Is NPC1 p.Val231fs (c.692_693del) pathogenic?

NPC1 p.Val231fs (c.692693del) is classified 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.Val231fs (c.692_693del)?

NPC1 p.Val231fs (c.692_693del) is associated with Niemann-Pick disease, type C1 (ClinVar).

How common is NPC1 p.Val231fs (c.692_693del) in the general population?

NPC1 p.Val231fs (c.692_693del) 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.Val231fs

c.692_693del · rs2511303464 · VCV1705808

Pathogenic Single submitter

Classification

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	predicted	premature termination codon in exon 6 of 25
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.7	GERP 1.8, 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.Val231fs
Coding: c.692_693del
MANE Select: NM_000271
dbSNP: rs2511303464
Type: Microsatellite
Location: chr18:23560419 (GRCh38)
Gene constraint: LOEUF 0.676 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.35 · 20 PDB
Residue 231: a disulfide bond; 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.Val231Leu Uncertain significance ⚠ same residue
NPC1 c.1757_1757+1del Pathogenic/Likely pathogenic ★★ same condition
NPC1 p.Arg341fs Pathogenic/Likely pathogenic ★★ same condition
NPC1 p.Gln119fs Pathogenic ★★ same condition
NPC1 p.Ser151fs Pathogenic ★★ same condition
NPC1 p.Trp381fs Pathogenic/Likely pathogenic ★★ same condition
NPC1 c.3592-7_3592-5del Uncertain significance ★★ same condition
NPC1 p.Pro253_Pro254insGlnPro Uncertain significance ★★ 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-val231fs (accessed [today's date]).

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