NPC1 p.Asp180=
c.540C>T · rs143656971 · VCV471944
Benign/Likely benign
Multiple submitters
Classification
Benign/Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 9 submitters
gnomAD v4.1
Rare
low-frequency (popmax 1.71%, amr)
Conditions
2
Inborn genetic diseases
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 -12 | GERP -3 |
| Overall | ||
| CADD | 0.105 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
1.71%
Admixed American · 1,029/60,016 alleles
Filtering AF
1.63%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 1.59%
Overall
0.217%
3,508/1,614,120 alleles · low-frequency
exomes 3,070/1,461,838 · genomes 438/152,282 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Admixed Americangrpmax | 1.71% | 58 |
| Finnishnot grpmax-eligible | 0.298% | 335 |
| European (non-Finnish) | 0.174% | 574 |
| Remaining individualsnot grpmax-eligible | 0.152% | 658 |
| African / African-American | 0.128% | 782 |
| Amishnot grpmax-eligible | 0.11% | 910 |
| Ashkenazi Jewishnot grpmax-eligible | 0.0507% | 1,974 |
| East Asian | 0.0446% | 2,244 |
| Middle Eastern | 0.033% | 3,031 |
| South Asian | 0.00329% | 30,357 |
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.Asp180=
- Coding
- c.540C>T
- MANE Select
- NM_000271
- dbSNP
- rs143656971
- Type
- single nucleotide variant
- Location
- chr18:23561451 (GRCh38)
- Gene constraint
- LOEUF 0.676 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 85.35 · 20 PDB
- Residue 180
- the 'important for cholesterol binding and cholesterol transfer from npc1 to liposomes' region
Similar variants
- 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
- NPC1 c.2604+1G>A 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-asp180 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown