Is NPC2 p.Val39= (c.117G>T) pathogenic?

NPC2 p.Val39= (c.117G>T) is classified Likely benign in NPC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-20). Very rare (popmax 0.00342%, amr); Associated with Niemann-Pick disease, type C2.

What condition is associated with NPC2 p.Val39= (c.117G>T)?

NPC2 p.Val39= (c.117G>T) is associated with Niemann-Pick disease, type C2 (ClinVar).

How common is NPC2 p.Val39= (c.117G>T) in the general population?

NPC2 p.Val39= (c.117G>T) is very rare (popmax 0.00342%, amr) (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.Val39=

c.117G>T · rs1483609858 · VCV2962550

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00342%, amr)

Conditions

Niemann-Pick disease, type C2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>T here scores Δ0.21 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1.1	GERP -0.24, phastCons 1
Overall
CADD	8.279	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00342% Admixed American · 2/58,400 alleles

Filtering AF 0.000568% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000213%

Overall 0.000125% 2/1,603,086 alleles · very rare exomes 2/1,450,846 · genomes 0/152,240 · joint denominator

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.Val39=
Coding: c.117G>T
MANE Select: NM_006432
dbSNP: rs1483609858
Type: single nucleotide variant
Location: chr14:74486402 (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.Val39Met Uncertain significance ★★ ⚠ 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-val39 (accessed [today's date]).

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