Is NPC1 p.Pro540Ser (c.1618C>T) pathogenic?

NPC1 p.Pro540Ser (c.1618C>T) is classified Uncertain significance in NPC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2016-06-21). AlphaMissense: likely pathogenic (0.7894); Ultra-rare (popmax 0.01%, amr).

How common is NPC1 p.Pro540Ser (c.1618C>T) in the general population?

NPC1 p.Pro540Ser (c.1618C>T) is ultra-rare (popmax 0.01%, amr) (gnomAD).

What do computational predictors say about NPC1 p.Pro540Ser (c.1618C>T)?

AlphaMissense predicts likely pathogenic (score 0.7894) — an in-silico prediction, not a clinical call.

NPC1 p.Pro540Ser

c.1618C>T · rs886044064 · VCV289032

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7894 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.01%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7894	likely pathogenic
REVEL	0.855	moderately pathogenic-leaning
SaProt	LLR -11.54	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 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 54 kb · p 0.0029 · regional, not allelic
Overall
CADD	27.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.01% Admixed American · 6/60,000 alleles

Filtering AF 0.00428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.000372% 6/1,613,944 alleles · ultra-rare exomes 5/1,461,794 · genomes 1/152,150 · joint denominator

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.Pro540Ser
Coding: c.1618C>T
MANE Select: NM_000271
dbSNP: rs886044064
Type: single nucleotide variant
Location: chr18:23551663 (GRCh38)
Gene constraint: LOEUF 0.676 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.35 · 20 PDB

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

Similar variants

NPC1 p.Pro540Arg Likely pathogenic ★ same residue
NPC1 p.Pro540= Likely benign ★ same residue
NPC1 p.Pro540fs Pathogenic ★ same residue
NPC1 c.1554-1009G>A Pathogenic ★★ same type
NPC1 c.1757+1G>A Likely pathogenic ★★ same type
NPC1 c.1947+5G>C Pathogenic/Likely pathogenic ★★ same type
NPC1 c.2130+1G>A Pathogenic ★★ same type
NPC1 c.2245+1G>A Pathogenic/Likely pathogenic ★★ same type

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-pro540ser (accessed [today's date]).

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