Is NPC1 p.Ala1187= (c.3561G>T) pathogenic?

NPC1 p.Ala1187= (c.3561G>T) is classified Conflicting classifications of pathogenicity in NPC1 (ClinVar, Conflicting submitters, 12 submitters; last evaluated 2026-06-01). Rare (popmax 0.973%, mid); Associated with Inborn genetic diseases.

What condition is associated with NPC1 p.Ala1187= (c.3561G>T)?

NPC1 p.Ala1187= (c.3561G>T) is associated with Inborn genetic diseases, Niemann-Pick disease, type C1 (ClinVar).

How common is NPC1 p.Ala1187= (c.3561G>T) in the general population?

NPC1 p.Ala1187= (c.3561G>T) is rare (popmax 0.973%, mid) (gnomAD).

NPC1 p.Ala1187=

c.3561G>T · rs55724504 · VCV211683

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 12 submitters

gnomAD v4.1

Rare

rare (popmax 0.973%, mid)

Conditions

Inborn genetic diseases

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 -11	GERP -3.9
Overall
CADD	0.247	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.973% Middle Eastern · 59/6,062 alleles

Filtering AF 0.775% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.703%

Overall 0.223% 3,599/1,613,866 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.973%	103
Ashkenazi Jewishnot grpmax-eligible	0.871%	115
Admixed American	0.373%	268
Remaining individualsnot grpmax-eligible	0.314%	319
African / African-American	0.257%	389
European (non-Finnish)	0.22%	454
Finnishnot grpmax-eligible	0.105%	951
South Asian	0.00549%	18,216

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.Ala1187=
Coding: c.3561G>T
MANE Select: NM_000271
dbSNP: rs55724504
Type: single nucleotide variant
Location: chr18:23534476 (GRCh38)
Gene constraint: LOEUF 0.676 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.35 · 20 PDB
Residue 1187: 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

Also linked: Niemann-Pick disease, type C1

Similar variants

NPC1 p.Ala1187Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
NPC1 p.Ala1187Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
NPC1 p.Ala1187Val Conflicting classifications of pathogenicity ★ ⚠ same residue
NPC1 p.Ala1187fs 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

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-ala1187 (accessed [today's date]).

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