Is PDE5A p.Ala356Val (c.1067C>T) pathogenic?

PDE5A p.Ala356Val (c.1067C>T) is classified Uncertain significance in PDE5A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-05). AlphaMissense: likely benign (0.2717); Very rare (popmax 0.00775%, nfe).

How common is PDE5A p.Ala356Val (c.1067C>T) in the general population?

PDE5A p.Ala356Val (c.1067C>T) is very rare (popmax 0.00775%, nfe) (gnomAD).

What do computational predictors say about PDE5A p.Ala356Val (c.1067C>T)?

AlphaMissense predicts likely benign (score 0.2717) — an in-silico prediction, not a clinical call.

PDE5A p.Ala356Val

c.1067C>T · rs200428296 · VCV2353566

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2717 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00775%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2717	likely benign
REVEL	0.133	moderately benign-leaning
SaProt	LLR -4.71	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 130 kb · p 1.5e-08 · regional, not allelic
Overall
CADD	23.5	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 0.00775% European (non-Finnish) · 91/1,173,956 alleles

Filtering AF 0.00643% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00595%

Overall 0.00638% 102/1,599,712 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00775%	12,901
Remaining individualsnot grpmax-eligible	0.00647%	15,457
Finnishnot grpmax-eligible	0.0047%	21,282
East Asian	0.00455%	21,984
African / African-American	0.00271%	36,939

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.Ala356Val
Coding: c.1067C>T
MANE Select: NM_001083
dbSNP: rs200428296
Type: single nucleotide variant
Location: chr4:119562897 (GRCh38)
Gene constraint: LOEUF 0.704 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.32 · 50 PDB
Residue 356: 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-ala356val (accessed [today's date]).

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