Is NPC2 p.Cys93Phe (c.278G>T) pathogenic?

NPC2 p.Cys93Phe (c.278G>T) is classified Conflicting classifications of pathogenicity in NPC2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-12-05). AlphaMissense: likely pathogenic (0.9791); Very rare (popmax 0.0011%, sas); Associated with Niemann-Pick disease, type C2.

What condition is associated with NPC2 p.Cys93Phe (c.278G>T)?

NPC2 p.Cys93Phe (c.278G>T) is associated with Niemann-Pick disease, type C2 (ClinVar).

How common is NPC2 p.Cys93Phe (c.278G>T) in the general population?

NPC2 p.Cys93Phe (c.278G>T) is very rare (popmax 0.0011%, sas) (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.Cys93Phe (c.278G>T)?

AlphaMissense predicts likely pathogenic (score 0.9791) — an in-silico prediction, not a clinical call.

NPC2 p.Cys93Phe

c.278G>T · rs143960270 · VCV1210442

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9791 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Niemann-Pick disease, type C2

Computational evidence

Protein change
AlphaMissense	0.9791	likely pathogenic · top 7% in NPC2
REVEL	0.961	strongly pathogenic-leaning
SaProt	LLR -14.10	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 13 kb · p 0.22 · regional, not allelic
Overall
CADD	29.4	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 0.0011% South Asian · 1/91,072 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.000867% 14/1,614,140 alleles · very rare exomes 14/1,461,886 · genomes 0/152,254 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00312%	32,016
Remaining individualsnot grpmax-eligible	0.0016%	62,506
South Asiangrpmax	0.0011%	91,072
European (non-Finnish)	0.000847%	118,003

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Cys93Phe
Coding: c.278G>T
MANE Select: NM_006432
dbSNP: rs143960270
Type: single nucleotide variant
Location: chr14:74484500 (GRCh38)
Gene constraint: LOEUF 1.422 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.88 · 2 PDB
Residue 93: a UniProt-annotated variant site (in npc2; leads to the synthesis of misfolded recombinant proteins that colocalized with an endoplasmic reticulum marker; normally secreted but unable to correct cholesterol storage in npc2-deficient cells); an α-helix; a disulfide bond

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.Cys93= Likely benign ★ 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-cys93phe (accessed [today's date]).

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