Is BSCL2 p.Pro394Ala (c.1180C>G) pathogenic?

BSCL2 p.Pro394Ala (c.1180C>G) is classified Uncertain significance in BSCL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-16). AlphaMissense: likely benign (0.0568); Very rare (popmax 0.000169%, nfe); Associated with Charcot-Marie-Tooth disease type 2.

What condition is associated with BSCL2 p.Pro394Ala (c.1180C>G)?

BSCL2 p.Pro394Ala (c.1180C>G) is associated with Charcot-Marie-Tooth disease type 2 (ClinVar).

How common is BSCL2 p.Pro394Ala (c.1180C>G) in the general population?

BSCL2 p.Pro394Ala (c.1180C>G) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about BSCL2 p.Pro394Ala (c.1180C>G)?

AlphaMissense predicts likely benign (score 0.0568) — an in-silico prediction, not a clinical call.

BSCL2 p.Pro394Ala

c.1180C>G · VCV3716593

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0568 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Charcot-Marie-Tooth disease type 2

Computational evidence

Protein change
AlphaMissense	0.0568	likely benign
REVEL	0.22	benign-leaning
SaProt	LLR -5.92	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.5	GERP -3.7, phastCons 0.9
Regional constraint	o/e 1.03	unconstrained · MANE · 2,047 bp · p 0.6 · regional, not allelic
Overall
CADD	11.17	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 P330A vs ClinVar P394A) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,180,012 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,506 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.Pro394Ala
Coding: c.1180C>G
MANE Select: NM_001122955
Type: single nucleotide variant
Location: chr11:62690666 (GRCh38)
Gene constraint: LOEUF 0.869 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.09 · 1 PDB
Residue 394: the 'disordered' region

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

Similar variants

BSCL2 p.Pro394Thr Uncertain significance ★ ⚠ same residue
BSCL2 c.1006-2A>C Likely pathogenic ★★ same condition
BSCL2 c.486+1G>A Pathogenic/Likely pathogenic ★★ same condition
BSCL2 p.Ala276Pro Pathogenic ★★ same condition
BSCL2 p.Arg329Ter Pathogenic ★★ same condition
BSCL2 p.Asn152Ser Pathogenic ★★ ⚠ same condition
BSCL2 p.Glu253Ter Pathogenic ★★ same condition
BSCL2 p.Ser154Leu 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/bscl2-p-pro394ala (accessed [today's date]).

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