A Benign/Likely benign ★★ same type
PDE5A p.Arg740Lys Likely benign ★★ same type
PDE5A p.Glu119Val Benign/Likely benign ★★ same type
PDE5A p.Glu475= Benign/Likely benign ★★ same type
PDE5A p.Glu808= Benign ★★ same type
PDE5A p.Lys480Gln Benign ★★ same type
PDE5A p.Pro671= Benign ★★ same type
PDE5A p.Ala235Val 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/pde5a-p-leu727pro (accessed [today's date]).

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