Is PDE5A p.Arg777Gln (c.2330G>A) pathogenic?

PDE5A p.Arg777Gln (c.2330G>A) is classified Uncertain significance in PDE5A (ClinVar, Single submitter, 2 submitters; last evaluated 2025-04-03). AlphaMissense: likely benign (0.0864); Very rare (popmax 0.0033%, sas).

How common is PDE5A p.Arg777Gln (c.2330G>A) in the general population?

PDE5A p.Arg777Gln (c.2330G>A) is very rare (popmax 0.0033%, sas) (gnomAD).

What do computational predictors say about PDE5A p.Arg777Gln (c.2330G>A)?

AlphaMissense predicts likely benign (score 0.0864) — an in-silico prediction, not a clinical call.

PDE5A p.Arg777Gln

c.2330G>A · VCV3930065

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0864 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0033%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0864	likely benign
REVEL	0.579	indeterminate
SaProt	LLR -3.82	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP 0.021, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 130 kb · p 1.5e-08 · regional, not allelic
Overall
CADD	30.0	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 0.0033% South Asian · 3/90,796 alleles

Filtering AF 0.00115% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000974%

Overall 0.00187% 30/1,608,260 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0033%	30,265
Remaining individualsnot grpmax-eligible	0.00321%	31,115
African / African-American	0.00268%	37,310
East Asian	0.00223%	44,762
European (non-Finnish)	0.00179%	55,994
Admixed American	0.00167%	59,740

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.Arg777Gln
Coding: c.2330G>A
MANE Select: NM_001083
Type: single nucleotide variant
Location: chr4:119504537 (GRCh38)
Gene constraint: LOEUF 0.704 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.32 · 50 PDB
Residue 777: 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-arg777gln (accessed [today's date]).

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