Is BSCL2 p.Arg339Ter (c.1015C>T) pathogenic?

BSCL2 p.Arg339Ter (c.1015C>T) is classified Pathogenic in BSCL2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-07-29). Very rare (popmax 0.00891%, eas); Associated with severe neurodegenerative syndrome with lipodystrophy.

What condition is associated with BSCL2 p.Arg339Ter (c.1015C>T)?

BSCL2 p.Arg339Ter (c.1015C>T) is associated with severe neurodegenerative syndrome with lipodystrophy, congenital generalized lipodystrophy type 2, Berardinelli-Seip congenital lipodystrophy (ClinVar).

How common is BSCL2 p.Arg339Ter (c.1015C>T) in the general population?

BSCL2 p.Arg339Ter (c.1015C>T) is very rare (popmax 0.00891%, eas) (gnomAD).

BSCL2 p.Arg339Ter

Q: How is Progressive encephalopathy-severe neurodegeneration-lipodystrophy syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.1015C>T · rs137852974 · VCV4545

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00891%, eas)

Conditions

severe neurodegenerative syndrome with lipodystrophy

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	predicted	premature termination codon in exon 8 of 11
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.4	GERP 1.1, phastCons 1
Overall
CADD	52.0	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 0.00891% East Asian · 4/44,900 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.000558% 9/1,614,012 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00891%	11,225
Admixed American	0.00167%	59,992
European (non-Finnish)	0.000339%	295,006

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.Arg339Ter
Coding: c.1015C>T
MANE Select: NM_001122955
dbSNP: rs137852974
Type: single nucleotide variant
Location: chr11:62691132 (GRCh38)
Gene constraint: LOEUF 0.869 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.09 · 1 PDB
Residue 339: the 'disordered' region

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

Disease context

severe neurodegenerative syndrome with lipodystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: congenital generalized lipodystrophy type 2 Berardinelli-Seip congenital lipodystrophy

For Progressive encephalopathy-severe neurodegeneration-lipodystrophy syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

BSCL2 p.Arg339= Likely benign ★★ same residue
BSCL2 p.Arg339Gln Uncertain significance ★ ⚠ same residue
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-arg339ter (accessed [today's date]).

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