Is DUOX2 p.Phe591Ser (c.1772T>C) pathogenic?

DUOX2 p.Phe591Ser (c.1772T>C) is classified Uncertain significance in DUOX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-10). AlphaMissense: likely pathogenic (0.6993); Very rare (popmax 0.00907%, eas).

How common is DUOX2 p.Phe591Ser (c.1772T>C) in the general population?

DUOX2 p.Phe591Ser (c.1772T>C) is very rare (popmax 0.00907%, eas) (gnomAD).

What do computational predictors say about DUOX2 p.Phe591Ser (c.1772T>C)?

AlphaMissense predicts likely pathogenic (score 0.6993) — an in-silico prediction, not a clinical call.

DUOX2 p.Phe591Ser

c.1772T>C · rs914992230 · VCV1462084

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6993 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00907%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6993	likely pathogenic
REVEL	0.691	pathogenic-leaning
SaProt	LLR -3.86	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 17 kb · p 0.63 · regional, not allelic
Overall
CADD	25.3	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 0.00907% East Asian · 4/44,088 alleles

Filtering AF 0.00302% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00182%

Overall 0.00265% 42/1,585,834 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00907%	11,022
Admixed American	0.00559%	17,892
European (non-Finnish)	0.00283%	35,356
South Asian	0.00231%	43,282

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.Phe591Ser
Coding: c.1772T>C
MANE Select: NM_001363711
dbSNP: rs914992230
Type: single nucleotide variant
Location: chr15:45106891 (GRCh38)
Gene constraint: LOEUF 1.165 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.37
Residue 591: 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 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
DUOX2 c.3415+1G>C Likely pathogenic ★★ same type
DUOX2 c.3516-1G>C Pathogenic/Likely pathogenic ★★ same type
DUOX2 c.3693+1G>T Pathogenic/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-phe591ser (accessed [today's date]).

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