Is DUOX2 p.Ala554Val (c.1661C>T) pathogenic?

DUOX2 p.Ala554Val (c.1661C>T) is classified Uncertain significance in DUOX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-30). AlphaMissense: likely benign (0.0838); Very rare (popmax 0.00769%, sas); Associated with Inborn genetic diseases.

What condition is associated with DUOX2 p.Ala554Val (c.1661C>T)?

DUOX2 p.Ala554Val (c.1661C>T) is associated with Inborn genetic diseases (ClinVar).

How common is DUOX2 p.Ala554Val (c.1661C>T) in the general population?

DUOX2 p.Ala554Val (c.1661C>T) is very rare (popmax 0.00769%, sas) (gnomAD).

What do computational predictors say about DUOX2 p.Ala554Val (c.1661C>T)?

AlphaMissense predicts likely benign (score 0.0838) — an in-silico prediction, not a clinical call.

DUOX2 p.Ala554Val

c.1661C>T · VCV3274005

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0838 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00769%, sas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0838	likely benign
REVEL	0.101	moderately 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 2.1	GERP -0.28, phastCons 0.99
Regional constraint	o/e 1.01	unconstrained · MANE · 17 kb · p 0.63 · regional, not allelic
Overall
CADD	15.43	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 0.00769% South Asian · 7/91,082 alleles

Filtering AF 0.00359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00255%

Overall 0.000434% 7/1,614,222 alleles · very rare exomes 7/1,461,890 · genomes 0/152,332 · joint denominator

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.Ala554Val
Coding: c.1661C>T
MANE Select: NM_001363711
Type: single nucleotide variant
Location: chr15:45107377 (GRCh38)
Gene constraint: LOEUF 1.165 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.37
Residue 554: the 'peroxidase-like; mediates peroxidase activity' region

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.Ala554= Likely benign ★ 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-ala554val (accessed [today's date]).

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