Is NCF4 p.Arg8= (c.22C>A) pathogenic?

NCF4 p.Arg8= (c.22C>A) is classified Likely benign in NCF4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-27). Very rare (popmax 6.45e-05%).

How common is NCF4 p.Arg8= (c.22C>A) in the general population?

NCF4 p.Arg8= (c.22C>A) is very rare (popmax 6.45e-05%) (gnomAD).

NCF4 p.Arg8=

c.22C>A · VCV4947704

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 6.45e-05%)

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 4.7	GERP 0.53, phastCons 1
Overall
CADD	15.09	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.45e-05%

Overall 6.45e-05% 1/1,551,486 alleles · very rare exomes 1/1,399,146 · genomes 0/152,340 · joint denominator

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.Arg8=
Coding: c.22C>A
MANE Select: NM_000631
Type: single nucleotide variant
Location: chr22:36861193 (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 8: an α-helix

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

Similar variants

NCF4 p.Arg8Gln Uncertain significance ★★ ⚠ same residue
NCF4 p.Arg8Trp Uncertain significance ★ ⚠ same residue
NCF4 c.118-1G>A Pathogenic/Likely pathogenic ★★ same type
NCF4 c.759-40C>T Pathogenic ★★ same type
NCF4 p.Arg105Gln Pathogenic ★★ same type
NCF4 c.758+24C>T Uncertain significance ★★ same type
NCF4 c.758+32G>A Uncertain significance ★★ same type
NCF4 c.758+39T>A Uncertain significance ★★ same type

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-arg8 (accessed [today's date]).

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