Is NPC1 p.Asp868Ala (c.2603A>C) pathogenic?

NPC1 p.Asp868Ala (c.2603A>C) is classified Uncertain significance in NPC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-04). AlphaMissense: likely benign (0.0885); Absent from gnomAD v4.1.

How common is NPC1 p.Asp868Ala (c.2603A>C) in the general population?

NPC1 p.Asp868Ala (c.2603A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NPC1 p.Asp868Ala (c.2603A>C)?

AlphaMissense predicts likely benign (score 0.0885) — an in-silico prediction, not a clinical call.

NPC1 p.Asp868Ala

c.2603A>C · VCV3901765

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0885 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0885	likely benign
REVEL	0.379	indeterminate
SaProt	LLR -6.22	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
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	23.7	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: NPC1
Protein: p.Asp868Ala
Coding: c.2603A>C
MANE Select: NM_000271
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

Similar variants

NPC1 p.Asp868Val Uncertain significance ★★ ⚠ same residue
NPC1 c.1554-1009G>A Pathogenic ★★ same type
NPC1 c.1757+1G>A Likely pathogenic ★★ same type
NPC1 c.1947+5G>C Pathogenic/Likely pathogenic ★★ same type
NPC1 c.2130+1G>A Pathogenic ★★ same type
NPC1 c.2245+1G>A Pathogenic/Likely pathogenic ★★ same type
NPC1 c.2246-2A>G Pathogenic/Likely pathogenic ★★ same type
NPC1 c.2515-2A>G Pathogenic/Likely pathogenic ★★ same type

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-asp868ala (accessed [today's date]).

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