How is Chronic granulomatous disease inherited?

Typically Autosomal recessive, X-linked recessive (Orphanet). A genetic counselor can assess individual risk for a family.

NCF4 p.Ala21=

Q: Is NCF4 p.Ala21= (c.63C>T) pathogenic?

NCF4 p.Ala21= (c.63C>T) is classified Benign in NCF4 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-02). Common (popmax 9.23%, afr) — too common for a highly-penetrant pathogenic allele; Associated with granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 3.

Q: What condition is associated with NCF4 p.Ala21= (c.63C>T)?

NCF4 p.Ala21= (c.63C>T) is associated with granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 3 (ClinVar).

Q: How common is NCF4 p.Ala21= (c.63C>T) in the general population?

NCF4 p.Ala21= (c.63C>T) is common (popmax 9.23%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.63C>T · rs34373276 · VCV341548

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Common

common (popmax 9.23%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 3

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.91	GERP 0.42
Overall
CADD	7.253	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 9.23% African / African-American · 6,925/75,008 alleles

Filtering AF 9.05% ClinGen BA1/BS1 input FAF95, joint · FAF99 8.98%

Overall 0.489% 7,889/1,614,132 alleles · common exomes 3,902/1,461,868 · genomes 3,987/152,264 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	9.23%	11
Remaining individualsnot grpmax-eligible	0.629%	159
Admixed American	0.595%	168
Middle Eastern	0.297%	337
European (non-Finnish)	0.0155%	6,448
South Asian	0.0132%	7,590
East Asian	0.00223%	44,888

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: NCF4
Protein: p.Ala21=
Coding: c.63C>T
MANE Select: NM_000631
dbSNP: rs34373276
Type: single nucleotide variant
Location: chr22:36864075 (GRCh38)
Gene constraint: LOEUF 1.005 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 84.48 · 6 PDB
Residue 21: the px domain; a β-strand

Full NCF4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

NCF4 c.118-1G>A Pathogenic/Likely pathogenic ★★ same condition
NCF4 c.759-40C>T Pathogenic ★★ same condition
NCF4 p.Arg105Gln Pathogenic ★★ same condition
NCF4 c.758+24C>T Uncertain significance ★★ same condition
NCF4 c.758+32G>A Uncertain significance ★★ same condition
NCF4 c.758+39T>A Uncertain significance ★★ same condition
NCF4 c.758+51G>A Uncertain significance ★★ same condition
NCF4 c.758+62C>T Uncertain significance ★★ 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/ncf4-p-ala21 (accessed [today's date]).

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