Is CYBB p.Ala109Ser (c.325G>T) pathogenic?

CYBB p.Ala109Ser (c.325G>T) is classified Uncertain significance in CYBB (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-17). AlphaMissense: ambiguous (0.4189); Very rare (popmax 0.00102%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CYBB p.Ala109Ser (c.325G>T)?

CYBB p.Ala109Ser (c.325G>T) is associated with Inborn genetic diseases (ClinVar).

How common is CYBB p.Ala109Ser (c.325G>T) in the general population?

CYBB p.Ala109Ser (c.325G>T) is very rare (popmax 0.00102%, nfe) (gnomAD).

What do computational predictors say about CYBB p.Ala109Ser (c.325G>T)?

AlphaMissense predicts ambiguous (score 0.4189) — an in-silico prediction, not a clinical call.

CYBB p.Ala109Ser

c.325G>T · rs1556467120 · VCV2307663

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4189 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00102%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4189	ambiguous
REVEL	0.786	moderately pathogenic-leaning
SaProt	LLR -8.98	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 16 kb · p 0.00012 · regional, not allelic
Overall
CADD	26.1	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 0.00102% European (non-Finnish) · 9/880,104 alleles

Filtering AF 0.000481% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000348%

Overall 0.000833% 9/1,080,981 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: CYBB
Protein: p.Ala109Ser
Coding: c.325G>T
MANE Select: NM_000397
dbSNP: rs1556467120
Type: single nucleotide variant
Location: chrX:37792047 (GRCh38)
Structure: AlphaFold pLDDT 90.29 · 6 PDB
Residue 109: an α-helix; the ferric oxidoreductase domain

Full CYBB 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

CYBB p.Ala109Thr Uncertain significance ★ ⚠ same residue
CYBB p.Ala109= Likely benign ★ same residue
CYBB p.Ala224Ser Uncertain significance ★★ ⚠ same condition
CYBB p.Asn128Lys Uncertain significance ★★ ⚠ same condition
CYBB p.Glu402Asp Uncertain significance ★★ ⚠ same condition
CYBB p.Gly166Asp Uncertain significance ★★ ⚠ same condition
CYBB p.His449Arg Uncertain significance ★★ ⚠ same condition
CYBB p.Ile221Thr 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/cybb-p-ala109ser (accessed [today's date]).

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