Is NPC1 p.Arg372Trp (c.1114C>T) pathogenic?

NPC1 p.Arg372Trp (c.1114C>T) is classified Pathogenic/Likely pathogenic in NPC1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-11). AlphaMissense: likely benign (0.1269); Ultra-rare (popmax 0.0165%, mid); Associated with Niemann-Pick disease type C.

What condition is associated with NPC1 p.Arg372Trp (c.1114C>T)?

NPC1 p.Arg372Trp (c.1114C>T) is associated with Niemann-Pick disease type C, Niemann-Pick disease, type C1 (ClinVar).

How common is NPC1 p.Arg372Trp (c.1114C>T) in the general population?

NPC1 p.Arg372Trp (c.1114C>T) is ultra-rare (popmax 0.0165%, mid) (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.Arg372Trp (c.1114C>T)?

AlphaMissense predicts likely benign (score 0.1269) — an in-silico prediction, not a clinical call.

NPC1 p.Arg372Trp

c.1114C>T · rs1346436537 · VCV1066746

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1269 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Niemann-Pick disease type C

Computational evidence

Protein change
AlphaMissense	0.1269	likely benign ⚠ discordant with ClinVar
REVEL	0.617	indeterminate
SaProt	LLR -12.00	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.2	GERP -0.27, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 54 kb · p 0.0029 · regional, not allelic
Overall
CADD	25.0	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 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00207%

Overall 0.000958% 14/1,461,856 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
Admixed American	0.00833%	12,001
Remaining individualsnot grpmax-eligible	0.0016%	62,512
European (non-Finnish)	0.000593%	168,573

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.Arg372Trp
Coding: c.1114C>T
MANE Select: NM_000271
dbSNP: rs1346436537
Type: single nucleotide variant
Location: chr18:23556455 (GRCh38)
Gene constraint: LOEUF 0.676 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.35 · 20 PDB
Residue 372: 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 C — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Niemann-Pick disease, type C1

For Niemann-Pick disease type C (Orphanet):

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

Similar variants

NPC1 p.Arg372Gln Uncertain significance ★★ ⚠ same residue
NPC1 p.Arg372= Likely benign ★ same residue
NPC1 p.Arg372fs Likely 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

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-arg372trp (accessed [today's date]).

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