Is BSCL2 p.Leu427Pro (c.1280T>C) pathogenic?

BSCL2 p.Leu427Pro (c.1280T>C) is classified Conflicting classifications of pathogenicity in BSCL2 (ClinVar, Conflicting submitters, 21 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.1055); Rare (popmax 0.973%, mid); Associated with monogenic diabetes.

What condition is associated with BSCL2 p.Leu427Pro (c.1280T>C)?

BSCL2 p.Leu427Pro (c.1280T>C) is associated with monogenic diabetes, congenital generalized lipodystrophy type 2, hereditary spastic paraplegia 17 (ClinVar).

How common is BSCL2 p.Leu427Pro (c.1280T>C) in the general population?

BSCL2 p.Leu427Pro (c.1280T>C) is rare (popmax 0.973%, mid) (gnomAD).

What do computational predictors say about BSCL2 p.Leu427Pro (c.1280T>C)?

AlphaMissense predicts likely benign (score 0.1055) — an in-silico prediction, not a clinical call.

BSCL2 p.Leu427Pro

c.1280T>C · rs145649423 · VCV128532

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 21 submitters

AlphaMissense

likely benign

0.1055 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.973%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

monogenic diabetes

Computational evidence

Protein change
AlphaMissense	0.1055	likely benign
REVEL	0.257	benign-leaning
SaProt	LLR -5.15	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 5.2	GERP 0.99, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 2,047 bp · p 0.6 · regional, not allelic
Overall
CADD	18.93	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 L363P vs ClinVar L427P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.973% Middle Eastern · 59/6,062 alleles

Filtering AF 0.775% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.703%

Overall 0.295% 4,765/1,614,202 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.973%	103
Ashkenazi Jewishnot grpmax-eligible	0.618%	162
Admixed American	0.387%	259
Remaining individualsnot grpmax-eligible	0.338%	296
European (non-Finnish)	0.321%	312
South Asian	0.187%	536
Finnishnot grpmax-eligible	0.122%	821
Amishnot grpmax-eligible	0.11%	912
African / African-American	0.0586%	1,706

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.Leu427Pro
Coding: c.1280T>C
MANE Select: NM_001122955
dbSNP: rs145649423
Type: single nucleotide variant
Location: chr11:62690476 (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

monogenic diabetes — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

Similar variants

BSCL2 p.Leu427= Likely benign ★ same residue
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

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-leu427pro (accessed [today's date]).

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