Is NPC1 p.Asp182= (c.546C>T) pathogenic?

NPC1 p.Asp182= (c.546C>T) is classified Conflicting classifications of pathogenicity in NPC1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-04-02). Ultra-rare (popmax 0.016%, afr); Associated with Inborn genetic diseases.

What condition is associated with NPC1 p.Asp182= (c.546C>T)?

NPC1 p.Asp182= (c.546C>T) is associated with Inborn genetic diseases, Niemann-Pick disease, type C1 (ClinVar).

How common is NPC1 p.Asp182= (c.546C>T) in the general population?

NPC1 p.Asp182= (c.546C>T) is ultra-rare (popmax 0.016%, afr) (gnomAD).

NPC1 p.Asp182=

c.546C>T · rs572499557 · VCV501573

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.016%, afr)

Conditions

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 -5.7	GERP -3
Overall
CADD	1.029	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.016% African / African-American · 12/75,038 alleles

Filtering AF 0.0092% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00721%

Overall 0.00366% 59/1,614,120 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.016%	6,253
Remaining individualsnot grpmax-eligible	0.008%	12,502
South Asian	0.00439%	22,770
Finnishnot grpmax-eligible	0.00312%	32,016
European (non-Finnish)	0.00305%	32,777

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.Asp182=
Coding: c.546C>T
MANE Select: NM_000271
dbSNP: rs572499557
Type: single nucleotide variant
Location: chr18:23561445 (GRCh38)
Gene constraint: LOEUF 0.676 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.35 · 20 PDB
Residue 182: a turn; the 'important for cholesterol binding and cholesterol transfer from npc1 to liposomes' region; a disulfide bond

Full NPC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Niemann-Pick disease, type C1

Similar variants

NPC1 p.Asp182Asn Uncertain significance ★★ ⚠ 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
NPC1 c.2515-2A>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-asp182 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown