Is NOX3 p.Ser528Arg (c.1584C>A) pathogenic?

NOX3 p.Ser528Arg (c.1584C>A) is classified Uncertain significance in NOX3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-24). AlphaMissense: likely benign (0.2506); Very rare (popmax 0.00112%, sas).

How common is NOX3 p.Ser528Arg (c.1584C>A) in the general population?

NOX3 p.Ser528Arg (c.1584C>A) is very rare (popmax 0.00112%, sas) (gnomAD).

What do computational predictors say about NOX3 p.Ser528Arg (c.1584C>A)?

AlphaMissense predicts likely benign (score 0.2506) — an in-silico prediction, not a clinical call.

NOX3 p.Ser528Arg

c.1584C>A · VCV4121820

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2506 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00112%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2506	likely benign
REVEL	0.571	indeterminate
SaProt	LLR -9.28	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.1	GERP 0.023, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 59 kb · p 0.76 · regional, not allelic
Overall
CADD	21.8	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 0.00112% South Asian · 1/89,284 alleles

Overall 0.000656% 1/152,336 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: NOX3
Protein: p.Ser528Arg
Coding: c.1584C>A
MANE Select: NM_015718
Type: single nucleotide variant
Location: chr6:155396959 (GRCh38)
Gene constraint: LOEUF 1.2 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.84

Full NOX3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

NOX3 p.Ala106Thr Uncertain significance ★ ⚠ same type
NOX3 p.Ala119Glu Uncertain significance ★ ⚠ same type
NOX3 p.Ala141Thr Uncertain significance ★ ⚠ same type
NOX3 p.Ala247Glu Uncertain significance ★ ⚠ same type
NOX3 p.Ala318Val Uncertain significance ★ ⚠ same type
NOX3 p.Ala343Val Uncertain significance ★ ⚠ same type
NOX3 p.Ala361Thr Uncertain significance ★ ⚠ same type
NOX3 p.Ala407Thr 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/nox3-p-ser528arg (accessed [today's date]).

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