Is NCF4 p.Ser299= (c.897G>A) pathogenic?

NCF4 p.Ser299= (c.897G>A) is classified Benign/Likely benign in NCF4 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2024-11-28). Common (popmax 22.8%, afr) — too common for a highly-penetrant pathogenic allele.

NCF4 p.Ser299=

Q: How common is NCF4 p.Ser299= (c.897G>A) in the general population?

NCF4 p.Ser299= (c.897G>A) is common (popmax 22.8%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.897G>A · rs11552115 · VCV260303

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Common

common (popmax 22.8%, afr) — too common for a highly-penetrant pathogenic allele

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 -15	GERP -3.2
Overall
CADD	0.063	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 22.8% African / African-American · 17,043/74,914 alleles

Filtering AF 22.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 22.3%

Overall 8.28% 133,652/1,613,982 alleles · common exomes 115,424/1,461,856 · genomes 18,228/152,126 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	22.8%	4
Admixed American	16.6%	6
South Asian	10.8%	9
Middle Eastern	9.24%	11
Remaining individualsnot grpmax-eligible	9.11%	11
Ashkenazi Jewishnot grpmax-eligible	8.61%	12
European (non-Finnish)	6.96%	14
Finnishnot grpmax-eligible	5.82%	17
East Asian	4.66%	21
Amishnot grpmax-eligible	4.28%	23

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.Ser299=
Coding: c.897G>A
MANE Select: NM_000631
dbSNP: rs11552115
Type: single nucleotide variant
Location: chr22:36877700 (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 299: the pb1 domain

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

Similar variants

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
NCF4 c.758+51G>A Uncertain significance ★★ same type
NCF4 c.758+62C>T 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-ser299 (accessed [today's date]).

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