Is BSCL2 p.Arg454Ter (c.1360C>T) pathogenic?

BSCL2 p.Arg454Ter (c.1360C>T) is classified Conflicting classifications of pathogenicity in BSCL2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-02-21). Very rare (popmax 0.00237%, nfe); Associated with Charcot-Marie-Tooth disease type 2.

What condition is associated with BSCL2 p.Arg454Ter (c.1360C>T)?

BSCL2 p.Arg454Ter (c.1360C>T) is associated with Charcot-Marie-Tooth disease type 2, severe neurodegenerative syndrome with lipodystrophy (ClinVar).

How common is BSCL2 p.Arg454Ter (c.1360C>T) in the general population?

BSCL2 p.Arg454Ter (c.1360C>T) is very rare (popmax 0.00237%, nfe) (gnomAD).

BSCL2 p.Arg454Ter

c.1360C>T · rs138515091 · VCV1032980

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00237%, nfe)

Conditions

Charcot-Marie-Tooth disease type 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (11 of 11) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP -2.2, phastCons 1
Overall
CADD	40.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00237% European (non-Finnish) · 28/1,180,038 alleles

Filtering AF 0.00164% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00142%

Overall 0.00186% 30/1,613,980 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00237%	42,144
Admixed American	0.00167%	60,004
South Asian	0.0011%	91,078

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.Arg454Ter
Coding: c.1360C>T
MANE Select: NM_001122955
dbSNP: rs138515091
Type: single nucleotide variant
Location: chr11:62690396 (GRCh38)
Gene constraint: LOEUF 0.869 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.09 · 1 PDB

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: severe neurodegenerative syndrome with lipodystrophy

Similar variants

BSCL2 p.Arg454Gln Uncertain significance ★ ⚠ same residue
BSCL2 p.Arg454fs Pathogenic/Likely pathogenic ★★ same residue
BSCL2 p.Arg454Leu Uncertain significance ★ ⚠ same residue
BSCL2 c.1006-2A>C 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 p.Ala276Pro Pathogenic ★★ same condition
BSCL2 p.Arg329Ter 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-arg454ter (accessed [today's date]).

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