NPC2 p.Pro90=
c.270T>C · rs758503440 · VCV286701
Conflicting classifications of pathogenicity
Conflicting submitters
Classification
Conflicting classifications of pathogenicity
ClinVar
Review
Conflicting submitters ★☆☆☆
ClinVar · 4 submitters
gnomAD v4.1
Rare
very rare (popmax 0.00636%, nfe)
Conditions
2
Inborn genetic diseases
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| REVEL | 0.035 | moderately benign-leaning |
|---|---|---|
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 0.045 | GERP -2.2, phastCons 0.053 |
| Overall | ||
| CADD | 4.704 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.00636%
European (non-Finnish) · 75/1,180,036 alleles
Filtering AF
0.00519%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.00474%
Overall
0.00483%
78/1,614,026 alleles · very rare
exomes 70/1,461,890 · genomes 8/152,136 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| European (non-Finnish)grpmax | 0.00636% | 15,734 |
| African / African-American | 0.00267% | 37,450 |
| Remaining individualsnot grpmax-eligible | 0.0016% | 62,490 |
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
- NPC2
- Protein
- p.Pro90=
- Coding
- c.270T>C
- MANE Select
- NM_006432
- dbSNP
- rs758503440
- Type
- single nucleotide variant
- Location
- chr14:74484508 (GRCh38)
- Gene constraint
- LOEUF 1.422 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 92.88 · 2 PDB
Similar variants
- NPC2 c.190+5G>A Pathogenic/Likely pathogenic ★★ same condition
- NPC2 p.Cys47Ter Pathogenic ★★ same condition
- NPC2 p.Cys99Arg Pathogenic ★★ same condition
- NPC2 p.Gln45Ter Pathogenic/Likely pathogenic ★★ same condition
- NPC2 p.Glu118Ter Pathogenic ★★ same condition
- NPC2 p.Glu20Ter Pathogenic ★★ same condition
- NPC2 p.Met1Ile Pathogenic/Likely pathogenic ★★ same condition
- NPC2 p.Pro120Ser 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/npc2-p-pro90 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown