Is DUOX2 p.Ser855Phe (c.2564C>T) pathogenic?

DUOX2 p.Ser855Phe (c.2564C>T) is classified Uncertain significance in DUOX2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-09-20). AlphaMissense: likely benign (0.2697); Very rare (popmax 0.000339%, nfe).

How common is DUOX2 p.Ser855Phe (c.2564C>T) in the general population?

DUOX2 p.Ser855Phe (c.2564C>T) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about DUOX2 p.Ser855Phe (c.2564C>T)?

AlphaMissense predicts likely benign (score 0.2697) — an in-silico prediction, not a clinical call.

DUOX2 p.Ser855Phe

c.2564C>T · rs1051450369 · VCV392662

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2697 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2697	likely benign
REVEL	0.392	indeterminate
SaProt	LLR -9.59	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 17 kb · p 0.63 · regional, not allelic
Overall
CADD	26.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,180,028 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000274% 4/1,461,884 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.Ser855Phe
Coding: c.2564C>T
MANE Select: NM_001363711
dbSNP: rs1051450369
Type: single nucleotide variant
Location: chr15:45104050 (GRCh38)
Gene constraint: LOEUF 1.165 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.37
Residue 855: the ef-hand 2 domain; a disulfide bond

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

Similar variants

DUOX2 p.Ser855= Likely benign ★ 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
DUOX2 c.3516-1G>C Pathogenic/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-ser855phe (accessed [today's date]).

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