Is NPC1 p.Pro474Leu (c.1421C>T) pathogenic?

NPC1 p.Pro474Leu (c.1421C>T) is classified Pathogenic in NPC1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-09-04). AlphaMissense: ambiguous (0.4979); Very rare (popmax 0.00223%, eas); Associated with Cataplexy.

What condition is associated with NPC1 p.Pro474Leu (c.1421C>T)?

NPC1 p.Pro474Leu (c.1421C>T) is associated with Cataplexy, cerebellar ataxia, Niemann-Pick disease, type C1 (ClinVar).

How common is NPC1 p.Pro474Leu (c.1421C>T) in the general population?

NPC1 p.Pro474Leu (c.1421C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about NPC1 p.Pro474Leu (c.1421C>T)?

AlphaMissense predicts ambiguous (score 0.4979) — an in-silico prediction, not a clinical call.

NPC1 p.Pro474Leu

c.1421C>T · rs372445155 · VCV374049

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.4979 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Cataplexy

Computational evidence

Protein change
AlphaMissense	0.4979	ambiguous
REVEL	0.856	moderately pathogenic-leaning
SaProt	LLR -12.14	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.4, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 54 kb · p 0.0029 · regional, not allelic
Overall
CADD	26.0	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 0.00223% East Asian · 1/44,896 alleles

Filtering AF 0.0013% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00108%

Overall 0.00155% 25/1,613,884 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,896
European (non-Finnish)	0.00195%	51,300
African / African-American	0.00133%	74,916

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.Pro474Leu
Coding: c.1421C>T
MANE Select: NM_000271
dbSNP: rs372445155
Type: single nucleotide variant
Location: chr18:23554890 (GRCh38)
Gene constraint: LOEUF 0.676 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.35 · 20 PDB
Residue 474: a UniProt-annotated variant site (in npc1); a turn; a disulfide bond

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

Disease context

Cataplexy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: cerebellar ataxia Niemann-Pick disease, type C1

Similar variants

NPC1 p.Pro474= Likely benign ★★ same residue
NPC1 p.Pro474Ala 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
NPC1 c.2246-2A>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-pro474leu (accessed [today's date]).

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