Is NOX3 p.Pro149Ser (c.445C>T) pathogenic?

NOX3 p.Pro149Ser (c.445C>T) is classified Uncertain significance in NOX3 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-14). AlphaMissense: likely benign (0.0791); Ultra-rare (popmax 0.0125%, nfe).

How common is NOX3 p.Pro149Ser (c.445C>T) in the general population?

NOX3 p.Pro149Ser (c.445C>T) is ultra-rare (popmax 0.0125%, nfe) (gnomAD).

What do computational predictors say about NOX3 p.Pro149Ser (c.445C>T)?

AlphaMissense predicts likely benign (score 0.0791) — an in-silico prediction, not a clinical call.

NOX3 p.Pro149Ser

c.445C>T · rs374486371 · VCV2370088

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0791 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0125%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0791	likely benign
REVEL	0.337	indeterminate
SaProt	LLR -6.06	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 2.6	GERP 1.6, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 59 kb · p 0.76 · regional, not allelic
Overall
CADD	16.36	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 0.0125% European (non-Finnish) · 147/1,180,010 alleles

Filtering AF 0.0108% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0102%

Overall 0.0096% 155/1,613,976 alleles · ultra-rare exomes 149/1,461,846 · genomes 6/152,130 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0125%	8,027
Remaining individualsnot grpmax-eligible	0.0112%	8,926
African / African-American	0.00134%	74,900

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.Pro149Ser
Coding: c.445C>T
MANE Select: NM_015718
dbSNP: rs374486371
Type: single nucleotide variant
Location: chr6:155443314 (GRCh38)
Gene constraint: LOEUF 1.2 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.84
Residue 149: 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-pro149ser (accessed [today's date]).

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