Is CYBA p.Ser98Leu (c.293C>T) pathogenic?

CYBA p.Ser98Leu (c.293C>T) is classified Uncertain significance in CYBA (ClinVar, Multiple submitters, 6 submitters; last evaluated 2024-10-23). AlphaMissense: likely pathogenic (0.6333); Ultra-rare (popmax 0.0842%, mid); Associated with granulomatous disease, chronic, autosomal recessive, cytochrome b-negative.

How common is CYBA p.Ser98Leu (c.293C>T) in the general population?

CYBA p.Ser98Leu (c.293C>T) is ultra-rare (popmax 0.0842%, mid) (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.Ser98Leu (c.293C>T)?

AlphaMissense predicts likely pathogenic (score 0.6333) — an in-silico prediction, not a clinical call.

CYBA p.Ser98Leu

Q: What condition is associated with CYBA p.Ser98Leu (c.293C>T)?

CYBA p.Ser98Leu (c.293C>T) is associated with granulomatous disease, chronic, autosomal recessive, cytochrome b-negative, chronic granulomatous disease (ClinVar).

c.293C>T · rs201755210 · VCV664770

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.6333 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0842%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.6333	likely pathogenic
REVEL	0.498	indeterminate
SaProt	LLR -8.44	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.23 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 1.2, phastCons 1
Regional constraint	o/e 1.20	unconstrained · MANE · 7,657 bp · p 0.00077 · regional, not allelic
Overall
CADD	23.5	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 0.0842% Middle Eastern · 5/5,936 alleles

Filtering AF 0.065% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0594%

Overall 0.0133% 206/1,552,744 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0842%	1,187
South Asian	0.0804%	1,244
Remaining individualsnot grpmax-eligible	0.0249%	4,024
Admixed American	0.0115%	8,697
European (non-Finnish)	0.00912%	10,970
Finnishnot grpmax-eligible	0.00756%	13,227
East Asian	0.0048%	20,817
African / African-American	0.00136%	73,636

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.Ser98Leu
Coding: c.293C>T
MANE Select: NM_000101
dbSNP: rs201755210
Type: single nucleotide variant
Location: chr16:88646192 (GRCh38)
Gene constraint: LOEUF 1.726 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.28 · 7 PDB
Residue 98: 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

Also linked: chronic granulomatous disease

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.Ser98= 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
CYBA c.58+2T>C 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/cyba-p-ser98leu (accessed [today's date]).

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