Is NPC1 p.Asp700= (c.2100C>T) pathogenic?

NPC1 p.Asp700= (c.2100C>T) is classified Likely benign in NPC1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-03). Ultra-rare (popmax 0.0613%, afr); Associated with Inborn genetic diseases.

What condition is associated with NPC1 p.Asp700= (c.2100C>T)?

NPC1 p.Asp700= (c.2100C>T) is associated with Inborn genetic diseases, Niemann-Pick disease, type C1 (ClinVar).

How common is NPC1 p.Asp700= (c.2100C>T) in the general population?

NPC1 p.Asp700= (c.2100C>T) is ultra-rare (popmax 0.0613%, afr) (gnomAD).

NPC1 p.Asp700=

c.2100C>T · rs372517881 · VCV255693

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0613%, 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 5.9	GERP -0.017, phastCons 1
Overall
CADD	9.383	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0613% African / African-American · 46/75,016 alleles

Filtering AF 0.0472% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0422%

Overall 0.00353% 57/1,614,152 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0613%	1,631
Middle Eastern	0.0165%	6,062
Admixed American	0.00833%	12,005
Remaining individualsnot grpmax-eligible	0.008%	12,501

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.Asp700=
Coding: c.2100C>T
MANE Select: NM_000271
dbSNP: rs372517881
Type: single nucleotide variant
Location: chr18:23544374 (GRCh38)
Gene constraint: LOEUF 0.676 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.35 · 20 PDB
Residue 700: a UniProt-annotated variant site (in npc1); the ssd domain; an α-helix

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.Asp700fs 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-asp700 (accessed [today's date]).

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