Is NPC2 p.Leu49Pro (c.146T>C) pathogenic?

NPC2 p.Leu49Pro (c.146T>C) is classified Uncertain significance in NPC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-02). AlphaMissense: likely pathogenic (0.9807); Very rare (popmax 0.00111%, nfe); Associated with Niemann-Pick disease, type C2.

What condition is associated with NPC2 p.Leu49Pro (c.146T>C)?

NPC2 p.Leu49Pro (c.146T>C) is associated with Niemann-Pick disease, type C2 (ClinVar).

How common is NPC2 p.Leu49Pro (c.146T>C) in the general population?

NPC2 p.Leu49Pro (c.146T>C) is very rare (popmax 0.00111%, nfe) (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.Leu49Pro (c.146T>C)?

AlphaMissense predicts likely pathogenic (score 0.9807) — an in-silico prediction, not a clinical call.

NPC2 p.Leu49Pro

c.146T>C · rs1310092921 · VCV2171461

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9807 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00111%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Niemann-Pick disease, type C2

Computational evidence

Protein change
AlphaMissense	0.9807	likely pathogenic · top 7% in NPC2
REVEL	0.842	moderately pathogenic-leaning
SaProt	LLR -15.30	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 13 kb · p 0.22 · regional, not allelic
Overall
CADD	25.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00111% European (non-Finnish) · 13/1,176,304 alleles

Filtering AF 0.000617% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000475%

Overall 0.000872% 14/1,606,104 alleles · very rare exomes 13/1,453,880 · genomes 1/152,224 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00161%	62,228
European (non-Finnish)grpmax	0.00111%	90,485

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: NPC2
Protein: p.Leu49Pro
Coding: c.146T>C
MANE Select: NM_006432
dbSNP: rs1310092921
Type: single nucleotide variant
Location: chr14:74486373 (GRCh38)
Gene constraint: LOEUF 1.422 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.88 · 2 PDB
Residue 49: 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.Leu49= Likely benign ★ same residue
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

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-leu49pro (accessed [today's date]).

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