Is NOX4 p.Pro90Arg (c.269C>G) pathogenic?

NOX4 p.Pro90Arg (c.269C>G) is classified Uncertain significance in NOX4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-03). AlphaMissense: likely benign (0.1218); Very rare (popmax 0.000255%, nfe).

How common is NOX4 p.Pro90Arg (c.269C>G) in the general population?

NOX4 p.Pro90Arg (c.269C>G) is very rare (popmax 0.000255%, nfe) (gnomAD).

What do computational predictors say about NOX4 p.Pro90Arg (c.269C>G)?

AlphaMissense predicts likely benign (score 0.1218) — an in-silico prediction, not a clinical call.

NOX4 p.Pro90Arg

c.269C>G · VCV3921169

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1218 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000255%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1218	likely benign
REVEL	0.545	indeterminate
SaProt	LLR -4.61	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 9.9	GERP 1.4, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 164 kb · p 0.96 · regional, not allelic
Overall
CADD	23.2	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 0.000255% European (non-Finnish) · 3/1,176,570 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,608,922 alleles · very rare exomes 3/1,456,870 · genomes 0/152,052 · joint denominator

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: NOX4
Protein: p.Pro90Arg
Coding: c.269C>G
MANE Select: NM_016931
Type: single nucleotide variant
Location: chr11:89449520 (GRCh38)
Gene constraint: LOEUF 1.018 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.98
Residue 90: the ferric oxidoreductase domain

Full NOX4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

NOX4 c.1218-6C>T Benign ★★ same type
NOX4 p.Arg470Cys Benign ★★ same type
NOX4 p.Arg95= Likely benign ★★ same type
NOX4 p.Leu97Phe Likely benign ★★ same type
NOX4 p.Pro224= Likely benign ★★ same type
NOX4 p.Ala10Thr Uncertain significance ★ ⚠ same type
NOX4 p.Ala333Thr Uncertain significance ★ ⚠ same type
NOX4 p.Arg231Gln 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/nox4-p-pro90arg (accessed [today's date]).

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