Is BSCL2 p.Phe307Leu (c.921C>A) pathogenic?

BSCL2 p.Phe307Leu (c.921C>A) is classified Uncertain significance in BSCL2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-02-29). AlphaMissense: likely pathogenic (0.8811); Very rare (popmax 0.00533%, afr); Associated with severe neurodegenerative syndrome with lipodystrophy.

What condition is associated with BSCL2 p.Phe307Leu (c.921C>A)?

BSCL2 p.Phe307Leu (c.921C>A) is associated with severe neurodegenerative syndrome with lipodystrophy, congenital generalized lipodystrophy type 2, hereditary spastic paraplegia 17 (ClinVar).

How common is BSCL2 p.Phe307Leu (c.921C>A) in the general population?

BSCL2 p.Phe307Leu (c.921C>A) is very rare (popmax 0.00533%, afr) (gnomAD).

What do computational predictors say about BSCL2 p.Phe307Leu (c.921C>A)?

AlphaMissense predicts likely pathogenic (score 0.8811) — an in-silico prediction, not a clinical call.

BSCL2 p.Phe307Leu

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.921C>A · rs1041843205 · VCV2730293

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8811 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00533%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

severe neurodegenerative syndrome with lipodystrophy

Computational evidence

Protein change
AlphaMissense	0.8811	likely pathogenic
REVEL	0.619	indeterminate
SaProt	LLR -8.05	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP 1.3, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 2,047 bp · p 0.6 · regional, not allelic
Overall
CADD	24.9	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 F243L vs ClinVar F307L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00533% African / African-American · 4/75,054 alleles

Filtering AF 0.00174% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000274% 4/1,461,890 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.Phe307Leu
Coding: c.921C>A
MANE Select: NM_001122955
dbSNP: rs1041843205
Type: single nucleotide variant
Location: chr11:62691364 (GRCh38)
Gene constraint: LOEUF 0.869 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.09 · 1 PDB
Residue 307: 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 hereditary spastic paraplegia 17 Charcot-Marie-Tooth disease type 2 neuronopathy, distal hereditary motor, type 5C

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

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

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-phe307leu (accessed [today's date]).

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