Is NPC1 p.Pro1245fs (c.3732_3735del) pathogenic?

NPC1 p.Pro1245fs (c.37323735del) is classified Likely pathogenic in NPC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-30). Absent from gnomAD; Associated with Niemann-Pick disease, type C1.

What condition is associated with NPC1 p.Pro1245fs (c.3732_3735del)?

NPC1 p.Pro1245fs (c.3732_3735del) is associated with Niemann-Pick disease, type C1 (ClinVar).

How common is NPC1 p.Pro1245fs (c.3732_3735del) in the general population?

NPC1 p.Pro1245fs (c.3732_3735del) is absent from gnomAD (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.Pro1245fs

c.3732_3735del · rs2511176123 · VCV1705799

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

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	escapes	premature termination codon within the last 50 nt of the penultimate exon (24 of 25, 19 nt from its 3' end) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 4.9	GERP 0.83, phastCons 1

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

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: NPC1
Protein: p.Pro1245fs
Coding: c.3732_3735del
MANE Select: NM_000271
dbSNP: rs2511176123
Type: Deletion
Location: chr18:23533374 (GRCh38)
Gene constraint: LOEUF 0.676 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.35 · 20 PDB
Residue 1245: 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.Pro1245Arg Uncertain significance ★ ⚠ same residue
NPC1 p.Pro1245= 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

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-pro1245fs (accessed [today's date]).

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