Is NPC1 p.Val378fs (c.1133_1161del) pathogenic?

NPC1 p.Val378fs (c.11331161del) is classified Pathogenic in NPC1 (ClinVar, Single submitter, 2 submitters; last evaluated 2023-06-09). Very rare (popmax 0.00446%, eas); Associated with Niemann-Pick disease, type C1.

What condition is associated with NPC1 p.Val378fs (c.1133_1161del)?

NPC1 p.Val378fs (c.1133_1161del) is associated with Niemann-Pick disease, type C1 (ClinVar).

How common is NPC1 p.Val378fs (c.1133_1161del) in the general population?

NPC1 p.Val378fs (c.1133_1161del) is very rare (popmax 0.00446%, eas) (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.Val378fs

c.1133_1161del · rs1555637164 · VCV550364

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Conditions

Niemann-Pick disease, type C1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 8 of 25
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 4	GERP 0.84, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,870 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000137% 2/1,461,866 alleles · very rare

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.Val378fs
Coding: c.1133_1161del
MANE Select: NM_000271
dbSNP: rs1555637164
Type: Deletion
Location: chr18:23556408 (GRCh38)
Gene constraint: LOEUF 0.676 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.35 · 20 PDB
Residue 378: a UniProt-annotated variant site (in npc1)

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.Val378Ala Pathogenic/Likely pathogenic ★★ ⚠ same residue
NPC1 p.Ala696fs Pathogenic/Likely pathogenic ★★ same condition
NPC1 p.Asn916del Likely pathogenic ★★ same condition
NPC1 p.Gln710fs Pathogenic ★★ same condition
NPC1 p.Gln991fs Pathogenic ★★ same condition
NPC1 p.Gly1028fs Pathogenic ★★ same condition
NPC1 p.His641fs Pathogenic/Likely pathogenic ★★ same condition
NPC1 p.Ile1052del 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-val378fs (accessed [today's date]).

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