Is DUOX2 p.Phe319Ser (c.956T>C) pathogenic?

DUOX2 p.Phe319Ser (c.956T>C) is classified Uncertain significance in DUOX2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-13). AlphaMissense: likely benign (0.2415); Very rare (popmax 0.00153%, nfe); Associated with Inborn genetic diseases.

What condition is associated with DUOX2 p.Phe319Ser (c.956T>C)?

DUOX2 p.Phe319Ser (c.956T>C) is associated with Inborn genetic diseases (ClinVar).

How common is DUOX2 p.Phe319Ser (c.956T>C) in the general population?

DUOX2 p.Phe319Ser (c.956T>C) is very rare (popmax 0.00153%, nfe) (gnomAD).

What do computational predictors say about DUOX2 p.Phe319Ser (c.956T>C)?

AlphaMissense predicts likely benign (score 0.2415) — an in-silico prediction, not a clinical call.

DUOX2 p.Phe319Ser

c.956T>C · rs1037554590 · VCV1928747

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2415 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00153%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2415	likely benign
REVEL	0.121	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 8	GERP 1.9, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 17 kb · p 0.63 · regional, not allelic
Overall
CADD	23.9	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 0.00153% European (non-Finnish) · 18/1,180,016 alleles

Filtering AF 0.000953% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000787%

Overall 0.00118% 19/1,614,006 alleles · very rare exomes 18/1,461,860 · genomes 1/152,146 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,486
European (non-Finnish)grpmax	0.00153%	65,557

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Phe319Ser
Coding: c.956T>C
MANE Select: NM_001363711
dbSNP: rs1037554590
Type: single nucleotide variant
Location: chr15:45110512 (GRCh38)
Gene constraint: LOEUF 1.165 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.37
Residue 319: 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 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
DUOX2 p.Ala1306Thr 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-phe319ser (accessed [today's date]).

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