Is BSCL2 p.Ser462Tyr (c.1385C>A) pathogenic?

BSCL2 p.Ser462Tyr (c.1385C>A) is classified Uncertain significance in BSCL2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-05-22). AlphaMissense: ambiguous (0.3403); Very rare (popmax 0.000169%, nfe); Associated with congenital generalized lipodystrophy type 2.

What condition is associated with BSCL2 p.Ser462Tyr (c.1385C>A)?

BSCL2 p.Ser462Tyr (c.1385C>A) is associated with congenital generalized lipodystrophy type 2, hereditary spastic paraplegia 17, severe neurodegenerative syndrome with lipodystrophy (ClinVar).

How common is BSCL2 p.Ser462Tyr (c.1385C>A) in the general population?

BSCL2 p.Ser462Tyr (c.1385C>A) is very rare (popmax 0.000169%, nfe) (gnomAD).

How is Congenital generalized lipodystrophy inherited?

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

What do computational predictors say about BSCL2 p.Ser462Tyr (c.1385C>A)?

AlphaMissense predicts ambiguous (score 0.3403) — an in-silico prediction, not a clinical call.

BSCL2 p.Ser462Tyr

c.1385C>A · rs1945271930 · VCV1320708

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3403 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Conditions

congenital generalized lipodystrophy type 2

Computational evidence

Protein change
AlphaMissense	0.3403	ambiguous
REVEL	0.557	indeterminate
SaProt	LLR -9.55	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 2,047 bp · p 0.6 · regional, not allelic
Overall
CADD	26.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S398Y vs ClinVar S462Y) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,180,036 alleles

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

Overall 0.000137% 2/1,461,738 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.Ser462Tyr
Coding: c.1385C>A
MANE Select: NM_001122955
dbSNP: rs1945271930
Type: single nucleotide variant
Location: chr11:62690371 (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

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 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 p.Ser462Cys 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
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-ser462tyr (accessed [today's date]).

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