Is NPC1 p.Pro1000Ser (c.2998C>T) pathogenic?

NPC1 p.Pro1000Ser (c.2998C>T) is classified Uncertain significance in NPC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-18). AlphaMissense: likely benign (0.1914); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with NPC1 p.Pro1000Ser (c.2998C>T)?

NPC1 p.Pro1000Ser (c.2998C>T) is associated with Inborn genetic diseases (ClinVar).

How common is NPC1 p.Pro1000Ser (c.2998C>T) in the general population?

NPC1 p.Pro1000Ser (c.2998C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NPC1 p.Pro1000Ser (c.2998C>T)?

AlphaMissense predicts likely benign (score 0.1914) — an in-silico prediction, not a clinical call.

NPC1 p.Pro1000Ser

c.2998C>T · rs2058666890 · VCV1798591

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1914 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1914	likely benign
REVEL	0.814	moderately pathogenic-leaning
SaProt	LLR -8.71	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 1.6, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 54 kb · p 0.0029 · regional, not allelic
Overall
CADD	22.9	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: NPC1
Protein: p.Pro1000Ser
Coding: c.2998C>T
MANE Select: NM_000271
dbSNP: rs2058666890
Type: single nucleotide variant
Location: chr18:23538585 (GRCh38)
Gene constraint: LOEUF 0.676 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.35 · 20 PDB
Residue 1000: an α-helix

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NPC1 p.Pro1000= Likely benign ★ same residue
NPC1 p.Ala927Val Pathogenic/Likely pathogenic ★★ ⚠ same condition
NPC1 p.Cys177Tyr Pathogenic/Likely pathogenic ★★ same condition
NPC1 p.Ala1108Val Uncertain significance ★★ ⚠ same condition
NPC1 p.Ala181Thr Uncertain significance ★★ ⚠ same condition
NPC1 p.Arg1183His Uncertain significance ★★ ⚠ same condition
NPC1 p.Arg372Gln Uncertain significance ★★ ⚠ same condition
NPC1 p.Arg646Cys Uncertain significance ★★ ⚠ 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-pro1000ser (accessed [today's date]).

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