NPC1 p.Pro691=
c.2073G>A · rs113013085 · VCV194158
Benign/Likely benign
Multiple submitters
Classification
Benign/Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 16 submitters
gnomAD v4.1
Rare
low-frequency (popmax 1.12%, mid)
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 -20 | GERP -3.9 |
| Overall | ||
| CADD | 0.387 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
1.12%
Middle Eastern · 68/6,062 alleles
Filtering AF
1%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.983%
Overall
0.649%
10,474/1,614,158 alleles · low-frequency
exomes 9,731/1,461,872 · genomes 743/152,286 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Middle Easterngrpmax | 1.12% | 89 |
| South Asian | 1.06% | 94 |
| Ashkenazi Jewishnot grpmax-eligible | 1.03% | 97 |
| European (non-Finnish) | 0.703% | 142 |
| Remaining individualsnot grpmax-eligible | 0.627% | 159 |
| Finnishnot grpmax-eligible | 0.339% | 295 |
| Admixed American | 0.273% | 366 |
| African / African-American | 0.0853% | 1,172 |
| East Asian | 0.00223% | 44,894 |
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.Pro691=
- Coding
- c.2073G>A
- MANE Select
- NM_000271
- dbSNP
- rs113013085
- Type
- single nucleotide variant
- Location
- chr18:23544401 (GRCh38)
- Gene constraint
- LOEUF 0.676 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 85.35 · 20 PDB
- Residue 691
- a UniProt-annotated variant site (in npc1); the ssd domain; an α-helix
Similar variants
- NPC1 p.Pro691Ala Pathogenic/Likely pathogenic ★★ same residue
- NPC1 p.Pro691Gln Likely pathogenic ★★ same residue
- NPC1 p.Pro691Leu Pathogenic/Likely pathogenic ★★ same residue
- NPC1 p.Pro691Ser 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
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-pro691 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown