Is PDE5A p.Arg732Gln (c.2195G>A) pathogenic?

PDE5A p.Arg732Gln (c.2195G>A) is classified Uncertain significance in PDE5A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-20). AlphaMissense: ambiguous (0.5309); Very rare (popmax 0.00699%, afr).

How common is PDE5A p.Arg732Gln (c.2195G>A) in the general population?

PDE5A p.Arg732Gln (c.2195G>A) is very rare (popmax 0.00699%, afr) (gnomAD).

What do computational predictors say about PDE5A p.Arg732Gln (c.2195G>A)?

AlphaMissense predicts ambiguous (score 0.5309) — an in-silico prediction, not a clinical call.

PDE5A p.Arg732Gln

c.2195G>A · VCV4133848

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5309 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00699%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5309	ambiguous
REVEL	0.682	pathogenic-leaning
SaProt	LLR -8.91	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 130 kb · p 1.5e-08 · regional, not allelic
Overall
CADD	32.0	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 0.00699% African / African-American · 5/71,546 alleles

Filtering AF 0.00274% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00178%

Overall 0.000854% 12/1,405,180 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00699%	14,309
Remaining individualsnot grpmax-eligible	0.00332%	30,097
South Asian	0.0012%	83,490
European (non-Finnish)	0.000348%	287,036

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.Arg732Gln
Coding: c.2195G>A
MANE Select: NM_001083
Type: single nucleotide variant
Location: chr4:119505927 (GRCh38)
Gene constraint: LOEUF 0.704 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.32 · 50 PDB
Residue 732: 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-arg732gln (accessed [today's date]).

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