Is NPC1 p.Cys113= (c.339T>C) pathogenic?

NPC1 p.Cys113= (c.339T>C) is classified Likely benign in NPC1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-07-09). Absent from gnomAD v4.1; Associated with Niemann-Pick disease, type C1.

What condition is associated with NPC1 p.Cys113= (c.339T>C)?

NPC1 p.Cys113= (c.339T>C) is associated with Niemann-Pick disease, type C1 (ClinVar).

How common is NPC1 p.Cys113= (c.339T>C) in the general population?

NPC1 p.Cys113= (c.339T>C) 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.

NPC1 p.Cys113=

c.339T>C · rs2059164609 · VCV2857763

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Niemann-Pick disease, type C1

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 · A>C here scores Δ0.24 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1.6	GERP -1.4, phastCons 1
Overall
CADD	7.782	PHRED · no single calibrated threshold — expert panels disagree

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: NPC1
Protein: p.Cys113=
Coding: c.339T>C
MANE Select: NM_000271
dbSNP: rs2059164609
Type: single nucleotide variant
Location: chr18:23568947 (GRCh38)
Gene constraint: LOEUF 0.676 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.35 · 20 PDB
Residue 113: an α-helix; a disulfide bond; a UniProt-annotated variant site (in npc1; partially mislocalized from late endocytic organelles diffusely to the cell periphery; localizes to the endoplasmic reticulum rab7-negative endosomes and the cell surface; does not clear the lysosomal cholesterol accumulation in npc1-deficient cells)

Full NPC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Niemann-Pick disease, type C1 — 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

NPC1 p.Cys113Arg Pathogenic/Likely pathogenic ★★ same residue
NPC1 p.Cys113Ter Likely pathogenic ★ same residue
NPC1 p.Cys113Tyr Likely pathogenic ★ same residue
NPC1 c.1554-1009G>A Pathogenic ★★ same condition
NPC1 c.1757+1G>A Likely pathogenic ★★ same condition
NPC1 c.1947+5G>C Pathogenic/Likely pathogenic ★★ same condition
NPC1 c.2130+1G>A Pathogenic ★★ same condition
NPC1 c.2245+1G>A 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/npc1-p-cys113 (accessed [today's date]).

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