Is PDE5A p.Glu830Gln (c.2488G>C) pathogenic?

PDE5A p.Glu830Gln (c.2488G>C) is classified Uncertain significance in PDE5A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-22). AlphaMissense: likely benign (0.1591); Rare (popmax 0.105%, afr).

How common is PDE5A p.Glu830Gln (c.2488G>C) in the general population?

PDE5A p.Glu830Gln (c.2488G>C) is rare (popmax 0.105%, afr) (gnomAD).

What do computational predictors say about PDE5A p.Glu830Gln (c.2488G>C)?

AlphaMissense predicts likely benign (score 0.1591) — an in-silico prediction, not a clinical call.

PDE5A p.Glu830Gln

c.2488G>C · VCV3887256

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1591 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.105%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1591	likely benign
REVEL	0.387	indeterminate
SaProt	LLR -9.24	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.24 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 130 kb · p 1.5e-08 · regional, not allelic
Overall
CADD	23.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.105% African / African-American · 78/74,562 alleles

Filtering AF 0.0859% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.079%

Overall 0.00546% 87/1,593,080 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.105%	956
Admixed American	0.00667%	14,988
Remaining individualsnot grpmax-eligible	0.00647%	15,448
European (non-Finnish)	8.61e-05%	1,161,179

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.Glu830Gln
Coding: c.2488G>C
MANE Select: NM_001083
Type: single nucleotide variant
Location: chr4:119501172 (GRCh38)
Gene constraint: LOEUF 0.704 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.32 · 50 PDB
Residue 830: 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-glu830gln (accessed [today's date]).

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