Is CYBB p.Asn22Lys (c.66C>A) pathogenic?

CYBB p.Asn22Lys (c.66C>A) is classified Uncertain significance in CYBB (ClinVar, Single submitter, 2 submitters; last evaluated 2023-12-22). AlphaMissense: likely pathogenic (0.9988); Absent from gnomAD v4.1; Associated with granulomatous disease, chronic, X-linked.

What condition is associated with CYBB p.Asn22Lys (c.66C>A)?

CYBB p.Asn22Lys (c.66C>A) is associated with granulomatous disease, chronic, X-linked (ClinVar).

How common is CYBB p.Asn22Lys (c.66C>A) in the general population?

CYBB p.Asn22Lys (c.66C>A) is absent from gnomAD v4.1 (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.Asn22Lys (c.66C>A)?

AlphaMissense predicts likely pathogenic (score 0.9988) — an in-silico prediction, not a clinical call.

CYBB p.Asn22Lys

c.66C>A · rs193922450 · VCV208503

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9988 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

granulomatous disease, chronic, X-linked

Computational evidence

Protein change
AlphaMissense	0.9988	likely pathogenic · top 4% in CYBB
REVEL	0.66	pathogenic-leaning
SaProt	LLR -15.07	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.28	acceptor loss · deltas
Pangolin	Δ0.27	loss · gain 0.01 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP -5.2	GERP -3.1
Regional constraint	o/e 0.69	unconstrained · MANE · 16 kb · p 0.00012 · regional, not allelic
Overall
CADD	8.049	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CYBB
Protein: p.Asn22Lys
Coding: c.66C>A
MANE Select: NM_000397
dbSNP: rs193922450
Type: single nucleotide variant
Location: chrX:37782108 (GRCh38)
Structure: AlphaFold pLDDT 90.29 · 6 PDB
Residue 22: 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.Asn22= Likely benign ★★ same residue
CYBB p.Asn22Tyr Uncertain significance ★ ⚠ same residue
CYBB p.Asn22Ser Uncertain significance ★ ⚠ 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

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-asn22lys (accessed [today's date]).

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