Is NPC1 p.Ile858Val (c.2572A>G) pathogenic?

NPC1 p.Ile858Val (c.2572A>G) is classified Benign in NPC1 (ClinVar, Multiple submitters, 18 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0585); Common (popmax 65.4%, eas) — too common for a highly-penetrant pathogenic allele; Associated with Niemann-Pick disease, type C1.

What condition is associated with NPC1 p.Ile858Val (c.2572A>G)?

NPC1 p.Ile858Val (c.2572A>G) is associated with Niemann-Pick disease, type C1 (ClinVar).

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.Ile858Val (c.2572A>G)?

AlphaMissense predicts likely benign (score 0.0585) — an in-silico prediction, not a clinical call.

NPC1 p.Ile858Val

Q: How common is NPC1 p.Ile858Val (c.2572A>G) in the general population?

NPC1 p.Ile858Val (c.2572A>G) is common (popmax 65.4%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2572A>G · rs1805082 · VCV21135

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 18 submitters

AlphaMissense

likely benign

0.0585 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 65.4%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Niemann-Pick disease, type C1

Computational evidence

Protein change
AlphaMissense	0.0585	likely benign
REVEL	0.33	indeterminate
SaProt	LLR -7.83	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP 1.9, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 54 kb · p 0.0029 · regional, not allelic
Overall
CADD	20.6	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 65.4% East Asian · 29,327/44,832 alleles

Filtering AF 64.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 64.5%

Overall 48.7% 782,226/1,607,602 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	65.4%	2
Admixed American	62.7%	2
Finnishnot grpmax-eligible	50.4%	2
South Asian	49.3%	2
European (non-Finnish)	48.5%	2
Remaining individualsnot grpmax-eligible	46.8%	2
Amishnot grpmax-eligible	42.5%	2
African / African-American	37.5%	3
Middle Eastern	34.5%	3
Ashkenazi Jewishnot grpmax-eligible	30.4%	3

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.Ile858Val
Coding: c.2572A>G
MANE Select: NM_000271
dbSNP: rs1805082
Type: single nucleotide variant
Location: chr18:23540480 (GRCh38)
Gene constraint: LOEUF 0.676 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.35 · 20 PDB
Residue 858: a UniProt-annotated variant site (in); 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 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
NPC1 c.2604+1G>A 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-ile858val (accessed [today's date]).

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