Is PDE5A p.Ile778Thr (c.2333T>C) pathogenic?

PDE5A p.Ile778Thr (c.2333T>C) is classified Likely benign in PDE5A (ClinVar, Single submitter, 1 submitter; last evaluated 2018-06-16). AlphaMissense: likely benign (0.2299); Rare (popmax 0.35%, nfe).

How common is PDE5A p.Ile778Thr (c.2333T>C) in the general population?

PDE5A p.Ile778Thr (c.2333T>C) is rare (popmax 0.35%, nfe) (gnomAD).

What do computational predictors say about PDE5A p.Ile778Thr (c.2333T>C)?

AlphaMissense predicts likely benign (score 0.2299) — an in-silico prediction, not a clinical call.

PDE5A p.Ile778Thr

c.2333T>C · rs114886951 · VCV779419

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2299 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.35%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2299	likely benign
REVEL	0.719	pathogenic-leaning
SaProt	LLR -8.23	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>C here scores Δ0.38 · evaluated, not missing
Constraint at this position
Conservation	phyloP 11	GERP 2.1, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 130 kb · p 1.5e-08 · regional, not allelic
Overall
CADD	26.0	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 0.35% European (non-Finnish) · 4,071/1,161,796 alleles

Filtering AF 0.341% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.338%

Overall 0.279% 4,447/1,591,628 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.35%	285
Remaining individualsnot grpmax-eligible	0.323%	310
Admixed American	0.0893%	1,120
South Asian	0.0768%	1,302
African / African-American	0.0564%	1,773
Finnishnot grpmax-eligible	0.0189%	5,297
Middle Eastern	0.0167%	6,006

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.Ile778Thr
Coding: c.2333T>C
MANE Select: NM_001083
dbSNP: rs114886951
Type: single nucleotide variant
Location: chr4:119502654 (GRCh38)
Gene constraint: LOEUF 0.704 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.32 · 50 PDB
Residue 778: 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-ile778thr (accessed [today's date]).

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