NPC2 p.Ala72=
c.216C>T · rs773861377 · VCV1116187
Likely benign
Multiple submitters
Classification
Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 3 submitters
gnomAD v4.1
Rare
ultra-rare (popmax 0.0167%, amr)
Conditions
2
Inborn genetic diseases
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| REVEL | 0.027 | moderately benign-leaning |
|---|---|---|
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP -0.8 | GERP -3.8 |
| Overall | ||
| CADD | 6.829 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0167%
Admixed American · 10/59,986 alleles
Filtering AF
0.009%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.00681%
Overall
0.0018%
29/1,613,864 alleles · ultra-rare
exomes 24/1,461,886 · genomes 5/151,978 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Admixed Americangrpmax | 0.0167% | 5,999 |
| African / African-American | 0.00401% | 24,953 |
| Remaining individualsnot grpmax-eligible | 0.0032% | 31,243 |
| European (non-Finnish) | 0.00119% | 84,285 |
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.Ala72=
- Coding
- c.216C>T
- MANE Select
- NM_006432
- dbSNP
- rs773861377
- Type
- single nucleotide variant
- Location
- chr14:74484562 (GRCh38)
- Gene constraint
- LOEUF 1.422 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 92.88 · 2 PDB
- Residue 72
- a β-strand
Similar variants
- NPC2 p.Ala72fs Pathogenic/Likely pathogenic ★★ same residue
- 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
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-ala72 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown