Is DUOX2 p.Leu129Pro (c.386T>C) pathogenic?

DUOX2 p.Leu129Pro (c.386T>C) is classified Uncertain significance in DUOX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-06). AlphaMissense: likely pathogenic (0.793); Absent from gnomAD v4.1.

How common is DUOX2 p.Leu129Pro (c.386T>C) in the general population?

DUOX2 p.Leu129Pro (c.386T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DUOX2 p.Leu129Pro (c.386T>C)?

AlphaMissense predicts likely pathogenic (score 0.793) — an in-silico prediction, not a clinical call.

DUOX2 p.Leu129Pro

c.386T>C · rs1894432326 · VCV1485523

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.793 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.793	likely pathogenic
REVEL	0.37	indeterminate
SaProt	LLR -8.99	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.7, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 2,165 bp · p 0.98 · regional, not allelic
Overall
CADD	28.3	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: DUOX2
Protein: p.Leu129Pro
Coding: c.386T>C
MANE Select: NM_001363711
dbSNP: rs1894432326
Type: single nucleotide variant
Location: chr15:45111895 (GRCh38)
Gene constraint: LOEUF 1.165 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.37
Residue 129: the 'peroxidase-like; mediates peroxidase activity' region; a disulfide bond

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

Similar variants

DUOX2 p.Leu129Arg Uncertain significance ★★ ⚠ same residue
DUOX2 p.Leu129Phe Uncertain significance ★ ⚠ same residue
DUOX2 c.1040+1G>T Likely pathogenic ★★ same type
DUOX2 c.1831+2T>G Likely pathogenic ★★ same type
DUOX2 c.2335-1G>C Pathogenic/Likely pathogenic ★★ same type
DUOX2 c.2560+2T>C Likely pathogenic ★★ same type
DUOX2 c.3006-2A>G Likely pathogenic ★★ same type
DUOX2 c.3415+1G>C Likely pathogenic ★★ same type

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-leu129pro (accessed [today's date]).

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