Is NPC1 p.Cys967Phe (c.2900G>T) pathogenic?

NPC1 p.Cys967Phe (c.2900G>T) is classified Uncertain significance in NPC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-26). AlphaMissense: likely pathogenic (0.9818); Absent from gnomAD v4.1; Associated with NPC1-related disorder.

What condition is associated with NPC1 p.Cys967Phe (c.2900G>T)?

NPC1 p.Cys967Phe (c.2900G>T) is associated with NPC1-related disorder (ClinVar).

How common is NPC1 p.Cys967Phe (c.2900G>T) in the general population?

NPC1 p.Cys967Phe (c.2900G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NPC1 p.Cys967Phe (c.2900G>T)?

AlphaMissense predicts likely pathogenic (score 0.9818) — an in-silico prediction, not a clinical call.

NPC1 p.Cys967Phe

c.2900G>T · VCV4854023

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9818 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

NPC1-related disorder

Computational evidence

Protein change
AlphaMissense	0.9818	likely pathogenic · top 4% in NPC1
REVEL	0.92	moderately pathogenic-leaning
SaProt	LLR -13.78	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 7.6	GERP 1.6, 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

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

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.Cys967Phe
Coding: c.2900G>T
MANE Select: NM_000271
Type: single nucleotide variant
Location: chr18:23539366 (GRCh38)
Gene constraint: LOEUF 0.676 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.35 · 20 PDB
Residue 967: a disulfide bond

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

Disease context

NPC1-related disorder

Similar variants

NPC1 p.Cys967Ter Likely pathogenic ★ same residue
NPC1 c.1947+5G>C Pathogenic/Likely pathogenic ★★ same condition
NPC1 p.Arg1186His Pathogenic/Likely pathogenic ★★ same condition
NPC1 p.Arg404Gln Pathogenic ★★ ⚠ same condition
NPC1 p.Arg958Gln Pathogenic/Likely pathogenic ★★ ⚠ same condition
NPC1 p.Asn968Ser Pathogenic/Likely pathogenic ★★ ⚠ same condition
NPC1 p.Gln921Ter Pathogenic ★★ same condition
NPC1 p.Gly248Val 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-cys967phe (accessed [today's date]).

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