Is BSCL2 p.Arg89Pro (c.266G>C) pathogenic?

BSCL2 p.Arg89Pro (c.266G>C) is classified Uncertain significance in BSCL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-12-17). AlphaMissense: likely pathogenic (0.7849); Very rare (popmax 0.00167%, amr); Associated with Charcot-Marie-Tooth disease type 2.

What condition is associated with BSCL2 p.Arg89Pro (c.266G>C)?

BSCL2 p.Arg89Pro (c.266G>C) is associated with Charcot-Marie-Tooth disease type 2 (ClinVar).

How common is BSCL2 p.Arg89Pro (c.266G>C) in the general population?

BSCL2 p.Arg89Pro (c.266G>C) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about BSCL2 p.Arg89Pro (c.266G>C)?

AlphaMissense predicts likely pathogenic (score 0.7849) — an in-silico prediction, not a clinical call.

BSCL2 p.Arg89Pro

c.266G>C · rs780387759 · VCV648966

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7849 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Charcot-Marie-Tooth disease type 2

Computational evidence

Protein change
AlphaMissense	0.7849	likely pathogenic
REVEL	0.849	moderately pathogenic-leaning
SaProt	LLR -11.03	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 7.7	GERP 2.3, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 13 kb · p 0.65 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R25P vs ClinVar R89P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,008 alleles

Overall 0.000657% 1/152,200 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: BSCL2
Protein: p.Arg89Pro
Coding: c.266G>C
dbSNP: rs780387759
Type: single nucleotide variant
Location: chr11:62705439 (GRCh38)

Full BSCL2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Charcot-Marie-Tooth disease type 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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/bscl2-p-arg89pro (accessed [today's date]).

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