Is BSCL2 p.Cys298= (c.894C>T) pathogenic?

BSCL2 p.Cys298= (c.894C>T) is classified Conflicting classifications of pathogenicity in BSCL2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-04-02). Ultra-rare (popmax 0.0165%, mid); Associated with congenital generalized lipodystrophy type 2.

What condition is associated with BSCL2 p.Cys298= (c.894C>T)?

BSCL2 p.Cys298= (c.894C>T) is associated with congenital generalized lipodystrophy type 2, hereditary spastic paraplegia 17, severe neurodegenerative syndrome with lipodystrophy (ClinVar).

How common is BSCL2 p.Cys298= (c.894C>T) in the general population?

BSCL2 p.Cys298= (c.894C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

How is Congenital generalized lipodystrophy inherited?

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

BSCL2 p.Cys298=

c.894C>T · VCV3599921

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Conditions

congenital generalized lipodystrophy type 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.71	GERP -4.6
Overall
CADD	12.29	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000616% 9/1,461,872 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
South Asian	0.0022%	45,542
Remaining individualsnot grpmax-eligible	0.0016%	62,510
Finnishnot grpmax-eligible	0.00156%	64,028
European (non-Finnish)	0.000339%	295,008

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.Cys298=
Coding: c.894C>T
MANE Select: NM_001122955
Type: single nucleotide variant
Location: chr11:62691391 (GRCh38)
Gene constraint: LOEUF 0.869 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.09 · 1 PDB
Residue 298: the 'disordered' region

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

Disease context

congenital generalized lipodystrophy type 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary spastic paraplegia 17 severe neurodegenerative syndrome with lipodystrophy Charcot-Marie-Tooth disease type 2 neuronopathy, distal hereditary motor, type 5C

For Congenital generalized lipodystrophy (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy, Neonatal
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

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
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-cys298 (accessed [today's date]).

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