Is LRBA p.Leu684= (c.2050C>T) pathogenic?

LRBA p.Leu684= (c.2050C>T) is classified Conflicting classifications of pathogenicity in LRBA (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-09-21). Ultra-rare (popmax 0.0228%, amr); Associated with combined immunodeficiency due to LRBA deficiency.

What condition is associated with LRBA p.Leu684= (c.2050C>T)?

LRBA p.Leu684= (c.2050C>T) is associated with combined immunodeficiency due to LRBA deficiency (ClinVar).

How common is LRBA p.Leu684= (c.2050C>T) in the general population?

LRBA p.Leu684= (c.2050C>T) is ultra-rare (popmax 0.0228%, amr) (gnomAD).

LRBA p.Leu684=

Q: How is Syndromic autoimmune enteropathy due to LRBA deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.2050C>T · rs149148368 · VCV593258

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0228%, amr)

Conditions

combined immunodeficiency due to LRBA deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.4	GERP 0.31, phastCons 1
Overall
CADD	7.23	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0228% Admixed American · 13/56,928 alleles

Filtering AF 0.0135% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0107%

Overall 0.0074% 114/1,539,894 alleles · ultra-rare exomes 99/1,387,916 · genomes 15/151,978 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0228%	4,379
Middle Eastern	0.0171%	5,850
Remaining individualsnot grpmax-eligible	0.01%	9,951
European (non-Finnish)	0.0082%	12,200
Finnishnot grpmax-eligible	0.00157%	63,556
African / African-American	0.00138%	72,726

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: LRBA
Protein: p.Leu684=
Coding: c.2050C>T
MANE Select: NM_001364905
dbSNP: rs149148368
Type: single nucleotide variant
Location: chr4:150896411 (GRCh38)
Gene constraint: LOEUF 0.515 · pLI <0.01 (gnomAD)

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

Disease context

combined immunodeficiency due to LRBA deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Syndromic autoimmune enteropathy due to LRBA deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy

Similar variants

LRBA c.216+1G>C Pathogenic/Likely pathogenic ★★ same condition
LRBA c.2259-2A>G Likely pathogenic ★★ same condition
LRBA c.2767-2A>G Likely pathogenic ★★ same condition
LRBA c.4159-1G>T Likely pathogenic ★★ same condition
LRBA c.5518+2T>C Likely pathogenic ★★ same condition
LRBA c.5519-1G>A Likely pathogenic ★★ same condition
LRBA c.5646-2A>T Pathogenic ★★ same condition
LRBA p.Arg1445Ter Pathogenic ★★ same condition

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/lrba-p-leu684 (accessed [today's date]).

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