Is CYBB p.Ala394Val (c.1181C>T) pathogenic?

CYBB p.Ala394Val (c.1181C>T) is classified Uncertain significance in CYBB (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-27). AlphaMissense: likely pathogenic (0.8556); Very rare (popmax 0.000447%, nfe); Associated with granulomatous disease, chronic, X-linked.

What condition is associated with CYBB p.Ala394Val (c.1181C>T)?

CYBB p.Ala394Val (c.1181C>T) is associated with granulomatous disease, chronic, X-linked (ClinVar).

How common is CYBB p.Ala394Val (c.1181C>T) in the general population?

CYBB p.Ala394Val (c.1181C>T) is very rare (popmax 0.000447%, nfe) (gnomAD).

How is Chronic granulomatous disease inherited?

Typically Autosomal recessive, X-linked recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CYBB p.Ala394Val (c.1181C>T)?

AlphaMissense predicts likely pathogenic (score 0.8556) — an in-silico prediction, not a clinical call.

CYBB p.Ala394Val

c.1181C>T · rs1159898408 · VCV963979

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8556 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000447%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

granulomatous disease, chronic, X-linked

Computational evidence

Protein change
AlphaMissense	0.8556	likely pathogenic
REVEL	0.874	moderately pathogenic-leaning
SaProt	LLR -8.48	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1, phastCons 1
Regional constraint	o/e 0.59	unconstrained · MANE · 9,586 bp · p 2.3e-09 · regional, not allelic
Overall
CADD	25.2	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 0.000447% European (non-Finnish) · 4/894,949 alleles

Filtering AF 0.000105% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.1e-05%

Overall 0.000331% 4/1,210,058 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.Ala394Val
Coding: c.1181C>T
MANE Select: NM_000397
dbSNP: rs1159898408
Type: single nucleotide variant
Location: chrX:37805035 (GRCh38)
Structure: AlphaFold pLDDT 90.29 · 6 PDB
Residue 394: the fad-binding fr-type domain; an α-helix

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

Disease context

granulomatous disease, chronic, X-linked — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Chronic granulomatous disease (Orphanet):

Inheritance: Autosomal recessive, X-linked recessive
Onset: Adolescent, Adult, Childhood, Infancy
Prevalence: 1-9 / 1 000 000 (Worldwide)

Similar variants

CYBB c.1315-2A>G Pathogenic/Likely pathogenic ★★ same condition
CYBB c.141+1G>T Pathogenic ★★ same condition
CYBB c.252+5G>A Pathogenic ★★ same condition
CYBB c.483+1G>A Pathogenic ★★ same condition
CYBB c.483+1G>T Pathogenic ★★ same condition
CYBB c.483+3A>T Likely pathogenic ★★ same condition
CYBB p.Ala156Thr Pathogenic/Likely pathogenic ★★ ⚠ same condition
CYBB p.Ala57Glu Pathogenic ★★ 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-ala394val (accessed [today's date]).

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