Is NPC1 p.Phe345fs (c.1033_1034del) pathogenic?

NPC1 p.Phe345fs (c.10331034del) is classified Pathogenic in NPC1 (ClinVar, Single submitter, 2 submitters; last evaluated 2022-12-11). Very rare (popmax 0.00223%, eas); Associated with Niemann-Pick disease, type C1.

What condition is associated with NPC1 p.Phe345fs (c.1033_1034del)?

NPC1 p.Phe345fs (c.1033_1034del) is associated with Niemann-Pick disease, type C1 (ClinVar).

How common is NPC1 p.Phe345fs (c.1033_1034del) in the general population?

NPC1 p.Phe345fs (c.1033_1034del) is very rare (popmax 0.00223%, 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.Phe345fs

c.1033_1034del · rs1057516950 · VCV371030

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00223%, 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 5	GERP 0.7, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,886 alleles

Overall 6.84e-05% 1/1,461,876 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.Phe345fs
Coding: c.1033_1034del
MANE Select: NM_000271
dbSNP: rs1057516950
Type: Deletion
Location: chr18:23556535 (GRCh38)
Gene constraint: LOEUF 0.676 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.35 · 20 PDB
Residue 345: 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.Phe345Ser Uncertain significance ★ ⚠ 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-phe345fs (accessed [today's date]).

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