Is DUOX2 p.Pro1520Ser (c.4558C>T) pathogenic?

DUOX2 p.Pro1520Ser (c.4558C>T) is classified Uncertain significance in DUOX2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-14). AlphaMissense: likely benign (0.3252); Very rare (popmax 0.000254%, nfe); Associated with Inborn genetic diseases.

What condition is associated with DUOX2 p.Pro1520Ser (c.4558C>T)?

DUOX2 p.Pro1520Ser (c.4558C>T) is associated with Inborn genetic diseases (ClinVar).

How common is DUOX2 p.Pro1520Ser (c.4558C>T) in the general population?

DUOX2 p.Pro1520Ser (c.4558C>T) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about DUOX2 p.Pro1520Ser (c.4558C>T)?

AlphaMissense predicts likely benign (score 0.3252) — an in-silico prediction, not a clinical call.

DUOX2 p.Pro1520Ser

c.4558C>T · rs1893837403 · VCV2494441

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3252 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3252	likely benign
REVEL	0.828	moderately pathogenic-leaning
SaProt	LLR -6.71	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 17 kb · p 0.63 · regional, not allelic
Overall
CADD	23.5	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 0.000254% European (non-Finnish) · 3/1,180,034 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,614,042 alleles · very rare

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.Pro1520Ser
Coding: c.4558C>T
MANE Select: NM_001363711
dbSNP: rs1893837403
Type: single nucleotide variant
Location: chr15:45094239 (GRCh38)
Gene constraint: LOEUF 1.165 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.37

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DUOX2 p.Pro1520Ala Uncertain significance ★★ ⚠ same residue
DUOX2 c.513+1G>C Pathogenic/Likely pathogenic ★★ same condition
DUOX2 p.Arg434Ter Pathogenic ★★ same condition
DUOX2 p.Arg625Ter Pathogenic/Likely pathogenic ★★ same condition
DUOX2 c.3693+5G>C Uncertain significance ★★ same condition
DUOX2 p.Ala1133Pro Uncertain significance ★★ ⚠ same condition
DUOX2 p.Ala1138Thr Uncertain significance ★★ ⚠ same condition
DUOX2 p.Ala1230Ser Uncertain significance ★★ ⚠ 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-pro1520ser (accessed [today's date]).

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