Is PDE5A p.Glu475= (c.1425G>A) pathogenic?

PDE5A p.Glu475= (c.1425G>A) is classified Benign/Likely benign in PDE5A (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-02-01). Rare (popmax 0.406%, nfe).

How common is PDE5A p.Glu475= (c.1425G>A) in the general population?

PDE5A p.Glu475= (c.1425G>A) is rare (popmax 0.406%, nfe) (gnomAD).

PDE5A p.Glu475=

c.1425G>A · rs148360694 · VCV779420

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.406%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.31	GERP -2, phastCons 0.12
Overall
CADD	6.565	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.406% European (non-Finnish) · 4,790/1,179,834 alleles

Filtering AF 0.396% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.392%

Overall 0.354% 5,711/1,613,854 alleles · rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.936%	107
Remaining individualsnot grpmax-eligible	0.488%	205
European (non-Finnish)grpmax	0.406%	246
South Asian	0.193%	517
Middle Eastern	0.132%	758
Admixed American	0.132%	759
African / African-American	0.0667%	1,500
Finnishnot grpmax-eligible	0.0406%	2,463

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Glu475=
Coding: c.1425G>A
MANE Select: NM_001083
dbSNP: rs148360694
Type: single nucleotide variant
Location: chr4:119542606 (GRCh38)
Gene constraint: LOEUF 0.704 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.32 · 50 PDB
Residue 475: the gaf 2 domain

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.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-glu475 (accessed [today's date]).

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