Benign
Single submitter
Classification
Benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Common
common (popmax 7.81%, eas) — 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 | <0.2 | no splice effect predicted · four deltas, not one · how we know |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP -1.4 | GERP -2.4 |
| Overall | ||
| CADD | 6.711 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
7.81%
East Asian · 3,505/44,860 alleles
Filtering AF
7.6%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 7.51%
Overall
0.253%
4,089/1,613,036 alleles · common
exomes 3,733/1,460,776 · genomes 356/152,260 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| East Asiangrpmax | 7.81% | 13 |
| South Asian | 0.426% | 235 |
| Remaining individualsnot grpmax-eligible | 0.227% | 440 |
| Middle Eastern | 0.033% | 3,031 |
| African / African-American | 0.032% | 3,127 |
| Admixed American | 0.00333% | 30,010 |
| European (non-Finnish) | 0.0022% | 45,385 |
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
- NOTCH4
- Protein
- p.Phe186=
- Coding
- c.558C>T
- MANE Select
- NM_004557
- dbSNP
- rs2071281
- Type
- single nucleotide variant
- Location
- chr6:32221219 (GRCh38)
- Gene constraint
- LOEUF 0.866 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 62.04 · 3 PDB
- Residue 186
- the egf-like 4 domain
Similar variants
- NOTCH4 p.Ala526= Benign ★★ same type
- NOTCH4 p.Cys815Gly Benign/Likely benign ★★ same type
- NOTCH4 p.Gln1469= Benign/Likely benign ★★ same type
- NOTCH4 p.Leu1610= Benign ★★ same type
- NOTCH4 p.Val600Leu Likely benign ★★ same type
- NOTCH4 c.5299-1G>A Uncertain significance ★ same type
- NOTCH4 c.5299-1G>T Uncertain significance ★ same type
- NOTCH4 p.Ala1022Thr 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/notch4-p-phe186 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown