Is NPC1 p.Ser300= (c.900C>T) pathogenic?

NPC1 p.Ser300= (c.900C>T) is classified Likely benign in NPC1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-06). Ultra-rare (popmax 0.0164%, mid); Associated with Inborn genetic diseases.

What condition is associated with NPC1 p.Ser300= (c.900C>T)?

NPC1 p.Ser300= (c.900C>T) is associated with Inborn genetic diseases, Niemann-Pick disease, type C1 (ClinVar).

How common is NPC1 p.Ser300= (c.900C>T) in the general population?

NPC1 p.Ser300= (c.900C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

NPC1 p.Ser300=

c.900C>T · rs377728310 · VCV1147565

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

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 -5.4	GERP -3.6
Overall
CADD	4.475	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00162%

Overall 0.00161% 26/1,613,122 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
African / African-American	0.00668%	14,981
East Asian	0.00223%	44,892
European (non-Finnish)	0.00161%	62,086

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.Ser300=
Coding: c.900C>T
MANE Select: NM_000271
dbSNP: rs377728310
Type: single nucleotide variant
Location: chr18:23557172 (GRCh38)
Gene constraint: LOEUF 0.676 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.35 · 20 PDB

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.Ser300Cys 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-ser300 (accessed [today's date]).

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