Is NPC2 p.Ser56= (c.168C>T) pathogenic?

NPC2 p.Ser56= (c.168C>T) is classified Conflicting classifications of pathogenicity in NPC2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-07-28). Very rare (popmax 0.00802%, afr); Associated with Inborn genetic diseases.

What condition is associated with NPC2 p.Ser56= (c.168C>T)?

NPC2 p.Ser56= (c.168C>T) is associated with Inborn genetic diseases, Niemann-Pick disease, type C2 (ClinVar).

How common is NPC2 p.Ser56= (c.168C>T) in the general population?

NPC2 p.Ser56= (c.168C>T) is very rare (popmax 0.00802%, afr) (gnomAD).

NPC2 p.Ser56=

c.168C>T · rs761208847 · VCV500945

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00802%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.197	benign-leaning
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.6	GERP -0.3, phastCons 1
Overall
CADD	11.54	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00802% African / African-American · 6/74,826 alleles

Filtering AF 0.00412% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00374%

Overall 0.00425% 68/1,601,458 alleles · very rare exomes 63/1,449,286 · genomes 5/152,172 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00802%	12,471
European (non-Finnish)	0.0052%	19,241
Remaining individualsnot grpmax-eligible	0.00161%	62,050

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.Ser56=
Coding: c.168C>T
MANE Select: NM_006432
dbSNP: rs761208847
Type: single nucleotide variant
Location: chr14:74486351 (GRCh38)
Gene constraint: LOEUF 1.422 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.88 · 2 PDB
Residue 56: a β-strand

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Niemann-Pick disease, type C2

Similar variants

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
NPC2 p.Pro120Ser 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-ser56 (accessed [today's date]).

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