Is NPC2 p.Asp91= (c.273T>C) pathogenic?

NPC2 p.Asp91= (c.273T>C) is classified Conflicting classifications of pathogenicity in NPC2 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-01-20). Rare (popmax 0.25%, eas); Associated with Inborn genetic diseases.

What condition is associated with NPC2 p.Asp91= (c.273T>C)?

NPC2 p.Asp91= (c.273T>C) is associated with Inborn genetic diseases, Niemann-Pick disease, type C1, Niemann-Pick disease, type C2 (ClinVar).

How common is NPC2 p.Asp91= (c.273T>C) in the general population?

NPC2 p.Asp91= (c.273T>C) is rare (popmax 0.25%, eas) (gnomAD).

NPC2 p.Asp91=

c.273T>C · rs151071820 · VCV715373

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

rare (popmax 0.25%, eas)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.284	benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.073	GERP -3.5, phastCons 0.11
Overall
CADD	6.014	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.25% East Asian · 112/44,884 alleles

Filtering AF 0.212% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.198%

Overall 0.023% 371/1,614,084 alleles · rare exomes 321/1,461,886 · genomes 50/152,198 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.25%	401
Finnishnot grpmax-eligible	0.241%	416
Remaining individualsnot grpmax-eligible	0.0224%	4,465
European (non-Finnish)	0.00763%	13,111
African / African-American	0.00133%	75,002

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.Asp91=
Coding: c.273T>C
MANE Select: NM_006432
dbSNP: rs151071820
Type: single nucleotide variant
Location: chr14:74484505 (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

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

Also linked: Niemann-Pick disease, type C1 Niemann-Pick disease, type C2

Similar variants

NPC2 p.Asp91Asn 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-asp91 (accessed [today's date]).

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