Is CYBA p.Pro142Leu (c.425C>T) pathogenic?

CYBA p.Pro142Leu (c.425C>T) is classified Uncertain significance in CYBA (ClinVar, Single submitter, 2 submitters; last evaluated 2021-08-31). AlphaMissense: likely benign (0.0923); Very rare (popmax 0.00275%, afr); Associated with granulomatous disease, chronic, autosomal recessive, cytochrome b-negative.

How common is CYBA p.Pro142Leu (c.425C>T) in the general population?

CYBA p.Pro142Leu (c.425C>T) is very rare (popmax 0.00275%, 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.Pro142Leu (c.425C>T)?

AlphaMissense predicts likely benign (score 0.0923) — an in-silico prediction, not a clinical call.

CYBA p.Pro142Leu

Q: What condition is associated with CYBA p.Pro142Leu (c.425C>T)?

CYBA p.Pro142Leu (c.425C>T) is associated with granulomatous disease, chronic, autosomal recessive, cytochrome b-negative, chronic granulomatous disease (ClinVar).

c.425C>T · rs909600062 · VCV1004956

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0923 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00275%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.0923	likely benign
REVEL	0.365	indeterminate
SaProt	LLR -7.65	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 0.96	GERP 0.43, phastCons 0.33
Regional constraint	o/e 1.20	unconstrained · MANE · 7,657 bp · p 0.00077 · regional, not allelic
Overall
CADD	17.73	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

Grpmax group 0.00275% African / African-American · 2/72,854 alleles

Filtering AF 0.000456% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000217%

Overall 0.000717% 11/1,534,526 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00275%	36,427
Remaining individualsnot grpmax-eligible	0.00167%	59,726
European (non-Finnish)	0.000698%	143,301

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.Pro142Leu
Coding: c.425C>T
MANE Select: NM_000101
dbSNP: rs909600062
Type: single nucleotide variant
Location: chr16:88643516 (GRCh38)
Gene constraint: LOEUF 1.726 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.28 · 7 PDB
Residue 142: the 'disordered' region

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.Pro142Arg Uncertain significance ★ ⚠ same residue
CYBA p.Pro142= Likely benign ★ same residue
CYBA p.Pro142Thr Uncertain significance ★ ⚠ 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

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-pro142leu (accessed [today's date]).

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