Is NPC1 p.Phe763= (c.2289T>C) pathogenic?

NPC1 p.Phe763= (c.2289T>C) is classified Likely benign in NPC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-03). Very rare (popmax 0.005%, amr); Associated with Niemann-Pick disease, type C1.

What condition is associated with NPC1 p.Phe763= (c.2289T>C)?

NPC1 p.Phe763= (c.2289T>C) is associated with Niemann-Pick disease, type C1 (ClinVar).

How common is NPC1 p.Phe763= (c.2289T>C) in the general population?

NPC1 p.Phe763= (c.2289T>C) is very rare (popmax 0.005%, amr) (gnomAD).

How is Niemann-Pick disease type C inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

NPC1 p.Phe763=

c.2289T>C · rs2058711785 · VCV1623856

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Conditions

Niemann-Pick disease, type C1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.54	GERP -3.9
Overall
CADD	4.344	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.005% Admixed American · 3/60,028 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000274% 4/1,461,894 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	20,009
European (non-Finnish)	8.47e-05%	1,180,048

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.Phe763=
Coding: c.2289T>C
MANE Select: NM_000271
dbSNP: rs2058711785
Type: single nucleotide variant
Location: chr18:23541390 (GRCh38)
Gene constraint: LOEUF 0.676 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.35 · 20 PDB
Residue 763: a UniProt-annotated variant site (in npc1); the ssd domain; an α-helix

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

Disease context

Niemann-Pick disease, type C1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Niemann-Pick disease type C (Orphanet):

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

Similar variants

NPC1 p.Phe763Leu Likely pathogenic ★ same residue
NPC1 p.Phe763fs Pathogenic ★ same residue
NPC1 p.Phe763Ser Uncertain significance ★ ⚠ 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-phe763 (accessed [today's date]).

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