Is CYBB p.Ile221Thr (c.662T>C) pathogenic?

CYBB p.Ile221Thr (c.662T>C) is classified Uncertain significance in CYBB (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-10-21). AlphaMissense: likely pathogenic (0.8194); Very rare (popmax 0.00657%, amr); Associated with Inborn genetic diseases.

How common is CYBB p.Ile221Thr (c.662T>C) in the general population?

CYBB p.Ile221Thr (c.662T>C) is very rare (popmax 0.00657%, amr) (gnomAD).

What do computational predictors say about CYBB p.Ile221Thr (c.662T>C)?

AlphaMissense predicts likely pathogenic (score 0.8194) — an in-silico prediction, not a clinical call.

CYBB p.Ile221Thr

Q: What condition is associated with CYBB p.Ile221Thr (c.662T>C)?

CYBB p.Ile221Thr (c.662T>C) is associated with Inborn genetic diseases, X-linked Mendelian susceptibility to mycobacterial diseases due to CYBB deficiency, granulomatous disease, chronic, X-linked (ClinVar).

c.662T>C · rs782096963 · VCV643505

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.8194 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00657%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8194	likely pathogenic
REVEL	0.793	moderately pathogenic-leaning
SaProt	LLR -7.00	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 7.9	GERP 1.7, phastCons 1
Regional constraint	o/e 1.17	unconstrained · MANE · 5,249 bp · p 0.15 · regional, not allelic
Overall
CADD	25.2	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 0.00657% Admixed American · 3/45,654 alleles

Filtering AF 0.00285% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00252%

Overall 0.00324% 39/1,204,690 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00657%	15,218
European (non-Finnish)	0.00393%	25,443
Remaining individualsnot grpmax-eligible	0.00211%	47,385

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.Ile221Thr
Coding: c.662T>C
MANE Select: NM_000397
dbSNP: rs782096963
Type: single nucleotide variant
Location: chrX:37796129 (GRCh38)
Structure: AlphaFold pLDDT 90.29 · 6 PDB
Residue 221: a turn; the ferric oxidoreductase domain

Full CYBB 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: X-linked Mendelian susceptibility to mycobacterial diseases due to CYBB deficiency granulomatous disease, chronic, X-linked chronic granulomatous disease

Similar variants

CYBB p.Ile221= Benign/Likely benign ★★ same residue
CYBB c.1151+2T>C Pathogenic ★★ same condition
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

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-ile221thr (accessed [today's date]).

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