Is NPC1 p.Cys976= (c.2928C>T) pathogenic?

NPC1 p.Cys976= (c.2928C>T) is classified Likely benign in NPC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-17). Ultra-rare (popmax 0.0384%, sas); Associated with Niemann-Pick disease, type C1.

What condition is associated with NPC1 p.Cys976= (c.2928C>T)?

NPC1 p.Cys976= (c.2928C>T) is associated with Niemann-Pick disease, type C1 (ClinVar).

How common is NPC1 p.Cys976= (c.2928C>T) in the general population?

NPC1 p.Cys976= (c.2928C>T) is ultra-rare (popmax 0.0384%, sas) (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.Cys976=

c.2928C>T · rs370766410 · VCV1134746

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0384%, sas)

Conditions

Niemann-Pick disease, type C1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.45	acceptor gain · deltas
Pangolin	Δ0.55	gain · loss 0.40 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP -0.15	GERP -2.7
Overall
CADD	17.91	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0384% South Asian · 35/91,088 alleles

Filtering AF 0.0283% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0249%

Overall 0.00297% 48/1,613,972 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0384%	2,603
African / African-American	0.00667%	14,988
Remaining individualsnot grpmax-eligible	0.0016%	62,488
European (non-Finnish)	0.000593%	168,574

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.Cys976=
Coding: c.2928C>T
MANE Select: NM_000271
dbSNP: rs370766410
Type: single nucleotide variant
Location: chr18:23538655 (GRCh38)
Gene constraint: LOEUF 0.676 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.35 · 20 PDB
Residue 976: a UniProt-annotated variant site (in npc1); a disulfide bond

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.Cys976Ter Pathogenic/Likely pathogenic ★★ same residue
NPC1 p.Cys976Arg 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

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-cys976 (accessed [today's date]).

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