Is PDE5A p.Arg740Lys (c.2219G>A) pathogenic?

PDE5A p.Arg740Lys (c.2219G>A) is classified Likely benign in PDE5A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-07-10). AlphaMissense: likely benign (0.0682); Rare (popmax 0.908%, nfe).

How common is PDE5A p.Arg740Lys (c.2219G>A) in the general population?

PDE5A p.Arg740Lys (c.2219G>A) is rare (popmax 0.908%, nfe) (gnomAD).

What do computational predictors say about PDE5A p.Arg740Lys (c.2219G>A)?

AlphaMissense predicts likely benign (score 0.0682) — an in-silico prediction, not a clinical call.

PDE5A p.Arg740Lys

c.2219G>A · rs139979143 · VCV708681

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0682 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.908%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0682	likely benign
REVEL	0.175	moderately benign-leaning
SaProt	LLR -5.05	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP 1.1, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 130 kb · p 1.5e-08 · regional, not allelic
Overall
CADD	16.96	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.908% European (non-Finnish) · 10,524/1,158,806 alleles

Filtering AF 0.894% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.888%

Overall 0.747% 11,719/1,567,908 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.908%	110
Remaining individualsnot grpmax-eligible	0.706%	142
Finnishnot grpmax-eligible	0.423%	236
South Asian	0.344%	291
Middle Eastern	0.22%	454
Admixed American	0.2%	500
African / African-American	0.131%	765
East Asian	0.00235%	42,576

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.Arg740Lys
Coding: c.2219G>A
MANE Select: NM_001083
dbSNP: rs139979143
Type: single nucleotide variant
Location: chr4:119505903 (GRCh38)
Gene constraint: LOEUF 0.704 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.32 · 50 PDB
Residue 740: 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.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
PDE5A p.Ala282Val 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-arg740lys (accessed [today's date]).

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