Is NPC1 p.Asp182Asn (c.544G>A) pathogenic?

NPC1 p.Asp182Asn (c.544G>A) is classified Uncertain significance in NPC1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-12-16). AlphaMissense: likely benign (0.0608); Ultra-rare (popmax 0.0573%, afr); Associated with Niemann-Pick disease, type C1.

What condition is associated with NPC1 p.Asp182Asn (c.544G>A)?

NPC1 p.Asp182Asn (c.544G>A) is associated with Niemann-Pick disease, type C1 (ClinVar).

How common is NPC1 p.Asp182Asn (c.544G>A) in the general population?

NPC1 p.Asp182Asn (c.544G>A) is ultra-rare (popmax 0.0573%, afr) (gnomAD).

How is Niemann-Pick disease type C inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about NPC1 p.Asp182Asn (c.544G>A)?

AlphaMissense predicts likely benign (score 0.0608) — an in-silico prediction, not a clinical call.

NPC1 p.Asp182Asn

c.544G>A · rs201021988 · VCV502363

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0608 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0573%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Niemann-Pick disease, type C1

Computational evidence

Protein change
AlphaMissense	0.0608	likely benign
REVEL	0.217	benign-leaning
SaProt	LLR -5.80	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2	GERP -3
Regional constraint	o/e 0.93	unconstrained · MANE · 54 kb · p 0.0029 · regional, not allelic
Overall
CADD	1.883	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0573% African / African-American · 43/75,046 alleles

Filtering AF 0.0436% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0389%

Overall 0.00285% 46/1,614,192 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0573%	1,745
Remaining individualsnot grpmax-eligible	0.0016%	62,510
South Asian	0.0011%	91,086
European (non-Finnish)	8.47e-05%	1,180,011

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.Asp182Asn
Coding: c.544G>A
MANE Select: NM_000271
dbSNP: rs201021988
Type: single nucleotide variant
Location: chr18:23561447 (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

Niemann-Pick disease, type C1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Niemann-Pick disease type C (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

NPC1 p.Asp182= Conflicting classifications of pathogenicity ★ 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-asp182asn (accessed [today's date]).

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