Is DUOX2 p.Pro609Ser (c.1825C>T) pathogenic?

DUOX2 p.Pro609Ser (c.1825C>T) is classified Conflicting classifications of pathogenicity in DUOX2 (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2026-02-01). AlphaMissense: likely pathogenic (0.8343); Rare (popmax 0.596%, mid); Associated with familial thyroid dyshormonogenesis.

What condition is associated with DUOX2 p.Pro609Ser (c.1825C>T)?

DUOX2 p.Pro609Ser (c.1825C>T) is associated with familial thyroid dyshormonogenesis, thyroid dyshormonogenesis 6 (ClinVar).

How common is DUOX2 p.Pro609Ser (c.1825C>T) in the general population?

DUOX2 p.Pro609Ser (c.1825C>T) is rare (popmax 0.596%, mid) (gnomAD).

How is Familial thyroid dyshormonogenesis inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about DUOX2 p.Pro609Ser (c.1825C>T)?

AlphaMissense predicts likely pathogenic (score 0.8343) — an in-silico prediction, not a clinical call.

DUOX2 p.Pro609Ser

c.1825C>T · rs201221237 · VCV316175

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

AlphaMissense

likely pathogenic

0.8343 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.596%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

familial thyroid dyshormonogenesis

Computational evidence

Protein change
AlphaMissense	0.8343	likely pathogenic
REVEL	0.472	indeterminate
SaProt	LLR -10.02	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 17 kb · p 0.63 · regional, not allelic
Overall
CADD	27.1	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 0.596% Middle Eastern · 36/6,040 alleles

Filtering AF 0.443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.389%

Overall 0.0148% 236/1,595,322 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.596%	168
Remaining individualsnot grpmax-eligible	0.0258%	3,873
Admixed American	0.0162%	6,162
European (non-Finnish)	0.0136%	7,370
South Asian	0.0102%	9,772
African / African-American	0.00934%	10,712

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.Pro609Ser
Coding: c.1825C>T
MANE Select: NM_001363711
dbSNP: rs201221237
Type: single nucleotide variant
Location: chr15:45106838 (GRCh38)
Gene constraint: LOEUF 1.165 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.37
Residue 609: a disulfide bond

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

Disease context

familial thyroid dyshormonogenesis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: thyroid dyshormonogenesis 6

For Familial thyroid dyshormonogenesis (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Worldwide)

Similar variants

DUOX2 p.Pro609= Likely benign ★ same residue
DUOX2 c.1831+2T>G Likely pathogenic ★★ same condition
DUOX2 c.2335-1G>C Pathogenic/Likely pathogenic ★★ same condition
DUOX2 c.2560+2T>C Likely pathogenic ★★ same condition
DUOX2 c.3006-2A>G Likely pathogenic ★★ same condition
DUOX2 c.3693+1G>T Pathogenic/Likely pathogenic ★★ same condition
DUOX2 c.4081-1G>A Likely pathogenic ★★ same condition
DUOX2 c.4239+1G>A Likely pathogenic ★★ same condition

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-pro609ser (accessed [today's date]).

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