Is DUOX2 p.Ser166Arg (c.498C>A) pathogenic?

DUOX2 p.Ser166Arg (c.498C>A) is classified Uncertain significance in DUOX2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-01-29). AlphaMissense: likely pathogenic (0.8023); Very rare (popmax 0.00951%, nfe); Associated with thyroid dyshormonogenesis 6.

What condition is associated with DUOX2 p.Ser166Arg (c.498C>A)?

DUOX2 p.Ser166Arg (c.498C>A) is associated with thyroid dyshormonogenesis 6 (ClinVar).

How common is DUOX2 p.Ser166Arg (c.498C>A) in the general population?

DUOX2 p.Ser166Arg (c.498C>A) is very rare (popmax 0.00951%, nfe) (gnomAD).

How is Genetic transient congenital hypothyroidism inherited?

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

What do computational predictors say about DUOX2 p.Ser166Arg (c.498C>A)?

AlphaMissense predicts likely pathogenic (score 0.8023) — an in-silico prediction, not a clinical call.

DUOX2 p.Ser166Arg

c.498C>A · rs370438048 · VCV316187

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8023 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00951%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

thyroid dyshormonogenesis 6

Computational evidence

Protein change
AlphaMissense	0.8023	likely pathogenic
REVEL	0.109	moderately benign-leaning
SaProt	LLR -4.19	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.7	GERP -0.4, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 2,165 bp · p 0.98 · regional, not allelic
Overall
CADD	23.8	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 0.00951% European (non-Finnish) · 112/1,177,420 alleles

Filtering AF 0.00806% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00754%

Overall 0.00722% 116/1,607,198 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00951%	10,513
Remaining individualsnot grpmax-eligible	0.00322%	31,071
Admixed American	0.00169%	59,214
Finnishnot grpmax-eligible	0.0016%	62,552

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.Ser166Arg
Coding: c.498C>A
MANE Select: NM_001363711
dbSNP: rs370438048
Type: single nucleotide variant
Location: chr15:45111783 (GRCh38)
Gene constraint: LOEUF 1.165 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.37
Residue 166: the 'peroxidase-like; mediates peroxidase activity' region; a disulfide bond

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

Disease context

thyroid dyshormonogenesis 6 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Genetic transient congenital hypothyroidism (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

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
DUOX2 c.513+1G>C Pathogenic/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-ser166arg (accessed [today's date]).

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