Is PDE5A p.Ala337Gly (c.1010C>G) pathogenic?

PDE5A p.Ala337Gly (c.1010C>G) is classified Uncertain significance in PDE5A (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-14). AlphaMissense: likely pathogenic (0.9077); Very rare (popmax 0.00561%, amr).

How common is PDE5A p.Ala337Gly (c.1010C>G) in the general population?

PDE5A p.Ala337Gly (c.1010C>G) is very rare (popmax 0.00561%, amr) (gnomAD).

What do computational predictors say about PDE5A p.Ala337Gly (c.1010C>G)?

AlphaMissense predicts likely pathogenic (score 0.9077) — an in-silico prediction, not a clinical call.

PDE5A p.Ala337Gly

c.1010C>G · rs183868303 · VCV2237436

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9077 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00561%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9077	likely pathogenic
REVEL	0.524	indeterminate
SaProt	LLR -11.49	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 130 kb · p 1.5e-08 · regional, not allelic
Overall
CADD	28.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00561% Admixed American · 3/53,476 alleles

Filtering AF 0.00149% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000813%

Overall 0.000252% 4/1,588,036 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00561%	17,825
Remaining individualsnot grpmax-eligible	0.00163%	61,332

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.Ala337Gly
Coding: c.1010C>G
MANE Select: NM_001083
dbSNP: rs183868303
Type: single nucleotide variant
Location: chr4:119562954 (GRCh38)
Gene constraint: LOEUF 0.704 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.32 · 50 PDB
Residue 337: the gaf 2 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-ala337gly (accessed [today's date]).

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