Is NPC2 p.Ser54Cys (c.161C>G) pathogenic?

NPC2 p.Ser54Cys (c.161C>G) is classified Uncertain significance in NPC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-17). AlphaMissense: ambiguous (0.5205); Very rare (popmax 8.51e-05%, nfe); Associated with Niemann-Pick disease, type C2.

What condition is associated with NPC2 p.Ser54Cys (c.161C>G)?

NPC2 p.Ser54Cys (c.161C>G) is associated with Niemann-Pick disease, type C2 (ClinVar).

How common is NPC2 p.Ser54Cys (c.161C>G) in the general population?

NPC2 p.Ser54Cys (c.161C>G) is very rare (popmax 8.51e-05%, 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.Ser54Cys (c.161C>G)?

AlphaMissense predicts ambiguous (score 0.5205) — an in-silico prediction, not a clinical call.

NPC2 p.Ser54Cys

c.161C>G · rs2506107142 · VCV2011423

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5205 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.51e-05%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Niemann-Pick disease, type C2

Computational evidence

Protein change
AlphaMissense	0.5205	ambiguous
REVEL	0.723	pathogenic-leaning
SaProt	LLR -11.42	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 13 kb · p 0.22 · regional, not allelic
Overall
CADD	26.9	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.51e-05% European (non-Finnish) · 1/1,175,032 alleles

Overall 6.24e-05% 1/1,603,832 alleles · very rare exomes 1/1,451,518 · genomes 0/152,314 · 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.Ser54Cys
Coding: c.161C>G
MANE Select: NM_006432
dbSNP: rs2506107142
Type: single nucleotide variant
Location: chr14:74486358 (GRCh38)
Gene constraint: LOEUF 1.422 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.88 · 2 PDB
Residue 54: 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.Ser54Pro 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-ser54cys (accessed [today's date]).

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