Is BSCL2 p.Ala437Val (c.1310C>T) pathogenic?

BSCL2 p.Ala437Val (c.1310C>T) is classified Uncertain significance in BSCL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-23). AlphaMissense: likely benign (0.0819); Very rare (popmax 0.00134%, afr); Associated with severe neurodegenerative syndrome with lipodystrophy.

What condition is associated with BSCL2 p.Ala437Val (c.1310C>T)?

BSCL2 p.Ala437Val (c.1310C>T) is associated with severe neurodegenerative syndrome with lipodystrophy, congenital generalized lipodystrophy type 2, hereditary spastic paraplegia 17 (ClinVar).

How common is BSCL2 p.Ala437Val (c.1310C>T) in the general population?

BSCL2 p.Ala437Val (c.1310C>T) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about BSCL2 p.Ala437Val (c.1310C>T)?

AlphaMissense predicts likely benign (score 0.0819) — an in-silico prediction, not a clinical call.

BSCL2 p.Ala437Val

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.1310C>T · rs751558047 · VCV1696444

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0819 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

severe neurodegenerative syndrome with lipodystrophy

Computational evidence

Protein change
AlphaMissense	0.0819	likely benign
REVEL	0.223	benign-leaning
SaProt	LLR -7.49	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.71	GERP 2.1, phastCons 0.18
Regional constraint	o/e 1.03	unconstrained · MANE · 2,047 bp · p 0.6 · regional, not allelic
Overall
CADD	16.54	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM A373V vs ClinVar A437V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00134% African / African-American · 1/74,888 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000342% 5/1,461,736 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,888
European (non-Finnish)	0.000339%	295,001

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.Ala437Val
Coding: c.1310C>T
MANE Select: NM_001122955
dbSNP: rs751558047
Type: single nucleotide variant
Location: chr11:62690446 (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

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 neuronopathy, distal hereditary motor, type 5C

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

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

BSCL2 p.Ala437Pro Uncertain significance ★★ same residue
BSCL2 p.Ala437= Likely benign ★ 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-ala437val (accessed [today's date]).

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