Is LRBA p.Arg1997Cys (c.5989C>T) pathogenic?

LRBA p.Arg1997Cys (c.5989C>T) is classified Benign/Likely benign in LRBA (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.1626); Low-frequency (popmax 3.08%, nfe); Associated with combined immunodeficiency due to LRBA deficiency.

What condition is associated with LRBA p.Arg1997Cys (c.5989C>T)?

LRBA p.Arg1997Cys (c.5989C>T) is associated with combined immunodeficiency due to LRBA deficiency (ClinVar).

How common is LRBA p.Arg1997Cys (c.5989C>T) in the general population?

LRBA p.Arg1997Cys (c.5989C>T) is low-frequency (popmax 3.08%, nfe) (gnomAD).

What do computational predictors say about LRBA p.Arg1997Cys (c.5989C>T)?

AlphaMissense predicts likely benign (score 0.1626) — an in-silico prediction, not a clinical call.

LRBA p.Arg1997Cys

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.5989C>T · rs35879351 · VCV403052

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.1626 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 3.08%, nfe)

Conditions

combined immunodeficiency due to LRBA deficiency

Computational evidence

Protein change
AlphaMissense	0.1626	likely benign
REVEL	0.362	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.82 · evaluated, not missing
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	33.0	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 3.08% European (non-Finnish) · 36,335/1,179,930 alleles

Filtering AF 3.05% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.04%

Overall 2.7% 43,553/1,613,952 alleles · low-frequency exomes 40,351/1,461,754 · genomes 3,202/152,198 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	3.83%	26
European (non-Finnish)grpmax	3.08%	32
Middle Eastern	2.97%	34
Remaining individualsnot grpmax-eligible	2.67%	37
Ashkenazi Jewishnot grpmax-eligible	2.19%	46
Admixed American	1.43%	70
South Asian	1.14%	88
Amishnot grpmax-eligible	1.1%	91
African / African-American	0.491%	204
East Asian	0.00669%	14,951

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg1997Cys
Coding: c.5989C>T
MANE Select: NM_001364905
dbSNP: rs35879351
Type: single nucleotide variant
Location: chr4:150599064 (GRCh38)
Gene constraint: LOEUF 0.515 · pLI <0.01 (gnomAD)
Residue 1997: a UniProt-annotated variant site (in)

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.Arg1997His 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-arg1997cys (accessed [today's date]).

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