Is DUOX2 p.Ser199= (c.597G>C) pathogenic?

DUOX2 p.Ser199= (c.597G>C) is classified Conflicting classifications of pathogenicity in DUOX2 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-06-01). Rare (popmax 0.573%, mid); Associated with thyroid dyshormonogenesis 6.

What condition is associated with DUOX2 p.Ser199= (c.597G>C)?

DUOX2 p.Ser199= (c.597G>C) is associated with thyroid dyshormonogenesis 6 (ClinVar).

How common is DUOX2 p.Ser199= (c.597G>C) in the general population?

DUOX2 p.Ser199= (c.597G>C) is rare (popmax 0.573%, mid) (gnomAD).

How is Genetic transient congenital hypothyroidism inherited?

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

DUOX2 p.Ser199=

c.597G>C · rs2467828 · VCV733640

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

rare (popmax 0.573%, mid)

Conditions

thyroid dyshormonogenesis 6

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.9	GERP -2.9
Overall
CADD	1.365	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.573% Middle Eastern · 25/4,364 alleles

Filtering AF 0.398% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.34%

Overall 0.135% 2,088/1,551,282 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.573%	175
South Asian	0.191%	524
African / African-American	0.174%	575
Remaining individualsnot grpmax-eligible	0.158%	631
European (non-Finnish)	0.141%	710
Admixed American	0.0989%	1,012
Ashkenazi Jewishnot grpmax-eligible	0.0105%	9,513
Finnishnot grpmax-eligible	0.00882%	11,339
East Asian	0.00242%	41,290

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.Ser199=
Coding: c.597G>C
MANE Select: NM_001363711
dbSNP: rs2467828
Type: single nucleotide variant
Location: chr15:45111502 (GRCh38)
Gene constraint: LOEUF 1.165 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.37
Residue 199: 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 p.Ser199fs Pathogenic ★ same residue
DUOX2 p.Ser199Leu Uncertain significance ★ ⚠ 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

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-ser199 (accessed [today's date]).

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