NPC1 p.Pro543fs
c.1628del · rs1555635957 · VCV556403
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Consequence | frameshift | predicted loss-of-function |
|---|---|---|
| NMD | predicted | premature termination codon in exon 10 of 25 |
| Splicing | ||
| SpliceAI | — | not assessed · substitutions only |
| Constraint at this position | ||
| Conservation | phyloP -9.3 | GERP -3.6 |
| Overall | ||
| CADD | 34.0 | PHRED · no single calibrated threshold — expert panels disagree |
Predicted loss-of-function is descriptive, not an applied PVS1 code.
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Remaining individualsnot grpmax-eligible | 0.0016% | 62,468 |
| South Asiangrpmax | 0.0011% | 91,086 |
| European (non-Finnish) | 0.00017% | 589,849 |
Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.
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.Pro543fs
- Coding
- c.1628del
- MANE Select
- NM_000271
- dbSNP
- rs1555635957
- Type
- Deletion
- Location
- chr18:23551653 (GRCh38)
- Gene constraint
- LOEUF 0.676 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 85.35 · 20 PDB
- Residue 543
- a UniProt-annotated variant site (in npc1); an α-helix
Disease context
Niemann-Pick disease, type C1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatmentsAlso linked: Niemann-Pick disease type C
For Niemann-Pick disease type C (Orphanet):
- Inheritance
- Autosomal recessive
- Onset
- All ages
- Prevalence
- 1-9 / 100 000 (Europe)
Similar variants
- NPC1 p.Pro543Leu Pathogenic ★★ same residue
- NPC1 p.Pro543= Likely benign ★★ same residue
- NPC1 p.Pro543Ser Likely pathogenic ★ ⚠ same residue
- NPC1 p.Ala34fs Pathogenic ★★ same condition
- NPC1 p.Ala696fs Pathogenic/Likely pathogenic ★★ same condition
- NPC1 p.Asn916del Likely pathogenic ★★ same condition
- NPC1 p.Gln710fs Pathogenic ★★ same condition
- NPC1 p.Gln991fs 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-pro543fs (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown