Is CYBB p.Val243Ala (c.728T>C) pathogenic?

CYBB p.Val243Ala (c.728T>C) is classified Uncertain significance in CYBB (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-03). AlphaMissense: likely benign (0.0924); Absent from gnomAD v4.1; Associated with granulomatous disease, chronic, X-linked.

What condition is associated with CYBB p.Val243Ala (c.728T>C)?

CYBB p.Val243Ala (c.728T>C) is associated with granulomatous disease, chronic, X-linked, X-linked Mendelian susceptibility to mycobacterial diseases due to CYBB deficiency (ClinVar).

How common is CYBB p.Val243Ala (c.728T>C) in the general population?

CYBB p.Val243Ala (c.728T>C) 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.Val243Ala (c.728T>C)?

AlphaMissense predicts likely benign (score 0.0924) — an in-silico prediction, not a clinical call.

CYBB p.Val243Ala

c.728T>C · rs1929377773 · VCV2584605

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0924 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,206,313)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

granulomatous disease, chronic, X-linked

Computational evidence

Protein change
AlphaMissense	0.0924	likely benign
REVEL	0.348	indeterminate
SaProt	LLR -6.84	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -6.7	GERP -2.5
Regional constraint	o/e 1.17	unconstrained · MANE · 5,249 bp · p 0.15 · regional, not allelic
Overall
CADD	0.001	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

No allele count reported in gnomAD v4.1 (AN 1,206,313). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: CYBB
Protein: p.Val243Ala
Coding: c.728T>C
MANE Select: NM_000397
dbSNP: rs1929377773
Type: single nucleotide variant
Location: chrX:37799008 (GRCh38)
Structure: AlphaFold pLDDT 90.29 · 6 PDB
Residue 243: an α-helix; the ferric oxidoreductase domain

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

Also linked: X-linked Mendelian susceptibility to mycobacterial diseases due to CYBB deficiency

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.Val243Leu Conflicting classifications of pathogenicity ★ ⚠ 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
CYBB p.Ala156Thr Pathogenic/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-val243ala (accessed [today's date]).

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