Is LRBA p.Ala116fs (c.345dup) pathogenic?

LRBA p.Ala116fs (c.345dup) is classified Pathogenic in LRBA (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-29). Very rare (popmax 8.47e-05%, nfe); Associated with combined immunodeficiency due to LRBA deficiency.

What condition is associated with LRBA p.Ala116fs (c.345dup)?

LRBA p.Ala116fs (c.345dup) is associated with combined immunodeficiency due to LRBA deficiency (ClinVar).

How common is LRBA p.Ala116fs (c.345dup) in the general population?

LRBA p.Ala116fs (c.345dup) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

LRBA p.Ala116fs

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.345dup · rs746082628 · VCV2442233

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

combined immunodeficiency due to LRBA deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 3 of 57
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.6	GERP 2.9, phastCons 1
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,179,990 alleles

Overall 0.000657% 1/152,092 alleles · very rare

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.Ala116fs
Coding: c.345dup
MANE Select: NM_001364905
dbSNP: rs746082628
Type: Duplication
Location: chr4:150928936 (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 p.Asn2716fs Pathogenic/Likely pathogenic ★★ same condition
LRBA p.Leu2836_Phe2837insLeu Uncertain significance ★★ same condition
LRBA c.1015-10dup Benign/Likely benign ★★ same condition
LRBA c.2068-19dup Benign/Likely benign ★★ same condition
LRBA c.217-10dup Benign ★★ same condition
LRBA c.217-11_217-10dup Benign/Likely benign ★★ same condition
LRBA c.5581-5dup Benign/Likely benign ★★ same condition
LRBA c.5755-10dup Benign/Likely benign ★★ 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-ala116fs (accessed [today's date]).

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