Is BSCL2 p.Pro72Ala (c.214C>G) pathogenic?

BSCL2 p.Pro72Ala (c.214C>G) is classified Uncertain significance in BSCL2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-05-22). AlphaMissense: likely benign (0.0922); Very rare (popmax 0.00133%, afr); Associated with Charcot-Marie-Tooth disease type 2.

What condition is associated with BSCL2 p.Pro72Ala (c.214C>G)?

BSCL2 p.Pro72Ala (c.214C>G) is associated with Charcot-Marie-Tooth disease type 2, congenital generalized lipodystrophy type 2, hereditary spastic paraplegia 17 (ClinVar).

How common is BSCL2 p.Pro72Ala (c.214C>G) in the general population?

BSCL2 p.Pro72Ala (c.214C>G) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about BSCL2 p.Pro72Ala (c.214C>G)?

AlphaMissense predicts likely benign (score 0.0922) — an in-silico prediction, not a clinical call.

BSCL2 p.Pro72Ala

c.214C>G · rs2083513120 · VCV945927

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0922 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Charcot-Marie-Tooth disease type 2

Computational evidence

Protein change
AlphaMissense	0.0922	likely benign
REVEL	0.553	indeterminate
SaProt	LLR -3.08	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 8.4	GERP 0.26, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 13 kb · p 0.65 · regional, not allelic
Overall
CADD	24.1	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 P8A vs ClinVar P72A) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/74,942 alleles

Overall 0.000657% 1/152,208 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.Pro72Ala
Coding: c.214C>G
dbSNP: rs2083513120
Type: single nucleotide variant
Location: chr11:62705491 (GRCh38)

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

Disease context

Charcot-Marie-Tooth disease type 2 — 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 5C

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-pro72ala (accessed [today's date]).

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