Is NPC1 p.Arg978Cys (c.2932C>T) pathogenic?

NPC1 p.Arg978Cys (c.2932C>T) is classified Pathogenic/Likely pathogenic in NPC1 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2025-12-28). AlphaMissense: likely benign (0.2367); Very rare (popmax 0.000847%, nfe); Associated with Niemann-Pick disease type C.

What condition is associated with NPC1 p.Arg978Cys (c.2932C>T)?

NPC1 p.Arg978Cys (c.2932C>T) is associated with Niemann-Pick disease type C, Niemann-Pick disease, type C1 (ClinVar).

How common is NPC1 p.Arg978Cys (c.2932C>T) in the general population?

NPC1 p.Arg978Cys (c.2932C>T) is very rare (popmax 0.000847%, nfe) (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.Arg978Cys (c.2932C>T)?

AlphaMissense predicts likely benign (score 0.2367) — an in-silico prediction, not a clinical call.

NPC1 p.Arg978Cys

c.2932C>T · rs28942108 · VCV2976

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.2367 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000847%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Niemann-Pick disease type C

Computational evidence

Protein change
AlphaMissense	0.2367	likely benign ⚠ discordant with ClinVar
REVEL	0.812	moderately pathogenic-leaning
SaProt	LLR -9.54	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	Δ0.24	acceptor gain · deltas
Pangolin	Δ0.23	gain · loss 0.13 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 12	GERP 1.5, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 54 kb · p 0.0029 · regional, not allelic
Overall
CADD	34.0	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 0.000847% European (non-Finnish) · 10/1,179,958 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.000889% 13/1,461,700 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,803
Finnishnot grpmax-eligible	0.00156%	63,966
European (non-Finnish)grpmax	0.000847%	117,996

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg978Cys
Coding: c.2932C>T
MANE Select: NM_000271
dbSNP: rs28942108
Type: single nucleotide variant
Location: chr18:23538651 (GRCh38)
Gene constraint: LOEUF 0.676 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.35 · 20 PDB
Residue 978: a UniProt-annotated variant site (in npc1); a β-strand; a disulfide bond

Full NPC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Niemann-Pick disease type C — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Niemann-Pick disease, type C1

For Niemann-Pick disease type C (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

NPC1 p.Arg978Ser Likely pathogenic ★★ ⚠ same residue
NPC1 p.Arg978His Conflicting classifications of pathogenicity ★ ⚠ 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-arg978cys (accessed [today's date]).

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