Is NPC1 p.Ser617fs (c.1849dup) pathogenic?

NPC1 p.Ser617fs (c.1849dup) is classified Pathogenic/Likely pathogenic in NPC1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-12-26). Absent from gnomAD; Associated with Niemann-Pick disease, type C1.

What condition is associated with NPC1 p.Ser617fs (c.1849dup)?

NPC1 p.Ser617fs (c.1849dup) is associated with Niemann-Pick disease, type C1 (ClinVar).

How common is NPC1 p.Ser617fs (c.1849dup) in the general population?

NPC1 p.Ser617fs (c.1849dup) 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.Ser617fs

c.1849dup · rs2058769608 · VCV847972

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

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	predicted	premature termination codon in exon 12 of 25
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.7	GERP 0.95, 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.Ser617fs
Coding: c.1849dup
MANE Select: NM_000271
dbSNP: rs2058769608
Type: Duplication
Location: chr18:23545057 (GRCh38)
Gene constraint: LOEUF 0.676 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.35 · 20 PDB
Residue 617: a turn

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 c.3591+2dup Pathogenic/Likely pathogenic ★★ same condition
NPC1 p.Ala1192fs Pathogenic/Likely pathogenic ★★ same condition
NPC1 p.Asn1137fs Pathogenic/Likely pathogenic ★★ same condition
NPC1 p.Asn589Ter Pathogenic ★★ same condition
NPC1 p.Asp325fs Pathogenic ★★ same condition
NPC1 p.Glu895fs Pathogenic ★★ same condition
NPC1 p.Ile1099fs Pathogenic ★★ same condition
NPC1 p.Pro733fs 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-ser617fs (accessed [today's date]).

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