Is NPC2 p.Lys134= (c.402A>G) pathogenic?

NPC2 p.Lys134= (c.402A>G) is classified Likely benign in NPC2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2020-05-18). Very rare (popmax 0.00133%, afr); Associated with NPC2-related disorder.

What condition is associated with NPC2 p.Lys134= (c.402A>G)?

NPC2 p.Lys134= (c.402A>G) is associated with NPC2-related disorder (ClinVar).

How common is NPC2 p.Lys134= (c.402A>G) in the general population?

NPC2 p.Lys134= (c.402A>G) is very rare (popmax 0.00133%, afr) (gnomAD).

NPC2 p.Lys134=

c.402A>G · rs2506099906 · VCV3054766

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

NPC2-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.16	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.25	GERP -3.8
Overall
CADD	0.228	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,068 alleles

Overall 6.2e-05% 1/1,614,186 alleles · very rare exomes 1/1,461,848 · genomes 0/152,338 · 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.Lys134=
Coding: c.402A>G
MANE Select: NM_006432
dbSNP: rs2506099906
Type: single nucleotide variant
Location: chr14:74480741 (GRCh38)
Gene constraint: LOEUF 1.422 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.88 · 2 PDB

Full NPC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

NPC2-related disorder

Similar variants

NPC2 p.Lys134Gln Uncertain significance ★ ⚠ same residue
NPC2 c.441+30G>A Uncertain significance same condition
NPC2 c.441+66A>T Uncertain significance same condition
NPC2 c.441+24G>A Likely benign same condition
NPC2 c.-10_-9insGCG Likely benign same condition
NPC2 c.190+5G>A Pathogenic/Likely pathogenic ★★ same type
NPC2 p.Cys47Ter Pathogenic ★★ same type
NPC2 p.Cys99Arg Pathogenic ★★ same type

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-lys134 (accessed [today's date]).

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