Is NPC1 p.Ser1197= (c.3591C>T) pathogenic?

NPC1 p.Ser1197= (c.3591C>T) is classified Uncertain significance in NPC1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-10-30). Ultra-rare (popmax 0.044%, afr); Associated with Niemann-Pick disease, type C1.

What condition is associated with NPC1 p.Ser1197= (c.3591C>T)?

NPC1 p.Ser1197= (c.3591C>T) is associated with Niemann-Pick disease, type C1 (ClinVar).

How common is NPC1 p.Ser1197= (c.3591C>T) in the general population?

NPC1 p.Ser1197= (c.3591C>T) is ultra-rare (popmax 0.044%, afr) (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.Ser1197=

c.3591C>T · rs191776973 · VCV593823

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.044%, afr)

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 -2.7	GERP -3.9
Overall
CADD	2.321	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.044% African / African-American · 33/75,006 alleles

Filtering AF 0.0321% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0281%

Overall 0.00566% 91/1,609,118 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.044%	2,273
Remaining individualsnot grpmax-eligible	0.0128%	7,797
Admixed American	0.00833%	12,004
East Asian	0.00669%	14,951
South Asian	0.0044%	22,747
European (non-Finnish)	0.00323%	30,962

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.Ser1197=
Coding: c.3591C>T
MANE Select: NM_000271
dbSNP: rs191776973
Type: single nucleotide variant
Location: chr18:23534446 (GRCh38)
Gene constraint: LOEUF 0.676 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.35 · 20 PDB

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.Ser1197Phe Likely 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
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-ser1197 (accessed [today's date]).

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