Is NPC1 p.Asp944= (c.2832C>T) pathogenic?

NPC1 p.Asp944= (c.2832C>T) is classified Conflicting classifications of pathogenicity in NPC1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-04-08). Ultra-rare (popmax 0.0209%, sas); Associated with Niemann-Pick disease, type C1.

What condition is associated with NPC1 p.Asp944= (c.2832C>T)?

NPC1 p.Asp944= (c.2832C>T) is associated with Niemann-Pick disease, type C1 (ClinVar).

How common is NPC1 p.Asp944= (c.2832C>T) in the general population?

NPC1 p.Asp944= (c.2832C>T) is ultra-rare (popmax 0.0209%, sas) (gnomAD).

How is Niemann-Pick disease type C inherited?

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

NPC1 p.Asp944=

c.2832C>T · rs780019300 · VCV326255

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0209%, sas)

Conditions

Niemann-Pick disease, type C1

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 -7.6	GERP -3.3
Overall
CADD	1.85	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0209% South Asian · 19/90,886 alleles

Filtering AF 0.0136% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0114%

Overall 0.00297% 48/1,613,678 alleles · ultra-rare exomes 41/1,461,356 · genomes 7/152,322 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0209%	4,783
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,784
Remaining individualsnot grpmax-eligible	0.0032%	31,245
Finnishnot grpmax-eligible	0.00312%	32,011
European (non-Finnish)	0.00186%	53,629
Admixed American	0.00167%	59,986

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.Asp944=
Coding: c.2832C>T
MANE Select: NM_000271
dbSNP: rs780019300
Type: single nucleotide variant
Location: chr18:23539434 (GRCh38)
Gene constraint: LOEUF 0.676 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.35 · 20 PDB
Residue 944: a UniProt-annotated variant site (in npc1); an α-helix

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.Asp944Asn 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
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-asp944 (accessed [today's date]).

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