Is DUOX2 p.Arg422Pro (c.1265G>C) pathogenic?

DUOX2 p.Arg422Pro (c.1265G>C) is classified Uncertain significance in DUOX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-26). AlphaMissense: likely pathogenic (0.8986); Very rare (popmax 0.00167%, amr).

How common is DUOX2 p.Arg422Pro (c.1265G>C) in the general population?

DUOX2 p.Arg422Pro (c.1265G>C) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about DUOX2 p.Arg422Pro (c.1265G>C)?

AlphaMissense predicts likely pathogenic (score 0.8986) — an in-silico prediction, not a clinical call.

DUOX2 p.Arg422Pro

c.1265G>C · rs201135069 · VCV1977460

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8986 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8986	likely pathogenic · top 9% in DUOX2
REVEL	0.794	moderately pathogenic-leaning
SaProt	LLR -5.35	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	Δ0.41	acceptor gain · deltas
Pangolin	Δ0.22	gain · loss 0.09 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 4.9	GERP 0.85, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 17 kb · p 0.63 · regional, not allelic
Overall
CADD	33.0	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 0.00167% Admixed American · 1/60,030 alleles

Overall 0.000137% 2/1,461,884 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,030
Remaining individualsnot grpmax-eligible	0.0016%	62,508

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: DUOX2
Protein: p.Arg422Pro
Coding: c.1265G>C
MANE Select: NM_001363711
dbSNP: rs201135069
Type: single nucleotide variant
Location: chr15:45108922 (GRCh38)
Gene constraint: LOEUF 1.165 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.37
Residue 422: the 'peroxidase-like; mediates peroxidase activity' region; a disulfide bond

Full DUOX2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DUOX2 p.Arg422Cys Uncertain significance ★★ ⚠ same residue
DUOX2 p.Arg422His Uncertain significance ★★ ⚠ same residue
DUOX2 p.Arg422Gly Uncertain significance ★ ⚠ same residue
DUOX2 c.1040+1G>T Likely pathogenic ★★ same type
DUOX2 c.1831+2T>G Likely pathogenic ★★ same type
DUOX2 c.2335-1G>C Pathogenic/Likely pathogenic ★★ same type
DUOX2 c.2560+2T>C Likely pathogenic ★★ same type
DUOX2 c.3006-2A>G Likely pathogenic ★★ 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/duox2-p-arg422pro (accessed [today's date]).

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