Is LBX1 p.Arg76= (c.228C>T) pathogenic?

LBX1 p.Arg76= (c.228C>T) is classified Benign in LBX1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-05-04). Common (popmax 29.5%, nfe) — too common for a highly-penetrant pathogenic allele.

LBX1 p.Arg76=

Q: How common is LBX1 p.Arg76= (c.228C>T) in the general population?

LBX1 p.Arg76= (c.228C>T) is common (popmax 29.5%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.228C>T · rs941909 · VCV1294899

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 29.5%, nfe) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.3	GERP -1.6, phastCons 1
Overall
CADD	11.55	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 29.5% European (non-Finnish) · 339,456/1,149,340 alleles

Filtering AF 29.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 29.4%

Overall 25.8% 401,160/1,555,180 alleles · common exomes 369,458/1,402,942 · genomes 31,702/152,238 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	29.5%	3
Finnishnot grpmax-eligible	24.4%	4
Remaining individualsnot grpmax-eligible	23.7%	4
Ashkenazi Jewishnot grpmax-eligible	19.8%	5
Amishnot grpmax-eligible	19.1%	5
Admixed American	17%	6
Middle Eastern	11.7%	9
African / African-American	10.6%	9
South Asian	8.97%	11
East Asian	5.72%	17

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.Arg76=
Coding: c.228C>T
MANE Select: NM_006562
dbSNP: rs941909
Type: single nucleotide variant
Location: chr10:101228588 (GRCh38)
Gene constraint: LOEUF 0.753 · pLI 0.45 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.61

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

Similar variants

LBX1 p.Arg76Cys Uncertain significance ★ ⚠ same residue
LBX1 p.Pro238= Benign ★★ same type
LBX1 p.Ala107Val Uncertain significance ★ ⚠ same type
LBX1 p.Ala228Pro 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

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-arg76 (accessed [today's date]).

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