Is NPC1 p.Asp868Val (c.2603A>T) pathogenic?

NPC1 p.Asp868Val (c.2603A>T) is classified Uncertain significance in NPC1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-13). AlphaMissense: likely benign (0.1131); Very rare (popmax 0.000177%, nfe); Associated with Inborn genetic diseases.

What condition is associated with NPC1 p.Asp868Val (c.2603A>T)?

NPC1 p.Asp868Val (c.2603A>T) is associated with Inborn genetic diseases, Niemann-Pick disease, type C1 (ClinVar).

How common is NPC1 p.Asp868Val (c.2603A>T) in the general population?

NPC1 p.Asp868Val (c.2603A>T) is very rare (popmax 0.000177%, nfe) (gnomAD).

What do computational predictors say about NPC1 p.Asp868Val (c.2603A>T)?

AlphaMissense predicts likely benign (score 0.1131) — an in-silico prediction, not a clinical call.

NPC1 p.Asp868Val

c.2603A>T · rs1210438129 · VCV1963490

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1131 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000177%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1131	likely benign
REVEL	0.557	indeterminate
SaProt	LLR -6.27	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>C here scores Δ0.70 · evaluated, not missing
Pangolin	Δ0.51	loss · gain 0.02 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 5	GERP 0.81, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 54 kb · p 0.0029 · regional, not allelic
Overall
CADD	24.6	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 0.000177% European (non-Finnish) · 2/1,132,584 alleles

Filtering AF 2.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000142% 2/1,407,526 alleles · very rare

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.Asp868Val
Coding: c.2603A>T
MANE Select: NM_000271
dbSNP: rs1210438129
Type: single nucleotide variant
Location: chr18:23540449 (GRCh38)
Gene constraint: LOEUF 0.676 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.35 · 20 PDB
Residue 868: a β-strand

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.Asp868Ala 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
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-asp868val (accessed [today's date]).

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