Is NPC1 p.Phe747Ser (c.2240T>C) pathogenic?

NPC1 p.Phe747Ser (c.2240T>C) is classified Uncertain significance in NPC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-27). AlphaMissense: ambiguous (0.3545); Very rare (popmax 0.00537%, afr); Associated with Niemann-Pick disease, type C1.

What condition is associated with NPC1 p.Phe747Ser (c.2240T>C)?

NPC1 p.Phe747Ser (c.2240T>C) is associated with Niemann-Pick disease, type C1 (ClinVar).

How common is NPC1 p.Phe747Ser (c.2240T>C) in the general population?

NPC1 p.Phe747Ser (c.2240T>C) is very rare (popmax 0.00537%, afr) (gnomAD).

How is Niemann-Pick disease type C inherited?

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

What do computational predictors say about NPC1 p.Phe747Ser (c.2240T>C)?

AlphaMissense predicts ambiguous (score 0.3545) — an in-silico prediction, not a clinical call.

NPC1 p.Phe747Ser

c.2240T>C · rs1490823282 · VCV1428085

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3545 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00537%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Niemann-Pick disease, type C1

Computational evidence

Protein change
AlphaMissense	0.3545	ambiguous
REVEL	0.902	moderately pathogenic-leaning
SaProt	LLR -7.93	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 54 kb · p 0.0029 · regional, not allelic
Overall
CADD	27.1	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 0.00537% African / African-American · 4/74,518 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000251% 4/1,593,312 alleles · very rare exomes 1/1,441,248 · genomes 3/152,064 · 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.Phe747Ser
Coding: c.2240T>C
MANE Select: NM_000271
dbSNP: rs1490823282
Type: single nucleotide variant
Location: chr18:23543460 (GRCh38)
Gene constraint: LOEUF 0.676 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.35 · 20 PDB
Residue 747: 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.Phe747Leu 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
NPC1 c.2246-2A>G Pathogenic/Likely pathogenic ★★ same condition
NPC1 c.2515-2A>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-phe747ser (accessed [today's date]).

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