Is LRBA p.Arg1981Cys (c.5941C>T) pathogenic?

LRBA p.Arg1981Cys (c.5941C>T) is classified Uncertain significance in LRBA (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-04-03). AlphaMissense: likely benign (0.2751); Ultra-rare (popmax 0.0893%, afr); Associated with combined immunodeficiency due to LRBA deficiency.

What condition is associated with LRBA p.Arg1981Cys (c.5941C>T)?

LRBA p.Arg1981Cys (c.5941C>T) is associated with combined immunodeficiency due to LRBA deficiency (ClinVar).

How common is LRBA p.Arg1981Cys (c.5941C>T) in the general population?

LRBA p.Arg1981Cys (c.5941C>T) is ultra-rare (popmax 0.0893%, afr) (gnomAD).

What do computational predictors say about LRBA p.Arg1981Cys (c.5941C>T)?

AlphaMissense predicts likely benign (score 0.2751) — an in-silico prediction, not a clinical call.

LRBA p.Arg1981Cys

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.5941C>T · rs148699393 · VCV934488

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2751 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0893%, afr)

Conditions

combined immunodeficiency due to LRBA deficiency

Computational evidence

Protein change
AlphaMissense	0.2751	likely benign
REVEL	0.378	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.9, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 749 kb · p 0.0015 · regional, not allelic
Overall
CADD	34.0	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 0.0893% African / African-American · 67/75,024 alleles

Filtering AF 0.0721% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0659%

Overall 0.00737% 119/1,614,000 alleles · ultra-rare exomes 62/1,461,728 · genomes 57/152,272 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0893%	1,120
Admixed American	0.00666%	15,004
Remaining individualsnot grpmax-eligible	0.0048%	20,835
European (non-Finnish)	0.00347%	28,779
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
South Asian	0.00329%	30,358

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.Arg1981Cys
Coding: c.5941C>T
MANE Select: NM_001364905
dbSNP: rs148699393
Type: single nucleotide variant
Location: chr4:150599112 (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.Arg1981His Uncertain significance ★★ same residue
LRBA p.Arg1981Leu 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

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-arg1981cys (accessed [today's date]).

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