Is DUOX2 p.Pro207fs (c.618dup) pathogenic?

DUOX2 p.Pro207fs (c.618dup) is classified Pathogenic in DUOX2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-07-01). Ultra-rare (popmax 0.0474%, sas); Associated with congenital hypothyroidism.

What condition is associated with DUOX2 p.Pro207fs (c.618dup)?

DUOX2 p.Pro207fs (c.618dup) is associated with congenital hypothyroidism (ClinVar).

How common is DUOX2 p.Pro207fs (c.618dup) in the general population?

DUOX2 p.Pro207fs (c.618dup) is ultra-rare (popmax 0.0474%, sas) (gnomAD).

DUOX2 p.Pro207fs

c.618dup · rs772809435 · VCV3031356

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0474%, sas)

Conditions

congenital hypothyroidism

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 6 of 34
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.2	GERP -3.4
Overall
CADD	22.8	PHRED · no single calibrated threshold — expert panels disagree
Region caveats
Repeat context	seg dup	· reads may not map uniquely · confidence, not pathogenicity

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0474% South Asian · 40/84,320 alleles

Filtering AF 0.0357% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0317%

Overall 0.00271% 42/1,550,466 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0474%	2,108
Remaining individualsnot grpmax-eligible	0.00167%	59,950
European (non-Finnish)	8.69e-05%	1,150,406

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.Pro207fs
Coding: c.618dup
MANE Select: NM_001363711
dbSNP: rs772809435
Type: Duplication
Location: chr15:45111480 (GRCh38)
Gene constraint: LOEUF 1.165 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.37
Residue 207: 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

congenital hypothyroidism — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DUOX2 p.Pro207Ser Uncertain significance ★ ⚠ same residue
DUOX2 p.Arg1110Ter Pathogenic/Likely pathogenic ★★ same condition
DUOX2 p.Arg376Trp Pathogenic/Likely pathogenic ★★ ⚠ same condition
DUOX2 p.Ala1323Thr Uncertain significance ★★ ⚠ same condition
DUOX2 p.Arg1492Cys Uncertain significance ★★ ⚠ same condition
DUOX2 p.Arg422Cys Uncertain significance ★★ ⚠ same condition
DUOX2 c.3416-1G>A Likely pathogenic ★ same condition
DUOX2 c.2922-14_2925del Conflicting classifications of pathogenicity ★ 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-pro207fs (accessed [today's date]).

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