NOTCH3 p.Val583=
c.1749G>A · rs373985781 · VCV1807395
Conflicting classifications of pathogenicity
Conflicting submitters
Classification
Conflicting classifications of pathogenicity
ClinVar
Review
Conflicting submitters ★☆☆☆
ClinVar · 3 submitters
gnomAD v4.1
Rare
very rare (popmax 0.00525%, nfe)
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal. | ||
| Splicing | ||
| SpliceAI | Δ0.33 | donor gain · deltas |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP 0.4 | GERP -3.7, phastCons 0.97 |
| Overall | ||
| CADD | 16.67 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.00525%
European (non-Finnish) · 62/1,180,028 alleles
Filtering AF
0.00418%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.0038%
Overall
0.00434%
70/1,613,968 alleles · very rare
exomes 65/1,461,738 · genomes 5/152,230 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| European (non-Finnish)grpmax | 0.00525% | 19,033 |
| Remaining individualsnot grpmax-eligible | 0.0048% | 20,829 |
| East Asian | 0.00446% | 22,442 |
| African / African-American | 0.004% | 24,985 |
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
- NOTCH3
- Protein
- p.Val583=
- Coding
- c.1749G>A
- MANE Select
- NM_000435
- dbSNP
- rs373985781
- Type
- single nucleotide variant
- Location
- chr19:15187196 (GRCh38)
- Gene constraint
- LOEUF 0.566 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 61.79 · 6 PDB
- Residue 583
- the egf-like 15; calcium-binding domain
Similar variants
- NOTCH3 p.Val583Met Uncertain significance ★ ⚠ same residue
- NOTCH3 c.341-2A>G Pathogenic ★★ same type
- NOTCH3 c.341-2A>T Pathogenic ★★ same type
- NOTCH3 p.Arg1006Cys Pathogenic ★★ ⚠ same type
- NOTCH3 p.Arg1076Cys Pathogenic/Likely pathogenic ★★ ⚠ same type
- NOTCH3 p.Arg110Cys Pathogenic ★★ same type
- NOTCH3 p.Arg133Cys Pathogenic/Likely pathogenic ★★ same type
- NOTCH3 p.Arg141Cys Pathogenic ★★ 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/notch3-p-val583 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown