Is DUOX2 p.Arg677Ser (c.2031G>C) pathogenic?

DUOX2 p.Arg677Ser (c.2031G>C) is classified Uncertain significance in DUOX2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-23). AlphaMissense: likely benign (0.1289); Very rare (popmax 0.00801%, afr).

How common is DUOX2 p.Arg677Ser (c.2031G>C) in the general population?

DUOX2 p.Arg677Ser (c.2031G>C) is very rare (popmax 0.00801%, afr) (gnomAD).

What do computational predictors say about DUOX2 p.Arg677Ser (c.2031G>C)?

AlphaMissense predicts likely benign (score 0.1289) — an in-silico prediction, not a clinical call.

DUOX2 p.Arg677Ser

c.2031G>C · rs199896919 · VCV1437459

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1289 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00801%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.1289	likely benign
REVEL	0.009	strongly benign-leaning
SaProt	—	withheld · numbering disagrees past residue 25 · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.072	GERP -0.65
Regional constraint	o/e 1.01	unconstrained · MANE · 17 kb · p 0.63 · regional, not allelic
Overall
CADD	5.913	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 is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00801% African / African-American · 6/74,908 alleles

Filtering AF 0.00347% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00229%

Overall 0.000682% 11/1,613,990 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00801%	12,485
Admixed American	0.00167%	60,000
European (non-Finnish)	0.000339%	295,006

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.Arg677Ser
Coding: c.2031G>C
MANE Select: NM_001363711
dbSNP: rs199896919
Type: single nucleotide variant
Location: chr15:45106242 (GRCh38)
Gene constraint: LOEUF 1.165 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.37
Residue 677: a disulfide bond

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

Similar variants

DUOX2 p.Arg677Gly Uncertain significance ★ ⚠ same residue
DUOX2 p.Arg677Thr Uncertain significance ★ ⚠ same residue
DUOX2 p.Arg677= 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

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-arg677ser (accessed [today's date]).

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