Is NCF2 p.Lys181Arg (c.542A>G) pathogenic?

NCF2 p.Lys181Arg (c.542A>G) is classified Benign/Likely benign in NCF2 (ClinVar, Multiple submitters, 12 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0563); Common (popmax 62.8%, eas) — too common for a highly-penetrant pathogenic allele; Associated with granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 2.

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 NCF2 p.Lys181Arg (c.542A>G)?

AlphaMissense predicts likely benign (score 0.0563) — an in-silico prediction, not a clinical call.

NCF2 p.Lys181Arg

Q: What condition is associated with NCF2 p.Lys181Arg (c.542A>G)?

NCF2 p.Lys181Arg (c.542A>G) is associated with granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 2 (ClinVar).

Q: How common is NCF2 p.Lys181Arg (c.542A>G) in the general population?

NCF2 p.Lys181Arg (c.542A>G) is common (popmax 62.8%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.542A>G · rs2274064 · VCV256116

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 12 submitters

AlphaMissense

likely benign

0.0563 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 62.8%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 2

Computational evidence

Protein change
AlphaMissense	0.0563	likely benign
REVEL	0.084	moderately benign-leaning
SaProt	LLR -6.85	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.57	GERP -0.96, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 34 kb · p 1.3e-05 · regional, not allelic
Overall
CADD	16.6	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 62.8% East Asian · 28,154/44,844 alleles

Filtering AF 62.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 61.9%

Overall 48.4% 780,388/1,613,334 alleles · common exomes 710,885/1,461,330 · genomes 69,503/152,004 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	62.8%	2
Admixed American	61.9%	2
Amishnot grpmax-eligible	56.6%	2
South Asian	50.4%	2
European (non-Finnish)	48.1%	2
Finnishnot grpmax-eligible	47.8%	2
Remaining individualsnot grpmax-eligible	47.3%	2
Ashkenazi Jewishnot grpmax-eligible	39.2%	3
African / African-American	35.9%	3
Middle Eastern	35.1%	3

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: NCF2
Protein: p.Lys181Arg
Coding: c.542A>G
MANE Select: NM_000433
dbSNP: rs2274064
Type: single nucleotide variant
Location: chr1:183573252 (GRCh38)
Gene constraint: LOEUF 0.799 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 78.99 · 7 PDB
Residue 181: a UniProt-annotated variant site (in)

Full NCF2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 2 — 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

NCF2 c.257+1G>A Pathogenic/Likely pathogenic ★★ same condition
NCF2 c.366+1G>A Pathogenic ★★ same condition
NCF2 c.714-2A>G Likely pathogenic ★★ same condition
NCF2 p.Ala202Val Pathogenic/Likely pathogenic ★★ same condition
NCF2 p.Arg102Ter Pathogenic ★★ same condition
NCF2 p.Arg184Ter Pathogenic/Likely pathogenic ★★ same condition
NCF2 p.Arg66Ter Pathogenic ★★ same condition
NCF2 p.Arg77Ter 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/ncf2-p-lys181arg (accessed [today's date]).

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