Is NPC1 p.Pro1007Ala (c.3019C>G) pathogenic?

NPC1 p.Pro1007Ala (c.3019C>G) is classified Pathogenic in NPC1 (ClinVar, Multiple submitters, 30 submitters; last evaluated 2026-08-03). AlphaMissense: likely pathogenic (0.5984); Ultra-rare (popmax 0.0219%, nfe); Associated with NPC1-related disorder.

What condition is associated with NPC1 p.Pro1007Ala (c.3019C>G)?

NPC1 p.Pro1007Ala (c.3019C>G) is associated with NPC1-related disorder, cerebellar ataxia, Niemann-Pick disease, type C1 (ClinVar).

How common is NPC1 p.Pro1007Ala (c.3019C>G) in the general population?

NPC1 p.Pro1007Ala (c.3019C>G) is ultra-rare (popmax 0.0219%, nfe) (gnomAD).

What do computational predictors say about NPC1 p.Pro1007Ala (c.3019C>G)?

AlphaMissense predicts likely pathogenic (score 0.5984) — an in-silico prediction, not a clinical call.

NPC1 p.Pro1007Ala

c.3019C>G · rs80358257 · VCV2966

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 30 submitters

AlphaMissense

likely pathogenic

0.5984 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0219%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

NPC1-related disorder

Computational evidence

Protein change
AlphaMissense	0.5984	likely pathogenic ✓ concordant with ClinVar
REVEL	0.91	moderately pathogenic-leaning
SaProt	LLR -9.22	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 54 kb · p 0.0029 · regional, not allelic
Overall
CADD	26.8	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 0.0219% European (non-Finnish) · 258/1,180,008 alleles

Filtering AF 0.0196% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0188%

Overall 0.0171% 276/1,614,108 alleles · ultra-rare exomes 246/1,461,864 · genomes 30/152,244 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0219%	4,574
Finnishnot grpmax-eligible	0.00937%	10,669
Admixed American	0.00833%	12,002
African / African-American	0.00533%	18,758
Remaining individualsnot grpmax-eligible	0.0048%	20,835

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.Pro1007Ala
Coding: c.3019C>G
MANE Select: NM_000271
dbSNP: rs80358257
Type: single nucleotide variant
Location: chr18:23538564 (GRCh38)
Gene constraint: LOEUF 0.676 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.35 · 20 PDB
Residue 1007: a UniProt-annotated variant site (in npc1); an α-helix

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

Disease context

NPC1-related disorder

Also linked: cerebellar ataxia Niemann-Pick disease, type C1 Niemann-Pick disease type C

Similar variants

NPC1 p.Pro1007Leu Pathogenic ★★ 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-pro1007ala (accessed [today's date]).

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