Benign/Likely benign
Multiple submitters
Classification
Benign/Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 8 submitters
gnomAD v4.1
Rare
low-frequency (popmax 2.26%, afr)
Conditions
2
Inborn genetic diseases
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 -20 | GERP -3.9 |
| Overall | ||
| CADD | 0.115 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
2.26%
African / African-American · 1,692/75,024 alleles
Filtering AF
2.17%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 2.13%
Overall
0.117%
1,896/1,614,116 alleles · low-frequency
exomes 912/1,461,858 · genomes 984/152,258 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| African / African-Americangrpmax | 2.26% | 44 |
| Admixed American | 0.132% | 760 |
| Remaining individualsnot grpmax-eligible | 0.128% | 781 |
| Middle Eastern | 0.0495% | 2,021 |
| East Asian | 0.00891% | 11,222 |
| South Asian | 0.00769% | 13,011 |
| Ashkenazi Jewishnot grpmax-eligible | 0.00338% | 29,602 |
| European (non-Finnish) | 0.00254% | 39,334 |
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
- NPC1
- Protein
- p.Pro887=
- Coding
- c.2661G>A
- MANE Select
- NM_000271
- dbSNP
- rs9949660
- Type
- single nucleotide variant
- Location
- chr18:23539945 (GRCh38)
- Gene constraint
- LOEUF 0.676 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 85.35 · 20 PDB
- Residue 887
- a β-strand
Similar variants
- NPC1 p.Pro887Leu Pathogenic/Likely pathogenic ★★ ⚠ same residue
- NPC1 c.1554-1009G>A Pathogenic ★★ same condition
- NPC1 c.1757+1G>A Likely pathogenic ★★ same condition
- NPC1 c.1947+5G>C Pathogenic/Likely pathogenic ★★ same condition
- NPC1 c.2130+1G>A Pathogenic ★★ same condition
- NPC1 c.2245+1G>A Pathogenic/Likely pathogenic ★★ same condition
- NPC1 c.2246-2A>G Pathogenic/Likely pathogenic ★★ same condition
- NPC1 c.2515-2A>G Pathogenic/Likely 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/npc1-p-pro887 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown