NOTCH4 p.Pro85=
c.255C>T · rs8192569 · VCV1228635
Benign
Single submitter
Classification
Benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Common
common (popmax 29.8%, 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 | <0.2 | no splice effect predicted · four deltas, not one · how we know |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP -0.24 | GERP -3 |
| Overall | ||
| CADD | 3.771 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
29.8%
African / African-American · 22,169/74,392 alleles
Filtering AF
29.5%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 29.3%
Overall
10.9%
175,431/1,607,786 alleles · common
exomes 151,089/1,455,732 · genomes 24,342/152,054 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| African / African-Americangrpmax | 29.8% | 3 |
| East Asian | 23.8% | 4 |
| South Asian | 20.5% | 5 |
| Remaining individualsnot grpmax-eligible | 12.3% | 8 |
| Admixed American | 11.3% | 9 |
| Middle Eastern | 11.2% | 9 |
| European (non-Finnish) | 8.62% | 12 |
| Finnishnot grpmax-eligible | 8.58% | 12 |
| Ashkenazi Jewishnot grpmax-eligible | 7.73% | 13 |
| Amishnot grpmax-eligible | 2.85% | 35 |
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.Pro85=
- Coding
- c.255C>T
- MANE Select
- NM_004557
- dbSNP
- rs8192569
- Type
- single nucleotide variant
- Location
- chr6:32222707 (GRCh38)
- Gene constraint
- LOEUF 0.866 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 62.04 · 3 PDB
- Residue 85
- the egf-like 2 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-pro85 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown