Is NPC2 p.Pro84fs (c.249_250insAATTCCA) pathogenic?

NPC2 p.Pro84fs (c.249250insAATTCCA) is classified Likely pathogenic in NPC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-12). No gnomAD frequency available for this variant; Associated with Niemann-Pick disease, type C2.

What condition is associated with NPC2 p.Pro84fs (c.249_250insAATTCCA)?

NPC2 p.Pro84fs (c.249_250insAATTCCA) is associated with Niemann-Pick disease, type C2 (ClinVar).

How common is NPC2 p.Pro84fs (c.249_250insAATTCCA) in the general population?

NPC2 p.Pro84fs (c.249_250insAATTCCA) is no gnomAD frequency available for this variant (gnomAD).

How is Niemann-Pick disease type C inherited?

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

NPC2 p.Pro84fs

c.249_250insAATTCCA · rs2506104570 · VCV1724387

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 C2

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 3 of 5
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 4.6	GERP 0.82, 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: NPC2
Protein: p.Pro84fs
Coding: c.249_250insAATTCCA
MANE Select: NM_006432
dbSNP: rs2506104570
Type: Insertion
Location: chr14:74484528 (GRCh38)
Gene constraint: LOEUF 1.422 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.88 · 2 PDB
Residue 84: a β-strand

Full NPC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Niemann-Pick disease, type C2 — 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

NPC2 p.Pro84= Likely benign ★ same residue
NPC2 p.Thr7fs Pathogenic same condition
NPC2 c.190+5G>A Pathogenic/Likely pathogenic ★★ same condition
NPC2 p.Ala72fs Pathogenic/Likely pathogenic ★★ same condition
NPC2 p.Cys47Ter Pathogenic ★★ same condition
NPC2 p.Cys99Arg Pathogenic ★★ same condition
NPC2 p.Gln45Ter Pathogenic/Likely pathogenic ★★ same condition
NPC2 p.Glu118Ter 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/npc2-p-pro84fs (accessed [today's date]).

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