Is PDE5A p.Ile340Thr (c.1019T>C) pathogenic?

PDE5A p.Ile340Thr (c.1019T>C) is classified Uncertain significance in PDE5A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-07). AlphaMissense: likely pathogenic (0.9718); Absent from gnomAD v4.1.

How common is PDE5A p.Ile340Thr (c.1019T>C) in the general population?

PDE5A p.Ile340Thr (c.1019T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PDE5A p.Ile340Thr (c.1019T>C)?

AlphaMissense predicts likely pathogenic (score 0.9718) — an in-silico prediction, not a clinical call.

PDE5A p.Ile340Thr

c.1019T>C · rs1727795885 · VCV3210741

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9718 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9718	likely pathogenic
REVEL	0.851	moderately pathogenic-leaning
SaProt	LLR -10.89	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 130 kb · p 1.5e-08 · regional, not allelic
Overall
CADD	26.2	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PDE5A
Protein: p.Ile340Thr
Coding: c.1019T>C
MANE Select: NM_001083
dbSNP: rs1727795885
Type: single nucleotide variant
Location: chr4:119562945 (GRCh38)
Gene constraint: LOEUF 0.704 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.32 · 50 PDB
Residue 340: 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-ile340thr (accessed [today's date]).

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