Is NPC1 p.Arg711Ser (c.2133A>C) pathogenic?

NPC1 p.Arg711Ser (c.2133A>C) is classified Uncertain significance in NPC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-10). AlphaMissense: likely pathogenic (0.8626); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with NPC1 p.Arg711Ser (c.2133A>C)?

NPC1 p.Arg711Ser (c.2133A>C) is associated with Inborn genetic diseases (ClinVar).

How common is NPC1 p.Arg711Ser (c.2133A>C) in the general population?

NPC1 p.Arg711Ser (c.2133A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NPC1 p.Arg711Ser (c.2133A>C)?

AlphaMissense predicts likely pathogenic (score 0.8626) — an in-silico prediction, not a clinical call.

NPC1 p.Arg711Ser

c.2133A>C · rs985068341 · VCV2242765

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8626 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8626	likely pathogenic
REVEL	0.865	moderately pathogenic-leaning
SaProt	LLR -9.54	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3	GERP 1.8, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 54 kb · p 0.0029 · regional, not allelic
Overall
CADD	23.6	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

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.Arg711Ser
Coding: c.2133A>C
MANE Select: NM_000271
dbSNP: rs985068341
Type: single nucleotide variant
Location: chr18:23543567 (GRCh38)
Gene constraint: LOEUF 0.676 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.35 · 20 PDB
Residue 711: the ssd domain

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

Similar variants

NPC1 p.Arg711Gly Uncertain significance ★★ ⚠ same residue
NPC1 p.Arg711= Likely benign ★ same residue
NPC1 p.Ala927Val Pathogenic/Likely pathogenic ★★ ⚠ same condition
NPC1 p.Cys177Tyr Pathogenic/Likely pathogenic ★★ same condition
NPC1 p.Ala1108Val Uncertain significance ★★ ⚠ same condition
NPC1 p.Ala181Thr Uncertain significance ★★ ⚠ same condition
NPC1 p.Arg1183His Uncertain significance ★★ ⚠ same condition
NPC1 p.Arg372Gln Uncertain significance ★★ ⚠ 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-arg711ser (accessed [today's date]).

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