Is NPC2 p.Ile147Val (c.439A>G) pathogenic?

NPC2 p.Ile147Val (c.439A>G) is classified Uncertain significance in NPC2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2025-03-18). AlphaMissense: ambiguous (0.3654); Absent from gnomAD v4.1; Associated with Niemann-Pick disease, type C2.

What condition is associated with NPC2 p.Ile147Val (c.439A>G)?

NPC2 p.Ile147Val (c.439A>G) is associated with Niemann-Pick disease, type C2 (ClinVar).

How common is NPC2 p.Ile147Val (c.439A>G) in the general population?

NPC2 p.Ile147Val (c.439A>G) is absent from gnomAD v4.1 (gnomAD).

How is Niemann-Pick disease type C inherited?

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

What do computational predictors say about NPC2 p.Ile147Val (c.439A>G)?

AlphaMissense predicts ambiguous (score 0.3654) — an in-silico prediction, not a clinical call.

NPC2 p.Ile147Val

c.439A>G · VCV4058987

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3654 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Niemann-Pick disease, type C2

Computational evidence

Protein change
AlphaMissense	0.3654	ambiguous
REVEL	0.367	indeterminate
SaProt	LLR -8.13	tolerated
Splicing
SpliceAI	Δ0.79	donor gain · deltas
Pangolin	Δ0.24	gain · loss 0.10 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 3.7	GERP 0.83, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 13 kb · p 0.22 · regional, not allelic
Overall
CADD	25.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: NPC2
Protein: p.Ile147Val
Coding: c.439A>G
MANE Select: NM_006432
Type: single nucleotide variant
Location: chr14:74480704 (GRCh38)
Gene constraint: LOEUF 1.422 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.88 · 2 PDB
Residue 147: 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 c.190+5G>A 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
NPC2 p.Glu20Ter Pathogenic ★★ same condition
NPC2 p.Met1Ile Pathogenic/Likely pathogenic ★★ same condition
NPC2 p.Pro120Ser 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/npc2-p-ile147val (accessed [today's date]).

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