Is CYBA p.Arg164Cys (c.490C>T) pathogenic?

CYBA p.Arg164Cys (c.490C>T) is classified Uncertain significance in CYBA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-28). AlphaMissense: likely pathogenic (0.8391); Ultra-rare (popmax 0.018%, afr); Associated with granulomatous disease, chronic, autosomal recessive, cytochrome b-negative.

What condition is associated with CYBA p.Arg164Cys (c.490C>T)?

CYBA p.Arg164Cys (c.490C>T) is associated with granulomatous disease, chronic, autosomal recessive, cytochrome b-negative (ClinVar).

How common is CYBA p.Arg164Cys (c.490C>T) in the general population?

CYBA p.Arg164Cys (c.490C>T) is ultra-rare (popmax 0.018%, 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 CYBA p.Arg164Cys (c.490C>T)?

AlphaMissense predicts likely pathogenic (score 0.8391) — an in-silico prediction, not a clinical call.

CYBA p.Arg164Cys

c.490C>T · rs751340079 · VCV2383641

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8391 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.018%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

granulomatous disease, chronic, autosomal recessive, cytochrome b-negative

Computational evidence

Protein change
AlphaMissense	0.8391	likely pathogenic
REVEL	0.812	moderately pathogenic-leaning
SaProt	LLR -10.86	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.3	GERP 1.6, phastCons 1
Regional constraint	o/e 1.20	unconstrained · MANE · 7,657 bp · p 0.00077 · regional, not allelic
Overall
CADD	31.0	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

Grpmax group 0.018% African / African-American · 13/72,092 alleles

Filtering AF 0.0106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00842%

Overall 0.0017% 26/1,533,294 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.018%	5,546
Admixed American	0.00593%	16,867
Remaining individualsnot grpmax-eligible	0.00504%	19,842
East Asian	0.00495%	20,203
South Asian	0.00239%	41,800
European (non-Finnish)	0.000262%	381,205

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: CYBA
Protein: p.Arg164Cys
Coding: c.490C>T
MANE Select: NM_000101
dbSNP: rs751340079
Type: single nucleotide variant
Location: chr16:88643451 (GRCh38)
Gene constraint: LOEUF 1.726 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.28 · 7 PDB
Residue 164: the 'disordered' region; an α-helix

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

Disease context

granulomatous disease, chronic, autosomal recessive, cytochrome b-negative — 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

CYBA p.Arg164His Uncertain significance ★★ ⚠ same residue
CYBA p.Arg164= Likely benign ★ same residue
CYBA c.128+2T>C Likely pathogenic ★★ same condition
CYBA c.204-2A>G Pathogenic/Likely pathogenic ★★ same condition
CYBA c.287+1G>T Pathogenic/Likely pathogenic ★★ same condition
CYBA c.287+2T>C Pathogenic/Likely pathogenic ★★ same condition
CYBA c.288-1G>T Pathogenic/Likely pathogenic ★★ same condition
CYBA c.369+1G>A 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/cyba-p-arg164cys (accessed [today's date]).

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