Is BSCL2 p.Pro398Arg (c.1193C>G) pathogenic?

BSCL2 p.Pro398Arg (c.1193C>G) is classified Uncertain significance in BSCL2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-11-03). AlphaMissense: likely benign (0.0763); Ultra-rare (popmax 0.0165%, mid); Associated with Charcot-Marie-Tooth disease type 2.

What condition is associated with BSCL2 p.Pro398Arg (c.1193C>G)?

BSCL2 p.Pro398Arg (c.1193C>G) is associated with Charcot-Marie-Tooth disease type 2 (ClinVar).

How common is BSCL2 p.Pro398Arg (c.1193C>G) in the general population?

BSCL2 p.Pro398Arg (c.1193C>G) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about BSCL2 p.Pro398Arg (c.1193C>G)?

AlphaMissense predicts likely benign (score 0.0763) — an in-silico prediction, not a clinical call.

BSCL2 p.Pro398Arg

c.1193C>G · rs778931376 · VCV450639

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0763 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Charcot-Marie-Tooth disease type 2

Computational evidence

Protein change
AlphaMissense	0.0763	likely benign
REVEL	0.479	indeterminate
SaProt	LLR -6.36	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 9.9	GERP 2.2, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 2,047 bp · p 0.6 · regional, not allelic
Overall
CADD	23.4	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 P334R vs ClinVar P398R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.00199% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00175%

Overall 0.00274% 40/1,461,560 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
Admixed American	0.00333%	30,018
European (non-Finnish)	0.0028%	35,758
Remaining individualsnot grpmax-eligible	0.0016%	62,494
Finnishnot grpmax-eligible	0.00157%	63,762
African / African-American	0.00133%	75,056
South Asian	0.0011%	91,082

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.Pro398Arg
Coding: c.1193C>G
dbSNP: rs778931376
Type: single nucleotide variant
Location: chr11:62690653 (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

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-pro398arg (accessed [today's date]).

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