Is NPC1 p.Gln92Arg (c.275A>G) pathogenic?

NPC1 p.Gln92Arg (c.275A>G) is classified Conflicting classifications of pathogenicity in NPC1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2023-05-23). AlphaMissense: likely pathogenic (0.5892); Very rare (popmax 8.48e-05%, nfe); Associated with Niemann-Pick disease, type C1.

What condition is associated with NPC1 p.Gln92Arg (c.275A>G)?

NPC1 p.Gln92Arg (c.275A>G) is associated with Niemann-Pick disease, type C1 (ClinVar).

How common is NPC1 p.Gln92Arg (c.275A>G) in the general population?

NPC1 p.Gln92Arg (c.275A>G) is very rare (popmax 8.48e-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 NPC1 p.Gln92Arg (c.275A>G)?

AlphaMissense predicts likely pathogenic (score 0.5892) — an in-silico prediction, not a clinical call.

NPC1 p.Gln92Arg

c.275A>G · rs2145544354 · VCV2138138

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.5892 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Niemann-Pick disease, type C1

Computational evidence

Protein change
AlphaMissense	0.5892	likely pathogenic
REVEL	0.608	indeterminate
SaProt	LLR -7.48	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.8, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 54 kb · p 0.0029 · regional, not allelic
Overall
CADD	23.6	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 8.48e-05% European (non-Finnish) · 1/1,179,466 alleles

Overall 6.84e-05% 1/1,461,154 alleles · very rare

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: NPC1
Protein: p.Gln92Arg
Coding: c.275A>G
MANE Select: NM_000271
dbSNP: rs2145544354
Type: single nucleotide variant
Location: chr18:23572086 (GRCh38)
Gene constraint: LOEUF 0.676 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.35 · 20 PDB
Residue 92: an α-helix; a disulfide bond; a UniProt-annotated variant site (in npc1)

Full NPC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Niemann-Pick disease, type C1 — 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

NPC1 p.Gln92Ter Pathogenic ★ same residue
NPC1 c.1554-1009G>A Pathogenic ★★ same condition
NPC1 c.1757+1G>A Likely pathogenic ★★ same condition
NPC1 c.1947+5G>C Pathogenic/Likely pathogenic ★★ same condition
NPC1 c.2130+1G>A Pathogenic ★★ same condition
NPC1 c.2245+1G>A Pathogenic/Likely pathogenic ★★ same condition
NPC1 c.2246-2A>G Pathogenic/Likely pathogenic ★★ same condition
NPC1 c.2515-2A>G 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/npc1-p-gln92arg (accessed [today's date]).

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