Is LRBA p.Ala1004= (c.3012A>G) pathogenic?

LRBA p.Ala1004= (c.3012A>G) is classified Likely benign in LRBA (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-11-23). Very rare (popmax 0.00737%, nfe); Associated with combined immunodeficiency due to LRBA deficiency.

What condition is associated with LRBA p.Ala1004= (c.3012A>G)?

LRBA p.Ala1004= (c.3012A>G) is associated with combined immunodeficiency due to LRBA deficiency (ClinVar).

How common is LRBA p.Ala1004= (c.3012A>G) in the general population?

LRBA p.Ala1004= (c.3012A>G) is very rare (popmax 0.00737%, nfe) (gnomAD).

LRBA p.Ala1004=

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.3012A>G · rs371296941 · VCV724830

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00737%, 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.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.48	GERP -5.9, phastCons 0.003
Overall
CADD	2.168	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00737% European (non-Finnish) · 87/1,179,960 alleles

Filtering AF 0.00605% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00565%

Overall 0.00545% 88/1,613,968 alleles · very rare exomes 79/1,461,712 · genomes 9/152,256 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00737%	13,563
Remaining individualsnot grpmax-eligible	0.0016%	62,484

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.Ala1004=
Coding: c.3012A>G
MANE Select: NM_001364905
dbSNP: rs371296941
Type: single nucleotide variant
Location: chr4:150852698 (GRCh38)
Gene constraint: LOEUF 0.515 · pLI <0.01 (gnomAD)
Residue 1004: the 'disordered' region

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.Ala1004Val Uncertain significance ★ ⚠ same residue
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

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-ala1004 (accessed [today's date]).

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