Is NCF4 p.Arg151His (c.452G>A) pathogenic?

NCF4 p.Arg151His (c.452G>A) is classified Uncertain significance in NCF4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-12). AlphaMissense: ambiguous (0.5333); Very rare (popmax 0.00934%, afr).

How common is NCF4 p.Arg151His (c.452G>A) in the general population?

NCF4 p.Arg151His (c.452G>A) is very rare (popmax 0.00934%, afr) (gnomAD).

What do computational predictors say about NCF4 p.Arg151His (c.452G>A)?

AlphaMissense predicts ambiguous (score 0.5333) — an in-silico prediction, not a clinical call.

NCF4 p.Arg151His

c.452G>A · VCV3403348

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5333 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00934%, afr)

Computational evidence

Protein change
AlphaMissense	0.5333	ambiguous
REVEL	0.312	indeterminate
SaProt	LLR -7.44	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 1.4, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 17 kb · p 0.18 · regional, not allelic
Overall
CADD	34.0	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 0.00934% African / African-American · 7/74,908 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00312%

Overall 0.00167% 27/1,612,542 alleles · very rare exomes 19/1,460,366 · genomes 8/152,176 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00934%	10,701
South Asian	0.00878%	11,386
Remaining individualsnot grpmax-eligible	0.0032%	31,238
Admixed American	0.00167%	60,000
Finnishnot grpmax-eligible	0.0016%	62,552
European (non-Finnish)	0.000678%	147,505

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.Arg151His
Coding: c.452G>A
MANE Select: NM_000631
Type: single nucleotide variant
Location: chr22:36870524 (GRCh38)
Gene constraint: LOEUF 1.005 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 84.48 · 6 PDB

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

Similar variants

NCF4 p.Arg151Cys 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
NCF4 c.758+51G>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-arg151his (accessed [today's date]).

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