Is NPC1 p.Pro691Gln (c.2072C>A) pathogenic?

NPC1 p.Pro691Gln (c.2072C>A) is classified Likely pathogenic in NPC1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-10-14). AlphaMissense: likely pathogenic (0.9931); Very rare (popmax 8.47e-05%, nfe); Associated with Niemann-Pick disease.

What condition is associated with NPC1 p.Pro691Gln (c.2072C>A)?

NPC1 p.Pro691Gln (c.2072C>A) is associated with Niemann-Pick disease, Niemann-Pick disease, type C1, Niemann-Pick disease type C (ClinVar).

How common is NPC1 p.Pro691Gln (c.2072C>A) in the general population?

NPC1 p.Pro691Gln (c.2072C>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about NPC1 p.Pro691Gln (c.2072C>A)?

AlphaMissense predicts likely pathogenic (score 0.9931) — an in-silico prediction, not a clinical call.

NPC1 p.Pro691Gln

c.2072C>A · rs1555634422 · VCV986365

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9931 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Niemann-Pick disease

Computational evidence

Protein change
AlphaMissense	0.9931	likely pathogenic ✓ concordant with ClinVar · top 2% in NPC1
REVEL	0.941	strongly pathogenic-leaning
SaProt	LLR -16.30	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 54 kb · p 0.0029 · regional, not allelic
Overall
CADD	29.7	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 8.47e-05% European (non-Finnish) · 1/1,180,026 alleles

Overall 6.84e-05% 1/1,461,884 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.Pro691Gln
Coding: c.2072C>A
MANE Select: NM_000271
dbSNP: rs1555634422
Type: single nucleotide variant
Location: chr18:23544402 (GRCh38)
Gene constraint: LOEUF 0.676 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.35 · 20 PDB
Residue 691: a UniProt-annotated variant site (in npc1); 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 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

Similar variants

NPC1 p.Pro691Ala Pathogenic/Likely pathogenic ★★ same residue
NPC1 p.Pro691Leu Pathogenic/Likely pathogenic ★★ same residue
NPC1 p.Pro691= Benign/Likely benign ★★ same residue
NPC1 p.Pro691Ser Likely 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

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-pro691gln (accessed [today's date]).

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