Is NPC1 p.Cys63Arg (c.187T>C) pathogenic?

NPC1 p.Cys63Arg (c.187T>C) is classified Likely pathogenic in NPC1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-24). AlphaMissense: likely pathogenic (0.9933); Very rare (popmax 0.0011%, sas); Associated with Niemann-Pick disease, type C1.

What condition is associated with NPC1 p.Cys63Arg (c.187T>C)?

NPC1 p.Cys63Arg (c.187T>C) is associated with Niemann-Pick disease, type C1, Niemann-Pick disease type C (ClinVar).

How common is NPC1 p.Cys63Arg (c.187T>C) in the general population?

NPC1 p.Cys63Arg (c.187T>C) 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 NPC1 p.Cys63Arg (c.187T>C)?

AlphaMissense predicts likely pathogenic (score 0.9933) — an in-silico prediction, not a clinical call.

NPC1 p.Cys63Arg

c.187T>C · rs747049347 · VCV2138139

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9933 · 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 C1

Computational evidence

Protein change
AlphaMissense	0.9933	likely pathogenic ✓ concordant with ClinVar · top 2% in NPC1
REVEL	0.977	strongly pathogenic-leaning
SaProt	LLR -13.62	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 11	GERP 1.8, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 54 kb · p 0.0029 · regional, not allelic
Overall
CADD	26.1	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 · 1/91,066 alleles

Overall 0.000124% 2/1,612,158 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,066
European (non-Finnish)	8.48e-05%	1,178,660

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.Cys63Arg
Coding: c.187T>C
MANE Select: NM_000271
dbSNP: rs747049347
Type: single nucleotide variant
Location: chr18:23572174 (GRCh38)
Gene constraint: LOEUF 0.676 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.35 · 20 PDB
Residue 63: 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

Also linked: Niemann-Pick disease type C

For Niemann-Pick disease type C (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

NPC1 p.Cys63Ser Likely pathogenic ★ same residue
NPC1 p.Cys63Tyr Likely pathogenic ★ same residue
NPC1 p.Cys63= Likely benign ★ 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

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-cys63arg (accessed [today's date]).

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