Is NPC2 p.Val39Met (c.115G>A) pathogenic?

NPC2 p.Val39Met (c.115G>A) is classified Uncertain significance in NPC2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-03-03). AlphaMissense: likely pathogenic (0.7302); Very rare (popmax 0.00341%, nfe); Associated with Niemann-Pick disease, type C2.

What condition is associated with NPC2 p.Val39Met (c.115G>A)?

NPC2 p.Val39Met (c.115G>A) is associated with Niemann-Pick disease, type C2 (ClinVar).

How common is NPC2 p.Val39Met (c.115G>A) in the general population?

NPC2 p.Val39Met (c.115G>A) is very rare (popmax 0.00341%, 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.Val39Met (c.115G>A)?

AlphaMissense predicts likely pathogenic (score 0.7302) — an in-silico prediction, not a clinical call.

NPC2 p.Val39Met

c.115G>A · rs80358261 · VCV8483

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.7302 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00341%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Niemann-Pick disease, type C2

Computational evidence

Protein change
AlphaMissense	0.7302	likely pathogenic
REVEL	0.802	moderately pathogenic-leaning
SaProt	LLR -12.33	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 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 13 kb · p 0.22 · regional, not allelic
Overall
CADD	26.6	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 0.00341% European (non-Finnish) · 40/1,174,100 alleles

Filtering AF 0.00257% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00226%

Overall 0.00262% 42/1,602,146 alleles · very rare exomes 40/1,449,990 · genomes 2/152,156 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00341%	29,353
Admixed American	0.00172%	58,266
African / African-American	0.00134%	74,826

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.Val39Met
Coding: c.115G>A
MANE Select: NM_006432
dbSNP: rs80358261
Type: single nucleotide variant
Location: chr14:74486404 (GRCh38)
Gene constraint: LOEUF 1.422 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.88 · 2 PDB
Residue 39: a UniProt-annotated variant site (in npc2; results in the synthesis of functional recombinant proteins correctly targeted to lysosomes); 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.Val39= 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-val39met (accessed [today's date]).

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