Is NPC1 p.Ala659Val (c.1976C>T) pathogenic?

NPC1 p.Ala659Val (c.1976C>T) is classified Uncertain significance in NPC1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-01-18). AlphaMissense: likely benign (0.1463); Very rare (popmax 0.00333%, amr); Associated with Niemann-Pick disease, type C1.

What condition is associated with NPC1 p.Ala659Val (c.1976C>T)?

NPC1 p.Ala659Val (c.1976C>T) is associated with Niemann-Pick disease, type C1 (ClinVar).

How common is NPC1 p.Ala659Val (c.1976C>T) in the general population?

NPC1 p.Ala659Val (c.1976C>T) is very rare (popmax 0.00333%, amr) (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.Ala659Val (c.1976C>T)?

AlphaMissense predicts likely benign (score 0.1463) — an in-silico prediction, not a clinical call.

NPC1 p.Ala659Val

c.1976C>T · rs140786703 · VCV1302033

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1463 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Niemann-Pick disease, type C1

Computational evidence

Protein change
AlphaMissense	0.1463	likely benign
REVEL	0.284	benign-leaning
SaProt	LLR -3.68	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP -0.079, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 54 kb · p 0.0029 · regional, not allelic
Overall
CADD	22.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/60,002 alleles

Filtering AF 0.00196% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00168%

Overall 0.00235% 38/1,614,056 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,001
European (non-Finnish)	0.00271%	36,876
East Asian	0.00223%	44,904
Remaining individualsnot grpmax-eligible	0.0016%	62,484
African / African-American	0.00133%	74,928
South Asian	0.0011%	91,082

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.Ala659Val
Coding: c.1976C>T
MANE Select: NM_000271
dbSNP: rs140786703
Type: single nucleotide variant
Location: chr18:23544498 (GRCh38)
Gene constraint: LOEUF 0.676 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.35 · 20 PDB
Residue 659: 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.Ala659= Likely benign ★★ same residue
NPC1 p.Ala659Thr Uncertain significance ★ ⚠ 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-ala659val (accessed [today's date]).

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