Is BEX2 p.Leu126Pro (c.377T>C) pathogenic?

BEX2 p.Leu126Pro (c.377T>C) is classified Uncertain significance in BEX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-13). AlphaMissense: likely pathogenic (0.9331); Very rare (popmax 0.00615%, nfe).

How common is BEX2 p.Leu126Pro (c.377T>C) in the general population?

BEX2 p.Leu126Pro (c.377T>C) is very rare (popmax 0.00615%, nfe) (gnomAD).

What do computational predictors say about BEX2 p.Leu126Pro (c.377T>C)?

AlphaMissense predicts likely pathogenic (score 0.9331) — an in-silico prediction, not a clinical call.

BEX2 p.Leu126Pro

c.377T>C · rs755044953 · VCV3133758

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9331 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00615%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9331	likely pathogenic · top 1% in BEX2
REVEL	0.312	indeterminate
SaProt	LLR -6.54	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 6.8	GERP 2.4, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 383 bp · p 0.55 · regional, not allelic
Overall
CADD	21.2	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00615% European (non-Finnish) · 55/894,695 alleles

Filtering AF 0.00483% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00434%

Overall 0.00472% 57/1,208,157 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00615%	16,267
Remaining individualsnot grpmax-eligible	0.0021%	47,574
African / African-American	0.00176%	56,678

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: BEX2
Protein: p.Leu126Pro
Coding: c.377T>C
MANE Select: NM_032621
dbSNP: rs755044953
Type: single nucleotide variant
Location: chrX:103309600 (GRCh38)
Structure: AlphaFold pLDDT 68.93
Residue 126: the 'disordered' region

Full BEX2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BEX2 p.Asn32Asp Benign ★★ same type
BEX2 c.-12G>A Uncertain significance ★ same type
BEX2 c.-48C>G Uncertain significance ★ same type
BEX2 c.-60G>A Uncertain significance ★ same type
BEX2 c.-62G>A Uncertain significance ★ same type
BEX2 c.-72G>A Uncertain significance ★ same type
BEX2 c.-75G>A Uncertain significance ★ same type
BEX2 c.-75G>C Uncertain significance ★ same type

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/bex2-p-leu126pro (accessed [today's date]).

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