Is CYBA p.Pro159Ser (c.475C>T) pathogenic?

CYBA p.Pro159Ser (c.475C>T) is classified Uncertain significance in CYBA (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-11). AlphaMissense: likely pathogenic (0.8671); Ultra-rare (popmax 0.0813%, sas); Associated with Inborn genetic diseases.

How common is CYBA p.Pro159Ser (c.475C>T) in the general population?

CYBA p.Pro159Ser (c.475C>T) is ultra-rare (popmax 0.0813%, sas) (gnomAD).

What do computational predictors say about CYBA p.Pro159Ser (c.475C>T)?

AlphaMissense predicts likely pathogenic (score 0.8671) — an in-silico prediction, not a clinical call.

CYBA p.Pro159Ser

Q: What condition is associated with CYBA p.Pro159Ser (c.475C>T)?

CYBA p.Pro159Ser (c.475C>T) is associated with Inborn genetic diseases, granulomatous disease, chronic, autosomal recessive, cytochrome b-negative, chronic granulomatous disease (ClinVar).

c.475C>T · rs558222148 · VCV638954

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8671 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0813%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8671	likely pathogenic
REVEL	0.702	pathogenic-leaning
SaProt	LLR -9.74	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 1.20	unconstrained · MANE · 7,657 bp · p 0.00077 · regional, not allelic
Overall
CADD	25.2	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 0.0813% South Asian · 68/83,648 alleles

Filtering AF 0.0657% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.06%

Overall 0.00483% 74/1,532,188 alleles · ultra-rare exomes 67/1,379,992 · genomes 7/152,196 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0813%	1,230
Remaining individualsnot grpmax-eligible	0.00336%	29,767
Admixed American	0.00197%	50,714
European (non-Finnish)	0.000262%	381,333

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.Pro159Ser
Coding: c.475C>T
MANE Select: NM_000101
dbSNP: rs558222148
Type: single nucleotide variant
Location: chr16:88643466 (GRCh38)
Gene constraint: LOEUF 1.726 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.28 · 7 PDB
Residue 159: the 'disordered' region; an α-helix

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: granulomatous disease, chronic, autosomal recessive, cytochrome b-negative chronic granulomatous disease

Similar variants

CYBA p.Pro159Leu Uncertain significance ★ ⚠ same residue
CYBA p.Pro159= 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-pro159ser (accessed [today's date]).

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