Is LRBA p.Thr2522Pro (c.7564A>C) pathogenic?

LRBA p.Thr2522Pro (c.7564A>C) is classified Conflicting classifications of pathogenicity in LRBA (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2026-03-01). AlphaMissense: likely benign (0.1135); Rare (popmax 0.899%, nfe); Associated with combined immunodeficiency due to LRBA deficiency.

What condition is associated with LRBA p.Thr2522Pro (c.7564A>C)?

LRBA p.Thr2522Pro (c.7564A>C) is associated with combined immunodeficiency due to LRBA deficiency (ClinVar).

How common is LRBA p.Thr2522Pro (c.7564A>C) in the general population?

LRBA p.Thr2522Pro (c.7564A>C) is rare (popmax 0.899%, nfe) (gnomAD).

What do computational predictors say about LRBA p.Thr2522Pro (c.7564A>C)?

AlphaMissense predicts likely benign (score 0.1135) — an in-silico prediction, not a clinical call.

LRBA p.Thr2522Pro

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.7564A>C · rs62346982 · VCV439869

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.1135 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.899%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

combined immunodeficiency due to LRBA deficiency

Computational evidence

Protein change
AlphaMissense	0.1135	likely benign
REVEL	0.244	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.51	GERP -0.65, phastCons 0.19
Regional constraint	o/e 0.95	unconstrained · MANE · 749 kb · p 0.0015 · regional, not allelic
Overall
CADD	16.09	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM T2533P vs ClinVar T2522P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.899% European (non-Finnish) · 10,608/1,179,398 alleles

Filtering AF 0.885% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.879%

Overall 0.698% 11,260/1,612,060 alleles · rare exomes 10,581/1,459,936 · genomes 679/152,124 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.899%	111
Remaining individualsnot grpmax-eligible	0.413%	242
Finnishnot grpmax-eligible	0.22%	454
Amishnot grpmax-eligible	0.219%	456
Ashkenazi Jewishnot grpmax-eligible	0.173%	579
African / African-American	0.151%	663
Admixed American	0.118%	849
Middle Eastern	0.0496%	2,016
South Asian	0.0154%	6,475

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.Thr2522Pro
Coding: c.7564A>C
MANE Select: NM_001364905
dbSNP: rs62346982
Type: single nucleotide variant
Location: chr4:150321257 (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-thr2522pro (accessed [today's date]).

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