Is LRBA p.Pro644Leu (c.1931C>T) pathogenic?

LRBA p.Pro644Leu (c.1931C>T) is classified Uncertain significance in LRBA (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-07-31). AlphaMissense: likely benign (0.1574); Very rare (popmax 0.00992%, sas); Associated with combined immunodeficiency due to LRBA deficiency.

What condition is associated with LRBA p.Pro644Leu (c.1931C>T)?

LRBA p.Pro644Leu (c.1931C>T) is associated with combined immunodeficiency due to LRBA deficiency (ClinVar).

How common is LRBA p.Pro644Leu (c.1931C>T) in the general population?

LRBA p.Pro644Leu (c.1931C>T) is very rare (popmax 0.00992%, sas) (gnomAD).

What do computational predictors say about LRBA p.Pro644Leu (c.1931C>T)?

AlphaMissense predicts likely benign (score 0.1574) — an in-silico prediction, not a clinical call.

LRBA p.Pro644Leu

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.1931C>T · rs371718439 · VCV845723

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1574 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00992%, sas)

Conditions

combined immunodeficiency due to LRBA deficiency

Computational evidence

Protein change
AlphaMissense	0.1574	likely benign
REVEL	0.336	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.8, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 749 kb · p 0.0015 · regional, not allelic
Overall
CADD	25.3	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00992% South Asian · 9/90,714 alleles

Filtering AF 0.00515% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00377%

Overall 0.00336% 54/1,608,692 alleles · very rare exomes 43/1,456,940 · genomes 11/151,752 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00992%	10,079
Admixed American	0.00501%	19,947
European (non-Finnish)	0.00323%	30,960
African / African-American	0.00268%	37,329
Remaining individualsnot grpmax-eligible	0.00161%	62,220
Finnishnot grpmax-eligible	0.00157%	63,846

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.Pro644Leu
Coding: c.1931C>T
MANE Select: NM_001364905
dbSNP: rs371718439
Type: single nucleotide variant
Location: chr4:150897812 (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.Pro644Ser Uncertain significance ★ ⚠ same residue
LRBA p.Pro644= Likely benign ★ 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

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-pro644leu (accessed [today's date]).

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