Is DUOX2 p.Pro138= (c.414C>T) pathogenic?

DUOX2 p.Pro138= (c.414C>T) is classified Conflicting classifications of pathogenicity in DUOX2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2018-07-27). Ultra-rare (popmax 0.0107%, nfe); Associated with thyroid dyshormonogenesis 6.

What condition is associated with DUOX2 p.Pro138= (c.414C>T)?

DUOX2 p.Pro138= (c.414C>T) is associated with thyroid dyshormonogenesis 6 (ClinVar).

How common is DUOX2 p.Pro138= (c.414C>T) in the general population?

DUOX2 p.Pro138= (c.414C>T) is ultra-rare (popmax 0.0107%, nfe) (gnomAD).

How is Genetic transient congenital hypothyroidism inherited?

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

DUOX2 p.Pro138=

c.414C>T · rs757849047 · VCV753718

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0107%, nfe)

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 -5.9	GERP -3.4
Overall
CADD	2.978	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0107% European (non-Finnish) · 126/1,180,006 alleles

Filtering AF 0.00911% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00855%

Overall 0.00824% 133/1,613,650 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0107%	9,365
Remaining individualsnot grpmax-eligible	0.008%	12,496
Admixed American	0.00167%	59,988
African / African-American	0.00133%	74,940

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.Pro138=
Coding: c.414C>T
MANE Select: NM_001363711
dbSNP: rs757849047
Type: single nucleotide variant
Location: chr15:45111867 (GRCh38)
Gene constraint: LOEUF 1.165 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.37
Residue 138: the 'peroxidase-like; mediates peroxidase activity' region; a disulfide bond; a UniProt-annotated variant site (in)

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-pro138 (accessed [today's date]).

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