Is PDE5A p.Arg222His (c.665G>A) pathogenic?

PDE5A p.Arg222His (c.665G>A) is classified Uncertain significance in PDE5A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-06). AlphaMissense: likely benign (0.1349); Ultra-rare (popmax 0.0801%, afr).

How common is PDE5A p.Arg222His (c.665G>A) in the general population?

PDE5A p.Arg222His (c.665G>A) is ultra-rare (popmax 0.0801%, afr) (gnomAD).

What do computational predictors say about PDE5A p.Arg222His (c.665G>A)?

AlphaMissense predicts likely benign (score 0.1349) — an in-silico prediction, not a clinical call.

PDE5A p.Arg222His

c.665G>A · rs200971951 · VCV2455704

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1349 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0801%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1349	likely benign
REVEL	0.28	benign-leaning
SaProt	LLR -10.01	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.7, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 130 kb · p 1.5e-08 · regional, not allelic
Overall
CADD	29.4	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 0.0801% African / African-American · 60/74,908 alleles

Filtering AF 0.0638% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.058%

Overall 0.00706% 114/1,614,044 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0801%	1,248
Admixed American	0.0283%	3,530
Remaining individualsnot grpmax-eligible	0.0176%	5,681
South Asian	0.00769%	13,011
East Asian	0.00223%	44,898
European (non-Finnish)	0.00153%	65,558

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.Arg222His
Coding: c.665G>A
MANE Select: NM_001083
dbSNP: rs200971951
Type: single nucleotide variant
Location: chr4:119606785 (GRCh38)
Gene constraint: LOEUF 0.704 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.32 · 50 PDB
Residue 222: the gaf 1 domain; a β-strand

Full PDE5A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PDE5A p.Arg222Cys Uncertain significance ★ ⚠ same residue
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

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-arg222his (accessed [today's date]).

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