Is LBX1 p.Ala228Pro (c.682G>C) pathogenic?

LBX1 p.Ala228Pro (c.682G>C) is classified Uncertain significance in LBX1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-30). AlphaMissense: likely benign (0.0706); Ultra-rare (popmax 0.0175%, afr).

How common is LBX1 p.Ala228Pro (c.682G>C) in the general population?

LBX1 p.Ala228Pro (c.682G>C) is ultra-rare (popmax 0.0175%, afr) (gnomAD).

What do computational predictors say about LBX1 p.Ala228Pro (c.682G>C)?

AlphaMissense predicts likely benign (score 0.0706) — an in-silico prediction, not a clinical call.

LBX1 p.Ala228Pro

c.682G>C · VCV4046444

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0706 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0175%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.0706	likely benign
REVEL	0.449	indeterminate
SaProt	LLR -6.02	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.4	GERP -0.1, phastCons 1
Regional constraint	o/e 1.18	unconstrained · MANE · 259 bp · p 0.05 · regional, not allelic
Overall
CADD	21.8	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0175% African / African-American · 13/74,400 alleles

Filtering AF 0.0103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00818%

Overall 0.001% 16/1,594,852 alleles · ultra-rare exomes 5/1,442,676 · genomes 11/152,176 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0175%	5,723
Remaining individualsnot grpmax-eligible	0.00325%	30,771
Admixed American	0.0017%	58,788

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: LBX1
Protein: p.Ala228Pro
Coding: c.682G>C
MANE Select: NM_006562
Type: single nucleotide variant
Location: chr10:101227434 (GRCh38)
Gene constraint: LOEUF 0.753 · pLI 0.45 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.61
Residue 228: the 'disordered' region

Full LBX1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

LBX1 p.Arg76= Benign ★★ same type
LBX1 p.Pro238= Benign ★★ same type
LBX1 p.Ala107Val Uncertain significance ★ ⚠ same type
LBX1 p.Ala241Asp Uncertain significance ★ ⚠ same type
LBX1 p.Ala241Ser Uncertain significance ★ ⚠ same type
LBX1 p.Ala56Ser Uncertain significance ★ ⚠ same type
LBX1 p.Ala67Thr Uncertain significance ★ ⚠ same type
LBX1 p.Ala74Glu 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/lbx1-p-ala228pro (accessed [today's date]).

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