Is NCF4 p.Thr36Pro (c.106A>C) pathogenic?

NCF4 p.Thr36Pro (c.106A>C) is classified Likely benign in NCF4 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-05-28). AlphaMissense: ambiguous (0.3955); Common (popmax 6.8%, amr) — too common for a highly-penetrant pathogenic allele; Associated with granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 3.

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 NCF4 p.Thr36Pro (c.106A>C)?

AlphaMissense predicts ambiguous (score 0.3955) — an in-silico prediction, not a clinical call.

NCF4 p.Thr36Pro

Q: What condition is associated with NCF4 p.Thr36Pro (c.106A>C)?

NCF4 p.Thr36Pro (c.106A>C) is associated with granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 3 (ClinVar).

Q: How common is NCF4 p.Thr36Pro (c.106A>C) in the general population?

NCF4 p.Thr36Pro (c.106A>C) is common (popmax 6.8%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.106A>C · rs200818199 · VCV803684

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3955 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 6.8%, amr) — too common for a highly-penetrant pathogenic allele

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.3955	ambiguous
REVEL	0.261	benign-leaning
SaProt	LLR -11.07	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.9	GERP 1.5, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 17 kb · p 0.18 · regional, not allelic
Overall
CADD	24.9	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 6.8% Admixed American · 4,040/59,386 alleles

Filtering AF 6.63% ClinGen BA1/BS1 input FAF95, joint · FAF99 6.56%

Overall 1.28% 20,540/1,601,114 alleles · common

Ancestry group	Frequency	1 in
Admixed Americangrpmax	6.8%	15
East Asian	4.34%	23
Finnishnot grpmax-eligible	3.25%	31
South Asian	2.27%	44
Ashkenazi Jewishnot grpmax-eligible	2.2%	45
African / African-American	1.21%	83
Remaining individualsnot grpmax-eligible	1.02%	98
European (non-Finnish)	0.711%	141
Middle Eastern	0.448%	223

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.Thr36Pro
Coding: c.106A>C
MANE Select: NM_000631
dbSNP: rs200818199
Type: single nucleotide variant
Location: chr22:36864118 (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 36: 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 p.Thr36Ile Uncertain significance ★★ ⚠ same residue
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

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-thr36pro (accessed [today's date]).

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