Is CYBB p.Leu281Ile (c.841C>A) pathogenic?

CYBB p.Leu281Ile (c.841C>A) is classified Uncertain significance in CYBB (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-16). AlphaMissense: likely benign (0.0698); Very rare (popmax 0.00351%, afr); Associated with granulomatous disease, chronic, X-linked.

What condition is associated with CYBB p.Leu281Ile (c.841C>A)?

CYBB p.Leu281Ile (c.841C>A) is associated with granulomatous disease, chronic, X-linked (ClinVar).

How common is CYBB p.Leu281Ile (c.841C>A) in the general population?

CYBB p.Leu281Ile (c.841C>A) is very rare (popmax 0.00351%, afr) (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.Leu281Ile (c.841C>A)?

AlphaMissense predicts likely benign (score 0.0698) — an in-silico prediction, not a clinical call.

CYBB p.Leu281Ile

c.841C>A · rs1422144712 · VCV3022152

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0698 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00351%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

granulomatous disease, chronic, X-linked

Computational evidence

Protein change
AlphaMissense	0.0698	likely benign
REVEL	0.196	benign-leaning
SaProt	LLR -5.75	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.2	GERP -1.1, phastCons 0.96
Regional constraint	o/e 1.17	unconstrained · MANE · 5,249 bp · p 0.15 · regional, not allelic
Overall
CADD	11.61	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 and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00351% African / African-American · 2/56,951 alleles

Filtering AF 0.000582% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000218%

Overall 0.000166% 2/1,207,194 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.Leu281Ile
Coding: c.841C>A
MANE Select: NM_000397
dbSNP: rs1422144712
Type: single nucleotide variant
Location: chrX:37801292 (GRCh38)
Structure: AlphaFold pLDDT 90.29 · 6 PDB
Residue 281: the ferric oxidoreductase 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 p.Leu281Phe Uncertain significance ★ ⚠ same residue
CYBB p.Leu281= Likely benign ★ same residue
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

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-leu281ile (accessed [today's date]).

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