Is BSCL2 p.Pro357Ser (c.1069C>T) pathogenic?

BSCL2 p.Pro357Ser (c.1069C>T) is classified Uncertain significance in BSCL2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-08-02). AlphaMissense: likely benign (0.0734); Very rare (popmax 0.00593%, nfe); Associated with Charcot-Marie-Tooth disease type 2.

What condition is associated with BSCL2 p.Pro357Ser (c.1069C>T)?

BSCL2 p.Pro357Ser (c.1069C>T) is associated with Charcot-Marie-Tooth disease type 2, congenital generalized lipodystrophy type 2, hereditary spastic paraplegia 17 (ClinVar).

How common is BSCL2 p.Pro357Ser (c.1069C>T) in the general population?

BSCL2 p.Pro357Ser (c.1069C>T) is very rare (popmax 0.00593%, nfe) (gnomAD).

What do computational predictors say about BSCL2 p.Pro357Ser (c.1069C>T)?

AlphaMissense predicts likely benign (score 0.0734) — an in-silico prediction, not a clinical call.

BSCL2 p.Pro357Ser

c.1069C>T · rs781022347 · VCV476816

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0734 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00593%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Charcot-Marie-Tooth disease type 2

Computational evidence

Protein change
AlphaMissense	0.0734	likely benign
REVEL	0.15	moderately benign-leaning
SaProt	LLR -6.10	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.37 · evaluated, not missing
Constraint at this position
Conservation	phyloP 2.3	GERP -4.1, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 2,047 bp · p 0.6 · regional, not allelic
Overall
CADD	14.7	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 P293S vs ClinVar P357S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00593% European (non-Finnish) · 70/1,180,036 alleles

Filtering AF 0.00478% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00439%

Overall 0.0044% 71/1,614,072 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00593%	16,858
Remaining individualsnot grpmax-eligible	0.0016%	62,488

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.Pro357Ser
Coding: c.1069C>T
MANE Select: NM_001122955
dbSNP: rs781022347
Type: single nucleotide variant
Location: chr11:62691078 (GRCh38)
Gene constraint: LOEUF 0.869 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.09 · 1 PDB
Residue 357: 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

Also linked: congenital generalized lipodystrophy type 2 hereditary spastic paraplegia 17 severe neurodegenerative syndrome with lipodystrophy neuronopathy, distal hereditary motor, type 5C

Similar variants

BSCL2 p.Pro357= Uncertain significance ★★ same residue
BSCL2 c.1006-2A>C Likely pathogenic ★★ same condition
BSCL2 c.1006-2A>G Pathogenic/Likely pathogenic ★★ same condition
BSCL2 c.486+1G>A Pathogenic/Likely pathogenic ★★ same condition
BSCL2 c.631-1G>C Pathogenic/Likely pathogenic ★★ same condition
BSCL2 c.766-2A>G Pathogenic ★★ same condition
BSCL2 p.Ala276Pro Pathogenic ★★ same condition
BSCL2 p.Arg202Ter 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-pro357ser (accessed [today's date]).

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