Is NCF4 p.Ser37Arg (c.111C>A) pathogenic?

NCF4 p.Ser37Arg (c.111C>A) is classified Uncertain significance in NCF4 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-07-26). AlphaMissense: ambiguous (0.4753); Very rare (popmax 8.48e-05%, nfe); Associated with granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 3.

How common is NCF4 p.Ser37Arg (c.111C>A) in the general population?

NCF4 p.Ser37Arg (c.111C>A) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

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.Ser37Arg (c.111C>A)?

AlphaMissense predicts ambiguous (score 0.4753) — an in-silico prediction, not a clinical call.

NCF4 p.Ser37Arg

Q: What condition is associated with NCF4 p.Ser37Arg (c.111C>A)?

NCF4 p.Ser37Arg (c.111C>A) is associated with granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 3 (ClinVar).

c.111C>A · rs1939860899 · VCV1025577

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4753 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.4753	ambiguous
REVEL	0.248	benign-leaning
SaProt	LLR -5.52	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 0.36	GERP -2.9, phastCons 0.46
Regional constraint	o/e 0.94	unconstrained · MANE · 17 kb · p 0.18 · regional, not allelic
Overall
CADD	17.03	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 8.48e-05% European (non-Finnish) · 1/1,178,560 alleles

Overall 6.85e-05% 1/1,460,260 alleles · very rare

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.Ser37Arg
Coding: c.111C>A
dbSNP: rs1939860899
Type: single nucleotide variant
Location: chr22:36864123 (GRCh38)

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)

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-ser37arg (accessed [today's date]).

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