Is NPC1 p.Ala764Ser (c.2290G>T) pathogenic?

NPC1 p.Ala764Ser (c.2290G>T) is classified Likely pathogenic in NPC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-29). AlphaMissense: likely benign (0.2336); Very rare (popmax 0.00133%, afr); Associated with Niemann-Pick disease, type C1.

What condition is associated with NPC1 p.Ala764Ser (c.2290G>T)?

NPC1 p.Ala764Ser (c.2290G>T) is associated with Niemann-Pick disease, type C1 (ClinVar).

How common is NPC1 p.Ala764Ser (c.2290G>T) in the general population?

NPC1 p.Ala764Ser (c.2290G>T) is very rare (popmax 0.00133%, 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.Ala764Ser (c.2290G>T)?

AlphaMissense predicts likely benign (score 0.2336) — an in-silico prediction, not a clinical call.

NPC1 p.Ala764Ser

c.2290G>T · rs2511222745 · VCV2810642

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2336 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Niemann-Pick disease, type C1

Computational evidence

Protein change
AlphaMissense	0.2336	likely benign ⚠ discordant with ClinVar
REVEL	0.673	pathogenic-leaning
SaProt	LLR -9.71	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 5.9	GERP 0.99, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 54 kb · p 0.0029 · regional, not allelic
Overall
CADD	24.6	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 0.00133% African / African-American · 1/75,060 alleles

Overall 6.84e-05% 1/1,461,892 alleles · very rare

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.Ala764Ser
Coding: c.2290G>T
MANE Select: NM_000271
dbSNP: rs2511222745
Type: single nucleotide variant
Location: chr18:23541389 (GRCh38)
Gene constraint: LOEUF 0.676 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.35 · 20 PDB
Residue 764: 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.Ala764Val Pathogenic ★★ same residue
NPC1 p.Ala764= Conflicting classifications of pathogenicity ★ same residue
NPC1 p.Ala764Glu Pathogenic ★ 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-ala764ser (accessed [today's date]).

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