NPC1 p.Pro474=
c.1422G>A · rs367900403 · VCV1646795
Likely benign
Multiple submitters
Classification
Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 3 submitters
gnomAD v4.1
Rare
very rare (popmax 0.00329%, sas)
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 -13 | GERP -2.8 |
| Overall | ||
| CADD | 0.312 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.00329%
South Asian · 3/91,078 alleles
Filtering AF
0.00188%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.00164%
Overall
0.00217%
35/1,613,828 alleles · very rare
exomes 32/1,461,670 · genomes 3/152,158 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| South Asiangrpmax | 0.00329% | 30,359 |
| European (non-Finnish) | 0.00263% | 38,059 |
| African / African-American | 0.00133% | 74,918 |
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.Pro474=
- Coding
- c.1422G>A
- MANE Select
- NM_000271
- dbSNP
- rs367900403
- Type
- single nucleotide variant
- Location
- chr18:23554889 (GRCh38)
- Gene constraint
- LOEUF 0.676 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 85.35 · 20 PDB
- Residue 474
- a UniProt-annotated variant site (in npc1); a turn
Similar variants
- NPC1 p.Pro474Leu Pathogenic ★★ same residue
- NPC1 p.Pro474Ala 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
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-pro474 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown