Is NOX3 p.Pro274Ser (c.820C>T) pathogenic?

NOX3 p.Pro274Ser (c.820C>T) is classified Uncertain significance in NOX3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-01). AlphaMissense: likely benign (0.3031); Rare (popmax 0.119%, amr).

How common is NOX3 p.Pro274Ser (c.820C>T) in the general population?

NOX3 p.Pro274Ser (c.820C>T) is rare (popmax 0.119%, amr) (gnomAD).

What do computational predictors say about NOX3 p.Pro274Ser (c.820C>T)?

AlphaMissense predicts likely benign (score 0.3031) — an in-silico prediction, not a clinical call.

NOX3 p.Pro274Ser

c.820C>T · VCV4121812

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3031 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.119%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3031	likely benign
REVEL	0.817	moderately pathogenic-leaning
SaProt	LLR -12.39	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 59 kb · p 0.76 · regional, not allelic
Overall
CADD	26.3	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 0.119% Admixed American · 71/59,910 alleles

Filtering AF 0.0963% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0882%

Overall 0.0642% 1,035/1,611,788 alleles · rare

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	1.21%	83
Admixed Americangrpmax	0.119%	844
European (non-Finnish)	0.0762%	1,312
Remaining individualsnot grpmax-eligible	0.0577%	1,734
Middle Eastern	0.0495%	2,021
Finnishnot grpmax-eligible	0.011%	9,107
African / African-American	0.0107%	9,359
South Asian	0.0011%	90,950

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro274Ser
Coding: c.820C>T
MANE Select: NM_015718
Type: single nucleotide variant
Location: chr6:155430914 (GRCh38)
Gene constraint: LOEUF 1.2 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.84
Residue 274: the ferric oxidoreductase domain

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-pro274ser (accessed [today's date]).

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