NIPBL p.Pro226=
c.678G>A · rs192822119 · VCV159209
Conflicting classifications of pathogenicity
Conflicting submitters
Classification
Conflicting classifications of pathogenicity
ClinVar
Review
Conflicting submitters ★☆☆☆
ClinVar · 2 submitters
gnomAD v4.1
Rare
ultra-rare (popmax 0.0164%, mid)
Conditions
1
Cornelia de Lange syndrome 1
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 1.3 | GERP -0.82, phastCons 1 |
| Overall | ||
| CADD | 14.82 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0164%
Middle Eastern · 1/6,082 alleles
Filtering AF
0.00255%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.00162%
Overall
0.00143%
23/1,613,402 alleles · ultra-rare
exomes 20/1,461,332 · genomes 3/152,070 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Middle Easterngrpmax | 0.0164% | 6,082 |
| African / African-American | 0.00668% | 14,976 |
| Remaining individualsnot grpmax-eligible | 0.0048% | 20,819 |
| East Asian | 0.00223% | 44,852 |
| South Asian | 0.0011% | 91,064 |
| European (non-Finnish) | 0.00102% | 98,297 |
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
- NIPBL
- Protein
- p.Pro226=
- Coding
- c.678G>A
- MANE Select
- NM_133433
- dbSNP
- rs192822119
- Type
- single nucleotide variant
- Location
- chr5:36970943 (GRCh38)
- Gene constraint
- LOEUF 0.057 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
- Residue 226
- the 'disordered' region
Similar variants
- NIPBL p.Pro226Leu Likely benign ★★ same residue
- NIPBL c.3304+1G>A Pathogenic/Likely pathogenic ★★ same condition
- NIPBL c.358+1G>T Pathogenic ★★ same condition
- NIPBL c.3855+5G>A Pathogenic/Likely pathogenic ★★ same condition
- NIPBL c.5329-15A>G Pathogenic ★★ same condition
- NIPBL c.5575-1G>A Likely pathogenic ★★ same condition
- NIPBL c.5709+1G>A Pathogenic/Likely pathogenic ★★ same condition
- NIPBL c.5808+1G>A Pathogenic ★★ same condition
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/nipbl-p-pro226 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown