Is CYBB p.His209Arg (c.626A>G) pathogenic?

CYBB p.His209Arg (c.626A>G) is classified Conflicting classifications of pathogenicity in CYBB (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-02-13). AlphaMissense: likely pathogenic (0.9935); Absent from gnomAD v4.1; Associated with CYBB-related disorders.

What condition is associated with CYBB p.His209Arg (c.626A>G)?

CYBB p.His209Arg (c.626A>G) is associated with CYBB-related disorders, granulomatous disease, chronic, X-linked (ClinVar).

How common is CYBB p.His209Arg (c.626A>G) in the general population?

CYBB p.His209Arg (c.626A>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CYBB p.His209Arg (c.626A>G)?

AlphaMissense predicts likely pathogenic (score 0.9935) — an in-silico prediction, not a clinical call.

CYBB p.His209Arg

c.626A>G · rs151344482 · VCV68399

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.9935 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CYBB-related disorders

Computational evidence

Protein change
AlphaMissense	0.9935	likely pathogenic
REVEL	0.988	strongly pathogenic-leaning
SaProt	LLR -10.25	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 11	GERP 1.7, phastCons 1
Regional constraint	o/e 1.17	unconstrained · MANE · 5,249 bp · p 0.15 · regional, not allelic
Overall
CADD	25.4	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CYBB
Protein: p.His209Arg
Coding: c.626A>G
MANE Select: NM_000397
dbSNP: rs151344482
Type: single nucleotide variant
Location: chrX:37796093 (GRCh38)
Structure: AlphaFold pLDDT 90.29 · 6 PDB
Residue 209: an α-helix; the ferric oxidoreductase 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 p.His209Tyr Uncertain significance ★ ⚠ same residue
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

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-his209arg (accessed [today's date]).

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