Is CYBB p.Pro339His (c.1016C>A) pathogenic?

CYBB p.Pro339His (c.1016C>A) is classified Pathogenic in CYBB (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-03-05). AlphaMissense: likely pathogenic (0.9984); Very rare (popmax 0.000112%, nfe); Associated with CYBB-related disorders.

What condition is associated with CYBB p.Pro339His (c.1016C>A)?

CYBB p.Pro339His (c.1016C>A) is associated with CYBB-related disorders, granulomatous disease, chronic, X-linked (ClinVar).

How common is CYBB p.Pro339His (c.1016C>A) in the general population?

CYBB p.Pro339His (c.1016C>A) is very rare (popmax 0.000112%, nfe) (gnomAD).

What do computational predictors say about CYBB p.Pro339His (c.1016C>A)?

AlphaMissense predicts likely pathogenic (score 0.9984) — an in-silico prediction, not a clinical call.

CYBB p.Pro339His

c.1016C>A · rs151344470 · VCV68368

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9984 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000112%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CYBB-related disorders

Computational evidence

Protein change
AlphaMissense	0.9984	likely pathogenic ✓ concordant with ClinVar · top 4% in CYBB
REVEL	0.988	strongly pathogenic-leaning
SaProt	LLR -14.71	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 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.59	unconstrained · MANE · 9,586 bp · p 2.3e-09 · regional, not allelic
Overall
CADD	27.8	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 0.000112% European (non-Finnish) · 1/895,260 alleles

Overall 9.11e-05% 1/1,097,875 alleles · very rare

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: CYBB
Protein: p.Pro339His
Coding: c.1016C>A
MANE Select: NM_000397
dbSNP: rs151344470
Type: single nucleotide variant
Location: chrX:37803995 (GRCh38)
Structure: AlphaFold pLDDT 90.29 · 6 PDB
Residue 339: a β-strand; the fad-binding fr-type domain; a binding site; a UniProt-annotated variant site (in cgdx)

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

Disease context

CYBB-related disorders

Also linked: granulomatous disease, chronic, X-linked

Similar variants

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
CYBB p.Ala57Glu 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-pro339his (accessed [today's date]).

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