Is PDE5A p.Ser78Thr (c.232T>A) pathogenic?

PDE5A p.Ser78Thr (c.232T>A) is classified Uncertain significance in PDE5A (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-23). AlphaMissense: likely benign (0.0622); Very rare (popmax 8.47e-05%, nfe).

How common is PDE5A p.Ser78Thr (c.232T>A) in the general population?

PDE5A p.Ser78Thr (c.232T>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about PDE5A p.Ser78Thr (c.232T>A)?

AlphaMissense predicts likely benign (score 0.0622) — an in-silico prediction, not a clinical call.

PDE5A p.Ser78Thr

c.232T>A · rs1027737715 · VCV2246593

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0622 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0622	likely benign
REVEL	0.015	strongly benign-leaning
SaProt	LLR -6.61	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>C here scores Δ0.37 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.5	GERP -3.7, phastCons 0.001
Regional constraint	o/e 0.82	unconstrained · MANE · 130 kb · p 1.5e-08 · regional, not allelic
Overall
CADD	7.811	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 8.47e-05% European (non-Finnish) · 1/1,180,026 alleles

Overall 0.000657% 1/152,164 alleles · very rare

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.Ser78Thr
Coding: c.232T>A
MANE Select: NM_001083
dbSNP: rs1027737715
Type: single nucleotide variant
Location: chr4:119607218 (GRCh38)
Gene constraint: LOEUF 0.704 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.32 · 50 PDB
Residue 78: the 'disordered' region

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

Similar variants

PDE5A p.Ser78Pro 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-ser78thr (accessed [today's date]).

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