Is NPC1 p.Val327fs (c.978del) pathogenic?

NPC1 p.Val327fs (c.978del) is classified Pathogenic in NPC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-31). Associated with Niemann-Pick disease, type C1.

What condition is associated with NPC1 p.Val327fs (c.978del)?

NPC1 p.Val327fs (c.978del) is associated with Niemann-Pick disease, type C1 (ClinVar).

How is Niemann-Pick disease type C inherited?

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

NPC1 p.Val327fs

c.978del · VCV3724367

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

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 2	GERP -3.3, phastCons 0.98

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

Variant & gene context

Gene: NPC1
Protein: p.Val327fs
Coding: c.978del
MANE Select: NM_000271
Type: Deletion
Location: chr18:23556591 (GRCh38)
Gene constraint: LOEUF 0.676 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.35 · 20 PDB
Residue 327: 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.Val327= Likely benign ★ 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-val327fs (accessed [today's date]).

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