Is LRBA p.Ala449= (c.1347A>G) pathogenic?

LRBA p.Ala449= (c.1347A>G) is classified Benign in LRBA (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-04). Common (popmax 25.2%, sas) — too common for a highly-penetrant pathogenic allele; Associated with combined immunodeficiency due to LRBA deficiency.

What condition is associated with LRBA p.Ala449= (c.1347A>G)?

LRBA p.Ala449= (c.1347A>G) is associated with combined immunodeficiency due to LRBA deficiency (ClinVar).

LRBA p.Ala449=

Q: How common is LRBA p.Ala449= (c.1347A>G) in the general population?

LRBA p.Ala449= (c.1347A>G) is common (popmax 25.2%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

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.1347A>G · rs1201208 · VCV1166827

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Common

common (popmax 25.2%, sas) — too common for a highly-penetrant pathogenic allele

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 -0.38	GERP -5.9, phastCons 0.2
Overall
CADD	8.164	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 25.2% South Asian · 22,966/90,978 alleles

Filtering AF 25% ClinGen BA1/BS1 input FAF95, joint · FAF99 24.9%

Overall 7.3% 117,723/1,612,554 alleles · common exomes 100,952/1,460,468 · genomes 16,771/152,086 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	25.2%	4
African / African-American	20%	5
Finnishnot grpmax-eligible	14.7%	7
Admixed American	11.3%	9
Middle Eastern	9.67%	10
East Asian	8.78%	11
Remaining individualsnot grpmax-eligible	8.21%	12
Ashkenazi Jewishnot grpmax-eligible	6.93%	14
Amishnot grpmax-eligible	5.37%	19
European (non-Finnish)	4.4%	23

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.Ala449=
Coding: c.1347A>G
MANE Select: NM_001364905
dbSNP: rs1201208
Type: single nucleotide variant
Location: chr4:150908672 (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-ala449 (accessed [today's date]).

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